Protein degradation-targeting chimera compounds targeting BRAF, and composition and use thereof

Abstract

The present invention relates to protein degradation-targeting chimera compounds having a degradation and / or inhibitory activity against mutant BRAF, and further relates to a pharmaceutical composition containing same, and a preparation method therefor and the use thereof.

Description

Targeted chimeric compounds for BRAF protein degradation, their compositions and uses Technical Field

[0001] This invention belongs to the pharmaceutical field, and particularly relates to protein degradation-targeting chimeric compounds that have degradative and / or inhibitory activity against mutant BRAF, as well as pharmaceutical compositions comprising them, and methods for their preparation and uses. Background Technology

[0002] BRAF is a serine / threonine protein kinase belonging to the rapidly accelerating fibrosarcoma (RAF) family. It functions as a mitogen-activated pathway kinase (MAPKKK) in the MAPK / ERK signaling cascade. BRAF is typically triggered upon binding of its ligand to receptor tyrosine kinases (RTKs) such as epidermal growth factor receptor (EGFR or HER2). RTK phosphorylation leads to activation of RAS family GTPases, triggering BRAF homodimerization (BRAF-BRAF) or heterodimerization with other RAF proteins (BRAF-CRAF or BRAF-ARAF) to activate downstream signaling, including MEK and ERK, resulting in direct and indirect transcriptional regulation that controls normal cell growth, proliferation, and apoptosis.

[0003] The BRAF gene has a mutation rate of approximately 8% in all human tumors, most commonly found in melanoma (70-90%), thyroid cancer (30-50%), colorectal cancer (5-20%), ovarian cancer (5-30%), and non-small cell lung cancer (1-4%). ​​The most common BRAF mutation is V600E. This mutation is a class I activating mutant, strongly activating BRAF kinase activity. Other common activating mutations include class II mutations that are RAS-independent dimers and class III mutations that are RAS-dependent dimers.

[0004] Although the clinically available BRAF inhibitors vemurafenib, dabrafenib, and encorafenib have demonstrated significant therapeutic benefits, these drugs typically develop resistance within one year, including due to RAS mutations, BRAF V600E amplification, and BRAF V600E gene deletions or splice variants. These drugs are also ineffective against class II and class III BRAF mutants.

[0005] Protein degradation targeted chimera (PROTAC) technology is a technique that chemically induces polyubiquitination of target proteins (POIs) and degrades them via a ubiquitin-protease system (UPS). PROTAC compounds are bifunctional molecules composed of a target protein ligand and an E3 ubiquitin ligase ligand linked by an appropriate linker strand. They can simultaneously recruit both the target protein and the E3 ligase, thereby inducing ubiquitination and degradation of the target protein, and have broad application prospects and development potential.

[0006] Non-specific effects and the inability to target and modulate BRAF remain obstacles to the development of effective treatments; therefore, discovering novel compounds that can treat BRAF kinase mutation diseases and tumors resistant to available inhibitors remains a challenging task. Thus, there is still a need in the art to develop PROTAC compounds that are effective and specific against applicable BRAF mutations. This invention provides such compounds.

[0007] Invention Overview

[0008] This invention provides a novel protein degradation-targeting chimeric compound, a composition comprising the compound, and its uses. The compound exhibits degradative and / or inhibitory activity against mutant BRAFs (e.g., class I, II, and / or III mutant BRAFs), high selectivity, and / or excellent pharmacokinetic properties, and can be used to treat diseases and / or conditions mediated by mutant BRAFs.

[0009] To address this, the present invention adopts the following technical solution:

[0010] In one aspect, the present invention relates to compounds of formula (IA) or (IB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof:

[0011] in,

[0012] A1 is N or CR A1 ;

[0013] A2 is N or CR A2 ;

[0014] A3 is N or CR A3 ;

[0015] A4 is N or CR A4 ;

[0016] R A1 R A2 R A3 and R A4 Independently, it can be H, D, halogen, -OH, -CN, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0017] B1 is N or CR B1 ;

[0018] B2 is N or CR B2 ;

[0019] B3 is N or CR B3 ;

[0020] B4 is N or CR B4 ;

[0021] B5 is N or CR B5 ;

[0022] B6 is N or CR B6 ;

[0023] R B1 R B2 R B3 R B4 R B5 and R B6 Independently, it can be H, D, halogen, -OH, -CN, or C. 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0024] o is 1, 2, or 3;

[0025] Each X is independently O, NR X ,C(R X )2, C(O) or S(O)2;

[0026] Each R X Independently H, D or C 1-6 Alkyl; or R B1 With an R X Together with the atoms they are attached to, they form C 5-6 Cycloalkyl or 5-7 membered heterocyclic groups;

[0027] R N For H or C 1-6 alkyl;

[0028] R is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 5-10 heteroaryl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic or NR1R2; wherein the C 1-6 Alkyl, C 2-6alkenyl, C 2-6 alkynyl, phenyl, 5-10 heteroaryl, C 3-6 The cycloalkyl group and the 4-7-membered heterocyclic group are optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0029] R1 and R2 are independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups, or R1 and R2 together with the N atom to which they are attached to form a 4-7 membered monocyclic heterocycle, a 6-10 membered fused heterocycle, a 6-10 membered bridged heterocycle, or a 6-9 membered spirocyclic heterocycle; wherein the above groups are optionally surrounded by one or more atoms selected from D, halogen, -OH, -CN, C. 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0030] L is -S0-(L1) i -S1-(L2) j -S2-(L3) m -S3-(L4) n -S4-;

[0031] Among them, S0, S1, S2, S3, and S4 are independent chemical bonds, -O-, -NR. S -, -S-, -S(O)2-, -C(O)-, -C(O)-NR S -,-NR S -C(O)-, -NR S -C(O)-NR S -, -C(O)O-, -OC(O)-, -(CH2CH2O) k -, C 1-6 Alkylene, C 1-6 imide or C 1-6 Idemynyl; wherein each R S Independently H or C 1-6 Alkyl; k is 1, 2, 3, 4 or 5;

[0032] i is 0 or 1;

[0033] j is 0 or 1;

[0034] m is 0 or 1;

[0035] n is 0 or 1;

[0036] L1 is a divalent group selected from a benzene ring or a 5-6 membered heteroaromatic ring; wherein the above group is optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0037] Each L2, L3, and L4 is independently selected from C 1-6 Alkynes, 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered fused carbon rings, 6-10 membered fused heterocyclic rings, 6-10 membered bridged carbon rings, 6-10 membered bridged heterocyclic rings, 6-9 membered spirocyclic carbon rings, or 6-9 membered spirocyclic heterocyclic rings with divalent groups; wherein the above groups are optionally surrounded by one or more groups selected from D, halogens, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0038] U1 and U2 are each independently selected from the following formula (U A ), formula (U B ), formula (U C ), formula (U D ), formula (U E ), formula (U F () or formula (G):

[0039] in,

[0040] It can be a single bond or a double bond;

[0041] Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2;

[0042] Each W is independently a chemical bond, NH, O, C(O)NH, NHC(O), CH2 or CD2;

[0043] Each Q1 is independently C(O) or C(R5)2;

[0044] Each Q2 is independently either N or CH;

[0045] Each Q3 is independently either N or CR5;

[0046] Each P1, P2, P3, and P4 is independently N or CR6;

[0047] P5 and P6 are either N or C;

[0048] H1 is N, C, or CR7;

[0049] H2 and H3 are independently N, O, S, NR7, CR7, C(R7)2 or C(O);

[0050] Each R3 is independently H or C. 1-6 alkyl;

[0051] q can be 0, 1, 2, 3, 4, or 5;

[0052] d is 0 or 1;

[0053] Each R4 is independently D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups, or two R4 atoms on the same atom or two R4 atoms on adjacent atoms, together with the atoms they are attached to, form C. 3-7 Carbon rings or 4-7 membered heterocycles;

[0054] Each R5 is independently H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups, or two R5 atoms on the same atom together with the atoms they are attached to, form a C group. 3-7 Carbon rings or 4-7 membered heterocycles;

[0055] Each R6 is independently H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups, or two R6 atoms on adjacent atoms together with the atoms they are attached to, form C. 3-7 Carbon rings, 4-7 membered heterocycles, benzene rings, or 5-6 membered heteroaromatic rings;

[0056] Each R7 is independently H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups, or two R7 groups on the same atom or two R7 groups on adjacent atoms together with the atoms they are attached to, forming a C group. 3-7 Carbon rings, 4-7 membered heterocycles, benzene rings, or 5-6 membered heteroaromatic rings;

[0057] The premise is that when o is 1, X is an O atom, R1 is a methyl group and R2 is an ethyl group, U1 and U2 are not...

[0058] In some embodiments, the compounds of the present invention have at least one desired atom substituted with the isotope D in an amount higher than the natural abundance of the isotope, i.e., enriched.

[0059] In some embodiments, the compounds of the present invention comprise one or more deuterium atoms. In specific embodiments, the deuterium isotope content at the deuterated position is at least greater than 0.015% of the natural deuterium isotope content, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, and more preferably greater than 99%.

[0060] In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, and pharmaceutically acceptable excipients. In a specific embodiment, the compound of the present invention is provided in the pharmaceutical composition in an effective amount. In a specific embodiment, the compound of the present invention is provided in a therapeutically effective amount. In a specific embodiment, the compound of the present invention is provided in a preventatively effective amount.

[0061] In another aspect, the present invention provides a compound comprising the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, and pharmaceutically acceptable excipients, further comprising other therapeutic agents. In specific embodiments, the other therapeutic agents are another BRAF inhibitor, a MEK inhibitor, an immune checkpoint inhibitor, or an EGFR antibody. In specific embodiments, the other BRAF inhibitor is sorafenib, vemurafenib, dabrafenib, or cannefenib. In specific embodiments, the MEK inhibitor is trametinib or selumetinib. In specific embodiments, the immune checkpoint inhibitor is nivolumab, pembrolizumab, cimipril, ipilimumab, relatlimab, atezolizumab, avelumab, or durvalumab. In specific embodiments, the EGFR antibody is cetuximab or panitumumab.

[0062] In another aspect, the present invention provides a method for treating BRAF-mediated diseases, comprising administering to a subject an effective amount of the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates or compositions of the present invention.

[0063] In another aspect, the present invention provides compounds of the present invention or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or compositions thereof, for the treatment of diseases mediated by mutant BRAF.

[0064] In another aspect, the present invention provides the use of the compounds of the present invention or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or compositions of the present invention in the preparation of medicaments for treating diseases mediated by mutant BRAF.

[0065] In another aspect, the present invention provides the use of the compounds of the present invention or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or compositions of the present invention in the treatment of subjects with BRAF-mediated diseases.

[0066] In a specific implementation, the mutated BRAF is a type I, type II, or type III mutation, or any combination thereof. In a more specific implementation, non-limiting examples of type I mutations include V600 mutations, such as V600E, V600K, V600R, V600D, or V600N. In a more specific implementation, non-limiting examples of type II mutations include G469A, G469V, G469L, G469R, G469S, L597Q, L597R, L597S, L597V, K601E, K601N, G464E, G464V, G464R, R462I, I463S, E586K, F595L, A598V, T599I, or K301T. In a more specific implementation, non-restrictive examples of type III mutations include G466A, G466E, G466R, G466V, S467L, G469E, N581I, D594E, D594G, D594N, S467A, S467E, N581S, K483M, D594A, D594H, D594V, G596A, G596C, G596D, or G596R. In a more specific implementation, the BRAF mutation is G464I, N581T, L584F, E586K, G593D, G596C, S605I, S607F, N694T, E26A, V130M, L745L, or D284E. In a specific implementation, the mutated BRAF is a splice variant, such as p61-BRAF V600E. In a specific implementation, the mutated BRAF is a BRAF V600E / NRAS Q61K double mutation.

[0067] In a specific implementation plan, the disease mediated by mutated BRAF is cancer. In a more specific implementation plan, the diseases mediated by mutated BRAF include melanoma, triple-negative breast cancer, non-small cell lung cancer, colorectal cancer, microsatellite-stabilized colorectal cancer, thyroid cancer, ovarian cancer, cholangiocarcinoma, Eldheim-Chester disease, Langerhans histiocytosis, ganglioglioma, glioma, glioblastoma, piloblastic leukemia, multiple myeloma, pilocytic myxoid astrocytoma, anaplastic multiline xanthoastrocytoma, astrocytoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, pancreatic cancer, clear cell sarcoma of the chest, and salivary gland carcinoma.

[0068] Other objects and advantages of the invention will become apparent to those skilled in the art from the following detailed description, embodiments, and claims.

[0069] definition

[0070] Chemical definition

[0071] The definitions of specific functional groups and chemical terms are described in more detail below.

[0072] When listing a range of values, it is assumed that each value and the subranges within that range are included. For example, "C 1-6 Alkyl groups include C1, C2, C3, C4, C5, C6, and C6. 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0073] “C 1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms, also referred to herein as "lower alkyl". In some embodiments, C 1-4 Alkyl and C 1-3Alkyl groups are particularly preferred. Examples of such alkyl groups include, but are not limited to: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). Regardless of whether the alkyl group is preceded by "substituted," each alkyl group is optionally substituted independently, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents defined below.

[0074] “C 1-6 "Alkylide group" refers to =CRR, where R is H or C. 1-5 alkyl.

[0075] “C 2-6 "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon double bonds). The one or more carbon-carbon double bonds can be internal (e.g., in a 2-butenyl group) or terminal (e.g., in a 1-butenyl group). In some embodiments, C 2-4 Alkenyl groups are particularly preferred. Examples of such alkenyl groups include, but are not limited to: vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and so on. Regardless of whether the alkenyl group is preceded by "substituted," each alkenyl group is optionally substituted independently, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents defined below.

[0076] “C 2-6 "Alkyne" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, or 3 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon double bonds). In some embodiments, C 2-4 The alkynyl group is particularly preferred. In some embodiments, the alkynyl group does not contain any double bonds. One or more carbon triple bonds may be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). Examples of the alkynyl group include, but are not limited to: ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentyynyl (C5), hexynyl (C6), and so on. Regardless of whether the alkynyl group is preceded by the word "substituted," each alkynyl group is optionally substituted independently, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents defined below.

[0077] “C 1-6 "Alkoxy" refers to the group -OR, where R is a substituted or unsubstituted carbon group. 1-6 Alkyl group. In some embodiments, C 1-4 Alkoxy and C 1-3 Alkoxy groups are particularly preferred. Specific alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, and 1,2-dimethylbutoxy.

[0078] "Halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In some embodiments, the halogen group is F, Cl, or Br. In some embodiments, the halogen group is F or Cl. In some embodiments, the halogen group is F.

[0079] Therefore, "C" 1-6 "Halogenated alkyl" and "C" 1-6 "Haloalkoxy" refers to the above "C" 1-6 "alkyl" and "C" 1-6 "Alkoxy" is substituted with one or more halogen groups. In some embodiments, C 1-4 Halogenated alkyl groups are particularly preferred, and C4 groups are more preferred. 1- 3-Hydroalkyl and C 1-2 Halogenated alkyl groups. In some embodiments, C 1-4 Halogenated alkoxy groups are particularly preferred, and C4 is more preferred. 1-3 Halogenated alkoxy groups and C 1-2 Haloalkoxy groups. Exemplary haloalkyl groups include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc. Exemplary haloalkoxy groups include, but are not limited to: -OCH2F, -OCHF2, -OCF3, etc.

[0080] “C 1-6 Alkylene, C 1-6 "Ideinyl" and "C" 1-6 "Iso-ynyl group" refers to the group with the C group removed. 1-6 Alkyl, C 1-6 alkenyl and C 1-6 The other hydrogen atom of the alkynyl group forms a divalent group. In some embodiments, C 1-4 Alkylene, C 2-4 Alkylene and C 1-2 Alkylene is preferred. In some embodiments, C 2-4 C1- and C2-olefinic groups are preferred. In some embodiments, C1-olefinic groups are preferred.2-4 Alkyneyl groups and C2 alkyneyl groups are preferred. Examples of the alkylene groups include, but are not limited to: -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, and -CH2C(CH3). 2- Examples of the alkenyl group include, but are not limited to: -CH=CH-, -CH=CH-CH2-, -CH=C(CH3)-CH2-, -CH=CH-CH(CH3)-, -CH=CH-CH2-CH2-, -CH2-CH=CH-CH2-, and -CH2-CH=C(CH3)-CH2-. Examples of the alkenyl group include, but are not limited to: -C≡C-, -C≡C-CH2-, -C≡C-CH(CH3)-, -C≡C-CH2-CH2-, -CH2-C≡C-CH2-, and -CH2-C≡C-CH(CH3)-. Regardless of whether the alkylene, alkenyl, and alkyne groups are modified with "substituted", each of the alkylene, alkenyl, and alkyne groups is optionally substituted independently, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents defined below.

[0081] “C 3-10 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C 3-8 Cycloalkyl groups are preferred, C 3-6 Cycloalkyl groups are particularly preferred, and C10 is more preferred. 5-6 Cycloalkyl. Cycloalkyl can be monocyclic, bicyclic, or polycyclic. Bicyclic or polycyclic can be fused, spirocyclic, bridged, or a combination thereof. Bicyclic or polycyclic may include one or more aromatic rings, but the ring system as a whole is not aromatic, and in such cases, the number of carbons continues to indicate the number of carbons in the cycloalkyl system. Exemplary cycloalkyl groups include, but are not limited to: cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), bicyclo[1.1.1]pentyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), bicyclo[2.1.1]hexyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptanetrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9), etc. 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10), spiro[4.5]decyl(C 10 ), etc. Regardless of whether the cycloalkyl group is modified with "substituted", each of the cycloalkyl groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent, with suitable substituents defined as follows.

[0082] "3-10 membered heterocyclic group" refers to a group having a 3- to 10 membered non-aromatic ring system with a cyclic carbon atom and 1 to 4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclic groups containing one or more nitrogen atoms, the linking point can be a carbon or nitrogen atom, provided the valence allows. In some embodiments, 4- to 10 membered heterocyclic groups are preferred, which are 4- to 10 membered non-aromatic ring systems with a cyclic carbon atom and 1 to 4 cyclic heteroatoms; in some embodiments, 3- to 7 membered heterocyclic groups are preferred, which are 3- to 7 membered non-aromatic ring systems with a cyclic carbon atom and 1 to 3 cyclic heteroatoms; in some embodiments, 3- to 6 membered heterocyclic groups are particularly preferred, which are 3- to 6 membered non-aromatic ring systems with a cyclic carbon atom and 1 to 3 cyclic heteroatoms; more preferably, 5- to 6 membered heterocyclic groups are 5- to 6 membered non-aromatic ring systems with a cyclic carbon atom and 1 to 3 cyclic heteroatoms. The heterocyclic group can be monocyclic, bicyclic, or polycyclic. Bicyclic or polycyclic rings can be fused rings, spirocyclic rings, bridged rings, or combinations thereof. A bicyclic or polycyclic ring may include one or more aromatic or heteroaromatic rings, but the ring system as a whole is not aromatic. In such cases, the number of ring members continues to indicate the number of ring members in the heterocyclic ring system. Regardless of whether the heterocyclic group is preceded by "substituted," each of the heterocyclic groups is independently and optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents defined below.

[0083] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: azircyclopropane, oxacyclopropane, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azircyclobutane, oxacyclobutane, and thiorenyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolidinyl, and pyrrolidin-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: dioxasulfuranyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithianyl, and dioxane. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirheptanyl, oxeheptanyl, and thianyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirheptanyl, oxeheptanyl, and thianyl. Exemplary 5-membered heterocyclic groups fused with a C6 aryl ring include, but are not limited to: dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzozolinoneyl, etc. Exemplary 6-membered heterocyclic groups fused with a C6 aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0084] “C 6-14 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 shared π electrons arranged in a ring) having 6-14 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C... 10 Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen cyclic carbon atoms (“C14”). 14 "Aryl"; for example, anthracene). In some embodiments, C 6-10Aryl groups are particularly preferred, and more preferably C6 aryl groups. Aryl groups also include ring systems in which the aforementioned aryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the connection point is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. Regardless of whether the aryl group is preceded by the word "substituted," each aryl group may be optionally substituted independently, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents defined below.

[0085] "5-10-membered heteroaryl" refers to a group comprising a 4n+2 aromatic ring system of a 5-10-membered monocyclic or bicyclic ring having a ring carbon atom and 1-4 ring heteroatoms (e.g., having 6 or 10 shared π electrons arranged in a ring), wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, provided the valence allows. A heteroaryl bicyclic system may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the bonding point is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-6-membered heteroaryl is particularly preferred, which is a 4n+2 aromatic ring system of a 5-6-membered monocyclic or bicyclic ring having a ring carbon atom and 1-4 ring heteroatoms. In some embodiments, a 5-membered heteroaryl group is particularly preferred, which is a 4n+2 aromatic ring system of a 5-membered monocyclic or bicyclic ring having a cyclic carbon atom and 1-4 cyclic heteroatoms. Regardless of whether the heteroaryl group is preceded by "substituted", each of the heteroaryl groups is optionally substituted independently, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents defined as follows.

[0086] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrole, furanyl, and thiophene. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to: triazinyl and tetraazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azirheptatrienyl, oxaheptatrienyl, and thioheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to: naphridinyl, pteridinyl, quinolinyl, isoquinolinyl, zolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0087] A "fused ring" refers to a polycyclic group in which rings share two adjacent ring atoms and a chemical bond. It may contain one or more double or triple bonds and can contain 0 to 5 heteroatoms selected from N, S, O, P, Si, and their oxidation states. Fused rings are typically 5-20 membered, 5-14 membered, 5-12 membered, 6-12 membered, 5-10 membered, or 6-10 membered. Regardless of whether the fused ring is preceded by a "substituted" designation, each element of the fused ring can be independently and optionally substituted, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Suitable substituents are defined as follows.

[0088] A "spirocyclic ring" is a polycyclic group that shares a single carbon atom (called a spiro atom) between its rings. It can contain 0 or 1 double or triple bonds and 0 to 5 heteroatoms selected from N, S, O, P, Si, and their oxidation states. Spirocyclic rings are typically 6-14 membered, 6-12 membered, or 6-10 membered. Regardless of whether the spirocyclic ring is pre-modified with "substituents," each member of the spirocyclic ring can be independently and optionally substituted, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Suitable substituents are defined as follows.

[0089] A "bridged ring" refers to two rings sharing two non-adjacent ring atoms. It can contain one or more double or triple bonds and 0 to 5 heteroatoms selected from N, S, O, P, Si, and their oxidation states. Bridged rings are typically 5-20 membered, 5-14 membered, 5-12 membered, 6-12 membered, 5-10 membered, or 6-10 membered. Regardless of whether the bridged ring is preceded by a "substituted" modification, each member of the bridged ring can be independently and optionally substituted, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Suitable substituents are defined as follows.

[0090] Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa -ON(R) bb )2、-N(R bb )2、-N(R bb )3 + X - -N(OR) cc )R bb -SH, -SR aa -SSR cc -C(=O)R aa -CO2H, -CHO, -C(OR) cc )2、-CO2R aa -OC(=O)R aa -OCO2R aa -C(=O)N(R) bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa -NR bb CO2R aa -NR bb C(=O)N(R bb )2、-C(=NR bb )R aa -C(=NR) bb OR aa -OC(=NR) bb )R aa -OC(=NR) bb OR aa -C(=NR) bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb)2、-C(=O)NR bb SO2R aa -NR bb SO2R aa -SO2N(R) bb )2、-SO2R aa -SO2OR aa -OSO2R aa -S(=O)R aa -OS(=O)R aa 、-Si(R aa )3、-OSi(R aa 3. -C(=S)N(R) bb )2、-C(=O)SR aa -C(=S)SR aa -SC(=S)SR aa -SC(=O)SR aa -OC(=O)SR aa -SC(=O)OR aa -SC(=O)R aa -P(=O)2R aa -OP(=O)2R aa -P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(R cc )3、-B(R aa 2. -B(OR) cc )2、-BR aa (OR cc ), alkyl, haloalkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0091] Or the two hydrogen-bearing groups on the carbon atom: =O, =S, =NN(R) bb )2、=NNR bb C(=O)R aa =NNR bb C(=O)OR aa =NNR bb S(=O)2R aa =NR bb or = NOR cc replace;

[0092] R aa Each of them is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R aa Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0093] R bb Each is independently selected from: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R bb Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. ddGroup substitution;

[0094] R cc Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R cc Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0095] R dd Each is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee -ON(R) ff )2、-N(R ff )2,、-N(R ff )3 + X - -N(OR) ee )R ff -SH, -SR ee -SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee -OCO2R ee -C(=O)N(R) ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee -NR ff CO2R ee -NR ff C(=O)N(R ff )2、-C(=NR ff OR ee -OC(=NR) ff )R ee -OC(=NR) ff OR ee -C(=NR) ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee -SO2N(R) ff )2、-SO2Ree -SO2OR ee -OSO2R ee -S(=O)R ee 、-Si(R ee )3、-OSi(R ee 3. -C(=S)N(R) ff )2、-C(=O)SR ee -C(=S)SR ee -SC(=S)SR ee -P(=O)2R ee -P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee 2. Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution, or two geminal radicals dd Substituents can combine to form =O or =S;

[0096] R ee Each is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, aryl, heterocyclic, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently surrounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0097] R ff Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R ff The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0098] R gg Each of these is independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C) 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - -NH(C 1-6 Alkyl)2 + X - -NH2(C1-6 alkyl) + X - -NH3 + X - -N(OC) 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl groups, -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl group, -CO2H, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1- 6-alkyl), -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2、-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6 Alkyl)2、-NHC(=O)NH(C 1-6 Alkyl groups, -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl), -OC (=NH)(C 1-6 Alkyl group), -OC (=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 Alkyl)2、-C(=NH)NH(C 1-6 Alkyl groups, -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2、-OC(NH)NH(C 1-6 Alkyl groups, -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2、-SO2NH(C 1-6 Alkyl groups, -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C) 1-6 Alkyl)3、-OSi(C 1-6Alkyl)3, -C(=S)N(C 1-6 Alkyl)2、C(=S)NH(C 1-6 Alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1- 6-alkyl, -SC(=S)SC 1-6 Alkyl group, -P(=O)2(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl)2、-OP(=O)(C 1-6 Alkyl)2、-OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 carbocyclic, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two ethryl groups gg Substituents can combine to form =O or =S; where X - It is a counterion.

[0099] Exemplary substituents on the nitrogen atom include, but are not limited to: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) bb )R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R atoms attached to a nitrogen atom. ccThe groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, wherein R aa R bb R cc and R dd As stated above.

[0100] "Deuterated" or "D" refers to the substitution of one or more hydrogen atoms in a compound or group by deuterium; deuteration can be monosubstituted, disubstituted, polysubstituted, or total substituted. The terms "one or more deuterated" and "one or more deuterated" are used interchangeably.

[0101] "Non-deuterated compounds" refer to compounds containing a deuterium atom ratio no higher than the natural deuterium isotope content (0.015%).

[0102] The content of deuterium isotopes at the deuterated position is at least 0.015% greater than the content of natural deuterium isotopes, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, and more preferably greater than 99%.

[0103] The term "pharmaceutically acceptable salt" refers to those salts that, within the bounds of reliable medical judgment, are suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of this invention include salts derived from suitable inorganic and organic acids and inorganic and organic bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or salts formed with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid. Salts formed using methods conventional in the art are also included, such as ion exchange methods. Other pharmaceutically acceptable salts include: adipic acid salts, alginate salts, ascorbate salts, aspartate salts, benzenesulfonate salts, benzoate salts, bisulfate salts, borate salts, butyrate salts, camphorate salts, camphor sulfonate salts, citrate salts, cyclopentylpropionate salts, diglucuronate salts, dodecyl sulfate salts, ethanesulfonate salts, formate salts, fumarate salts, gluconate salts, glyceryl phosphate salts, glucuronate salts, hemisulfate salts, heptarate salts, hexanoate salts, hydroiodate salts, 2-hydroxy-ethanesulfonate salts, lactobionate salts, lactate salts, laurate salts, lauryl sulfate salts, malate salts, maleate salts, malonate salts, methanesulfonate salts, 2-naphthalenesulfonate salts, nicotinate salts, nitrate salts, oleate salts, oxalate salts, palmitate salts, dihydroxynaphthalate salts, pectin ester salts, persulfate salts, 3-phenylpropionate salts, phosphate salts, picrate salts, p-pentanoate salts, propionate salts, stearate salts, succinate salts, sulfate salts, tartrate salts, thiocyanate salts, p-toluenesulfonate salts, undecanoate salts, valerate salts, etc. Pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4 Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically acceptable salts, if appropriate, include non-toxic ammonium salts, quaternary ammonium salts, and amine cations that form with counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonates, and aryl sulfonates.

[0104] The term "subject" in the administration includes, but is not limited to: humans (i.e., men or women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0105] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0106] Unless otherwise stated, the term “treatment” as used herein includes effects that occur when a subject has a specific disease, disorder, or condition, which reduce the severity of the disease, disorder, or condition, or delay or slow the development of the disease, disorder, or condition (“therapeutic treatment”), and also includes effects that occur before a subject begins to have a specific disease, disorder, or condition (“preventive treatment”).

[0107] The term "combination" and related terms refer to the simultaneous or sequential administration of the therapeutic agents of the present invention. For example, the compounds of the present invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or simultaneously with another therapeutic agent in a single unit dosage form. Detailed Implementation

[0108] compound

[0109] In this document, “compound of the present invention” refers to a compound of formula (I) (including subsets thereof), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0110] In one embodiment, the present invention relates to compounds of formula (IA) or (IB), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates:

[0111] in,

[0112] A1 is N or CR A1 ;

[0113] A2 is N or CR A2 ;

[0114] A3 is N or CR A3 ;

[0115] A4 is N or CR A4 ;

[0116] R A1 R A2 R A3 and R A4 Independently, it can be H, D, halogen, -OH, -CN, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0117] B1 is N or CR B1 ;

[0118] B2 is N or CR B2 ;

[0119] B3 is N or CR B3 ;

[0120] B4 is N or CR B4 ;

[0121] B5 is N or CR B5 ;

[0122] B6 is N or CR B6 ;

[0123] R B1 R B2 R B3 R B4 R B5 and R B6 Independently, it can be H, D, halogen, -OH, -CN, or C. 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0124] o is 1, 2, or 3;

[0125] Each X is independently O, NR X C(R) X )2, C(O) or S(O)2;

[0126] Each R X Independently H, D or C 1-6 Alkyl; or R B1 With an R X Together with the atoms they are attached to, they form C 5-6 Cycloalkyl or 5-7 membered heterocyclic groups;

[0127] R N For H or C 1-6 alkyl;

[0128] R is C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 5-10 heteroaryl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic or NR1R2; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 5-10 heteroaryl, C 3-6 The cycloalkyl group and the 4-7-membered heterocyclic group are optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0129] R1 and R2 are independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups, or R1 and R2 together with the N atom to which they are attached to form a 4-7 membered monocyclic heterocycle, a 6-10 membered fused heterocycle, a 6-10 membered bridged heterocycle, or a 6-9 membered spirocyclic heterocycle; wherein the above groups are optionally surrounded by one or more atoms selected from D, halogen, -OH, -CN, C. 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0130] L is -S0-(L1) i -S1-(L2) j -S2-(L3) m -S3-(L4) n -S4-;

[0131] Among them, S0, S1, S2, S3, and S4 are independent chemical bonds, -O-, -NR. S -, -S-, -S(O)2-, -C(O)-, -C(O)-NR S -,-NR S -C(O)-, -NR S -C(O)-NR S -, -C(O)O-, -OC(O)-, -(CH2CH2O) k -, C 1-6 Alkylene, C 1-6 imide or C 1-6 Idemynyl; wherein each R S Independently H or C 1-6 Alkyl; k is 1, 2, 3, 4 or 5;

[0132] i is 0 or 1;

[0133] j is 0 or 1;

[0134] m is 0 or 1;

[0135] n is 0 or 1;

[0136] L1 is a divalent group selected from a benzene ring or a 5-6 membered heteroaromatic ring; wherein the above group is optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0137] Each L2, L3, and L4 is independently selected from C 1-6 Alkynes, 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered fused carbon rings, 6-10 membered fused heterocyclic rings, 6-10 membered bridged carbon rings, 6-10 membered bridged heterocyclic rings, 6-9 membered spirocyclic carbon rings, or 6-9 membered spirocyclic heterocyclic rings with divalent groups; wherein the above groups are optionally surrounded by one or more groups selected from D, halogens, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0138] U1 and U2 are each independently selected from the following formula (U A ), formula (U B ), formula (U C ), formula (U D ), formula (U E ), formula (U F () or formula (G):

[0139] in,

[0140] It can be a single bond or a double bond;

[0141] Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2;

[0142] Each W is independently a chemical bond, NH, O, C(O)NH, NHC(O), CH2 or CD2;

[0143] Each Q1 is independently C(O) or C(R5)2;

[0144] Each Q2 is independently either N or CH;

[0145] Each Q3 is independently either N or CR5;

[0146] Each P1, P2, P3, and P4 is independently N or CR6;

[0147] P5 and P6 are either N or C;

[0148] H1 is N, C, or CR7;

[0149] H2 and H3 are independently N, O, S, NR7, CR7, C(R7)2 or C(O);

[0150] Each R3 is independently H or C. 1-6 alkyl;

[0151] q can be 0, 1, 2, 3, 4, or 5;

[0152] d is 0 or 1;

[0153] Each R4 is independently D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups, or two R4 atoms on the same atom or two R4 atoms on adjacent atoms, together with the atoms they are attached to, form C. 3-7 Carbon rings or 4-7 membered heterocycles;

[0154] Each R5 is independently H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups, or two R5 atoms on the same atom together with the atoms they are attached to, form a C group. 3-7 Carbon rings or 4-7 membered heterocycles;

[0155] Each R6 is independently H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups, or two R6 atoms on adjacent atoms together with the atoms they are attached to, form C. 3-7 Carbon rings, 4-7 membered heterocycles, benzene rings, or 5-6 membered heteroaromatic rings;

[0156] Each R7 is independently H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6Haloalkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups, or two R7 groups on the same atom or two R7 groups on adjacent atoms together with the atoms they are attached to, forming a C group. 3-7 Carbon rings, 4-7 membered heterocycles, benzene rings, or 5-6 membered heteroaromatic rings;

[0157] The premise is that when o is 1, X is an O atom, R1 is a methyl group and R2 is an ethyl group, U1 and U2 are not...

[0158] In another embodiment, the present invention relates to compounds of formula (IA) or (IB), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates:

[0159] in,

[0160] A1 is N or CR A1 ;

[0161] A2 is N or CR A2 ;

[0162] A3 is N or CR A3 ;

[0163] A4 is N or CR A4 ;

[0164] R A1 R A2 R A3 and R A4 Independently, it can be H, D, halogen, -OH, -CN, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0165] B1 is N or CR B1 ;

[0166] B2 is N or CR B2 ;

[0167] B3 is N or CR B3 ;

[0168] B4 is N or CR B4 ;

[0169] B5 is N or CR B5 ;

[0170] B6 is N or CR B6 ;

[0171] R B1R B2 R B3 R B4 R B5 and R B6 Independently, it can be H, D, halogen, -OH, -CN, or C. 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0172] o is 1, 2, or 3;

[0173] Each X is independently O, NR X C(R) X )2, C(O) or S(O)2;

[0174] Each R X Independently H, D or C 1-6 Alkyl; or R B1 With an R X Together with the atoms they are attached to, they form C 5-6 Cycloalkyl or 5-7 membered heterocyclic groups;

[0175] R N For H or C 1-6 alkyl;

[0176] R is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 5-10 heteroaryl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic or NR1R2; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 5-10 heteroaryl, C 3-6 The cycloalkyl group and the 4-7-membered heterocyclic group are optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0177] R1 and R2 are independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups, or R1 and R2 together with the N atom to which they are attached to form a 4-7 membered monocyclic heterocycle, a 6-10 membered fused heterocycle, a 6-10 membered bridged heterocycle, or a 6-9 membered spirocyclic heterocycle; wherein the above groups are optionally surrounded by one or more atoms selected from D, halogen, -OH, -CN, C. 1-6-alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0178] L is -S0-(L1) i -S1-(L2) j -S2-(L3) m -S3-(L4) n -S4-;

[0179] Among them, S0, S1, S2, S3, and S4 are independent chemical bonds, -O-, -NR. S -, -S-, -S(O)2-, -C(O)-, -C(O)-NR S -,-NR S -C(O)-, -NR S -C(O)-NR S -, -C(O)O-, -OC(O)-, -(CH2CH2O) k -, C 1-6 Alkylene, C 1-6 imide or C 1-6 Idemynyl; wherein each R S Independently H or C 1-6 Alkyl; k is 1, 2, 3, 4 or 5;

[0180] i is 0 or 1;

[0181] j is 0 or 1;

[0182] m is 0 or 1;

[0183] n is 0 or 1;

[0184] L1 is a divalent group selected from a benzene ring or a 5-6 membered heteroaromatic ring; wherein the above group is optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0185] Each L2, L3, and L4 is independently selected from C 1-6 Alkynes, 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered fused carbon rings, 6-10 membered fused heterocyclic rings, 6-10 membered bridged carbon rings, 6-10 membered bridged heterocyclic rings, 6-9 membered spirocyclic carbon rings, or 6-9 membered spirocyclic heterocyclic rings with divalent groups; wherein the above groups are optionally surrounded by one or more groups selected from D, halogens, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0186] U1 is selected from the following formula (U A ), formula (U B ), formula (U C ), formula (U D ), formula (U E ), formula (U F () or formula (G):

[0187] U2 is selected from the following formula (U A ), formula (U B ), formula (U F ), formula (U G ), formula (U H (or formula (J):)

[0188] in,

[0189] It can be a single bond or a double bond;

[0190] Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2;

[0191] Each W is independently a chemical bond, NH, O, C(O)NH, NHC(O), CH2 or CD2;

[0192] Each Q1 is independently C(O) or C(R5)2;

[0193] Each Q2 is independently either N or CH;

[0194] Each Q3 is independently either N or CR5;

[0195] Each P1, P2, P3, and P4 is independently N or CR6;

[0196] P5 and P6 are either N or C;

[0197] H1 is N, C, or CR7;

[0198] H2 and H3 are independently N, O, S, NR7, CR7, C(R7)2 or C(O);

[0199] Each R3 is independently H or C. 1-6 alkyl;

[0200] q can be 0, 1, 2, 3, 4, or 5;

[0201] d is 0 or 1;

[0202] Each R4 is independently D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups, or two R4 atoms on the same atom or two R4 atoms on adjacent atoms, together with the atoms they are attached to, form C. 3-7 Carbon rings or 4-7 membered heterocycles;

[0203] Each R5 is independently H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups, or two R5 atoms on the same atom together with the atoms they are attached to, form a C group. 3-7 Carbon rings or 4-7 membered heterocycles;

[0204] Each R6 is independently H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups, or two R6 atoms on adjacent atoms together with the atoms they are attached to, form C. 3-7 Carbon rings, 4-7 membered heterocycles, benzene rings, or 5-6 membered heteroaromatic rings;

[0205] Each R7 is independently H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups, or two R7 groups on the same atom or two R7 groups on adjacent atoms together with the atoms they are attached to, forming a C group. 3-7 Carbon rings, 4-7 membered heterocycles, benzene rings, or 5-6 membered heteroaromatic rings;

[0206] The premise is that when o is 1, X is an O atom, R1 is methyl and R2 is ethyl, U1 is the formula (U A ), formula (U B ) or formula (U F ).

[0207] In another embodiment, the present invention relates to compounds of formula (IA) or (IB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, which are compounds of formula (IIA) or (IIB).

[0208] Wherein, R, R A1 R A2 R B1 X, L, U1 and U2 are as defined above.

[0209] In another embodiment, the present invention relates to a compound of formula (IA), (IB), (IIA) or (IIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein X is O.

[0210] In another embodiment, the present invention relates to a compound of formula (IA), (IB), (IIA) or (IIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein X is NH.

[0211] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein R is C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic or NR1R2; wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl group and the 4-7-membered heterocyclic group are optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0212] R1 and R2 are independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups, or R1 and R2 together with the N atom to which they are attached to form a 4-7 membered monocyclic heterocycle, a 6-10 membered fused heterocycle, a 6-10 membered bridged heterocycle, or a 6-9 membered spirocyclic heterocycle; wherein the above groups are optionally surrounded by one or more atoms selected from D, halogen, -OH, -CN, C. 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substitution of halogenated alkoxy groups.

[0213] In another embodiment, the present invention relates to a compound of formula (IA), (IB), (IIA) or (IIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R is -N(Me)(Et).

[0214] In another embodiment, the present invention relates to a compound of formula (IA), (IB), (IIA) or (IIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R is NR1R2.

[0215] R1 and R2, together with the N atom they are attached to, form a 4-7 membered monocyclic heterocycle, a 6-10 membered fused heterocycle, a 6-10 membered bridged heterocycle, or a 6-9 membered spirocyclic heterocycle; wherein the above groups are optionally surrounded by one or more atoms selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substitution of halogenated alkoxy groups.

[0216] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein R is...

[0217] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein R is...

[0218] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein R is...

[0219] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA) or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein L is -(L1). i -(L2)-S2-S3-(L4) - ;

[0220] Where S2 is a chemical bond, -C(O)-, -C(O)-NR S -or-NR S -C(O)-; where each R S Independently H or C 1-6 alkyl;

[0221] S3 is -C 1-6 alkylene-;

[0222] i is 0 or 1;

[0223] L1 is a divalent group selected from a benzene ring or a 5-6 membered heteroaromatic ring; wherein the above group is optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0224] L2 is a divalent group selected from 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered fused carbon rings, 6-10 membered fused heterocyclic rings, 6-10 membered bridged carbon rings, 6-10 membered bridged heterocyclic rings, 6-9 membered spirocyclic carbon rings, or 6-9 membered spirocyclic heterocyclic rings; wherein the above groups are optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0225] L4 is selected from C 1-6 Alkynes, 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered fused carbon rings, 6-10 membered fused heterocyclic rings, 6-10 membered bridged carbon rings, 6-10 membered bridged heterocyclic rings, 6-9 membered spirocyclic carbon rings, or 6-9 membered spirocyclic heterocyclic rings with divalent groups; wherein the above groups are optionally surrounded by one or more groups selected from D, halogens, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substitution of halogenated alkoxy groups.

[0226] In one embodiment of L, S2 is a chemical bond.

[0227] In another implementation of L, S2 is -C(O)-.

[0228] In another implementation of L, S2 is -C(O)-NR S -or-NR S -C(O)-.

[0229] In another embodiment of L, S3 is a methylene group.

[0230] In another implementation of L, i is 0.

[0231] In another implementation of L, i is 1.

[0232] In another embodiment of L, L1 is a divalent group selected from benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, pyrrole ring, furan ring, thiophene ring, imidazole ring, pyrazole ring, oxazole ring, isoxazole ring, thiazole ring, or isothiazole ring.

[0233] In another embodiment of L, L1 is a divalent group selected from a benzene ring or a 5-6 membered heteroaromatic ring having one or two N atoms.

[0234] In another embodiment of L, L2 is a divalent group selected from 4-7 membered monocyclic heterocyclic groups, 6-10 membered fused heterocyclic groups, 6-10 membered bridged heterocyclic groups, or 6-9 membered spirocyclic heterocyclic groups; wherein the above groups are optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substitution of halogenated alkoxy groups.

[0235] In another implementation of L, L2 is The above-mentioned groups are optionally surrounded by one or more elements selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substitution of halogenated alkoxy groups.

[0236] In another embodiment of L, L4 is selected from C. 1-6 Alkynes, 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered bridged carbon rings, or 6-10 membered bridged heterocyclic rings with divalent groups; wherein the above groups are optionally surrounded by one or more groups selected from D, halogens, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substitution of halogenated alkoxy groups.

[0237] In another implementation of L, L4 is The above-mentioned groups are optionally surrounded by one or more elements selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substitution of halogenated alkoxy groups.

[0238] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein U1 and U2 are independently selected from the following formula (U A ) or formula (U B ):

[0239] in,

[0240] Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2;

[0241] Each Q1 is independently C(O) or C(R5)2;

[0242] Each P1, P2, and P3 is independently N or CR6;

[0243] Each R3 is independently H or C. 1-6 alkyl;

[0244] q can be 0, 1, 2, 3, 4, or 5;

[0245] d is 0 or 1;

[0246] Each R4 is independently D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups, or two R4 atoms on the same atom or two R4 atoms on adjacent atoms, together with the atoms they are attached to, form C. 3-7 Carbon rings or 4-7 membered heterocycles;

[0247] Each R5 is independently H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups, or two R5 atoms on the same atom together with the atoms they are attached to, form a C group. 3-7 Carbon rings or 4-7 membered heterocycles;

[0248] Each R6 is independently H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups, or two R6 atoms on adjacent atoms together with the atoms they are attached to, form C. 3-7 Carbon ring, 4-7 membered heterocyclic ring, benzene ring or 5-6 membered heteroaromatic ring.

[0249] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein,

[0250] U1 and U2 are independently selected from the following formula (U A1 ) or formula (U B1 ):

[0251] in,

[0252] Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2;

[0253] Each Q1 is independently C(O) or C(R5)2;

[0254] Each R3 is independently H or C. 1-6 alkyl;

[0255] p is 0, 1, or 2;

[0256] q can be 0, 1, 2, 3, 4, or 5;

[0257] Each R4 is independently D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups, or two R4 atoms on the same atom or two R4 atoms on adjacent atoms, together with the atoms they are attached to, form C. 3-7 Carbon rings or 4-7 membered heterocycles;

[0258] Each R5 is independently H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1- 6-Hydroalkoxy groups, or two R5 atoms on the same atom together with the atoms they are attached to, form C. 3-7 Carbon rings or 4-7 membered heterocycles;

[0259] Each R6 is independently D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups, or two R6 atoms on adjacent atoms together with the atoms they are attached to, form C. 3-7 Carbon ring, 4-7 membered heterocyclic ring, benzene ring or 5-6 membered heteroaromatic ring.

[0260] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein,

[0261] U1 and U2 are independently selected from the following formula (U A1 ) or formula (U B1 ):

[0262] in,

[0263] Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2;

[0264] Each Q1 is independently C(O) or C(R5)2;

[0265] Each R3 is independently H or methyl;

[0266] p is 0, 1, or 2;

[0267] q is 0, 1, or 2;

[0268] Each R4 is independently D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups, or two R4 atoms on the same atom or two R4 atoms on adjacent atoms, together with the atoms they are attached to, form C. 3-7 Carbon rings or 4-7 membered heterocycles;

[0269] Each R5 is independently H, D, or halogen;

[0270] Each R6 is independently either D or halogen.

[0271] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein,

[0272] U1 and U2 are independently selected from the following formula (U A2 ) or formula (U B2 ):

[0273] Each Q1 is independently C(O) or CH2;

[0274] p is 0, 1, or 2;

[0275] Each R6 is independently either D or halogen.

[0276] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein,

[0277] U1 and U2 are independently selected from the following formula (U C ) or formula (U D ):

[0278] in,

[0279] Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2;

[0280] Each W is independently a chemical bond, NH, O, C(O)NH, NHC(O), CH2 or CD2;

[0281] Each Q2 is independently either N or CH;

[0282] Each P1, P2, P3, and P4 is independently N or CR6;

[0283] Each R3 is independently H or C. 1-6 alkyl;

[0284] q can be 0, 1, 2, 3, 4, or 5;

[0285] d is 0 or 1;

[0286] Each R4 is independently D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups, or two R4 atoms on the same atom or two R4 atoms on adjacent atoms, together with the atoms they are attached to, form C. 3-7 Carbon rings or 4-7 membered heterocycles;

[0287] Each R6 is independently H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups, or two R6 atoms on adjacent atoms together with the atoms they are attached to, form C. 3-7 Carbon ring, 4-7 membered heterocyclic ring, benzene ring or 5-6 membered heteroaromatic ring.

[0288] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein,

[0289] U1 and U2 are independently selected from the following formula (U C1 ) or formula (U D1 ):

[0290] in,

[0291] Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2;

[0292] Each W is independently a chemical bond, NH, O, C(O)NH, NHC(O), CH2 or CD2;

[0293] Each Q2 is independently either N or CH;

[0294] Each P1 is independently either N or CR6;

[0295] Each R3 is independently H or C. 1-6 alkyl;

[0296] q can be 0, 1, 2, 3, 4, or 5;

[0297] Each R4 is independently D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups, or two R4 atoms on the same atom or two R4 atoms on adjacent atoms, together with the atoms they are attached to, form C. 3-7 Carbon rings or 4-7 membered heterocycles;

[0298] p is 0, 1, or 2;

[0299] Each R6 is independently H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups, or two R6 atoms on adjacent atoms together with the atoms they are attached to, form C. 3-7 Carbon ring, 4-7 membered heterocyclic ring, benzene ring or 5-6 membered heteroaromatic ring.

[0300] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein,

[0301] U1 and U2 are independently defined by the following formula (U C1 ) or formula (U D1 ):

[0302] in,

[0303] Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2;

[0304] Each W is independently a chemical bond, NH, O, C(O)NH, NHC(O), CH2 or CD2;

[0305] Each Q2 is independently either N or CH;

[0306] Each P1 is independently either N or CR6;

[0307] Each R3 is independently H or methyl;

[0308] p is 0, 1, or 2;

[0309] q is 0, 1, or 2;

[0310] Each R4 is independently D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy groups, or two R4 atoms on the same atom or two R4 atoms on adjacent atoms, together with the atoms they are attached to, form C. 3-7 Carbon rings or 4-7 membered heterocycles;

[0311] Each R6 is independently H, D, or halogen.

[0312] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein,

[0313] U1 and U2 are independently defined by the following formula (U C2 ) or formula (U D2 ):

[0314] in,

[0315] Each W is independently a chemical bond, NH, C(O)NH or NHC(O);

[0316] Each Q2 is independently either N or CH;

[0317] Each P1 is independently either N or CR6;

[0318] p is 0, 1, or 2;

[0319] Each R6 is independently H, D, or halogen.

[0320] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein,

[0321] U1 and U2 are independently selected from the following formula (U E ):

[0322] in,

[0323] It can be a single bond or a double bond;

[0324] Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2;

[0325] Each Q2 is independently either N or CH;

[0326] Each P1, P2, P3, and P4 is independently N or CR6;

[0327] P5 and P6 are either N or C;

[0328] H1 is N, C, or CR7;

[0329] H2 and H3 are independently N, O, S, NR7, CR7, C(R7)2 or C(O);

[0330] Each R3 is independently H or C. 1-6 alkyl;

[0331] q can be 0, 1, 2, 3, 4, or 5;

[0332] d is 0 or 1;

[0333] Each R4 is independently D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6Haloalkoxy groups, or two R4 atoms on the same atom or two R4 atoms on adjacent atoms, together with the atoms they are attached to, form C. 3-7 Carbon rings or 4-7 membered heterocycles;

[0334] Each R6 is independently H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups, or two R6 atoms on adjacent atoms together with the atoms they are attached to, form C. 3-7 Carbon rings, 4-7 membered heterocycles, benzene rings, or 5-6 membered heteroaromatic rings;

[0335] Each R7 is independently H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups, or two R7 groups on the same atom or two R7 groups on adjacent atoms together with the atoms they are attached to, forming a C group. 3-7 Carbon ring, 4-7 membered heterocyclic ring, benzene ring or 5-6 membered heteroaromatic ring.

[0336] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein,

[0337] U1 and U2 are independently selected from the following formula (U E1 ), formula (U E2 ), formula (U E3 ), formula (U E4 ), formula (U E5 ), formula (U E6 ), formula (U E7 ), formula (U E15 ) or formula (U E16 ):

[0338] in,

[0339] Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2;

[0340] Each Q2 is independently either N or CH;

[0341] Each P1, P2, P3, and P4 is independently N or CR6;

[0342] Each R3 is independently H or C. 1-6 alkyl;

[0343] q can be 0, 1, 2, 3, 4, or 5;

[0344] d is 0 or 1;

[0345] Each R4 is independently D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups, or two R4 atoms on the same atom or two R4 atoms on adjacent atoms, together with the atoms they are attached to, form C. 3-7 Carbon rings or 4-7 membered heterocycles;

[0346] Each R6 is independently H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups, or two R6 atoms on adjacent atoms together with the atoms they are attached to, form C. 3-7 Carbon rings, 4-7 membered heterocycles, benzene rings, or 5-6 membered heteroaromatic rings;

[0347] Each R7 is independently H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups.

[0348] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein,

[0349] U1 and U2 are independently selected from the following formula (U E1 ), formula (U E2 ), formula (U E3 ), formula (U E4 ), formula (U E5 ), formula (U E6 ), formula (U E7 ), formula (U E15 ) or formula (U E16 ):

[0350] in,

[0351] Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2;

[0352] Each Q2 is independently either N or CH;

[0353] Each P1, P2, P3, and P4 is independently N or CR6;

[0354] Each R3 is independently H or methyl;

[0355] q is 0, 1, or 2;

[0356] Each R4 is independently D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups, or two R4 atoms on the same atom or two R4 atoms on adjacent atoms, together with the atoms they are attached to, form C. 3-7 Carbon rings or 4-7 membered heterocycles;

[0357] Each R6 is independently H, D, or halogen;

[0358] Each R7 is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups.

[0359] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein,

[0360] U1 and U2 are independently selected from the following formula (U E8 ), formula (U E9 ), formula (U E10 ), formula (U E11 ), formula (U E12 ), formula (U E13 ), formula (U E14 ), formula (U E17 ) or formula (U E18 ):

[0361] in,

[0362] Each Q2 is independently either N or CH;

[0363] p is 0, 1, or 2;

[0364] Each R6 is independently either D or halogen;

[0365] Each R7 is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups.

[0366] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein,

[0367] U1 and U2 are independently selected from the following formula ((U F ):

[0368] in,

[0369] V represents a chemical bond, such as C(O), NH, O, S, S(O)2, CH2, or CD2;

[0370] Each Q3 is independently either N or CR5;

[0371] Each P1, P2, and P3 is independently N or CR6;

[0372] Each R3 is independently H or C. 1-6 alkyl;

[0373] q can be 0, 1, 2, 3, 4, or 5;

[0374] d is 0 or 1;

[0375] Each R4 is independently D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups, or two R4 atoms on the same atom or two R4 atoms on adjacent atoms, together with the atoms they are attached to, form C. 3-7 Carbon rings or 4-7 membered heterocycles;

[0376] Each R5 is independently H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0377] Each R6 is independently H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6Halogenated alkoxy groups, or two R6 atoms on adjacent atoms together with the atoms they are attached to, form C. 3-7 Carbon ring, 4-7 membered heterocyclic ring, benzene ring or 5-6 membered heteroaromatic ring.

[0378] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein,

[0379] U1 and U2 are independently selected from the following formula ((U F1 ):

[0380] in,

[0381] V represents a chemical bond, such as C(O), NH, O, S, S(O)2, CH2, or CD2;

[0382] Each Q3 is independently either N or CR5;

[0383] Each R3 is independently H or methyl;

[0384] p is 0, 1, or 2;

[0385] q is 0, 1, or 2;

[0386] Each R4 is independently D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups, or two R4 atoms on the same atom or two R4 atoms on adjacent atoms, together with the atoms they are attached to, form C. 3-7 Carbon rings or 4-7 membered heterocycles;

[0387] Each R5 is independently H, D, or halogen;

[0388] Each R6 is independently either D or halogen.

[0389] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein,

[0390] U1 and U2 are independently selected from the following formula ((U F2 ):

[0391] in,

[0392] Each Q3 is independently either N or CR5;

[0393] Each R5 is independently H, D, or halogen;

[0394] p is 0, 1, or 2;

[0395] Each R6 is independently either D or halogen.

[0396] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein,

[0397] U1 and U2 are independently selected from the following formula (U G ):

[0398] in,

[0399] V represents a chemical bond, such as C(O), NH, O, S, S(O)2, CH2, or CD2;

[0400] Each P1, P2, P3, and P4 is independently N or CR6;

[0401] Each R6 is independently H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups, or two R6 atoms on adjacent atoms together with the atoms they are attached to, form C. 3-7 Carbon ring, 4-7 membered heterocyclic ring, benzene ring or 5-6 membered heteroaromatic ring.

[0402] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein,

[0403] U1 and U2 are independently selected from the following formula (U G1 ):

[0404] in,

[0405] V represents a chemical bond, such as C(O), NH, O, S, S(O)2, CH2, or CD2;

[0406] p is 0, 1, or 2;

[0407] Each R6 is independently either D or halogen.

[0408] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein,

[0409] U1 and U2 are independently selected from the following formula (U G2 ):

[0410] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein,

[0411] U2 is the following formula (U H ) or formula (U J ):

[0412] in,

[0413] Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2;

[0414] Each P1, P2, P3, and P4 is independently N or CR6;

[0415] Each R3 is independently H or C. 1-6 alkyl;

[0416] q can be 0, 1, 2, 3, 4, or 5;

[0417] d is 0 or 1;

[0418] Each R4 is independently D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups, or two R4 atoms on the same atom or two R4 atoms on adjacent atoms, together with the atoms they are attached to, form C. 3-7 Carbon rings or 4-7 membered heterocycles;

[0419] Each R6 is independently H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups, or two R6 atoms on adjacent atoms together with the atoms they are attached to, form C. 3-7 Carbon ring, 4-7 membered heterocyclic ring, benzene ring or 5-6 membered heteroaromatic ring.

[0420] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein,

[0421] U2 is the following formula (U H1 ) or formula (U J1 ):

[0422] in,

[0423] Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2;

[0424] Each P1 is independently either N or CR6;

[0425] Each R3 is independently H or C. 1-6 alkyl;

[0426] q can be 0, 1, 2, 3, 4, or 5;

[0427] Each R4 is independently D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups, or two R4 atoms on the same atom or two R4 atoms on adjacent atoms, together with the atoms they are attached to, form C. 3-7 Carbon rings or 4-7 membered heterocycles;

[0428] p is 0, 1, or 2;

[0429] Each R6 is independently H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups, or two R6 atoms on adjacent atoms together with the atoms they are attached to, form C. 3-7 Carbon ring, 4-7 membered heterocyclic ring, benzene ring or 5-6 membered heteroaromatic ring.

[0430] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein,

[0431] U2 is the following formula (U H1 ) and formula (U J1 ):

[0432] in,

[0433] Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2;

[0434] Each P1 is independently either N or CR6;

[0435] Each R3 is independently H or methyl;

[0436] p is 0, 1, or 2;

[0437] q is 0, 1, or 2;

[0438] Each R4 is independently D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups, or two R4 atoms on the same atom or two R4 atoms on adjacent atoms, together with the atoms they are attached to, form C. 3-7 Carbon rings or 4-7 membered heterocycles;

[0439] Each R6 is independently H, D, or halogen.

[0440] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein,

[0441] U2 is the following formula (U H2 ) or formula (U J2 ):

[0442] in,

[0443] Each P1 is independently either N or CR6;

[0444] p is 0, 1, or 2;

[0445] Each R6 is independently H, D, or halogen.

[0446] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein,

[0447] U1 and U2 are independently selected from the following formula (U A1 ), formula (U B1 ), formula (U C1 ), formula (U D1), formula (U E1 ), formula (U E2 ), formula (U E3 ), formula (U E4 ), formula (U E5 ), formula (U E6 ), formula (U E7 ), formula (U E15 ), formula (U E16 ), formula (U F1 ) or formula (U G1 ):

[0448] in,

[0449] Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2;

[0450] Each W is independently a chemical bond, NH, O, C(O)NH, NHC(O), CH2 or CD2;

[0451] Each Q1 is independently C(O) or C(R5)2;

[0452] Each Q2 is independently either N or CH;

[0453] Each Q3 is independently either N or CR5;

[0454] Each P1, P2, P3, and P4 is independently N or CR6;

[0455] P5 and P6 are either N or C;

[0456] Each R3 is independently H or C. 1-6 alkyl;

[0457] p is 0, 1, or 2;

[0458] q can be 0, 1, 2, 3, 4, or 5;

[0459] d is 0 or 1;

[0460] Each R4 is independently D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups, or two R4 atoms on the same atom or two R4 atoms on adjacent atoms, together with the atoms they are attached to, form C. 3-7 Carbon rings or 4-7 membered heterocycles;

[0461] Each R5 is independently H, D, halogen, -OH, -CN, C 1-6Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups, or two R5 atoms on the same atom together with the atoms they are attached to, form a C group. 3-7 Carbon rings or 4-7 membered heterocycles;

[0462] Each R6 is independently H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups, or two R6 atoms on adjacent atoms together with the atoms they are attached to, form C. 3-7 Carbon rings, 4-7 membered heterocycles, benzene rings, or 5-6 membered heteroaromatic rings;

[0463] Each R7 is independently H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups, or two R7 groups on the same atom or two R7 groups on adjacent atoms together with the atoms they are attached to, forming a C group. 3-7 Carbon ring, 4-7 membered heterocyclic ring, benzene ring or 5-6 membered heteroaromatic ring.

[0464] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein,

[0465] U1 and U2 are independently selected from the following formula (U A1 ), formula (U B1 ), formula (U C1 ), formula (U D1 ), formula (U E1 ), formula (U E2 ), formula (U E3 ), formula (U E4 ), formula (U E5 ), formula (U E6 ), formula (U E7 ), formula (U E15 ), formula (U E16 ), formula (U F1 ) or formula (U G1 ):

[0466] in,

[0467] Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2;

[0468] Each W is independently a chemical bond, NH, O, C(O)NH, NHC(O), CH2 or CD2;

[0469] Each Q1 is independently C(O) or C(R5)2;

[0470] Each Q2 is independently either N or CH;

[0471] Each Q3 is independently either N or CR5;

[0472] Each P1, P2, P3, and P4 is independently N or CR6;

[0473] Each R3 is independently H or methyl;

[0474] p is 0 or 1;

[0475] q is 0, 1, or 2;

[0476] Each R4 is independently D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups, or two R4 atoms on the same atom or two R4 atoms on adjacent atoms, together with the atoms they are attached to, form C. 3-7 Carbon rings or 4-7 membered heterocycles;

[0477] Each R5 is independently H, D, or halogen;

[0478] Each R6 is independently H, D, or halogen;

[0479] Each R7 is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups.

[0480] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein,

[0481] U1 and U2 are independently selected from the following formula (U A1 ), formula (U B1 ), formula (U D1 ), formula (U E1 ), formula (U E5 ), formula (UE7 ), formula (U E15 ), formula (U E16 ), or formula (U) G1 ):

[0482] in,

[0483] Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2;

[0484] Each W is independently a chemical bond, NH, O, C(O)NH, NHC(O), CH2 or CD2;

[0485] Each Q1 is independently C(O) or C(R5)2;

[0486] Each Q2 is independently either N or CH;

[0487] Each P1, P2, and P3 is independently N or CR6;

[0488] Each R3 is independently H or methyl;

[0489] p is 0, 1, or 2;

[0490] q is 0, 1, or 2;

[0491] Each R4 is independently D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups, or two R4 atoms on the same atom or two R4 atoms on adjacent atoms, together with the atoms they are attached to, form C. 3-7 Carbon rings or 4-7 membered heterocycles;

[0492] Each R5 is independently H, D, or halogen;

[0493] Each R6 is independently H, D, or halogen;

[0494] Each R7 is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups.

[0495] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein,

[0496] U1 and U2 are independently selected from the following formula (UA2 ), formula (U B2 ), formula (U C2 ), formula (U D2 ), formula (U E8 ), formula (U E9 ), formula (U E10 ), formula (U E11 ), formula (U E12 ), formula (U E13 ), formula (U E14 ), formula (U E17 ), formula (U E18 ), formula (U F2 ) or formula (U G2 ):

[0497] in,

[0498] Each W is independently a chemical bond, NH, C(O)NH or NHC(O);

[0499] Each Q1 is independently C(O) or CH2;

[0500] Each Q2 is independently either N or CH;

[0501] Each Q3 is independently either N or CR5;

[0502] Each P1 is independently either N or CR6;

[0503] Each R5 is independently H, D, or halogen;

[0504] p is 0, 1, or 2;

[0505] Each R6 is independently H, D, or halogen;

[0506] Each R7 is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups.

[0507] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein,

[0508] U1 and U2 are independently selected from the following formula (U A2 ), formula (U B2 ), formula (U D2 ), formula (U E8 ), formula (U E12 ), formula (U E14 ), formula (UE17 ), formula (U E18 ) or formula (U G2 ):

[0509] in,

[0510] Each W is independently a chemical bond, NH, C(O)NH or NHC(O);

[0511] Each Q1 is independently C(O) or CH2;

[0512] Each Q2 is independently either N or CH;

[0513] Each P1 is independently either N or CR6;

[0514] p is 0, 1, 2 or 3;

[0515] Each R6 is independently H, D, or halogen;

[0516] Each R7 is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups.

[0517] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein,

[0518] U2 is selected from the following formula (U A1 ), formula (U B1 ), formula (U F1 ), formula (U G1 ), formula (U H1 ) or formula (U J1 ):

[0519] in,

[0520] Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2;

[0521] Each Q1 is independently C(O) or C(R5)2;

[0522] Each Q3 is independently either N or CR5;

[0523] Each P1 is independently either N or CR6;

[0524] Each R3 is independently H or C. 1-6 alkyl;

[0525] p is 0, 1, or 2;

[0526] q can be 0, 1, 2, 3, 4, or 5;

[0527] Each R4 is independently D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups, or two R4 atoms on the same atom or two R4 atoms on adjacent atoms, together with the atoms they are attached to, form C. 3-7 Carbon rings or 4-7 membered heterocycles;

[0528] Each R5 is independently H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups, or two R5 atoms on the same atom together with the atoms they are attached to, form a C group. 3-7 Carbon rings or 4-7 membered heterocycles;

[0529] Each R6 is independently H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups, or two R6 atoms on adjacent atoms together with the atoms they are attached to, form C. 3-7 Carbon ring, 4-7 membered heterocyclic ring, benzene ring or 5-6 membered heteroaromatic ring.

[0530] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein,

[0531] U2 is selected from the following formula (U A1 ), formula (U B1 ), formula (U F1 ), formula (U G1 ), formula (U H1 ) or formula (U J1 ):

[0532] in,

[0533] Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2;

[0534] Each Q1 is independently C(O) or C(R5)2;

[0535] Each Q3 is independently either N or CR5;

[0536] Each P1 is independently either N or CR6;

[0537] Each R3 is independently H or methyl;

[0538] p is 0, 1, or 2;

[0539] q is 0, 1, or 2;

[0540] Each R4 is independently D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups, or two R4 atoms on the same atom or two R4 atoms on adjacent atoms, together with the atoms they are attached to, form C. 3-7 Carbon rings or 4-7 membered heterocycles;

[0541] R5 is H, D, or a halogen;

[0542] Each R6 is independently H, D, or halogen.

[0543] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein,

[0544] U2 is selected from the following formula (U A1 ), formula (U B1 ), formula (U G1 ), formula (U H1 ) or formula (U J1 ):

[0545] in,

[0546] Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2;

[0547] Each Q1 is independently C(O) or C(R5)2;

[0548] Each P1 is independently either N or CR6;

[0549] Each R3 is independently H or methyl;

[0550] p is 0, 1, or 2;

[0551] q is 0, 1, or 2;

[0552] Each R4 is independently D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy groups, or two R4 atoms on the same atom or two R4 atoms on adjacent atoms, together with the atoms they are attached to, form C. 3-7 Carbon rings or 4-7 membered heterocycles;

[0553] Each R5 is independently H, D, or halogen;

[0554] Each R6 is independently H, D, or halogen;

[0555] Each R7 is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups.

[0556] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein,

[0557] U2 is selected from the following formula (U A2 ), formula (U B2 ), formula (U F2 ), formula (U G2 ) formula (U H2 ) and formula (U J2 ):

[0558] in,

[0559] Each Q1 is independently C(O) or CH2;

[0560] Each Q3 is independently either N or CR5;

[0561] Each P1 is independently either N or CR6;

[0562] Each R5 is independently H, D, or halogen;

[0563] p is 0, 1, or 2;

[0564] Each R6 is independently H, D, or halogen.

[0565] In another embodiment, the present invention relates to compounds of formula (IA), (IB), (IIA), or (IIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein,

[0566] U2 is selected from the following formula (U A2 ), formula (U B2 ), formula (U G2 ) formula (U H2 ) and formula (U J2 ):

[0567] in,

[0568] Each Q1 is independently C(O) or CH2;

[0569] Each P1 is independently either N or CR6;

[0570] p is 0, 1, or 2;

[0571] Each R6 is independently H, D, or halogen.

[0572] In another embodiment, the present invention relates to compounds of formula (IIIA) or (IIIB), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof.

[0573] in,

[0574] X is either O or NH;

[0575] R A1 and R A2 Independently, it can be H, D, halogen, -OH, -CN, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0576] R B1 For H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0577] R1 and R2 are independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6Cycloalkyl or 4-7 membered heterocyclic groups, where R1 and R2 together with the N atom to which they are attached form a 4-7 membered monocyclic heterocycle, a 6-10 membered fused heterocycle, a 6-10 membered bridged heterocycle, or a 6-9 membered spirocyclic heterocycle; wherein the above groups are optionally surrounded by one or more atoms selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0578] i is 0 or 1;

[0579] L1 is a divalent group selected from a benzene ring or a 5-6 membered heteroaromatic ring; wherein the above group is optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0580] L2 is a divalent group selected from 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered fused carbon rings, 6-10 membered fused heterocyclic rings, 6-10 membered bridged carbon rings, 6-10 membered bridged heterocyclic rings, 6-9 membered spirocyclic carbon rings, or 6-9 membered spirocyclic heterocyclic rings; wherein the above groups are optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0581] L4 is a divalent group selected from 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered fused carbon rings, 6-10 membered fused heterocyclic rings, 6-10 membered bridged carbon rings, 6-10 membered bridged heterocyclic rings, 6-9 membered spirocyclic carbon rings, or 6-9 membered spirocyclic heterocyclic rings; wherein the above groups are optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0582] U1 is selected from the following formula (U A1 ), formula (U B1 ), formula (U D1 ) or formula (U E1 ):

[0583] U2 is selected from the following formula (U A1 ), formula (U B1 ), formula (UH1 ) or formula (U J1 ):

[0584] in,

[0585] Each V is an independent chemical bond;

[0586] Each W is independently a chemical bond, NH, O, C(O)NH, NHC(O), CH2 or CD2;

[0587] Each Q1 is independently C(O) or C(R5)2;

[0588] Each Q2 is independently either N or CH;

[0589] Each P1, P2, and P3 is independently N or CR6;

[0590] Each R3 is independently H or methyl;

[0591] p is 0, 1, or 2;

[0592] q is 0, 1, or 2;

[0593] Each R4 is independently D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups, or two R4 atoms on the same atom or two R4 atoms on adjacent atoms, together with the atoms they are attached to, form C. 3-7 Carbon rings or 4-7 membered heterocycles;

[0594] Each R5 is independently H, D, or halogen;

[0595] Each R6 is independently H, D, or halogen;

[0596] Each R7 is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups.

[0597] In another embodiment, the present invention relates to a compound of formula (IIIA) or formula (IIIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein,

[0598] X is either O or NH;

[0599] R A1 and R A2 Independently H, D, halogen, -CN, methyl, halomethyl, methoxy or halomethoxy;

[0600] R B1 H, D, halogen, -CN, methyl, halomethyl, methoxy or halomethoxy;

[0601] R1 and R2 are independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups, or R1 and R2 together with the N atom to which they are attached to form a 4-7 membered monocyclic heterocycle, a 6-10 membered fused heterocycle, a 6-10 membered bridged heterocycle, or a 6-9 membered spirocyclic heterocycle; wherein the above groups are optionally surrounded by one or more atoms selected from D, halogen, -OH, -CN, C. 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0602] i is 0 or 1;

[0603] L1 is a divalent group selected from a benzene ring or a 5-6 membered heteroaromatic ring having 1 or 2 N atoms, optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0604] L2 is a divalent group selected from 4-7 membered monocyclic heterocycles, 6-10 membered fused heterocycles, 6-10 membered bridged heterocycles, or 6-9 membered spirocyclic heterocycles; wherein the above groups are optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0605] L4 is a divalent group selected from 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered bridged carbon rings, or 6-10 membered bridged heterocyclic rings; wherein the above group is optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0606] U1 is selected from the following formula (U A2 ), formula (U B2 ), formula (U D2 ) or formula (U E8 ):

[0607] U2 is selected from the following formula (U A2 ), formula (U B2 ), formula (U H2 ) and formula (U J2 ):

[0608] in,

[0609] Each W is independently a chemical bond, NH, C(O)NH or NHC(O);

[0610] Each Q1 is independently C(O) or CH2;

[0611] Each Q2 is independently either N or CH;

[0612] P1 is either N or CR6;

[0613] p is 0, 1, 2 or 3;

[0614] Each R6 is independently H, D, or halogen;

[0615] Each R7 is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups.

[0616] In another embodiment, the present invention relates to a compound of formula (IIIA) or formula (IIIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1 is methyl and R2 is ethyl.

[0617] In another embodiment, the present invention relates to a compound of formula (IIIA) or formula (IIIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R1 and R2, together with the N atom to which they are attached, form the following groups:

[0618] In another embodiment, the present invention relates to a compound of formula (IIIA) or formula (IIIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R1 and R2, together with the N atom to which they are attached, form the following ring:

[0619] In another embodiment, the present invention relates to a compound of formula (IIIA) or formula (IIIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R1 and R2 together with the N atom to which they are attached form

[0620] In another embodiment, the present invention relates to a compound of formula (IIIA) or formula (IIIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein L2 is The above-mentioned groups are optionally surrounded by one or more elements selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substitution of halogenated alkoxy groups.

[0621] In another embodiment, the present invention relates to a compound of formula (IIIA) or formula (IIIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein L2 is Preferably, L2 is More preferably, L2 is

[0622] In another embodiment, the present invention relates to a compound of formula (IIIA) or formula (IIIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein L4 is The above-mentioned groups are optionally surrounded by one or more elements selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substitution of halogenated alkoxy groups.

[0623] In another embodiment, the present invention relates to a compound of formula (IIIA) or formula (IIIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein L4 is The aforementioned groups are optionally substituted by one or more groups selected from D, halogens, or -OH.

[0624] In another embodiment, the present invention relates to a compound of formula (IIIA) or formula (IIIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein L4 is

[0625] In another embodiment, the present invention relates to a compound of formula (IIIA) or formula (IIIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein i is 1.

[0626] In another embodiment, the present invention relates to a compound of formula (IIIA) or formula (IIIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R A1 and R A2 Independently H, D, halogen, or -CN; R B1 It can be H, D, halogen, or -CN.

[0627] In another embodiment, the present invention relates to a compound of formula (IIIA) or formula (IIIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is O, R is R. A1 For CN, R A2 For F, R B1 For H.

[0628] In another embodiment, the present invention relates to a compound of formula (IIIA) or formula (IIIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is O, R is R. A1 For CN, R A2 For F, R B1 H is a divalent group of the benzene ring; L1 is a divalent group of the benzene ring.

[0629] In another embodiment, the present invention relates to a compound of formula (IIIA) or formula (IIIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is O, R is R. A1 For CN, R A2 For F, R B1 H is a divalent group of the benzene ring; L1 is a divalent group of the benzene ring; U1 is...

[0630] In another embodiment, the present invention relates to a compound of formula (IIIA) or formula (IIIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is N, RA1 For Cl, R A2 For F, R B1 For H.

[0631] In another embodiment, the present invention relates to a compound of formula (IIIA) or formula (IIIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is N, R A1 For Cl, R A2 For F, R B1 H is a divalent group of pyrazole; L1 is a divalent group of pyrazole.

[0632] In another embodiment, the present invention relates to a compound of formula (IIIA) or formula (IIIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is N, R A1 For Cl, R A2 For F, R B1 H is the hydrogen atom; L1 is the divalent group of pyrazole; U1 is...

[0633] In another embodiment, the present invention relates to a compound of formula (IIIA) or formula (IIIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein U1 is

[0634] In another embodiment, the present invention relates to a compound of formula (IIIA) or formula (IIIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein U2 is

[0635] In another embodiment, the present invention relates to compounds of formula (VIA) or (VIB), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates.

[0636] in,

[0637] X is either O or NH;

[0638] R A1 and R A2 Independently, it can be H, D, halogen, -OH, -CN, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0639] R B1 For H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0640] R1 and R2 are independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups, where R1 and R2 together with the N atom to which they are attached form a 4-7 membered monocyclic heterocycle, a 6-10 membered fused heterocycle, a 6-10 membered bridged heterocycle, or a 6-9 membered spirocyclic heterocycle; wherein the above groups are optionally surrounded by one or more atoms selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0641] L1 is a divalent group selected from a benzene ring or a 5-6 membered heteroaromatic ring; wherein the above group is optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0642] L4 is a divalent group selected from 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered fused carbon rings, 6-10 membered fused heterocyclic rings, 6-10 membered bridged carbon rings, 6-10 membered bridged heterocyclic rings, 6-9 membered spirocyclic carbon rings, or 6-9 membered spirocyclic heterocyclic rings; wherein the above groups are optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substitution of halogenated alkoxy groups.

[0643] In another embodiment, the present invention relates to a compound of formula (VIA) or (VIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein,

[0644] X is either O or NH;

[0645] R A1 and R A2 Independently H, D, halogen, -CN, methyl, halomethyl, methoxy or halomethoxy;

[0646] R B1 H, D, halogen, -CN, methyl, halomethyl, methoxy or halomethoxy;

[0647] R1 and R2 are independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups, or R1 and R2 together with the N atom to which they are attached to form a 4-7 membered monocyclic heterocycle, a 6-10 membered fused heterocycle, a 6-10 membered bridged heterocycle, or a 6-9 membered spirocyclic heterocycle; wherein the above groups are optionally surrounded by one or more atoms selected from D, halogen, -OH, -CN, C. 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0648] L1 is a divalent group selected from a benzene ring or a 5-6 membered heteroaromatic ring having 1 or 2 N atoms, optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0649] L4 is a divalent group selected from 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered bridged carbon rings, or 6-10 membered bridged heterocyclic rings; wherein the above group is optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy and C 1-6 Substitution of halogenated alkoxy groups.

[0650] In another embodiment, the present invention relates to a compound of formula (VIA) or (VIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1 is methyl and R2 is ethyl.

[0651] In another embodiment, the present invention relates to a compound of formula (VIA) or (VIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R1 and R2, together with the N atom to which they are attached, form the following ring:

[0652] In another embodiment, the present invention relates to a compound of formula (VIA) or (VIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R1 and R2, together with the N atom to which they are attached, form the following ring:

[0653] In another embodiment, the present invention relates to a compound of formula (VIA) or (VIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R1 and R2 together with the N atom to which they are attached form

[0654] In another embodiment, the present invention relates to a compound of formula (VIA) or (VIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein L4 is The above-mentioned groups are optionally surrounded by one or more elements selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substitution of halogenated alkoxy groups.

[0655] In another embodiment, the present invention relates to a compound of formula (VIA) or (VIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein L4 is The aforementioned groups are optionally substituted by one or more groups selected from D, halogens, or -OH.

[0656] In another embodiment, the present invention relates to a compound of formula (VIA) or (VIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein L4 is

[0657] In another embodiment, the present invention relates to a compound of formula (VIA) or (VIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R A1 and R A2 Independently H, D, halogen, or -CN; R B1 It can be H, D, halogen, or -CN.

[0658] In another embodiment, the present invention relates to a compound of formula (VIA) or (VIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is O, R A1 For CN, R A2 For F, R B1 For H.

[0659] In another embodiment, the present invention relates to a compound of formula (VIA) or (VIB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is N, R A1 For Cl, R A2 For F, R B1 For H.

[0660] In another embodiment, the present invention relates to a compound of formula (VA), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0661] in,

[0662] R A1 and R A2 Independently, it can be H, D, halogen, -OH, -CN, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0663] R B1 For H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0664] R1 and R2, together with the N atom they are attached to, form a 4-7 membered monocyclic heterocycle, a 6-10 membered fused heterocycle, a 6-10 membered bridged heterocycle, or a 6-9 membered spirocyclic heterocycle; wherein the above groups are optionally surrounded by one or more atoms selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0665] i is 0 or 1;

[0666] L1 is a divalent group selected from a 5-6 membered heteroaromatic ring having 1 or 2 N atoms, optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C.1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0667] L2 is a divalent group selected from 4-7 membered monocyclic heterocycles, 6-10 membered fused heterocycles, 6-10 membered bridged heterocycles, or 6-9 membered spirocyclic heterocycles; wherein the above groups are optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0668] L4 is a divalent group selected from 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered bridged carbon rings, or 6-10 membered bridged heterocyclic rings; wherein the above group is optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0669] U1 is selected from the following formula (U A1 ), formula (U B1 ), formula (U D1 ), formula (U E1 ), formula (U E2 ), formula (U E3 ), formula (U E4 ), formula (U E5 ), formula (U E6 ), formula (U E7 ), formula (U E15 ) or formula (U E16 ):

[0670] in,

[0671] Each V is an independent chemical bond;

[0672] Each W is independently a chemical bond, NH, O, C(O)NH, NHC(O), CH2 or CD2;

[0673] Each Q1 is independently C(O) or C(R5)2;

[0674] Each Q2 is independently either N or CH;

[0675] Each P1, P2, and P3 is independently N or CR6;

[0676] Each R3 is independently H or methyl;

[0677] p is 0, 1, or 2;

[0678] q is 0, 1, or 2;

[0679] Each R4 is independently D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups, or two R4 atoms on the same atom or two R4 atoms on adjacent atoms, together with the atoms they are attached to, form C. 3-7 Carbon rings or 4-7 membered heterocycles;

[0680] Each R5 is independently H, D, or halogen;

[0681] Each R6 is independently H, D, or halogen;

[0682] Each R7 is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups.

[0683] In another embodiment, the present invention relates to a compound of formula (VA), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein U1 is selected from the following formula (U A1 ), formula (U B1 ), formula (U D1 ) or formula (U E1 ).

[0684] In another embodiment, the present invention relates to a compound of formula (VA), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein U1 is selected from the following formula (U E2 ), formula (U E3 ), formula (U E4 ), formula (U E5 ), formula (U E6 ), formula (U E7 ), formula (U E15 ) or formula (U E16 ).

[0685] In another embodiment, the present invention relates to a compound of formula (VA), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein,

[0686] R A1 and R A2Independently H, D, halogen, -CN, methyl, halomethyl, methoxy or halomethoxy;

[0687] R B1 H, D, halogen, -CN, methyl, halomethyl, methoxy or halomethoxy;

[0688] R1 and R2, together with the N atom they are attached to, form a 4-7 membered monocyclic heterocycle, a 6-10 membered fused heterocycle, a 6-10 membered bridged heterocycle, or a 6-9 membered spirocyclic heterocycle; wherein the above groups are optionally surrounded by one or more atoms selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0689] i is 0 or 1;

[0690] L1 is a divalent group selected from a 5-6 membered heteroaromatic ring having 1 or 2 N atoms, optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0691] L2 is a divalent group selected from 4-7 membered monocyclic heterocycles, 6-10 membered fused heterocycles, 6-10 membered bridged heterocycles, or 6-9 membered spirocyclic heterocycles; wherein the above groups are optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0692] L4 is a divalent group selected from 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered bridged carbon rings, or 6-10 membered bridged heterocyclic rings; wherein the above group is optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0693] U1 is selected from the following formula (U A2 ), formula (U B2 ), (U D2 ), formula (U E8 ), formula (U E9 ), formula (U E10 ), formula (UE11 ), formula (U E12 ), formula (U E13 ), formula (U E14 ), formula (U E17 ) or formula (U E18 ):

[0694] in,

[0695] Each W is independently a chemical bond, NH, C(O)NH or NHC(O);

[0696] Each Q1 is independently C(O) or CH2;

[0697] Each Q2 is independently either N or CH;

[0698] P1 is either N or CR6;

[0699] p is 0, 1, 2 or 3;

[0700] Each R6 is independently H, D, or halogen;

[0701] Each R7 is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups.

[0702] In another embodiment, the present invention relates to a compound of formula (VA), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein U1 is selected from the following formula (U A2 ), formula (U B2 ), formula (U D2 ) or formula (U E8 ).

[0703] In another embodiment, the present invention relates to a compound of formula (VA), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein formula (U E9 ), formula (U E10 ), formula (U E11 ), formula (U E12 ), formula (U E13 ), formula (U E14 ), formula (U E17 ) or formula (U E18 ).

[0704] In another embodiment, the present invention relates to a compound of formula (VA), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein L1 is a divalent group selected from a 5-membered heteroaromatic ring having 1 or 2 N atoms, optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substitution of halogenated alkoxy groups.

[0705] In another embodiment, the present invention relates to a compound of formula (VA), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein L2 is The above-mentioned groups are optionally surrounded by one or more elements selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substitution of halogenated alkoxy groups.

[0706] In another embodiment, the present invention relates to a compound of formula (VA), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which is a compound of formula (VA-1) or formula (VA-2).

[0707] in,

[0708] R A1 and R A2 Independently H, D, halogen, -CN, methyl, halomethyl, methoxy or halomethoxy;

[0709] R B1 H, D, halogen, -CN, methyl, halomethyl, methoxy or halomethoxy;

[0710] R1 and R2, together with the N atom they are attached to, form a 4-7 membered monocyclic heterocycle, a 6-10 membered fused heterocycle, a 6-10 membered bridged heterocycle, or a 6-9 membered spirocyclic heterocycle; wherein the above groups are optionally surrounded by one or more atoms selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0711] L4 is a divalent group selected from 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered bridged carbon rings, or 6-10 membered bridged heterocyclic rings; wherein the above group is optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0712] U1 is selected from the following formula (U A2 ), formula (U B2 ), (U D2 ), formula (U E8 ), formula (U E9 ), formula (U E10 ), formula (U E11 ), formula (U E12 ), formula (U E13 ), formula (U E14 ), formula (U E17 ) or formula (U E18 ):

[0713] in,

[0714] Each W is independently a chemical bond, NH, C(O)NH or NHC(O);

[0715] Each Q1 is independently C(O) or CH2;

[0716] Each Q2 is independently either N or CH;

[0717] P1 is either N or CR6;

[0718] p is 0, 1, or 2;

[0719] Each R6 is independently H, D, or halogen;

[0720] Each R7 is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups.

[0721] In another embodiment, the present invention relates to a compound of formula (VA-1) or formula (VA-2), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein U1 is selected from the following formula (U A2 ), formula (U B2 ), formula (U D2 ) or formula (U E8 ).

[0722] In another embodiment, the present invention relates to a compound of formula (VA-1) or formula (VA-2), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein U1 is selected from the following formula (U E9 ), formula (U E10 ), formula (U E11 ), formula (U E12 ), formula (U E13 ), formula (U E14 ), formula (U E17 ) or formula (U E18 ).

[0723] In another embodiment, the present invention relates to compounds of formula (VA), formula (VA-1) or formula (VA-2), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein R1 and R2, together with the N atoms to which they are attached, form the following rings:

[0724] In another embodiment, the present invention relates to compounds of formula (VA), formula (VA-1) or formula (VA-2), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein R1 and R2, together with the N atoms to which they are attached, form the following rings:

[0725] In another embodiment, the present invention relates to a compound of formula (VA), formula (VA-1) or formula (VA-2), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1 and R2 together with the N atom to which they are attached form

[0726] In another embodiment, the present invention relates to a compound of formula (VA), formula (VA-1) or formula (VA-2), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L4 is

[0727] The above-mentioned groups are optionally surrounded by one or more elements selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substitution of halogenated alkoxy groups.

[0728] In another embodiment, the present invention relates to a compound of formula (VA), formula (VA-1) or formula (VA-2), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L4 is The aforementioned groups are optionally substituted by one or more groups selected from D, halogens, or -OH.

[0729] In another embodiment, the present invention relates to a compound of formula (VA), formula (VA-1) or formula (VA-2), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L4 is

[0730] In another embodiment, the present invention relates to compounds of formula (VA), formula (VA-1) or formula (VA-2), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein R A1 and R A2 Independently H, D, halogen, or -CN; R B1 It can be H, D, halogen, or -CN.

[0731] In another embodiment, the present invention relates to compounds of formula (VA), formula (VA-1) or formula (VA-2), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein R A1 For Cl, R A2 For F, R B1 For H.

[0732] In another embodiment, the present invention relates to a compound of formula (VA), formula (VA-1) or formula (VA-2), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein U1 is

[0733] In another embodiment, the present invention relates to a compound of formula (VA), formula (VA-1) or formula (VA-2), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein U1 is

[0734] In another embodiment, the present invention relates to a compound of formula (VA), formula (VA-1) or formula (VA-2), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein U1 is

[0735] In another embodiment, the present invention relates to (VIA) compounds, or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates thereof.

[0736] in,

[0737] R1 and R2, together with the N atom they are attached to, form a 4-7 membered monocyclic heterocycle, a 6-10 membered fused heterocycle, a 6-10 membered bridged heterocycle, or a 6-9 membered spirocyclic heterocycle; wherein the above groups are optionally surrounded by one or more atoms selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0738] i is 0 or 1;

[0739] L1 is a divalent group selected from a 5-6 membered heteroaromatic ring having 1 or 2 N atoms, optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0740] L2 is a divalent group selected from 4-7 membered monocyclic heterocycles, 6-10 membered fused heterocycles, 6-10 membered bridged heterocycles, or 6-9 membered spirocyclic heterocycles; wherein the above groups are optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0741] S2 is a chemical bond or -C(O)-;

[0742] L4 is a divalent group selected from 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered bridged carbon rings, or 6-10 membered bridged heterocyclic rings; wherein the above group is optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups;

[0743] U1 is selected from the following formula (U A1 ), formula (U B1 ), formula (U D1 ), formula (U E1), formula (U E2 ), formula (U E3 ), formula (U E4 ), formula (U E5 ), formula (U E6 ), formula (U E7 ), formula (U E15 ) or formula (U E16 ):

[0744] in,

[0745] Each V is an independent chemical bond;

[0746] Each W is independently a chemical bond, NH, O, C(O)NH, NHC(O), CH2 or CD2;

[0747] Each Q1 is independently C(O) or C(R5)2;

[0748] Each Q2 is independently either N or CH;

[0749] Each P1, P2, and P3 is independently N or CR6;

[0750] Each R3 is independently H or methyl;

[0751] p is 0, 1, or 2;

[0752] q is 0, 1, or 2;

[0753] Each R4 is independently D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups, or two R4 atoms on the same atom or two R4 atoms on adjacent atoms, together with the atoms they are attached to, form C. 3-7 Carbon rings or 4-7 membered heterocycles;

[0754] Each R5 is independently H, D, or halogen;

[0755] Each R6 is independently H, D, or halogen;

[0756] Each R7 is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups.

[0757] In another embodiment, the present invention relates to a (VIA) compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein U1 is selected from the following formula (U A2 ), formula (U B2 ), (U D2 ), formula (U E8 ), formula (U E9 ), formula (U E10 ), formula (U E11 ), formula (U E12 ), formula (U E13 ), formula (U E14 ), formula (U E17 ) or formula (U E18 ):

[0758] in,

[0759] Each W is independently a chemical bond, NH, C(O)NH or NHC(O);

[0760] Each Q1 is independently C(O) or CH2;

[0761] Each Q2 is independently either N or CH;

[0762] P1 is either N or CR6;

[0763] p is 0, 1, or 2;

[0764] Each R6 is independently H, D, or halogen;

[0765] Each R7 is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups.

[0766] In another embodiment, the present invention relates to a (VIA) compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein S2 is a chemical bond and U1 is selected from the following formula (U A2 ), formula (U B2 ) or (U D2 ):

[0767] in,

[0768] Each W is independently C(O)NH or NHC(O);

[0769] Each Q1 is independently C(O) or CH2;

[0770] Each Q2 is independently either N or CH;

[0771] P1 is either N or CR6;

[0772] p is 0, 1, or 2;

[0773] Each R6 is independently H, D, or halogen.

[0774] In another embodiment, the present invention relates to a (VIA) compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein S2 is -C(O)-, and U1 is selected from the following (U D2 ), formula (U E8 ), formula (U E9 ), formula (U E10 ), formula (U E11 ), formula (U E12 ), formula (U E13 ), formula (U E14 ), formula (U E17 ) or formula (U E18 ):

[0775] in,

[0776] Each W is independently a chemical bond or NH;

[0777] Each Q2 is independently either N or CH;

[0778] P1 is either N or CR6;

[0779] p is 0, 1, 2 or 3;

[0780] Each R6 is independently H, D, or halogen;

[0781] Each R7 is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups.

[0782] In another embodiment, the present invention relates to a (VIA) compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R1 and R2, together with the N atom to which they are attached, form the following ring:

[0783] In another embodiment, the present invention relates to a (VIA) compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R1 and R2, together with the N atom to which they are attached, form the following ring:

[0784] In another embodiment, the present invention relates to a (VIA) compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R1 and R2 together with the N atom to which they are attached form

[0785] In another embodiment, the present invention relates to (VIA) compounds, or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein i is 1 and L1 is a divalent group of the benzene ring.

[0786] In another embodiment, the present invention relates to (VIA) compounds, or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein i is 1 and L1 is a divalent group of the pyrazole ring.

[0787] In another embodiment, the present invention relates to (VIA) compounds, or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein i is 0.

[0788] In another embodiment, the present invention relates to a (VIA) compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein L2 is The above-mentioned groups are optionally surrounded by one or more elements selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substitution of halogenated alkoxy groups.

[0789] In another embodiment, the present invention relates to a (VIA) compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein L2 is Preferably, L2 is More preferably, L2 is

[0790] In another embodiment, the present invention relates to a (VIA) compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein L4 is The above-mentioned groups are optionally surrounded by one or more elements selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substitution of halogenated alkoxy groups.

[0791] In another embodiment, the present invention relates to a (VIA) compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein L4 is The aforementioned groups are optionally substituted by one or more groups selected from D, halogens, or -OH.

[0792] In another embodiment, the present invention relates to a (VIA) compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein L4 is

[0793] In another embodiment, the present invention relates to a compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, isotope variant, hydrate or solvate thereof, wherein the compound is selected from Table 1.

[0794] The compounds of this invention may include one or more asymmetric centers and therefore may exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of this invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. The isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0795] "Tautomers" refer to compounds in which one functional group changes its structure to become another functional group isomer, and can rapidly interconvert to each other, becoming two isomers in dynamic equilibrium. These two isomers are called tautomers.

[0796] Those skilled in the art will understand that organic compounds can form complexes with solvents, react in the solvent, or precipitate or crystallize out of the solvent. These complexes are called "solvates." When the solvent is water, the complex is called a "hydrate." This invention covers all solvates of the compounds of this invention.

[0797] The term "solvent" refers to a compound or its salt that is bound to a solvent and formed typically by a solvent decomposition reaction. This physical association may include hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein can be prepared, for example, in crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate will be separable, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvent" includes solvates in solution and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0798] The term "hydrate" refers to a compound that is bound to water. Typically, it is determined by the ratio of the number of water molecules contained in the hydrate to the number of molecules of the compound in the hydrate. Therefore, a hydrate of a compound can be represented, for example, by the general formula R·xH₂O, where R is the compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, e.g., hemihydrates (R·0.5H₂O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R·2H₂O) and hexahydrates (R·6H₂O)).

[0799] The compounds of this invention can be in amorphous or crystalline forms (crystalline or polymorphic). Furthermore, the compounds of this invention can exist in one or more crystalline forms. Therefore, this invention encompasses all amorphous or crystalline forms of the compounds of this invention within its scope. The term "polymorph" refers to the crystalline form of a compound (or its salts, hydrates, or solvates) with a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, photoelectric properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can lead to the dominance of one crystalline form. Various polymorphs of the compounds can be prepared by crystallization under different conditions.

[0800] The present invention also includes isotopically labeled compounds that are equivalent to those described in formula (I), but in which one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, for example... 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Other isotopes of the present invention containing the aforementioned isotopes and / or other atoms, their prodrugs, and pharmaceutically acceptable salts of said compounds or said prodrugs are all within the scope of this invention. Certain isotope-labeled compounds of the present invention, for example, those incorporating radioactive isotopes (e.g.,...) 3 H and 14 Those in category C) can be used for drug and / or substrate tissue distribution determination. Tritium, i.e. 3 H and carbon-14, i.e. 14 Carbon isotopes are particularly preferred because they are easy to prepare and detect. Subsequently, they are replaced by heavier isotopes, such as deuterium, i.e., 2 H, because higher metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, may be preferred in some cases. Isotope-labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared by using readily available isotope-labeled reagents instead of non-isotope-labeled reagents when performing the processes described below and / or the techniques disclosed in the examples and preparation examples.

[0801] Furthermore, prodrugs are also included in the context of this invention. As used herein, the term "prodrug" refers to a compound which is converted in vivo, for example, by hydrolysis in the blood, into its active form having a medical effect. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ACSSymposium Series, Vol. 14; Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; and D. Fleisher, S. Ramon, and H. Barbra, "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs," Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each of which is incorporated herein by reference.

[0802] A prodrug is any covalently bonded compound of the present invention that, when administered to a patient, releases the parent compound in vivo. Prodrugs are typically prepared by modifying functional groups in a manner that allows the modification to produce the parent compound through conventional operation or in vivo cleavage. Prodrugs include, for example, compounds of the present invention in which a hydroxyl, amino, or thiol group is bonded to any group, which, when administered to a patient, can cleave to form a hydroxyl, amino, or thiol group. Thus, representative examples of prodrugs include (but are not limited to) acetate / amide, formate / amide, and benzoate / amide derivatives of formula (I) with hydroxyl, thiol, and amino functional groups. Additionally, in the case of carboxylic acids (-COOH), esters, such as methyl esters, ethyl esters, etc., can be used. The ester itself may be active and / or hydrolyzable under in vivo conditions. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those groups that readily decompose in the body to release the parent acid or its salt.

[0803] Pharmaceutical compositions, formulations and kits

[0804] In another aspect, the present invention provides pharmaceutical compositions comprising the compound of the present invention (also referred to as the "active ingredient") and pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient. In some embodiments, the pharmaceutical composition comprises a preventatively effective amount of the active ingredient.

[0805] Pharmaceutically acceptable excipients used in this invention refer to non-toxic carriers, adjuvants, or mediators that do not impair the pharmacological activity of the compounds formulated together. Pharmaceutically acceptable carriers, adjuvants, or mediators that can be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid metaglycerides, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0806] The present invention also includes a kit (e.g., a pharmaceutical package). The provided kit may include the compounds of the present invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the compounds of the present invention and other therapeutic agents. In some embodiments, the provided kit may optionally include a third container containing pharmaceutical excipients for diluting or suspending the compounds of the present invention and / or other therapeutic agents. In some embodiments, the compounds of the present invention and other therapeutic agents provided in the first and second containers are combined to form a unit dosage form.

[0807] The pharmaceutical compositions provided by this invention can be administered via a variety of routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration via implantation, or other routes of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intra-synovial administration, intrasternal administration, intramenstrual administration, intralesional administration, and intracranial injection or infusion techniques.

[0808] Typically, an effective amount of the compound described herein is administered. The actual amount of compound administered may be determined by the physician based on relevant circumstances, including the condition being treated, the chosen route of administration, the compound actually administered, the individual patient's age, weight and response, the severity of the patient's symptoms, etc.

[0809] When used to prevent the conditions described in this invention, the compounds provided herein are administered to subjects at risk of developing the conditions, typically based on a physician's advice and under physician supervision, at the dosage levels described above. Subjects at risk of developing a specific condition generally include subjects with a family history of the condition, or those identified through genetic testing or screening as particularly susceptible to developing the condition.

[0810] The pharmaceutical compositions provided herein can also be administered long-term (“long-term administration”). Long-term administration means administering the compound or a pharmaceutical composition thereof over a prolonged period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may be administered indefinitely, such as for the remainder of the subject's life. In some embodiments, long-term administration is intended to provide a constant level of said compound in the blood over a prolonged period of time, such as within a therapeutic window.

[0811] Various methods of administration can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered by bolus injection, for instance, to rapidly increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active ingredient; for example, an intramuscular or subcutaneous bolus dose results in a slow release of the active ingredient, while a bolus dose delivered directly to a vein (e.g., via IV infusion) allows for a more rapid delivery, causing the concentration of the active ingredient in the blood to rapidly increase to an effective level. In other embodiments, the pharmaceutical composition can be administered in the form of a continuous infusion, for example, via IV infusion, thereby providing a steady-state concentration of the active ingredient in the subject's body. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition can be administered first, followed by a continuous infusion.

[0812] Oral compositions may be in the form of bulk liquid solutions, suspensions, or bulk powders. However, more commonly, the compositions are provided in unit dose form for the purpose of precise dosing. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined quantity of active substance and suitable pharmaceutical excipients suitable for producing the desired therapeutic effect. Typical unit dose forms include pre-filled, pre-measured ampoules or syringes for liquid compositions, or, in the case of solid compositions, pills, tablets, capsules, etc. In such compositions, the compound is typically a smaller component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various carriers or excipients useful for forming the desired dosage form, as well as processing aids.

[0813] For oral dosage, a typical regimen is one to five oral doses daily, particularly two to four oral doses, typically three oral doses. Using these dosage regimens, each dose provides approximately 0.01 to approximately 20 mg / kg of the compound of the invention, with preferred doses each providing approximately 0.1 to approximately 10 mg / kg, particularly approximately 1 to approximately 5 mg / kg.

[0814] To provide blood levels similar to or lower than those achieved with an injection dose, a transdermal dose is typically selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, more preferably about 0.1 to about 10% by weight, and even more preferably about 0.5 to about 15% by weight.

[0815] From approximately 1 to approximately 120 hours, especially 24 to 96 hours, the injection dose level ranges from approximately 0.1 mg / kg / hour to at least 10 mg / kg / hour. To obtain adequate steady-state levels, a preload bolus of approximately 0.1 mg / kg to approximately 10 mg / kg or more may also be administered. For human patients weighing 40 to 80 kg, the maximum total dose should not exceed approximately 2 g / day.

[0816] Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous carriers, as well as buffers, suspending and dispersing agents, colorants, flavoring agents, etc. Solid forms may include, for example, any of the following components, or compounds with similar properties: binders, such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients, such as starch or lactose; disintegrants, such as alginic acid, Primogel, or corn starch; lubricants, such as magnesium stearate; gliding agents, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavorings.

[0817] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline, or other injectable excipients known in the art. As previously described, in such compositions, the active compound is typically a smaller component, often about 0.05 to 10% by weight, with the remainder being injectable excipients, etc.

[0818] Transdermal compositions are typically formulated as topical ointments or creams containing an active ingredient. When formulated as an ointment, the active ingredient is typically combined with a paraffin-based or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with, for example, an oil-in-water emulsion base. Such transdermal formulations are well known in the art and generally include other components to enhance stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope of this invention.

[0819] The compounds of this invention can also be administered via transdermal devices. Therefore, transdermal drug delivery can be achieved using reservoirs or porous membrane types, or patches with various solid matrices.

[0820] The above-described components for oral, injectable, or topical administration are merely representative. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0821] The compounds of this invention can also be administered in a sustained-release form or from a sustained-release drug delivery system. Descriptions of representative sustained-release materials can be found at Remington's Pharmaceutical Sciences.

[0822] This invention also relates to pharmaceutically acceptable formulations of the compounds of this invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, respectively, composed of 6, 7, and 8 α-1,4-linked glucose units, optionally including one or more substituents on the linked sugar moieties, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfonyl ether substituted groups. In some embodiments, the cyclodextrin is a sulfonyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, for example, US 5,376,645. In some embodiments, the formulation comprises hexapropyl-β-cyclodextrin (e.g., 10-50% in water).

[0823] Indications

[0824] On the other hand, the use of the compound of formula (I) disclosed in this invention (including all individual embodiments and subsets thereof disclosed herein) or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvent compounds as a medicine.

[0825] In one embodiment, the present invention provides compounds that specifically degrade mutant BRAFs through targeted ubiquitination of the BRAF protein and subsequent proteasome degradation. The compounds of the present invention bind to the universally expressed E3 ligase protein cerebon (CRBN) and alter the substrate specificity of the CRBN E3 ubiquitin ligase complex, thereby leading to the recruitment and ubiquitination of mutant BRAFs (e.g., BRAF V600E).

[0826] In another embodiment, the compounds of the present invention can be used to treat diseases mediated by mutated BRAF, wherein the BRAF has been mutated from the wild-type. A variety of BRAF mutations are possible. In one specific embodiment, the BRAF mutation is a class I mutation, a class II mutation, or a class III mutation, or any combination thereof. In a more specific embodiment, non-limiting examples of class I mutations include V600 mutations, such as V600E, V600K, V600R, V600D, and V600N. In another, more specific implementation, non-restrictive examples of class II mutations include G469A, G469V, G469L, G469R, G469S, L597Q, L597R, L597S, L597V, K601E, K601N, G464E, G464V, G464R, R462I, I463S, E586K, F595L, A598V, T599I, and K301T. In another, more specific embodiment, non-limiting examples of type III mutations include G466A, G466E, G466R, G466V, S467L, G469E, N581I, D594E, D594G, D594N, S467A, S467E, N581S, K483M, D594A, D594H, D594V, G596A, G596C, G596D, and G596R. In yet another specific embodiment, the BRAF mutation is not a type I, type II, or type III mutation. In another, more specific implementation, non-limiting examples of non-Class I, Class II, or Class III mutations include G464I, N581T, L584F, E586K, G593D, G596C, S605I, S607F, N694T, E26A, V130M, L745L, and D284E.

[0827] In another specific implementation, the BRAF mutation is an exon 11 mutation.

[0828] In another specific implementation, the BRAF mutation is an exon 15 mutation.

[0829] In another specific implementation, the BRAF mutation is the V600 mutation.

[0830] In another specific implementation, the BRAF mutation is the V600E mutation.

[0831] In another specific implementation, the BRAF mutation is the V600K mutation.

[0832] In another specific implementation, the BRAF mutation is the V600R mutation.

[0833] In another specific implementation, the BRAF mutation is the V600D mutation.

[0834] In another specific implementation, the BRAF mutation is the G469 mutation.

[0835] In another specific implementation, the BRAF mutation is the G469A mutation.

[0836] In another specific implementation, the BRAF mutation is the G469V mutation.

[0837] In another specific implementation, the BRAF mutation is the G469L mutation.

[0838] In another specific implementation, the BRAF mutation is the G469R mutation.

[0839] In another specific implementation, the BRAF mutation is the G469S mutation.

[0840] In another specific implementation, the BRAF mutation is the G469E mutation.

[0841] In another specific implementation, the BRAF mutation is the L597 mutation.

[0842] In another specific implementation, the BRAF mutation is the L597 Q mutation.

[0843] In another specific implementation, the BRAF mutation is the L597R mutation.

[0844] In another specific implementation, the BRAF mutation is the L597S mutation.

[0845] In another specific implementation, the BRAF mutation is the L597V mutation.

[0846] In another specific implementation, the BRAF mutation is the G464 mutation.

[0847] In another specific implementation, the BRAF mutation is the G464E mutation.

[0848] In another specific implementation, the BRAF mutation is the G464V mutation.

[0849] In another specific implementation, the BRAF mutation is the G464R mutation.

[0850] In another specific implementation, the BRAF mutation is the G464I mutation.

[0851] In another specific implementation, the BRAF mutation is the G466 mutation.

[0852] In another specific implementation, the BRAF mutation is the G466A mutation.

[0853] In another specific implementation, the BRAF mutation is the G466E mutation.

[0854] In another specific implementation, the BRAF mutation is the G466R mutation.

[0855] In another specific implementation, the BRAF mutation is the G466V mutation.

[0856] In another specific implementation, the BRAF mutation is the K601 mutation.

[0857] In another specific implementation, the BRAF mutation is the K601E mutation.

[0858] In another specific implementation, the BRAF mutation is the K601N mutation.

[0859] In another embodiment, the compounds of the present invention treat diseases mediated by BRAF mutations, wherein the mutation is a splice variant, such as p61-BRAF V600E.

[0860] In another embodiment, the compounds of the present invention can be used to treat refractory double-mutant cancers. In yet another embodiment, the compounds of the present invention are used to treat diseases mediated by two or more mutant proteins, such as cancers mediated by the BRAF V600E / NRAS Q61K double mutant.

[0861] In another embodiment, the compounds of the present invention are used to treat cancers resistant to at least one BRAF inhibitor, such as cancers resistant to or already resistant to BRAF inhibitors selected from dabrafenib, trametinib, vemurafenib, and cannefenib.

[0862] In another embodiment, the compounds of the present invention are used to treat cancers that have developed escape mutations, such as BRAF V600E / NRAS Q61K double mutant cancers.

[0863] In another embodiment (red seal), the compounds of the present invention are used to treat melanoma. Non-limiting examples of melanoma include non-acromial cutaneous melanoma, acral melanoma, mucosal melanoma, uveal melanoma, and meningeal melanoma, each of which may be primary or metastatic.

[0864] In another embodiment, the compounds of the present invention are used to treat melanoma with V600 BRAF mutations.

[0865] In another embodiment, the compounds of the present invention are used to treat triple-negative breast cancer, such as triple-negative breast cancer with a G464VBRAF mutation.

[0866] In another embodiment, the compounds of the present invention are used to treat lung cancer, such as lung adenocarcinoma with a G466V BRAF mutation.

[0867] In another embodiment, the compound of the present invention is used to treat non-small cell lung cancer.

[0868] In another embodiment, the compound of the present invention is used to treat colorectal cancer.

[0869] In another embodiment, the compounds of the present invention are used to treat microsatellite-stabilized colorectal cancer.

[0870] In another embodiment, the compound of the present invention is used to treat thyroid cancer.

[0871] In another embodiment, the compound of the present invention is used to treat papillary thyroid carcinoma.

[0872] In another embodiment, the compound of the present invention is used to treat anaplastic thyroid cancer.

[0873] In another embodiment, the compound of the present invention is used to treat ovarian cancer.

[0874] In another embodiment, the compound of the present invention is used to treat cholangiocarcinoma.

[0875] In another embodiment, the compound of the present invention is used to treat Eldheim-Chester disease.

[0876] In another embodiment, the compound of the present invention is used to treat Langerhans cell histiocytosis.

[0877] In another embodiment, the compound of the present invention is used to treat ganglioglioma.

[0878] In another embodiment, the compound of the present invention is used to treat glioma.

[0879] In another embodiment, the compound of the present invention is used to treat glioblastoma.

[0880] In another embodiment, the compound of the present invention is used to treat hairy cell leukemia.

[0881] In another embodiment, the compound of the present invention is used to treat multiple myeloma.

[0882] In another embodiment, the compound of the present invention is used to treat pilocellular myxoid astrocytoma.

[0883] In another embodiment, the compound of the present invention is used to treat anaplastic multiline xanthoastrocytoma.

[0884] In another embodiment, the compound of the present invention is used to treat astrocytoma.

[0885] In another embodiment, the compound of the present invention is used to treat pancreatic cancer.

[0886] In another embodiment, the compound of the present invention is used to treat clear cell sarcoma of the chest.

[0887] In another embodiment, the compound of the present invention is used to treat salivary gland cancer.

[0888] In another embodiment, the compounds of the present invention are used to treat the following diseases: melanoma, triple-negative breast cancer, non-small cell lung cancer, colorectal cancer, microsatellite-stabilized colorectal cancer, thyroid cancer, ovarian cancer, cholangiocarcinoma, Eldheim-Chester disease, Langerhans histiocytosis, ganglioglioma, glioma, glioblastoma, piloblastic leukemia, multiple myeloma, pilocytic myxoid astrocytoma, anaplastic multiline xanthoastrocytoma, astrocytoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, pancreatic cancer, clear cell sarcoma of the chest, and salivary gland carcinoma.

[0889] In another implementation, BRAF-mediated symptoms include abnormal cell proliferation, including but not limited to solid or blood cancers.

[0890] In one specific implementation plan, hematological malignancies include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic lymphoma (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AML), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell leukemia (ALL), and acute myeloid leukemia with trilineage myelodysplastic syndromes. AML / TMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDS), myeloproliferative disorders (MPD), diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma (e.g., splenic marginal zone lymphoma, extranodal marginal zone B-cell lymphoma), Burkitt lymphoma, Waldenström macroglobulinemia (lymphoplasmacytic lymphoma), primary central nervous system lymphoma, small lymphocytic lymphoma, precursor B-cell lymphoblastic leukemia, hairy cell leukemia, mucosa-associated lymphoid tissue lymphoma, plasma cell myeloma, plasmacytoma, and multiple myeloma.

[0891] In another specific implementation, solid cancers include, but are not limited to, lung cancer (including small cell lung cancer and non-small cell lung cancer), breast cancer (including inflammatory breast cancer, ER-positive breast cancer, and triple-negative breast cancer), colon cancer, midline cancer, liver cancer, kidney cancer, prostate cancer (including castration-resistant prostate cancer), brain cancer (including glioma, glioblastoma, neuroblastoma, and medulloblastoma (including MYC-amplified medulloblastoma)), colorectal cancer, and nephroblastoma. Ewing sarcoma, rhabdomyosarcoma, ependymoma, head and neck cancer, melanoma, squamous cell carcinoma, ovarian cancer, pancreatic cancer (including pancreatic ductal carcinoma and pancreatic neuroendocrine tumors), osteosarcoma, giant cell tumor of bone, thyroid cancer, bladder cancer, urothelial carcinoma, vulvar cancer, endometrial cancer, mesothelioma, esophageal cancer, salivary gland cancer, gastric cancer, nasopharyngeal carcinoma, oral tumor, oral cavity cancer, gastrointestinal stromal tumor, NUT-midline carcinoma, testicular cancer, hepatocellular carcinoma, MYCN-driven solid tumors and NUT midline carcinoma.

[0892] combination therapy

[0893] The compounds of the present invention or pharmaceutically acceptable salts or pharmaceutical compositions thereof may be used alone or in combination with another compound or another bioactive agent or a second therapeutic agent of the present invention to treat subjects, such as subjects with mutated BRAF-mediated BRAF, including but not limited to those described herein.

[0894] The terms "bioactive agent" or "additional active agent" are used to describe pharmaceutical agents other than those selected according to the invention, which may be used in combination with or alternately with the compounds of the invention to achieve the desired therapeutic outcome. In one embodiment, the compounds and bioactive agents of the invention are administered in a manner that ensures their activity in vivo during overlapping time periods (e.g., time periods with overlapping Cmax, Tmax, AUC, or other pharmacokinetic parameters). In another embodiment, the compounds and bioactive agents of the invention are administered to a subject in need who does not have overlapping pharmacokinetic parameters, but whose therapeutic effect is influenced by the other drug.

[0895] In another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination with another BRAF inhibitor such as sorafenib, vemurafenib, dabrafenib, or caninefenib.

[0896] In another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination with a MEK inhibitor. In another specific embodiment, the MEK inhibitor is trametinib or selumetinib. In another specific embodiment, the MEK inhibitor is trametinib.

[0897] In another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination with an immune checkpoint inhibitor. In yet another specific embodiment, the immune checkpoint inhibitor is nivolumab, pembrolizumab, cimiprimab, ipilimumab, relatlimab, atezolizumab, avelumab, or durvalumab.

[0898] In another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination with an EGFR antibody. In another specific embodiment, the EGFR antibody is cetuximab or panitumumab.

[0899] Example

[0900] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, parts and percentages are parts by weight and weight percentages.

[0901] Typically, in the preparation process, each reaction is carried out in an inert solvent at room temperature to reflux temperature (e.g., 0°C to 100°C, preferably 0°C to 80°C). The reaction time is usually 0.1-60 hours, preferably 0.5-24 hours.

[0902] The abbreviations used in this article have the following meanings:

[0903] Pd(dppf)Cl2: [1,1'-bis(triphenylphosphine)ferrocene]palladium dichloride

[0904] Pd(PPh3)4: Tetra(triphenylphosphine)palladium

[0905] Pd(OAc)2: Palladium acetate

[0906] RuPhos-Pd-G3: Methanosyl(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II)

[0907] Xphos Pd-G3: Mesylate (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)

[0908] Brettphos Pd-G3: Methanesulfonic acid (2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)

[0909] NBS: N-bromosuccinimide

[0910] NIS: N-iodosuccinimide

[0911] DIAD: Diisopropyl azodicarbonate

[0912] AIBN: Azobisisobutyronitrile

[0913] HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate

[0914] DMAP: 4-Dimethylaminopyridine

[0915] B2Pin2: Pinaryl Boronate

[0916] NaBH3CN: Sodium cyanoborohydride

[0917] Dess-Martin: Oxidant

[0918] Et3N: Triethylamine

[0919] DIEA: N,N-Diisopropylethylamine

[0920] TFA: Trifluoroacetic acid

[0921] TBAB: Tetrabutylammonium bromide

[0922] DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

[0923] AcOH: Acetic acid

[0924] EtOAc: Ethyl acetate

[0925] KOAc: Potassium acetate

[0926] MeOH: Methanol

[0927] EtOH: Ethanol

[0928] DCM: Dichloromethane

[0929] THF: Tetrahydrofuran

[0930] DMF: N,N-Dimethylformamide

[0931] DMSO: Dimethyl sulfoxide

[0932] DPPA: Diphenyl azidophosphate

[0933] BTC: Three Lights

[0934] LDA: Lithium diisopropylamino

[0935] Preparation of intermediate L-1 compound 3-fluorozacriane-1-sulfonamide

[0936] The synthesis is performed using the following route:

[0937] Step 1: Synthesis of compound 3-fluorozacriane-1-sulfonyl chloride

[0938] 3-Fluoroazacyclobutane hydrochloride (11.1 g, 100.0 mmol), dichloromethane (80 mL), and triethylamine (20.2 g, 200.0 mmol) were added to a reaction flask. Sulfonyl chloride (14.8 g, 110.0 mmol) was added dropwise at 0 °C. After the addition was complete, the mixture was allowed to react at room temperature for 5 hours. The reaction was monitored by TLC until complete. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to obtain 14.7 g of a pale yellow oily liquid, with a yield of 85%.

[0939] Synthesis of intermediate L-1 in step 2

[0940] 14.7 g (85.0 mmol) of compound 3-fluorozacyclobutane-1-sulfonyl chloride was added to a reaction flask and dissolved in 60 mL of anhydrous THF. Under nitrogen protection, the mixture was cooled to 0 °C, and 105 mL (0.42 mol) of 4 N ammonia-methanol solution was slowly added dropwise. After the addition was complete, the mixture was brought to room temperature and stirred overnight. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 10.1 g of a pale yellow solid, with a yield of 77%. LC-MS (APCI): m / z = 155.1 (M+1) + .

[0941] Preparation of intermediate L-2 compound tert-butyl 4-(5-aminopyrazin-2-yl)piperidine-1-carboxylate

[0942] The synthesis is performed using the following route:

[0943] Step 1: Synthesis of compound tert-butyl 4-(5-aminopyrazin-2-yl)-3,6-dihydropyridine-1(2H)-formate

[0944] 5-Bromo-2-aminopyrazine (1.73 g, 10.0 mmol), N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (3.71 g, 12.0 mmol), Pd(dppf)Cl2 (366 mg, 0.5 mmol), and potassium phosphate (4.2 g, 20.0 mmol) were added to a reaction flask under nitrogen protection. 30 mL of anhydrous 1,4-dioxane was added, and the mixture was heated to 90 °C and stirred overnight. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 1.85 g of an off-white solid, in 67% yield. LC-MS (APCI): m / z = 277.4 (M+1) + .

[0945] Synthesis of intermediate L-2 in step 2

[0946] 1.85 g (6.7 mmol) of tert-butyl 4-(5-aminopyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate was added to a reaction flask and dissolved in 30 mL of tetrahydrofuran. A catalytic amount of 10% palladium on carbon was added, and the mixture was stirred at room temperature under hydrogen purging for 1–2 hours. The reaction was monitored by TLC until completion. The catalyst was removed by filtration, and the filtrate was concentrated and purified by silica gel column chromatography to give 1.64 g of an off-white solid, in 88% yield. LC-MS (APCI): m / z = 279.2 (M+1) + .

[0947] Preparation of intermediate L-3 compound methyl 3-((tert-butoxycarbonyl)amino)-2-chloro-6-fluorobenzoate

[0948] The synthesis is performed using the following route:

[0949] Step 1: Synthesis of compound methyl 3-amino-2-chloro-6-fluorobenzoate

[0950] Add 2-chloro-4-fluoroaniline (20.0 g, 137 mmol) to the reaction flask, dissolve it in 200 mL of anhydrous THF under nitrogen protection, cool to -78 °C, and slowly add 2.5 M n-butyllithium (60 mL, 150 mmol) dropwise. After the addition is complete, stir at low temperature for 15 minutes, then add 60 mL of anhydrous THF solution of 1,2-bis(chlorodimethylsilyl)ethane (31.0 g, 144 mmol) dropwise. Continue stirring for 15 minutes after the addition is complete. Add 2.5 M n-butyllithium (60 mL, 150 mmol) dropwise, and then raise the temperature to room temperature and stir for 0.5 hours. Cool to -78 °C again and add 2.5 M n-butyllithium (60 mL, 150 mmol) dropwise. Stir for 0.5 hours, then slowly add methyl chloroformate (14.3 g, 151 mmol) dropwise. After the addition is complete, raise the temperature to room temperature and stir overnight. After the reaction was monitored by TLC and cooled to 0℃, 110 ml of 4M dilute hydrochloric acid was slowly added dropwise to quench the reaction. Sodium bicarbonate was then added to adjust the pH to 8-9, followed by dilution with excess water. The mixture was extracted 3-4 times with ethyl acetate. The organic phases were combined, washed with saturated brine, and concentrated. The residue was purified by silica gel column chromatography to give 16.2 g of a pale yellow oily liquid, with a yield of 58%. LC-MS (APCI): m / z = 204.1 (M+1) + .

[0951] Step 2: Synthesis of compound methyl 3-((N,N-di-tert-butoxycarbonyl)amino)-2-chloro-6-fluorobenzoate

[0952] Methyl 3-amino-2-chloro-6-fluorobenzoate (16.2 g, 80 mmol), di-tert-butyl dicarbonate (38.4 g, 176 mmol), and triethylamine (20.2 g, 200 mmol) were added to a reaction flask and dissolved in 180 mL of tetrahydrofuran. DMAP (0.98 g, 8.0 mmol) was added in portions at room temperature. After addition, the mixture was stirred for 2–4 hours. The reaction was monitored by TLC until complete. The reaction solution was concentrated and purified by silica gel column chromatography to obtain 28.7 g of product, with a yield of 89%. LC-MS (APCI): m / z = 404.7 (M+1) + .

[0953] Synthesis of intermediate L-3 in step 3

[0954] Methyl 3-((N,N-di-tert-butoxycarbonyl)amino)-2-chloro-6-fluorobenzoate (28.7 g, 71.2 mmol), 220 mL of methanol, and anhydrous sodium carbonate (8.3 g, 78.3 mmol) were added to a reaction flask. The mixture was heated to 65 °C and reacted for 1–2 hours. The reaction was monitored by TLC until complete. Inorganic salts were removed by filtration. The filtrate was concentrated and purified by silica gel column chromatography to obtain 20.0 g of product, with a yield of 93%. LC-MS (APCI): m / z = 304.8 (M+1) + .

[0955] Preparation of intermediate L-4 compound N-(3-amino-2-chloro-4-fluorophenyl)-3-fluoroazacyclobutane-1-sulfonamide

[0956] The synthesis is performed using the following route:

[0957] Step 1: Synthesis of compound methyl 3-((N-(tert-butoxycarbonyl)-3-fluoroazacyclobutane)-1-sulfonamide)-2-chloro-6-fluorobenzoate

[0958] Intermediate L-3 (20.0 g, 66 mmol) was added to a reaction flask and dissolved in 120 mL of anhydrous THF. The mixture was cooled to 0 °C under nitrogen protection. 60% sodium hydride (5.3 g, 132 mmol) was added in portions. After the addition was complete, the mixture was brought to room temperature and stirred for 1 hour. Then, compound 3-fluorozacyclobutane-1-sulfonyl chloride (17.1 g, 99 mmol) was added, and the mixture was heated to 55 °C and stirred overnight. The reaction was monitored by TLC until completion. The reaction was quenched with a saturated aqueous solution of ammonium chloride. The mixture was extracted 3-4 times with ethyl acetate. The combined organic phases were washed with saturated brine, concentrated, and purified by silica gel column chromatography to give 20.6 g of a yellow solid, with a yield of 71%. LC-MS (APCI): m / z = 441.1 (M+1) + .

[0959] Step 2: Synthesis of compound 2-chloro-6-fluoro-3-((3-fluoroazacyclobutane)-1-sulfonamide)benzoic acid

[0960] Methyl 3-((N-(tert-butoxycarbonyl)-3-fluorozacriane)-1-sulfonamide)-2-chloro-6-fluorobenzoate (20.6 g, 46.8 mmol), 50 mL of tetrahydrofuran, and 50 mL of water were added to a reaction flask. Sodium hydroxide (9.36 g, 234 mmol) was added under ice bath conditions. After the addition was complete, the mixture was brought to room temperature and stirred overnight. The reaction was monitored by TLC until complete. The pH was adjusted to 3-4 with 4 M hydrochloric acid solution. The mixture was extracted 3-4 times with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated, and purified by silica gel column chromatography to give 11.1 g of a pale yellow solid, in 73% yield. LC-MS (APCI): m / z = 327.1 (M+1) + .

[0961] Synthesis of intermediate L-4 in step 3

[0962] Compounds 2-chloro-6-fluoro-3-((3-fluorozacricyclobutane)-1-sulfonamide)benzoic acid (11.1 g, 34.2 mmol), diphenyl azide phosphate (14.1 g, 51.2 mmol), and triethylamine (10.4 g, 103 mmol) were added to a reaction flask and dissolved in 100 mL of DMF. The mixture was stirred at room temperature for 1 hour, then 20 mL of purified water was added, and the mixture was heated to 80 °C and stirred for 4–6 hours. The reaction was monitored by TLC until completion. The reaction was quenched with an aqueous solution of saturated ammonium chloride, and the mixture was extracted 3–4 times with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated, and purified by silica gel column chromatography to obtain 5.2 g of a yellow solid, with a yield of 51%. LC-MS (APCI): m / z = 298.4 (M+1) + .

[0963] Preparation of intermediate L-5 compound 6-amino-3-bromo-2-chlorobenzoic acid

[0964] The synthesis is performed using the following route:

[0965] 2-Amino-6-chlorobenzoic acid (1.71 g, 10.0 mmol) was added to a reaction flask and dissolved in 20 mL of anhydrous DMF. NBS (2.67 g, 15.0 mmol) was added in portions at room temperature. After the addition was complete, the mixture was stirred overnight under nitrogen protection. The reaction was monitored by TLC until complete. The reaction was quenched with an aqueous solution of saturated ammonium chloride. The mixture was extracted 3-4 times with ethyl acetate. The combined organic phases were washed with saturated brine, concentrated, and purified by silica gel column chromatography to give 2.1 g of a yellow solid, in 85% yield. LC-MS (APCI): m / z = 249.7 (M+1) + .

[0966] Preparation of intermediate L-6 compound tert-butyl 5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-carboxylate

[0967] The synthesis is performed using the following route:

[0968] Step 1: Synthesis of compound tert-butyl 5-(4-bromophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

[0969] 2.12 g (10.0 mmol) of tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate, 4-bromoiodobenzene (4.23 g (15.0 mmol), cuprous iodide (190 mg (1.0 mmol), and L-proline (575 mg (5.0 mmol)) were added to a reaction flask. Under nitrogen protection, 15 mL of anhydrous DMSO was added, and the mixture was heated to 120 °C and stirred overnight. The reaction mixture was monitored by TLC until the starting material was fully reacted. The reaction solution was poured into 100 mL of ice water, and extracted 2-3 times with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated, and purified by silica gel column chromatography to obtain 2.1 g of a pale yellow oily liquid, yield 57%. LC-MS (APCI): m / z = 367.3 (M+1). + .

[0970] Synthesis of intermediate L-6 in step 2

[0971] 2.1 g (5.7 mmol) of tert-butyl 5-(4-bromophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate, 3.6 g (14.2 mmol) of pinacol diboronate, 208 mg (0.28 mmol) of Pd(dppf)Cl2, and 1.68 g (17.1 mmol) of potassium acetate were added to a reaction flask under nitrogen protection. 20 mL of DMF was added, and the mixture was heated to 90 °C and stirred for 6–8 hours. The reaction was monitored by TLC until completion. After cooling to room temperature, excess water was added for dilution, and the mixture was extracted 2–3 times with ethyl acetate. The combined organic phases were washed with saturated brine, concentrated, and purified by silica gel column chromatography to give 1.8 g of a yellow solid, yield 78%. LC-MS (APCI): m / z = 415.3 (M+1). + .

[0972] Preparation of intermediate L-7 compound ethyl(methyl)aminosulfonamide

[0973] The synthesis is performed using the following route:

[0974] A 7N ammonia-methanol solution (10 mL, 70.0 mmol) was added to the reaction flask. Under nitrogen protection, the mixture was cooled to 0°C, and ethyl(methyl)aminosulfonyl chloride (3.15 g, 20.0 mmol) was slowly added dropwise. After the addition was complete, the mixture was brought to room temperature and stirred for 1–2 hours. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the residue was purified by silica gel column chromatography to obtain 2.1 g of a colorless oily liquid, with a yield of 77%. LC-MS (APCI): m / z = 139.2 (M+1) + .

[0975] Preparation of intermediate L-8 compound tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-1-oxa-8-azaspiro[4.5]dec-2-en-8-carboxylic acid

[0976] The synthesis is performed using the following route:

[0977] Step 1: Synthesis of tert-butyl 3-((perfluorobutyl)sulfonyl)-1-oxa-8-azaspiro[4.5]dec-2-ene-8-carboxylate

[0978] 2.55 g (10.0 mmol) of tert-butyl 3-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate 131 and 3.62 g (12.0 mmol) of nonafluorobutanesulfonyl fluoride were added to a reaction flask and dissolved in 40 mL of anhydrous THF. DBU (3.04 g, 20.0 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred under nitrogen protection for 3-4 hours. The reaction was monitored by TLC until complete. Excess water was added to quench the reaction. The mixture was extracted 3-4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to obtain 4.69 g of a pale yellow oily liquid, with a yield of 90%. LC-MS (APCI): m / z = 522.7 (M+1) + .

[0979] Synthesis of intermediate L-8 in step 2

[0980] Compounds tert-butyl 3-((perfluorobutyl)sulfonyl)-1-oxa-8-azaspiro[4.5]dec-2-ene-8-carboxylate (2.0 g, 3.84 mmol), pinacol diboronate (2.44 g, 9.6 mmol), Pd(dppf)Cl2 (140 mg, 0.19 mmol), and potassium acetate (1.13 g, 11.5 mmol) were added to a reaction flask. Under nitrogen protection, 30 mL of 1,4-dioxane was added, and the mixture was heated to 90 °C and stirred overnight. The reaction was completed by TLC. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 0.94 g of a pale yellow solid, with a yield of 67%. LC-MS (APCI): m / z = 366.6 (M+1) + .

[0981] Preparation of intermediate L-9 compound N-(3-amino-2-chloro-4-fluorophenyl)-(N-ethyl-N-methylamino)-sulfonamide

[0982] The synthesis is performed using the following route:

[0983] Step 1: Synthesis of compound methyl 3-((tert-butoxycarbonyl)(N-ethyl-N-methylaminosulfonyl)amino)-2-chloro-6-fluorobenzoate

[0984] Intermediate L-3 (20.0 g, 66 mmol) was added to a reaction flask and dissolved in 120 mL of anhydrous THF. The mixture was cooled to 0 °C under nitrogen protection. 60% sodium hydride (5.3 g, 132 mmol) was added in portions. After the addition was complete, the mixture was brought to room temperature and stirred for 1 hour. Ethyl(methyl)aminosulfonyl chloride (15.6 g, 99 mmol) was added, and the mixture was heated to 55 °C and stirred overnight. The reaction was monitored by TLC until completion. The reaction was quenched with a saturated aqueous solution of ammonium chloride. The mixture was extracted 3-4 times with ethyl acetate. The combined organic phases were washed with saturated brine, concentrated, and purified by silica gel column chromatography to give 14.3 g of a yellow solid, with a yield of 51%. LC-MS (APCI): m / z = 425.4 (M+1) + .

[0985] Step 2: Synthesis of compound 2-chloro-3-((N-ethyl-N-methylaminosulfonyl)amino)-6-fluorobenzoic acid

[0986] 14.3 g (33.7 mmol) of methyl 3-((tert-butoxycarbonyl)(N-ethyl-N-methylaminosulfonyl)amino)-2-chloro-6-fluorobenzoate, 50 mL of tetrahydrofuran, and 50 mL of water were added to a reaction flask. Sodium hydroxide (9.36 g, 234 mmol) was added under ice bath conditions. After the addition was complete, the mixture was brought to room temperature and stirred overnight. The reaction was monitored by TLC until complete. The pH was adjusted to 3-4 with 4 M hydrochloric acid solution. The mixture was extracted 3-4 times with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated, and purified by silica gel column chromatography to give 5.12 g of a pale yellow solid, with a yield of 49%. LC-MS (APCI): m / z = 311.1 (M+1) + .

[0987] Synthesis of intermediate L-9 in step 3

[0988] Compounds 2-chloro-3-((N-ethyl-N-methylaminosulfonyl)amino)-6-fluorobenzoic acid (5.12 g, 16.5 mmol), diphenyl azide phosphate (7.1 g, 25.6 mmol), and triethylamine (5.2 g, 51.0 mmol) were added to a reaction flask and dissolved in 50 mL of DMF. The mixture was stirred at room temperature for 1 hour, then 10 mL of purified water was added, and the mixture was heated to 80 °C and stirred for 4–6 hours. The reaction was monitored by TLC until completion. The reaction was quenched with a saturated ammonium chloride aqueous solution, extracted 3–4 times with ethyl acetate, and the organic phases were combined, washed with saturated brine, concentrated, and purified by silica gel column chromatography to obtain 2.8 g of a yellow solid, with a yield of 60%. LC-MS (APCI): m / z = 282.4 (M+1) + .

[0989] Preparation of intermediate L-10 compound tert-butyl 2-(7-(2-cyano-3,6-difluorophenoxy)quinoxalin-2-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate

[0990] The synthesis is performed using the following route:

[0991] Step 1: Synthesis of compound 2-(7-hydroxyquinoxalin-2-yl)-2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester

[0992] 8-tert-butoxycarbonyl-2,8-diazaspiro[4.5]decane (1.7 g, 7.1 mmol), 3-chloroquinoxalin-6-ol (0.75 g, 4.2 mmol), Ruphos Pd-G3 (154 mg, 0.21 mmol), and cesium carbonate (1.11 g, 10.5 mmol) were added to a reaction flask. Under nitrogen protection, 20 mL of 1,4-dioxane was added, and the mixture was heated to 110 °C and stirred overnight. The reaction was monitored by TLC until completion. After cooling to room temperature, the solvent was removed by concentration. The residue was purified by silica gel column chromatography to give 1.17 g of an off-white solid, yield 43%. LC-MS (APCI): m / z = 385.2 (M+1) + .

[0993] Synthesis of intermediate L-10 in step 2

[0994] 0.88 g (2.3 mmol) of tert-butyl 2-(7-hydroxyquinoxalo-2-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate and 0.38 g (2.4 mmol) of 2,3,6-trifluorobenzonitrile (0.38 g (2.4 mmol)) were added to a reaction flask under nitrogen protection and dissolved in 10 mL of anhydrous DMF. Potassium tert-butoxide (0.51 g (4.6 mmol) was added in portions at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC until complete. The mixture was diluted with excess water, extracted 3-4 times with ethyl acetate, and the organic phases were combined. The mixture was washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 0.98 g of a pale yellow solid, in 82% yield. LC-MS (APCI): m / z = 522.7 (M+1) + .

[0995] Preparation of intermediate L-11 compound tert-butyl 6-(7-(2-cyano-3,6-difluorophenoxy)quinoxalin-2-yl)-2,6-diazaspiro[3,4]octane-2-carboxylate

[0996] Following the preparation method of intermediate L-10, tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (1.5 g, 7.1 mmol) was used to replace 8-tert-butoxycarbonyl-2,8-diazaspiro[4.5]decane (1.7 g, 7.1 mmol) to give 1.08 g of a pale yellow solid in 95% yield. LC-MS (APCI): m / z = 494.7 (M+1) + .

[0997] Preparation of intermediate L-12 compound 2-(7-(2-cyano-3,6-difluorophenoxy)quinoxalin-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester

[0998] Following the preparation method of intermediate L-10, tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (1.6 g, 7.1 mmol) was used to replace 8-tert-butoxycarbonyl-2,8-diazaspiro[4.5]decane (1.7 g, 7.1 mmol) to obtain 1.04 g of intermediate L-12, with a two-step yield of 49%. LC-MS (APCI): m / z = 508.2 (M+1) + .

[0999] Preparation of intermediate L-13 compound (S)-3-fluoropyrrolidine-1-sulfonamide

[1000] Following the preparation method for intermediate L-1, 3-fluorozacriane hydrochloride (11.1 g, 100.0 mmol) was replaced with (S)-3-fluoropyrrolidine hydrochloride (12.6 g, 100.0 mmol) to obtain 9.85 g of intermediate L-13, with a yield of 69%. LC-MS (APCI): m / z = 169.1 (M+1) + .

[1001] Preparation of intermediate L-14 compound (S)-N-(3-amino-2-chloro-4-fluorophenyl)-3-fluoropyrrolidine-1-sulfonamide

[1002] The synthesis is performed using the following route:

[1003] Step 1: Synthesis of methyl (S)-3-((N-(tert-butoxycarbonyl)-3-fluoropyrrolidine)-1-sulfonamide)-2-chloro-6-fluorobenzoate

[1004] Intermediate L-3 (20.0 g, 66 mmol) was added to the reaction flask and dissolved in 120 mL of anhydrous THF. The mixture was cooled to 0 °C under nitrogen protection. 60% sodium hydride (5.3 g, 132 mmol) was added in portions. After the addition was complete, the mixture was brought to room temperature and stirred for 1 hour. Then, (S)-3-fluoropyrrolidine-1-sulfonyl chloride (18.5 g, 99 mmol) was added, and the mixture was heated to 55 °C and stirred overnight. The reaction was monitored by TLC until completion. The reaction was quenched with saturated ammonium chloride aqueous solution, extracted 3-4 times with ethyl acetate, and the organic phases were combined, washed with saturated brine, concentrated, and purified by silica gel column chromatography to give 17.4 g of a yellow solid, yield 58%. LC-MS (APCI): m / z = 455.6 (M+1) + .

[1005] Step 2: Synthesis of (S)-3-((N-(tert-butoxycarbonyl)-3-fluoropyrrolidine)-1-sulfonamide)-2-chloro-6-fluorobenzoic acid

[1006] Methyl (S)-3-((N-(tert-butoxycarbonyl)-3-fluoropyrrolidine)-1-sulfonamide)-2-chloro-6-fluorobenzoate (17.4 g, 38.3 mmol), 50 mL of tetrahydrofuran, and 50 mL of water were added to a reaction flask. Sodium hydroxide (9.36 g, 234 mmol) was added under ice bath conditions. After the addition was complete, the mixture was brought to room temperature and stirred overnight. The reaction was monitored by TLC until completion. The pH was adjusted to 3-4 with 4 M hydrochloric acid solution, and the mixture was extracted 3-4 times with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated, and purified by silica gel column chromatography to give 10.7 g of a pale yellow solid, with a yield of 82%. LC-MS (APCI): m / z = 341.1 (M+1) + .

[1007] Synthesis of intermediate L-14 in step 3

[1008] (S)-3-((N-(tert-Butoxycarbonyl)-3-fluoropyrrolidine)-1-sulfonamide)-2-chloro-6-fluorobenzoic acid (10.7 g, 31.5 mmol), diphenyl azide phosphate (14.1 g, 51.2 mmol), and triethylamine (10.4 g, 103 mmol) were added to a reaction flask and dissolved in 100 mL of DMF. The mixture was stirred at room temperature for 1 hour, then 20 mL of purified water was added, and the mixture was heated to 80 °C and stirred for 4–6 hours. The reaction was monitored by TLC until completion. The reaction was quenched with a saturated ammonium chloride aqueous solution, and the mixture was extracted 3–4 times with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated, and purified by silica gel column chromatography to obtain 5.8 g of a yellow solid, with a yield of 59%. LC-MS (APCI): m / z = 312.4 (M+1) + .

[1009] Preparation of intermediate L-15 compound (R)-3-fluoropyrrolidine-1-sulfonamide

[1010] Following the preparation method for intermediate L-1, 3-fluorozacriane hydrochloride (11.1 g, 100.0 mmol) was replaced with (R)-3-fluoropyrrolidine hydrochloride (12.6 g, 100.0 mmol) to give 9.91 g of intermediate L-15, with a yield of 72%. LC-MS (APCI): m / z = 169.3 (M+1) + .

[1011] Preparation of intermediate L-17 compound 2-azaspiro[3.3]heptane-2-sulfonamide

[1012] Following the preparation method of intermediate L-1, 3-fluoroazacyclobutane hydrochloride (11.1 g, 100.0 mmol) was replaced with 2-azaspiro[3.3]heptane hydrochloride (13.3 g, 100.0 mmol) to obtain 6.91 g of intermediate L-17, with a yield of 51%. LC-MS (APCI): m / z = 177.1 (M+1) + .

[1013] Preparation of intermediate L-18 compound N-(3-amino-2-chloro-4-fluorophenyl)-2-azaspiro[3.3]heptane-2-sulfonamide

[1014] Following the preparation method of intermediate L-14, (S)-3-fluoropyrrolidine-1-sulfonyl chloride (18.5 g, 99 mmol) was replaced with 2-azaspiro[3.3]heptane-2-sulfonyl chloride (19.3 g, 99 mmol) to obtain 4.4 g of intermediate L-18, with a yield of 66%. LC-MS (APCI): m / z = 320.4 (M+1) + .

[1015] Preparation of intermediate L-19 compound N-(3-amino-2-chloro-4-fluorophenyl)-2,5-difluorobenzenesulfonamide

[1016] Following the preparation method of intermediate L-14, (S)-3-fluoropyrrolidine-1-sulfonyl chloride (18.5 g, 99 mmol) was replaced with 2,5-difluorobenzenesulfonyl chloride (21.0 g, 99 mmol) to give 3.6 g of yellow solid L-19, in 44% yield. LC-MS (APCI): m / z = 337.3 (M+1) + .

[1017] Preparation of intermediate L-20 compound 2,5-difluorobenzenesulfonamide

[1018] The synthesis is performed using the following route:

[1019] 2,5-Difluorobenzenesulfonyl chloride (16.3 g, 77.0 mmol) was added to a reaction flask and dissolved in 60 mL of anhydrous THF. Under nitrogen protection, the mixture was cooled to 0 °C, and 105 mL of 4N ammonia-methanol solution (0.42 mol) was slowly added dropwise. After the addition was complete, the mixture was brought to room temperature and stirred overnight. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 11.6 g of a pale yellow solid, with a yield of 78%. LC-MS (APCI): m / z = 194.1 (M+1) + .

[1020] Preparation of intermediate A-1 compound N-(2-cyano-4-fluoro-3-((4-oxo-3-(4-(piperazin-1-yl)phenyl)-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3-fluorozahexacyclic butane-1-sulfonamide hydrochloride

[1021] The synthesis is performed using the following route:

[1022] Step 1: Synthesis of compound tert-butyl 4-(4-(6-hydroxy-4-oxoquinazoline-3(4H)-yl)phenyl)piperazine-1-carboxylate

[1023] 2-Amino-5-hydroxybenzoic acid (1.53 g, 10.0 mmol), 4-(4-aminophenyl)piperazine-1-carboxylic acid tert-butyl ester (2.77 g, 10.0 mmol), triethyl orthoformate (2.22 g, 15.0 mmol), 1 mL acetic acid, and 30 mL anhydrous toluene were added to a reaction flask. After purging with nitrogen, the mixture was heated to 90 °C and reacted for 5–6 h. The reaction was monitored by TLC until completion. Excess water was added for dilution, and the mixture was extracted 3–4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to obtain 3.2 g of an off-white solid, in 76% yield. LC-MS (APCI): m / z = 423.2 (M+1) + .

[1024] Step 2: Synthesis of compound tert-butyl 4-(4-(6-(2-cyano-3,6-difluorophenoxy)-4-oxoquinazoline-3(4H)-yl)phenyl)piperazine-1-carboxylate

[1025] Compounds tert-butyl 4-(4-(6-hydroxy-4-oxoquinazoline-3(4H)-yl)phenyl)piperazine-1-carboxylate (3.2 g, 7.6 mmol) and 2,3,6-trifluorobenzonitrile (1.2 g, 7.6 mmol) were added to a reaction flask and dissolved in 15 mL of anhydrous DMF under nitrogen protection. Potassium tert-butoxide (1.02 g, 9.1 mmol) was added in portions at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC until complete. The mixture was diluted with excess water, extracted 3-4 times with ethyl acetate, and the organic phases were combined. The mixture was washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 3.7 g of a pale yellow solid, in 88% yield. LC-MS (APCI): m / z = 560.7 (M+1) + .

[1026] Step 3: Synthesis of compound tert-butyl 4-(4-(6-(2-cyano-6-fluoro-3-((3-fluoroazacyclobutane)-1-sulfonylamino)phenoxy)-4-oxoquinazolin-3(4H)-yl)phenyl)piperazine-1-carboxylate

[1027] Compound 4-(4-(6-(2-cyano-3,6-difluorophenoxy)-4-oxoquinazoline-3(4H)-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (3.7 g, 6.6 mmol), intermediate L-1 (1.2 g, 7.9 mmol), and cesium carbonate (3.2 g, 9.9 mmol) were added to a reaction flask under nitrogen protection. 20 mL of DMF was added, and the mixture was heated to 70 °C and stirred overnight. The reaction was monitored by TLC until completion. Excess water was added for dilution, and the mixture was extracted 3-4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 2.42 g of a yellow solid, in 53% yield. LC-MS (APCI): m / z = 694.2 (M+1) + .

[1028] Synthesis of intermediate A-1 in step 4

[1029] Compound tert-butyl 4-(4-(6-(2-cyano-6-fluoro-3-(((3-fluorozacricyclobutane)-1-sulfonamide)phenoxy)-4-oxoquinazoline-3(4H)-yl)phenyl)piperazine-1-carboxylate (100 mg, 0.14 mmol) and 4M 1,4-dioxane hydrochloride solution (3 mL, 12.0 mmol) were added to the reaction flask. The mixture was stirred at room temperature for 1–2 hours. After the reaction was complete as monitored by TLC, the solvent was removed by concentration. No purification was required before proceeding to the next reaction step. LC-MS (APCI): m / z = 594.3 (M+1) + .

[1030] Preparation of intermediate A-2 compound N-(2-cyano-4-fluoro-3-((4-oxo-3-(4-(piperidin-4-yl)phenyl)-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3-fluorozahexacyclic butane-1-sulfonamide hydrochloride

[1031] Following the preparation method of intermediate A-1, tert-butyl 4-(4-aminophenyl)piperidin-1-carboxylate (2.77 g, 10.0 mmol) was replaced with tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (2.77 g, 10.0 mmol) to obtain intermediate A-2, which was directly added to the next reaction without purification. LC-MS (APCI): m / z = 592.2 (M+1) + .

[1032] Preparation of intermediate A-3 compound N-(2-cyano-4-fluoro-3-((4-oxo-3-(5-(piperidin-4-yl)pyridin-2-yl)-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3-fluorozahexacyclic butane-1-sulfonamide hydrochloride

[1033] Following the preparation method of intermediate A-1, tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylic acid (tert-butyl ester) (2.78 g, 10.0 mmol) was replaced with tert-butyl 4-(6-aminopyridin-3-yl)piperidin-1-carboxylate (2.78 g, 10.0 mmol) to obtain intermediate A-3, which was directly added to the next reaction without purification. LC-MS (APCI): m / z = 594.4 (M+1) + .

[1034] Preparation of intermediate A-4 compound N-(2-cyano-4-fluoro-3-((4-oxo-3-(5-(piperidin-4-yl)pyrazin-2-yl)-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3-fluorozahexacyclic butane-1-sulfonamide hydrochloride

[1035] Following the preparation method of intermediate A-1, 4-(4-aminophenyl)piperazine-1-carboxylic acid tert-butyl ester (2.77 g, 10.0 mmol) was replaced with intermediate L-2 (2.78 g, 10.0 mmol) to obtain intermediate A-4, which was directly added to the next reaction without purification. LC-MS (APCI): m / z = 595.6 (M+1) + .

[1036] Preparation of intermediate A-5 compound N-(2-chloro-3-((5-chloro-4-oxo-3-(4-(piperidin-4-yl)phenyl)-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluorozahexacyclic butane-1-sulfonamide hydrochloride

[1037] The synthesis is performed using the following route:

[1038] Step 1: Synthesis of tert-butyl 4-(4-(6-bromo-5-chloro-4-oxoquinazoline-3(4H)-yl)phenyl)piperidine-1-carboxylic acid

[1039] Intermediate L-5 (2.48 g, 10.0 mmol), tert-butyl 4-(4-aminophenyl)piperidin-1-carboxylate (2.77 g, 10.0 mmol), triethyl orthoformate (2.22 g, 15.0 mmol), 1 mL acetic acid, and 30 mL anhydrous toluene were added to a reaction flask. After purging with nitrogen, the mixture was heated to 90 °C and reacted for 5–6 h. The reaction was monitored by TLC until completion. Excess water was added for dilution, and the mixture was extracted 3–4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to obtain 3.3 g of an off-white solid, in 64% yield. LC-MS (APCI): m / z = 518.2 (M+1)+ .

[1040] Step 2: Synthesis of compound tert-butyl 4-(4-(5-chloro-6-((2-chloro-6-fluoro-3-((3-fluoroazacyclobutane)-1-sulfonylamino)phenyl)amino)-4-oxoquinazoline-3(4H)-yl)phenyl)piperidine-1-carboxylic acid

[1041] The following compounds were added to a reaction flask: tert-butyl 4-(4-(6-bromo-5-chloro-4-oxoquinazoline-3(4H)-yl)phenyl)piperidin-1-carboxylate (1.1 g, 2.1 mmol), intermediate L-4 (0.95 g, 3.2 mmol), Ruphos Pd-G3 (35.1 mg, 0.04 mmol), cesium carbonate (1.4 g, 4.2 mmol), and 15 mL of anhydrous 1,4-dioxane. The mixture was heated to 100 °C for 12–16 hours under nitrogen protection. After the reaction was complete (TLC detection), the solvent was removed by concentration, and the product was purified by silica gel column chromatography to obtain 678 mg of product (yield 44%). LC-MS (APCI): m / z = 735.1 (M+1). + .

[1042] Synthesis of intermediate A-5 in step 3

[1043] Compound tert-butyl 4-(4-(5-chloro-6-((2-chloro-6-fluoro-3-(((3-fluorozacricyclobutane)-1-sulfonamide)phenyl)amino)-4-oxoquinazoline-3(4H)-yl)phenyl)piperidin-1-carboxylic acid (100 mg, 0.14 mmol) and 4M 1,4-dioxane hydrochloride solution (5 mL, 20 mmol) were added to the reaction flask. The mixture was stirred at room temperature for 1–2 hours. After the reaction was complete as monitored by TLC, the solvent was removed by concentration. No purification was required before proceeding to the next reaction step. LC-MS (APCI): m / z = 635.1 (M+1) + .

[1044] Preparation of intermediate A-6 compound N-(2-chloro-3-((5-chloro-4-oxo-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluorozahexacyclic butane-1-sulfonamide hydrochloride

[1045] Following the preparation method for intermediate A-5, 4-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester (2.77 g, 10.0 mmol) was replaced with 1-(1-tert-butoxycarbonyl-4-piperidinyl)-4-aminopyrazole (2.66 g, 10.0 mmol) to obtain intermediate A-6, which was directly added to the next reaction without purification. LC-MS (APCI): m / z = 625.1 (M+1)+ .

[1046] Preparation of intermediate A-7 compound N-(2-cyano-4-fluoro-3-((3-(4-(piperazin-1-yl)phenyl)quinoxalin-6-yl)oxy)phenyl)-3-fluorozahexacyclic butane-1-sulfonamide hydrochloride

[1047] The synthesis is performed using the following route:

[1048] Step 1: Synthesis of compound tert-butyl 4-(4-(7-hydroxyquinoxalo-2-yl)phenyl)piperazine-1-carboxylate

[1049] To a reaction flask, add 1.94 g (5.0 mmol) of 4-(4-tert-butoxycarbonyl-1-piperazinyl)phenylboronic acid pinacol ester, 0.75 g (4.2 mmol) of 3-chloroquinoxalin-6-ol, 154 mg (0.21 mmol) of Pd(dppf)Cl2, and 1.11 g (10.5 mmol) of anhydrous sodium carbonate. Under nitrogen protection, add 20 mL of 1,4-dioxane, heat to 100 °C, and stir overnight. After the reaction is complete, monitor by TLC. Cool to room temperature, concentrate to remove the solvent, and purify the residue by silica gel column chromatography to give 0.97 g of an off-white solid, yield 48%. LC-MS (APCI): m / z = 407.7 (M+1) + .

[1050] Step 2: Synthesis of compound tert-butyl 4-(4-(7-(2-cyano-3,6-difluorophenoxy)quinoxalin-2-yl)phenyl)piperazine-1-carboxylate

[1051] Compound 4-(4-(7-hydroxyquinoxalo-2-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (0.97 g, 2.4 mmol) and 2,3,6-trifluorobenzonitrile (0.38 g, 2.4 mmol) were added to a reaction flask and dissolved in 10 mL of anhydrous DMF under nitrogen protection. Potassium tert-butoxide (0.51 g, 4.6 mmol) was added in portions at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC until complete. The mixture was diluted with excess water, extracted 3-4 times with ethyl acetate, and the organic phases were combined. The mixture was washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 1.1 g of a pale yellow solid, in 83% yield. LC-MS (APCI): m / z = 544.7 (M+1) + .

[1052] Step 3: Synthesis of compound tert-butyl 4-(4-(7-(2-cyano-6-fluoro-3-((3-fluoroazacyclobutane)-1-sulfonamide)phenoxy)quinoxalin-2-yl)phenyl)piperazine-1-carboxylate

[1053] Compound 4-(4-(7-(2-cyano-3,6-difluorophenoxy)quinoxalin-2-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (1.1 g, 2.0 mmol), intermediate L-1 (0.46 g, 3.0 mmol), and cesium carbonate (1.3 g, 4.0 mmol) were added to a reaction flask. Under nitrogen protection, 10 mL of DMF was added, and the mixture was heated to 70 °C and stirred overnight. The reaction was monitored by TLC until completion. Excess water was added for dilution, and the mixture was extracted 3-4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 0.87 g of a yellow solid, in 64% yield. LC-MS (APCI): m / z = 678.2 (M+1) + .

[1054] Synthesis of intermediate A-7 in step 4

[1055] Compound 4-(4-(7-(2-cyano-6-fluoro-3-((3-fluorozacricyclobutane)-1-sulfonamide)phenoxy)quinoxalin-2-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (95 mg, 0.14 mmol) and 4M 1,4-dioxane hydrogen chloride solution (3 mL, 12.0 mmol) were added to the reaction flask. The mixture was stirred at room temperature for 1–2 hours. After the reaction was complete, the solvent was removed by TLC. The solution was then directly added to the next reaction step without purification. LC-MS (APCI): m / z = 578.6 (M+1) + .

[1056] Preparation of intermediate A-8 compound N-(2-cyano-4-fluoro-3-((3-(2-(piperazin-1-yl)pyrimidin-5-yl)quinoxalin-6-yl)oxy)phenyl)-3-fluorozahexacyclic butane-1-sulfonamide hydrochloride

[1057] Following the preparation method of intermediate A-7, 4-(4-tert-butoxycarbonyl-1-piperazinyl)pyrimidin-5-boronate pinacol ester (1.95 g, 5.0 mmol) was replaced with 2-(4-tert-butoxycarbonyl-1-piperazinyl)phenylboronate pinacol ester (1.95 g, 5.0 mmol) to obtain intermediate A-8, which was directly added to the next reaction without purification. LC-MS (APCI): m / z = 580.2 (M+1) + .

[1058] Preparation of intermediate A-9 compound N-(2-cyano-4-fluoro-3-((3-(4-(piperidin-4-yl)phenyl)quinoxalin-6-yl)oxy)phenyl)-3-fluorozahexacyclic butane-1-sulfonamide hydrochloride

[1059] Following the preparation method of intermediate A-7, 4-(4-tert-butoxycarbonyl-1-piperazinyl)phenylboronic acid pinacol ester (1.93 g, 5.0 mmol) was replaced with 4-(1-tert-butoxycarbonyl-1-piperazinyl)phenylboronic acid pinacol ester (1.93 g, 5.0 mmol) to obtain intermediate A-9, which was directly added to the next reaction without purification. LC-MS (APCI): m / z = 577.4 (M+1) + .

[1060] Preparation of intermediate A-10 compound N-(2-cyano-4-fluoro-3-((3-(4-(1-(prop-2-yn-1-yl)piperidin-4-yl)phenyl)quinoxalin-6-yl)oxy)phenyl)-3-fluoroazacyclobutane-1-sulfonamide

[1061] The synthesis is performed using the following route:

[1062] Intermediate A-9 (120 mg, 0.2 mmol), 2-propyn-1-methanesulfonic acid (40.2 mg, 0.3 mmol), triethylamine (51 mg, 0.5 mmol), and 5 mL of dichloromethane were added to a reaction flask. The mixture was stirred at room temperature for 3–4 hours. After the reaction was complete, the solvent was removed by concentration, and the product was purified by silica gel column chromatography to obtain 99.5 mg of a pale yellow oily liquid, with a yield of 81%. LC-MS (APCI): m / z = 615.2 (M+1) + .

[1063] Preparation of intermediate A-11 compound N-(3-((3-(2,6-diazaspiro[3,4]octane-6-yl)quinoxalin-6-yl)oxy)-2-cyano-4-fluorophenyl)-3-fluoroazacyclobutane-1-sulfonamide hydrochloride

[1064] The synthesis is performed using the following route:

[1065] Step 1: Synthesis of compound tert-butyl 6-(7-hydroxyquinoxalin-2-yl)-2,6-diazaspiro[3,4]octane-2-carboxylate

[1066] 1.5 g (7.1 mmol) of 2,6-diazaspiro[3.4]octane-2-carboxylic acid tert-butyl ester, 0.75 g (4.2 mmol) of 3-chloroquinoxalin-6-ol, 154 mg (0.21 mmol) of Ruphos Pd-G3, and 1.11 g (10.5 mmol) of cesium carbonate were added to a reaction flask under nitrogen protection. The mixture was heated to 110 °C and stirred overnight. The reaction was monitored by TLC until completion. After cooling to room temperature, the solvent was removed by concentration. The residue was purified by silica gel column chromatography to give 0.82 g of an off-white solid, yield 55%. LC-MS (APCI): m / z = 357.2 (M+1) + .

[1067] Step 2: Synthesis of compound 6-(7-(2-cyano-3,6-difluorophenoxy)quinoxalin-2-yl)-2,6-diazaspiro[3,4]octane-2-carboxylic acid tert-butyl ester

[1068] 0.82 g (2.3 mmol) of tert-butyl 6-(7-hydroxyquinoxalin-2-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate and 0.38 g (2.4 mmol) of 2,3,6-trifluorobenzonitrile were added to a reaction flask. Under nitrogen protection, 10 mL of anhydrous DMF was added to dissolve the compound. Potassium tert-butoxide (0.51 g, 4.6 mmol) was added in portions at 0 °C. The mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC until complete. The mixture was diluted with excess water, extracted 3-4 times with ethyl acetate, and the organic phases were combined. The mixture was washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 1.08 g of a pale yellow solid (95% yield). LC-MS (APCI): m / z = 494.7 (M+1) + .

[1069] Synthesis of compound tert-butyl 6-(7-(2-cyano-6-fluoro-3-((3-fluoroazacyclobutane)-1-sulfonamide)phenoxy)quinoxalin-2-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate in step 3

[1070] Compound 6-(7-(2-cyano-3,6-difluorophenoxy)quinoxalin-2-yl)-2,6-diazaspiro[3,4]octane-2-carboxylic acid tert-butyl ester (1.08 g, 2.2 mmol), intermediate L-1 (0.46 g, 3.0 mmol), and cesium carbonate (1.3 g, 4.0 mmol) were added to a reaction flask under nitrogen protection. 10 mL of DMF was added, and the mixture was heated to 70 °C and stirred overnight. The reaction was monitored by TLC until completion. Excess water was added for dilution, and the mixture was extracted 3-4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to obtain 0.65 g of a yellow solid, yield 47%. LC-MS (APCI): m / z = 628.6 (M+1) + .

[1071] Synthesis of intermediate A-11 in step 4

[1072] Compound 6-(7-(2-cyano-6-fluoro-3-((3-fluorozacricyclobutane)-1-sulfonamide)phenoxy)quinoxalin-2-yl)-2,6-diazaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (88 mg, 0.14 mmol) and 4 M 1,4-dioxane hydrochloride solution (3 ml, 12.0 mmol) were added to the reaction flask. The mixture was stirred at room temperature for 1-2 hours. After the reaction was completed by TLC monitoring, the solvent was removed by concentration. No purification was required before proceeding to the next step of the reaction. LC-MS (APCI): m / z = 528.4 (M+1) + .

[1073] Preparation of intermediate A-12 compound N-(2-cyano-4-fluoro-3-((3-(4-(hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)phenyl)quinoxalin-6-yl)oxy)phenyl)-3-fluoroazacyclobutane-1-sulfonamide hydrochloride

[1074] Following the preparation method of intermediate A-7, intermediate A-12 was obtained by replacing 4-(4-tert-butoxycarbonyl-1-piperazinyl)phenylboronic acid pinacol ester (1.94 g, 5.0 mmol) with intermediate L-6 (1.8 g, 4.3 mmol). This intermediate was then directly added to the next reaction step without purification. LC-MS (APCI): m / z = 604.4 (M+1) + .

[1075] Preparation of intermediate A-13 compound N-(2-cyano-4-fluoro-3-((3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)phenyl)-3-fluorozahexacyclic butane-1-sulfonamide hydrochloride

[1076] Following the preparation method for intermediate A-7, 4-(4-tert-butoxycarbonyl-1-piperazinyl)phenylboronic acid pinacol ester (1.94 g, 5.0 mmol) was replaced with 4-(4-boronic acid pinacol ester-1H-pyrazole-1-yl)piperidin-1-carboxylic acid tert-butyl ester (1.6 g, 4.3 mmol) to obtain intermediate A-13, which was directly added to the next reaction without purification. LC-MS (APCI): m / z = 566.3 (M+1) + .

[1077] Preparation of intermediate A-14 compound N-(3-((3-(2,7-diazaspiro[3.5]nonane-2-yl)quinoxalin-6-yl)oxy)-2-cyano-4-fluorophenyl)-3-fluoroazacyclobutane-1-sulfonamide hydrochloride

[1078] Following the preparation method of intermediate A-11, tert-butyl 2,6-diazaspiro[3.5]nonane-7-carboxylate (1.6 g, 7.1 mmol) was replaced with tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (1.5 g, 7.1 mmol) to obtain intermediate A-14, which was directly added to the next reaction without purification. LC-MS (APCI): m / z = 542.2 (M+1) + .

[1079] Preparation of intermediate A-15 compound N-(3-((3-(2,8-diazaspiro[4.5]decane-8-yl)quinoxalin-6-yl)oxy)-2-cyano-4-fluorophenyl)-3-fluoroazacyclobutane-1-sulfonamide hydrochloride

[1080] Following the preparation method of intermediate A-11, tert-butyl 2,6-diazaspiro[3,4]octane-2-carboxylate (1.5 g, 7.1 mmol) was replaced with 2-tert-butoxycarbonyl-2,8-diazaspiro[4,5]decane (1.7 g, 7.1 mmol) to obtain intermediate A-15, which was directly added to the next reaction without purification. LC-MS (APCI): m / z = 556.1 (M+1) + .

[1081] Preparation of intermediate A-16 compound N-(2-cyano-4-fluoro-3-((3-(4-(piperidin-4-yl)phenyl)quinoxalin-6-yl)oxy)phenyl)-((N-ethyl-N-methyl)amino)-sulfonamide hydrochloride

[1082] Following the preparation method of intermediate A-7, 4-(1-tert-butoxycarbonylpiperidin-4-yl)phenylboronic acid pinacol ester (1.93 g, 5.0 mmol) and intermediate L-7 (0.41 g, 3.0 mmol) were used to replace 4-(4-tert-butoxycarbonyl-1-piperazinyl)phenylboronic acid pinacol ester (1.94 g, 5.0 mmol) and intermediate L-1 (0.46 g, 3.0 mmol), respectively, to obtain intermediate A-16, which was directly added to the next reaction without purification. LC-MS (APCI): m / z = 561.2 (M+1) + .

[1083] Preparation of intermediate A-17 compound N-(2-cyano-4-fluoro-3-((3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)phenyl)-((N-ethyl-N-methyl)amino)-sulfonamide hydrochloride

[1084] Following the preparation method of intermediate A-7, 4-(4-tert-butyl borate-1H-pyrazole-1-yl)piperidin-1-carboxylic acid tert-butyl ester (1.6 g, 4.3 mmol) and intermediate L-7 (0.41 g, 3.0 mmol) were used to replace 4-(4-tert-butyloxycarbonyl-1-piperazinyl)phenylboronic acid pinacol ester (1.94 g, 5.0 mmol) and intermediate L-1 (0.46 g, 3.0 mmol), respectively, to obtain intermediate A-17, which was directly added to the next reaction without purification. LC-MS (APCI): m / z = 551.2 (M+1) + .

[1085] Preparation of intermediate A-18 compound N-(2-chloro-4-fluoro-3-((3-(4-(piperidin-4-yl)phenyl)quinoxalin-6-yl)amino)phenyl)-3-fluorozahexacyclic butane-1-sulfonamide hydrochloride

[1086] The synthesis is performed using the following route:

[1087] Step 1: Synthesis of compound tert-butyl 4-(4-(7-bromoquinoxalo-2-yl)phenyl)piperidine-1-carboxylate

[1088] To a reaction flask, add 1.94 g (5.0 mmol) of 4-(1-tert-butyloxycarbonyl-4-piperidinyl)phenylboronic acid pinacol ester, 1.46 g (6.0 mmol) of 7-bromo-2-chloroquinoxaline, 183 mg (0.25 mmol) of Pd(dppf)Cl2, and 1.1 g (10.0 mmol) of anhydrous sodium carbonate. Under nitrogen protection, add 30 mL of 1,4-dioxane and heat to 90 °C for 5–6 h. After the reaction is complete, monitor the reaction by TLC. After cooling to room temperature, concentrate to remove the solvent, and purify by silica gel column chromatography to obtain 1.49 g of off-white solid, yield: 64%. LC-MS (APCI): m / z = 468.2 (M+1) + .

[1089] Step 2: Synthesis of compound tert-butyl 4-(4-(7-((2-chloro-6-fluoro-3-((3-fluoroazacyclobutane)-1-sulfonamide)phenyl)amino)quinoxalin-2-yl)phenyl)piperidine-1-carboxylic acid

[1090] To a reaction flask, compound 4-(4-(7-bromoquinoxalo-2-yl)phenyl)piperidin-1-carboxylic acid tert-butyl ester (0.98 g, 2.1 mmol), intermediate L-4 (0.95 g, 3.2 mmol), Ruphos Pd-G3 (35.1 mg, 0.04 mmol), cesium carbonate (1.4 g, 4.2 mmol), and 15 mL of anhydrous 1,4-dioxane were added. The mixture was heated to 100 °C for 12–16 hours under nitrogen protection. After the reaction was complete as detected by TLC, the solvent was removed by concentration, and the product was purified by silica gel column chromatography to obtain 675 mg of product, with a yield of 47%. LC-MS (APCI): m / z = 685.1 (M+1) + .

[1091] Synthesis of intermediate A-18 in step 3

[1092] Compound tert-butyl 4-(4-(7-((2-chloro-6-fluoro-3-(((3-fluorozacricyclobutane)-1-sulfonamide)phenyl)amino)quinoxalin-2-yl)phenyl)piperidin-1-carboxylic acid (96 mg, 0.14 mmol) and 4 M 1,4-hydrodioxane chloride solution (5 mL, 20 mmol) were added to the reaction flask. The mixture was stirred at room temperature for 1–2 hours. After the reaction was complete, the solvent was removed by TLC. The solution was then concentrated and added directly to the next reaction step without purification. LC-MS (APCI): m / z = 585.1 (M+1) + .

[1093] Preparation of intermediate A-19 compound N-(2-chloro-4-fluoro-3-((3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinoxalin-6-yl)amino)phenyl)-3-fluorozahexacyclic butane-1-sulfonamide hydrochloride

[1094] Following the preparation method for intermediate A-18, 4-(1-tert-butoxycarbonyl-4-piperidinyl)pinacol ester (1.94 g, 5.0 mmol) was replaced with 4-(4-boronyl-1H-pyrazole-1-yl)piperidin-1-carboxylic acid tert-butyl ester (1.89 g, 5.0 mmol) to obtain intermediate A-19, which was directly added to the next reaction without purification. LC-MS (APCI): m / z = 575.7 (M+1) + .

[1095] Preparation of intermediate A-20 compound N-(2-cyano-4-fluoro-3-((3-(1-oxa-8-azaspiro[4,5]decane-3-yl)quinoxalin-6-yl)oxy)phenyl)-((N-ethyl-N-methyl)amino)-sulfonamide hydrochloride

[1096] The synthesis is performed using the following route:

[1097] Step 1: Synthesis of tert-butyl 3-(7-hydroxyquinoxalin-2-yl)-1-oxa-8-azaspiro[4.5]dec-2-ene-8-carboxylate

[1098] Intermediate L-8 (1.57 g, 4.3 mmol), 3-chloroquinoxalin-6-ol (1.36 g, 5.6 mmol), Pd(dppf)Cl2 (351 mg, 0.43 mmol), and anhydrous sodium carbonate (0.91 g, 8.6 mmol) were added to a reaction flask. Under nitrogen protection, 20 mL of 1,4-dioxane was added, and the mixture was heated to 90 °C and stirred overnight. The reaction was monitored by TLC until complete. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to obtain 0.54 g of a pale yellow solid, with a yield of 33%. LC-MS (APCI): m / z = 384.2 (M+1) + .

[1099] Step 2: Synthesis of compound tert-butyl 3-(7-hydroxyquinoxalin-2-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

[1100] 0.47 g (1.06 mmol) of tert-butyl 3-(7-hydroxyquinoxalin-2-yl)-1-oxa-8-azaspiro[4.5]dec-2-ene-8-carboxylic acid was added to a reaction flask and dissolved in 10 mL of ethyl acetate. A catalytic amount of palladium hydroxide on carbon was added, and the mixture was purged with hydrogen gas. The mixture was stirred at room temperature for 1-2 hours. After the reaction was complete as monitored by TLC, the catalyst was removed by filtration. The filtrate was concentrated and purified by silica gel column chromatography to obtain 303 mg of a yellow oily liquid, with a yield of 74%. LC-MS (APCI): m / z = 386.7 (M+1) + .

[1101] Step 3: Synthesis of compound tert-butyl 3-(7-(2-cyano-3,6-difluorophenoxy)quinoxalin-2-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

[1102] 3-(7-hydroxyquinoxalin-2-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (293 mg, 0.76 mmol) and 2,3,6-trifluorobenzonitrile (120 mg, 0.76 mmol) were added to a reaction flask and dissolved in 5 mL of anhydrous DMF under nitrogen protection. Potassium tert-butoxide (102 mg, 0.9 mmol) was added in portions at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC until complete. Excess water was added for dilution, and the mixture was extracted 3-4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to obtain 337 mg of a pale yellow solid, in 85% yield. LC-MS (APCI): m / z = 523.1 (M+1) + .

[1103] Synthesis of compound tert-butyl 3-(7-(2-cyano-3-((N-ethyl-N-methylaminosulfonyl)amino)-6-fluorophenoxy)quinoxalin-2-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate in step 4

[1104] Compound 3-(7-(2-cyano-3,6-difluorophenoxy)quinoxalin-2-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (337 mg, 0.65 mmol), intermediate L-7 (109 mg, 0.79 mmol), and cesium carbonate (320 mg, 0.99 mmol) were added to a reaction flask under nitrogen protection. 5 mL of DMF was added, and the mixture was heated to 70 °C and stirred overnight. The reaction was monitored by TLC until completion. Excess water was added for dilution, and the mixture was extracted 3-4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to obtain 245 mg of a yellow solid, yield 59%. LC-MS (APCI): m / z = 641.2 (M+1) + .

[1105] Step 5 Synthesis of intermediate A-20

[1106] Compound tert-butyl 3-(7-(2-cyano-3-((N-ethyl-N-methylaminosulfonyl)amino)-6-fluorophenoxy)quinoxalin-2-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid (90 mg, 0.14 mmol) and 4 M 1,4-dioxane hydrogen chloride solution (3 ml, 12.0 mmol) were added to the reaction flask. The mixture was stirred at room temperature for 1-2 hours. After the reaction was complete as monitored by TLC, the solvent was removed by concentration. No purification was required before proceeding to the next step of the reaction. LC-MS (APCI): m / z = 541.3 (M+1) + .

[1107] Preparation of intermediate A-21 compound N-(3-((3-(1-oxa-8-azaspiro[4.5]decane-3-yl)quinoxalin-6-yl)oxy)-2-cyano-4-fluorophenyl)-3-fluoroazacyclobutane-1-sulfonamide hydrochloride

[1108] Following the preparation method of intermediate A-20, intermediate L-7 (109 mg, 0.79 mmol) was replaced with intermediate L-2 (122 mg, 0.79 mmol) to obtain intermediate A-21, which was directly added to the next reaction without purification. LC-MS (APCI): m / z = 557.3 (M+1) + .

[1109] Preparation of intermediate A-22 compound N-(3-((3-(1-oxa-8-azaspiro[4.5]decane-3-yl)quinoxalin-6-yl)amino)-2-chloro-4-fluorophenyl)-3-fluoroazacyclobutane-1-sulfonamide hydrochloride

[1110] The synthesis is performed using the following route:

[1111] Step 1: Synthesis of tert-butyl 3-(7-bromoquinoxalin-2-yl)-1-oxa-8-azaspiro[4.5]dec-2-ene-8-carboxylic acid.

[1112] Intermediate L-8 (608 mg, 1.67 mmol), 7-bromo-2-chloroquinoxaline (490 mg, 2.0 mmol), Pd(dppf)Cl2 (61 mg, 0.08 mmol), and anhydrous sodium carbonate (367 mg, 3.3 mmol) were added to a reaction flask. Under nitrogen protection, 10 mL of 1,4-dioxane was added, and the mixture was heated to 90 °C and reacted for 5–6 h. The reaction was monitored by TLC until completion. After cooling to room temperature, the solvent was removed by concentration, and the mixture was purified by silica gel column chromatography to obtain 513 mg of an off-white solid, with a yield of 69%. LC-MS (APCI): m / z = 446.2 (M+1) + .

[1113] Step 2: Synthesis of compound tert-butyl 3-(7-((2-chloro-6-fluoro-3-((3-fluoroazacyclobutane)-1-sulfonylamino)phenyl)amino)quinoxalin-2-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid.

[1114] 3-(7-bromoquinoxalin-2-yl)-1-oxa-8-azaspiro[4.5]dec-2-ene-8-carboxylic acid tert-butyl ester (0.93 g, 2.1 mmol), intermediate L-4 (0.95 g, 3.2 mmol), Ruphos Pd-G3 (35.1 mg, 0.04 mmol), cesium carbonate (1.4 g, 4.2 mmol), and 15 mL of anhydrous 1,4-dioxane were added to a reaction flask. The mixture was heated to 100 °C under nitrogen protection and reacted for 12–16 hours. After the reaction was complete as detected by TLC, the solvent was removed by concentration, and the product was purified by silica gel column chromatography to obtain 502 mg of product, with a yield of 36%. LC-MS (APCI): m / z = 665.1 (M+1) + .

[1115] Synthesis of intermediate A-22 in step 3

[1116] Compound tert-butyl 3-(7-((2-chloro-6-fluoro-3-(((3-fluoroazacyclobutane)-1-sulfonamide)phenyl)amino)quinoxalin-2-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid (93 mg, 0.14 mmol) and 4 M 1,4-dioxane hydrochloride solution (5 ml, 20 mmol) were added to the reaction flask. The mixture was stirred at room temperature for 1-2 hours. After the reaction was completed by TLC monitoring, the solvent was removed by concentration. No purification was required before proceeding to the next step of the reaction. LC-MS (APCI): m / z = 565.6 (M+1) + .

[1117] Preparation of intermediate A-23 compound N-(3-((3-(1-oxa-8-azaspiro[4.5]decane-3-yl)quinoxalin-6-yl)amino)-2-chloro-4-fluorophenyl)-(N-ethyl-N-methylamino)-sulfonamide hydrochloride

[1118] Following the preparation method of intermediate A-22, intermediate L-4 (0.95 g, 3.2 mmol) was replaced with intermediate L-9 (0.90 g, 3.2 mmol) to obtain intermediate A-23, which was directly added to the next reaction without purification. LC-MS (APCI): m / z = 549.2 (M+1) + .

[1119] Preparation of intermediate A-24 compound (3S)-N-(3-((3-(1-oxa-8-azaspiro[4.5]decane-3-yl)quinoxalin-6-yl)amino)-2-chloro-4-fluorophenyl)-3-fluoropyrrolidine-1-sulfonamide hydrochloride

[1120] The synthesis is performed using the following route:

[1121] Step 1: Synthesis of (S)-3-(7-((2-chloro-6-fluoro-3-(((3-fluoropyrrolidine)-1-sulfonamide)phenyl)amino)quinoxalin-2-yl)-1-oxa-8-azaspiro[4.5]dec-2-ene-8-carboxylic acid tert-butyl ester

[1122] 3-(7-bromoquinoxalin-2-yl)-1-oxa-8-azaspiro[4.5]dec-2-ene-8-carboxylic acid tert-butyl ester (0.93 g, 2.1 mmol), intermediate L-14 (0.99 g, 3.2 mmol), Ruphos Pd-G3 (35.1 mg, 0.04 mmol), cesium carbonate (1.4 g, 4.2 mmol), and 15 mL of anhydrous 1,4-dioxane were added to the reaction flask. The mixture was heated to 100 °C under nitrogen protection and reacted for 12-16 hours. After the reaction was completed, the solvent was removed by TLC, and the product was purified by silica gel column chromatography to obtain 582 mg of product, with a yield of 41%. LC-MS (APCI): m / z = 677.5 (M+1) + .

[1123] Step 2 Synthesis of tert-butyl 3-(7-((2-chloro-6-fluoro-3-(((S)-3-fluoropyrrolidine)-1-sulfonamide)phenyl)amino)quinoxalin-2-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

[1124] (S)-3-(7-((2-chloro-6-fluoro-3-(((3-fluoropyrrolidine)-1-sulfonamide)phenyl)amino)quinoxalin-2-yl)-1-oxa-8-azaspiro[4.5]dec-2-ene-8-carboxylic acid tert-butyl ester (582 mg, 0.86 mmol) was added to the reaction flask, dissolved in 10 mL of tetrahydrofuran, and a catalytic amount of palladium on carbon was added. The mixture was purged with hydrogen three times, and stirred overnight at room temperature under a hydrogen balloon. The reaction was monitored by TLC until completion. The catalyst was removed by diatomaceous earth filtration. The filtrate was concentrated to give 536 mg of a pale yellow solid, with a yield of 92%. LC-MS (APCI): m / z = 679.5 (M+1) + .

[1125] Synthesis of intermediate A-24 in step 3

[1126] Add tert-butyl 3-(7-((2-chloro-6-fluoro-3-((((S)-3-fluoropyrrolidine)-1-sulfonamide)phenyl)amino)quinoxalin-2-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid (95 mg, 0.14 mmol) and 4 M 1,4-dioxane hydrochloride solution (5 ml, 20 mmol) to the reaction flask. Stir the mixture at room temperature for 1-2 hours. After the reaction is complete as monitored by TLC, concentrate the solution to remove the solvent. No purification is required; the solution is directly added to the next reaction step. LC-MS (APCI): m / z = 579.2 (M+1) + .

[1127] Preparation of intermediate A-25 compound (3R)-N-(3-((3-(1-oxa-8-azaspiro[4.5]decane-3-yl)quinoxalin-6-yl)amino)-2-chloro-4-fluorophenyl)-3-fluoropyrrolidine-1-sulfonamide hydrochloride

[1128] Following the preparation method of intermediate A-24, intermediate L-14 (0.99 g, 3.2 mmol) was replaced with intermediate L-16 (0.99 g, 3.2 mmol) to obtain intermediate A-25, which was directly added to the next reaction without purification. LC-MS (APCI): m / z = 579.1 (M+1) + .

[1129] Preparation of intermediate A-26 compound N-(3-((3-(1-oxa-8-azaspiro[4.5]decane-3-yl)quinoxalin-6-yl)amino)-2-chloro-4-fluorophenyl)-2-azaspiro[3.3]heptane-2-sulfonamide hydrochloride

[1130] Following the preparation method of intermediate A-24, intermediate L-14 (0.99 g, 3.2 mmol) was replaced with intermediate L-18 (1.02 g, 3.2 mmol) to obtain intermediate A-26, which was directly added to the next reaction without purification. LC-MS (APCI): m / z = 587.2 (M+1) + .

[1131] Preparation of intermediate A-27 compound N-(3-((3-(1-oxa-8-azaspiro[4.5]decane-3-yl)quinoxalin-6-yl)amino)-2-chloro-4-fluorophenyl)-2,5-difluorobenzenesulfonamide hydrochloride

[1132] Following the preparation method of intermediate A-24, intermediate L-14 (0.99 g, 3.2 mmol) was replaced with intermediate L-19 (1.07 g, 3.2 mmol) to obtain intermediate A-27, which was directly added to the next reaction without purification. LC-MS (APCI): m / z = 604.2 (M+1) + .

[1133] Preparation of intermediate A-28 compound (3S)-N-(3-((3-(1-oxa-8-azaspiro[4.5]decane-3-yl)quinoxalin-6-yl)oxy)-2-cyano-4-fluorophenyl)-3-fluoropyrrolidine-1-sulfonamide hydrochloride

[1134] The synthesis is performed using the following route:

[1135] Step 1: Synthesis of tert-butyl 3-(7-hydroxyquinoxalin-2-yl)-1-oxa-8-azaspiro[4.5]dec-2-ene-8-carboxylate

[1136] Intermediate L-8 (1.57 g, 4.3 mmol), 3-chloroquinoxalin-6-ol (1.36 g, 5.6 mmol), Pd(dppf)Cl2 (351 mg, 0.43 mmol), and anhydrous sodium carbonate (0.91 g, 8.6 mmol) were added to a reaction flask. Under nitrogen protection, 20 mL of 1,4-dioxane was added, and the mixture was heated to 90 °C and stirred overnight. The reaction was monitored by TLC until complete. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to obtain 0.54 g of a pale yellow solid, with a yield of 33%. LC-MS (APCI): m / z = 384.2 (M+1) + .

[1137] Step 2: Synthesis of compound tert-butyl 3-(7-hydroxyquinoxalin-2-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

[1138] 0.47 g (1.06 mmol) of tert-butyl 3-(7-hydroxyquinoxalin-2-yl)-1-oxa-8-azaspiro[4.5]dec-2-ene-8-carboxylic acid was added to a reaction flask and dissolved in 10 mL of ethyl acetate. A catalytic amount of palladium hydroxide on carbon was added, and the mixture was purged with hydrogen gas. The mixture was stirred at room temperature for 1-2 hours. After the reaction was complete as monitored by TLC, the catalyst was removed by filtration. The filtrate was concentrated and purified by silica gel column chromatography to obtain 303 mg of a yellow oily liquid, with a yield of 74%. LC-MS (APCI): m / z = 386.7 (M+1) + .

[1139] Step 3: Synthesis of compound tert-butyl 3-(7-(2-cyano-3,6-difluorophenoxy)quinoxalin-2-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

[1140] 3-(7-hydroxyquinoxalin-2-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (293 mg, 0.76 mmol) and 2,3,6-trifluorobenzonitrile (120 mg, 0.76 mmol) were added to a reaction flask and dissolved in 5 mL of anhydrous DMF under nitrogen protection. Potassium tert-butoxide (102 mg, 0.9 mmol) was added in portions at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC until complete. Excess water was added for dilution, and the mixture was extracted 3-4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to obtain 337 mg of a pale yellow solid, in 85% yield. LC-MS (APCI): m / z = 523.1 (M+1) + .

[1141] Synthesis of compound tert-butyl 3-(7-(2-cyano-6-fluoro-3-(((S)-3-fluoropyrrolidine)-1-sulfonamide)phenoxy)quinoxalin-2-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate in step 4

[1142] Compound 3-(7-(2-cyano-3,6-difluorophenoxy)quinoxalin-2-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (337 mg, 0.65 mmol), intermediate L-13 (133 mg, 0.79 mmol), and cesium carbonate (320 mg, 0.99 mmol) were added to a reaction flask under nitrogen protection. 5 mL of DMF was added, and the mixture was heated to 70 °C and stirred overnight. The reaction was monitored by TLC until completion. Excess water was added for dilution, and the mixture was extracted 3-4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to obtain 257 mg of a yellow solid, yield 59%. LC-MS (APCI): m / z = 671.2 (M+1)+ .

[1143] Step 5 Synthesis of intermediate A-28

[1144] Compound tert-butyl 3-(7-(2-cyano-6-fluoro-3-(((S)-3-fluoropyrrolidine)-1-sulfonamide)phenoxy)quinoxalin-2-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid (94 mg, 0.14 mmol) and 4 M 1,4-dioxane hydrochloride solution (3 ml, 12.0 mmol) were added to the reaction flask. The mixture was stirred at room temperature for 1-2 hours. After the reaction was completed by TLC monitoring, the solvent was removed by concentration. No purification was required before proceeding to the next reaction step. LC-MS (APCI): m / z = 571.3 (M+1) + .

[1145] Preparation of intermediate A-29 compound (3R)-N-(3-((3-(1-oxa-8-azaspiro[4.5]decane-3-yl)quinoxalin-6-yl)oxy)-2-cyano-4-fluorophenyl)-3-fluoropyrrolidine-1-sulfonamide hydrochloride

[1146] Following the preparation method of intermediate A-28, intermediate L-13 (133 mg, 0.79 mmol) was replaced with intermediate L-15 (133 mg, 0.79 mmol) to obtain intermediate A-29, which was directly added to the next reaction without purification. LC-MS (APCI): m / z = 571.2 (M+1) + .

[1147] Preparation of intermediate A-30 compound N-(3-((3-(1-oxa-8-azaspiro[4.5]decane-3-yl)quinoxalin-6-yl)oxy)-2-cyano-4-fluorophenyl)-2-azaspiro[3.3]heptane-2-sulfonamide hydrochloride

[1148] Following the preparation method of intermediate A-28, intermediate L-13 (133 mg, 0.79 mmol) was replaced with intermediate L-17 (139 mg, 0.79 mmol) to obtain intermediate A-30, which was directly added to the next reaction without purification. LC-MS (APCI): m / z = 578.3 (M+1) + .

[1149] Preparation of intermediate A-31 compound N-(3-((3-(1-oxa-8-azaspiro[4.5]decane-3-yl)quinoxalin-6-yl)oxy)-2-cyano-4-fluorophenyl)-2,5-difluorobenzenesulfonamide hydrochloride

[1150] Following the preparation method of intermediate A-28, intermediate L-13 (133 mg, 0.79 mmol) was replaced with intermediate L-20 (152 mg, 0.79 mmol) to obtain intermediate A-31, which was directly added to the next reaction without purification. LC-MS (APCI): m / z = 596.3 (M+1) + .

[1151] Preparation of intermediate B-1 compound 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidine-4-carboxaldehyde

[1152] The synthesis is performed using the following route:

[1153] Step 1: Synthesis of compound 2-(2,6-dioxopiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3-dione

[1154] 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (2.76 g, 10.0 mmol), 4-piperidinemethanol (1.38 g, 12.0 mmol), 20 mL DMF, and triethylamine (2.02 g, 20.0 mmol) were added to a reaction flask. The mixture was heated to 80 °C and stirred for 12 hours under nitrogen protection. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to obtain 2.48 g of a yellow solid, with a yield of 67%. LC-MS (APCI): m / z = 372.3 (M+1) + .

[1155] Synthesis of intermediate B-1 in step 2

[1156] Compound 2-(2,6-dioxopiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3-dione (2.48 g, 6.7 mmol) was added to a reaction flask and dissolved in 20 mL of dichloromethane. Dys-Martin oxidant (4.27 g, 10.1 mmol) was added in portions, and the mixture was stirred at room temperature for 1–2 hours. After the reaction was complete as monitored by TLC, the solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 1.2 g of a pale yellow solid, in 49% yield. LC-MS (APCI): m / z = 370.6 (M+1) + .

[1157] Preparation of intermediate B-2 compound N-(2,6-dioxopiperidin-3-yl)-5-(4-formylpiperidin-1-yl)-2-pyridinecarboxamide

[1158] The synthesis is performed using the following route:

[1159] Step 1: Synthesis of compound methyl 5-(4-(hydroxymethyl)piperidin-1-yl)-2-pyridinecarboxylate

[1160] 1.55 g (10.0 mmol) of methyl 5-fluoropyridinecarboxylate, 1.38 g (12.0 mmol) of 4-piperidinemethanol, 15 mL of DMF, and 2.02 g (20.0 mmol) of triethylamine were added to a reaction flask. The mixture was heated to 80 °C and stirred for 10 hours under nitrogen protection. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to obtain 2.27 g of a pale yellow solid, with a yield of 91%. LC-MS (APCI): m / z = 251.2 (M+1) + .

[1161] Step 2: Synthesis of compound 5-(4-(hydroxymethyl)piperidin-1-yl)-2-pyridinecarboxylic acid

[1162] Methyl 5-(4-(hydroxymethyl)piperidin-1-yl)-2-pyridinecarboxylate (2.27 g, 9.1 mmol), lithium hydroxide monohydrate (1.9 g, 45.4 mmol), 10 mL tetrahydrofuran, and 10 mL water were added to a reaction flask. The mixture was stirred at room temperature for 1–2 hours. The reaction was monitored by TLC until complete. The pH was adjusted to weakly acidic with 1 N dilute hydrochloric acid. The mixture was extracted 3–4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 1.8 g of a pale yellow solid, in 84% yield. LC-MS (APCI): m / z = 237.3 (M+1) + .

[1163] Step 3: Synthesis of compound N-(2,6-dioxopiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)-2-pyridinecarboxamide

[1164] Compounds 5-(4-(hydroxymethyl)piperidin-1-yl)-2-pyridinecarboxylic acid (1.8 g, 7.6 mmol), 3-amino-2,6-piperidinedione (1.5 g, 11.4 mmol), HATU (5.8 g, 15.2 mmol), and DIEA (2.9 g, 22.8 mmol) were added to a reaction flask and dissolved in 20 mL of anhydrous DMF under nitrogen protection. The mixture was stirred overnight at room temperature. After the reaction was complete, excess water was added for dilution, and the mixture was extracted 3-4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 1.66 g of a yellow solid, in 63% yield. LC-MS (APCI): m / z = 347.4 (M+1) + .

[1165] Synthesis of intermediate B-2 in step 4

[1166] N-(2,6-dioxopiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)-2-pyridinecarboxamide (1.66 g, 4.8 mmol) was added to a reaction flask and dissolved in 20 mL of dichloromethane. Dys-Martin oxidant (4.27 g, 10.1 mmol) was added in portions, and the mixture was stirred at room temperature for 1–2 hours. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 1.06 g of a pale yellow solid, in 64% yield. LC-MS (APCI): m / z = 345.5 (M+1) + .

[1167] Intermediate B-3-A compound N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-formylpiperidin-1-yl)benzamide and

[1168] Preparation of intermediate B-3-B compound N-(2,6-dioxopiperidin-3-yl)-4-fluoro-2-(4-formylpiperidin-1-yl)benzamide

[1169] The synthesis is performed using the following route:

[1170] Step 1: Synthesis of compounds methyl 2-fluoro-4-(4-(hydroxymethyl)piperidin-1-yl)benzoate and methyl 4-fluoro-2-(4-(hydroxymethyl)piperidin-1-yl)benzoate

[1171] 1.72 g (10.0 mmol) of methyl 2,4-difluorobenzoate and 1.38 g (12.0 mmol) of piperidinyl methanol were added to a reaction flask and dissolved in 15 mL of DMF. Triethylamine (2.02 g, 20.0 mmol) was then added. The mixture was heated to 80 °C and stirred for 10 hours under nitrogen protection. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the solution was purified by silica gel column chromatography to obtain 2.24 g of a pale yellow solid, with a yield of 84%. LC-MS (APCI): m / z = 268.2 (M+1) + .

[1172] Step 2: Synthesis of compounds 2-fluoro-4-(4-(hydroxymethyl)piperidin-1-yl)benzoic acid and 4-fluoro-2-(4-(hydroxymethyl)piperidin-1-yl)benzoic acid

[1173] A mixture of methyl 2-fluoro-4-(4-(hydroxymethyl)piperidin-1-yl)benzoate and methyl 4-fluoro-2-(4-(hydroxymethyl)piperidin-1-yl)benzoate (2.24 g, 8.4 mmol), lithium hydroxide monohydrate (1.9 g, 45.4 mmol), 10 mL tetrahydrofuran, and 10 mL water were added to a reaction flask. The mixture was stirred at room temperature for 1–2 hours. The reaction was monitored by TLC until complete. The pH was adjusted to weakly acidic with 1 N dilute hydrochloric acid. The mixture was extracted 3–4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 2.0 g of a pale yellow solid, 94% yield. LC-MS (APCI): m / z = 254.5 (M+1) + .

[1174] Step 3: Synthesis of compounds N-(2,6-dioxopiridin-3-yl)-2-fluoro-4-(4-(hydroxymethyl)piperidin-1-yl)benzamide and N-(2,6-dioxopiridin-3-yl)-4-fluoro-2-(4-(hydroxymethyl)piperidin-1-yl)benzamide

[1175] A mixture of 2-fluoro-4-(4-(hydroxymethyl)piperidin-1-yl)benzoic acid and 4-fluoro-2-(4-(hydroxymethyl)piperidin-1-yl)benzoic acid (2.0 g, 7.9 mmol), 3-amino-2,6-piperidinedione (1.5 g, 11.4 mmol), HATU (5.8 g, 15.2 mmol), and DIEA (2.9 g, 22.8 mmol) was added to a reaction flask under nitrogen protection. The mixture was dissolved in 20 mL of anhydrous DMF and stirred overnight at room temperature. The reaction was monitored by TLC until complete. Excess water was added for dilution, and the mixture was extracted 3-4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 2.12 g of a yellow solid, 74% yield. LC-MS (APCI): m / z = 364.7 (M+1) + .

[1176] Synthesis of intermediates B-3-A and B-3-B in step 4

[1177] A mixture of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(hydroxymethyl)piperidin-1-yl)benzamide and N-(2,6-dioxopiperidin-3-yl)-4-fluoro-2-(4-(hydroxymethyl)piperidin-1-yl)benzamide (2.12 g, 5.85 mmol) was added to a reaction flask and dissolved in 25 mL of dichloromethane. Dys-Martin oxidant (4.94 g, 11.7 mmol) was added in portions, and the mixture was stirred at room temperature for 2–4 hours. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 1.16 g of a pale yellow solid, 55% yield. LC-MS (APCI): m / z = 362.3 (M+1)+ .

[1178] Preparation of intermediate B-4 compound 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindololin-5-yl)pyrrolidine-3-carboxaldehyde

[1179] Following the preparation method of intermediate B-1, 4-piperidinemethanol (1.38 g, 12.0 mmol) was replaced with 3-hydroxymethylpyrrolidine hydrochloride (1.64 g, 12.0 mmol) to give intermediate B-4, a pale yellow solid of 0.91 g, in 44% yield. LC-MS (APCI): m / z = 356.4 (M+1) + .

[1180] Preparation of intermediate B-5 compound 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-carboxaldehyde

[1181] Following the preparation method of intermediate B-1, 4-piperidinemethanol (1.38 g, 12.0 mmol) was replaced with 3-azacyclobutanemethanol hydrochloride (1.48 g, 12.0 mmol) to give intermediate B-5, a pale yellow solid of 1.12 g, in 66% yield. LC-MS (APCI): m / z = 342.4 (M+1) + .

[1182] Preparation of intermediate B-6 compound N-(2,6-dioxopiperidin-3-yl)-5-(3-formylazetane-1-yl)-2-pyridinecarboxamide

[1183] Following the preparation method of intermediate B-2, 4-piperidinemethanol (1.38 g, 12.0 mmol) was replaced with 3-azacyclobutanemethanol hydrochloride (1.48 g, 12.0 mmol) to give intermediate B-6, a pale yellow solid, 1.08 g, in 67% yield. LC-MS (APCI): m / z = 317.5 (M+1) + .

[1184] Preparation of intermediate B-7 compound N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(3-formylazetane-1-yl)benzamide

[1185] Following the preparation method of intermediate B-2, methyl 5-fluoropyridinecarboxylate (1.55 g, 10.0 mmol) and 4-piperidinemethanol (1.38 g, 12.0 mmol) were replaced with methyl 2,4-difluorobenzoate (1.72 g, 10.0 mmol) and 3-azacyclobutanemethanol hydrochloride (1.48 g, 12.0 mmol), respectively, to obtain intermediate B-7, a pale yellow solid of 0.66 g, in yield of 52%. LC-MS (APCI): m / z = 334.3 (M+1) + .

[1186] Preparation of intermediate B-8 compound (3R)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindololin-5-yl)pyrrolidine-3-carboxaldehyde

[1187] The synthesis is performed using the following route:

[1188] Step 1: Synthesis of compound 2-(2,6-dioxopiperidin-3-yl)-5-((R)-3-(hydroxymethyl)pyrrolidine-1-yl)isoindoline-1,3-dione

[1189] 2-(2,6-dioxadiazine-3-yl)-5-fluoroisoindoline-1,3-dione (2.76 g, 10.0 mmol) and (R)-3-hydroxymethylpyrrolidine hydrochloride (1.64 g, 12.0 mmol) were added to a reaction flask and dissolved in 20 mL of DMF. Triethylamine (2.02 g, 20.0 mmol) was added, and the mixture was heated to 80 °C and stirred for 12 hours under nitrogen protection. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 1.31 g of a bright yellow solid, with a yield of 37%. LC-MS (APCI): m / z = 358.3 (M+1) + .

[1190] Synthesis of intermediate B-8 in step 2

[1191] Compound 2-(2,6-dioxopiperidin-3-yl)-5-((R)-3-(hydroxymethyl)pyrrolidine-1-yl)isoindoline-1,3-dione (1.31 g, 3.7 mmol) was added to a reaction flask and dissolved in 20 mL of dichloromethane. Dys-Martin oxidant (3.13 g, 7.4 mmol) was added in portions, and the mixture was stirred at room temperature for 1–2 hours. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the solution was purified by silica gel column chromatography to give 722 mg of a pale yellow solid, in 55% yield. LC-MS (APCI): m / z = 356.6 (M+1) + .

[1192] Preparation of intermediate B-9 compound (3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindololin-5-yl)pyrrolidine-3-carboxaldehyde

[1193] Following the preparation method of intermediate B-8, (R)-3-hydroxymethylpyrrolidine hydrochloride (1.64 g, 12.0 mmol) was replaced with (S)-3-hydroxymethylpyrrolidine hydrochloride (1.64 g, 12.0 mmol) to obtain 650 mg of intermediate B-9, with a two-step yield of 18%. LC-MS (APCI): m / z = 356.3 (M+1) + .

[1194] Preparation of intermediate B-10 compound 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-4-hydroxypiperidin-4-yl)acetic acid

[1195] The synthesis is performed using the following route:

[1196] Step 1: Synthesis of compound tert-butyl 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-4-hydroxypiperidin-4-yl)acetate

[1197] 2-(2,6-dioxadiazin-3-yl)-5-fluoro-isoindole-1,3-dione (1.38 g, 5.0 mmol), 2-(4-hydroxypiperidin-4-yl) tert-butyl acetate (1.29 g, 6.0 mmol), and triethylamine (1.01 g, 10.0 mmol) were added to a reaction flask. Under nitrogen protection, 10 mL of DMF was added, and the mixture was heated to 80 °C and stirred overnight. The reaction was monitored by TLC until completion. Excess water was added for dilution, and the mixture was extracted 3-4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 1.41 g of a yellow solid, 60% yield. LC-MS (APCI): m / z = 472.1 (M+1) + .

[1198] Synthesis of intermediate B-10 in step 2

[1199] Add 99 mg (0.21 mmol) of tert-butyl 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-4-hydroxypiperidin-4-yl)acetate and 3 mL (12.0 mmol) of 4 M 1,4-dioxane hydrochloride solution to the reaction flask. Stir the mixture at room temperature for 1–2 hours. After the reaction is complete as monitored by TLC, concentrate the solution to remove the solvent. No purification is required; the solution is directly added to the next reaction step. LC-MS (APCI): m / z = 416.2 (M+1) + .

[1200] Preparation of intermediate B-11 compound 2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetic acid

[1201] The synthesis is performed using the following route:

[1202] Step 1: Synthesis of compound 2-(1-(2-fluoro-4-nitrophenyl)-4-hydroxypiperidin-4-yl)tert-butyl acetate

[1203] 2-(4-hydroxypiperidin-4-yl)tert-butyl acetate (2.15 g, 10.0 mmol) and 3,4-difluoronitrobenzene (1.59 g, 10.0 mmol) were added to a reaction flask and dissolved in 15 mL of DMF. DIEA (2.58 g, 20.0 mmol) was slowly added dropwise. After the addition was complete, the mixture was heated to 100 °C and stirred for 3–4 hours. The reaction was monitored by TLC until complete. Excess water was added for dilution, and the mixture was extracted 3–4 times with ethyl acetate. The organic phases were combined, washed with saturated brine, and concentrated to remove the solvent. The residue was purified by silica gel column chromatography to give 2.97 g of a yellow solid, with a yield of 84%. LC-MS (APCI): m / z = 355.6 (M+1) + .

[1204] Step 2: Synthesis of compound 2-(1-(4-amino-2-fluorophenyl)-4-hydroxypiperidin-4-yl)tert-butyl acetate

[1205] 2.97 g (8.4 mmol) of 2-(1-(2-fluoro-4-nitrophenyl)-4-hydroxypiperidin-4-yl)tert-butyl acetate was added to a reaction flask and dissolved in 20 mL of methanol. Palladium on carbon (10% catalyst concentration) was added, and the mixture was purged with hydrogen gas three times. The mixture was then stirred at room temperature for 4-5 hours. The reaction was monitored by TLC until completion. The catalyst was removed by filtration, and the concentrated filtrate was used directly in the next reaction step without further purification. LC-MS (APCI): m / z = 325.3 (M+1) + .

[1206] Step 3: Synthesis of compound 2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)tert-butyl acetate

[1207] Compounds 2-(1-(4-amino-2-fluorophenyl)-4-hydroxypiperidin-4-yl)tert-butyl acetate (2.72 g, 8.4 mmol), 3-bromopiperidin-2,6-dione (3.22 g, 16.8 mmol), and sodium bicarbonate (1.76 g, 21.0 mmol) were added to a reaction flask and dissolved in 20 mL of DMF. The mixture was heated to 50 °C under nitrogen protection and stirred overnight. The reaction was monitored by TLC until completion. Excess water was added for dilution, and the mixture was extracted 3-4 times with ethyl acetate. The organic phases were combined, washed with saturated brine, and concentrated to remove the solvent. The residue was purified by silica gel column chromatography to give 2.16 g of a pale blue solid, with a yield of 59%. LC-MS (APCI): m / z = 436.6 (M+1) + .

[1208] Synthesis of intermediate B-11 in step 4

[1209] Compound 2-(1-(4-((2,6-dioxopiridine-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)tert-butyl acetate (91 mg, 0.21 mmol) and 4 M 1,4-dioxane hydrogen chloride solution (3 mL, 12.0 mmol) were added to the reaction flask. The mixture was stirred at room temperature for 1 hour. After the reaction was complete as monitored by TLC, the solvent was removed by concentration. No purification was required before proceeding to the next reaction step. LC-MS (APCI): m / z = 380.5 (M+1) + .

[1210] Intermediate B-12-A compound (S)-2-(1-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)-4-hydroxypiperidin-4-yl)acetic acid and

[1211] Preparation of compound B-12-B (S)-2-(1-(2-((2,6-dioxopiperidin-3-yl)carbamoyl)-5-fluorophenyl)-4-hydroxypiperidin-4-yl)acetic acid

[1212] The synthesis is performed using the following route:

[1213] Step 1: Synthesis of methyl 4-(4-(2-(tert-butoxy)-2-oxoethyl)-4-hydroxypiperidin-1-yl)-2-fluorobenzoate and methyl 2-(4-(2-(tert-butoxy)-2-oxoethyl)-4-hydroxypiperidin-1-yl)-4-fluorobenzoate

[1214] Methyl 2,4-difluorobenzoate (1.72 g, 10.0 mmol) and tert-butyl 2-(4-hydroxypiperidin-4-yl)acetate (2.58 g, 12.0 mmol) were added to a reaction flask and dissolved in 15 mL of DMF. Triethylamine (2.02 g, 20.0 mmol) was added, and the mixture was heated to 80 °C and stirred for 10 hours under nitrogen protection. The reaction was completed by TLC. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 2.82 g of a pale yellow solid, with a yield of 77%. LC-MS (APCI): m / z = 368.3 (M+1) + .

[1215] Step 2: Synthesis of compounds 4-(4-(2-(tert-butoxy)-2-oxoethyl)-4-hydroxypiperidin-1-yl)-2-fluorobenzoic acid and 2-(4-(2-(tert-butoxy)-2-oxoethyl)-4-hydroxypiperidin-1-yl)-4-fluorobenzoic acid

[1216] A mixture of methyl 4-(4-(2-(tert-butoxy)-2-oxoethyl)-4-hydroxypiperidin-1-yl)-2-fluorobenzoate and methyl 2-(4-(2-(tert-butoxy)-2-oxoethyl)-4-hydroxypiperidin-1-yl)-4-fluorobenzoate (2.82 g, 7.7 mmol), lithium hydroxide monohydrate (1.9 g, 45.4 mmol), 10 mL tetrahydrofuran, and 10 mL water were added to a reaction flask. The mixture was stirred at room temperature for 1–2 hours. The reaction was monitored by TLC until complete. The pH was adjusted to weakly acidic with 1 N dilute hydrochloric acid. The mixture was extracted 3–4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 2.47 g of a pale yellow solid, with a yield of 91%. LC-MS (APCI): m / z = 354.5 (M+1) + .

[1217] Synthesis of compounds (S)-2-(1-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)-4-hydroxypiperidin-4-yl)tert-butyl acetate and (S)-2-(1-(2-((2,6-dioxopiperidin-3-yl)carbamoyl)-5-fluorophenyl)-4-hydroxypiperidin-4-yl)tert-butyl acetate in step 3

[1218] A mixture of 4-(4-(2-(tert-butoxy)-2-oxoethyl)-4-hydroxypiperidin-1-yl)-2-fluorobenzoic acid and 2-(4-(2-(tert-butoxy)-2-oxoethyl)-4-hydroxypiperidin-1-yl)-4-fluorobenzoic acid (2.79 g, 7.9 mmol), (S)-3-amino-2,6-piperidinedione (1.5 g, 11.4 mmol), HATU (5.8 g, 15.2 mmol), and DIEA (2.9 g, 22.8 mmol) was added to a reaction flask. Under nitrogen protection, 20 mL of anhydrous DMF was added to dissolve the precipitate. The mixture was stirred overnight at room temperature. After the reaction was completed by TLC, excess water was added for dilution, and the mixture was extracted 3-4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 1.72 g of yellow solid, yield 47%. LC-MS (APCI): m / z = 464.6 (M+1) + .

[1219] Synthesis of intermediates B-12-A and B-12-B in step 4

[1220] A mixture of (S)-2-(1-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)-4-hydroxypiperidin-4-yl)tert-butyl acetate and (S)-2-(1-(2-((2,6-dioxopiperidin-3-yl)carbamoyl)-5-fluorophenyl)-4-hydroxypiperidin-4-yl)tert-butyl acetate (1.72 g, 3.7 mmol) and 4M 1,4-dioxane hydrogen chloride solution (10 mL, 40.0 mmol) were added to the reaction flask. The mixture was stirred at room temperature for 2–4 hours. The reaction was monitored by TLC until complete. The solvent was removed by concentration, and the mixture was directly added to the next reaction step without purification. LC-MS (APCI): m / z = 408.3 (M+1) + .

[1221] Preparation of intermediate B-13 compound (S)-2-(1-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)-4-hydroxypiperidin-4-yl)acetic acid

[1222] The synthesis is performed using the following route:

[1223] Step 1: Synthesis of compound methyl 5-(4-(2-(tert-butoxy)-2-oxoethyl)-4-hydroxypiperidin-1-yl)-2-pyridinecarboxylate

[1224] Methyl 5-fluoropyridinecarboxylate (1.55 g, 10.0 mmol) and tert-butyl 2-(4-hydroxypiperidin-4-yl)acetate (2.58 g, 12.0 mmol) were added to a reaction flask and dissolved in 15 mL of DMF. Triethylamine (2.02 g, 20.0 mmol) was added, and the mixture was heated to 80 °C and stirred for 10 hours under nitrogen protection. The reaction was completed by TLC. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 3.25 g of a pale yellow solid, with a yield of 93%. LC-MS (APCI): m / z = 351.2 (M+1) + .

[1225] Step 2: Synthesis of compound 5-(4-(2-(tert-butoxy)-2-oxoethyl)-4-hydroxypiperidin-1-yl)-2-pyridinecarboxylic acid

[1226] Methyl 5-(4-(2-(tert-butoxy)-2-oxoethyl)-4-hydroxypiperidin-1-yl)-2-pyridinecarboxylate (3.18 g, 9.1 mmol), lithium hydroxide monohydrate (1.9 g, 45.4 mmol), 10 mL tetrahydrofuran, and 10 mL water were added to a reaction flask. The mixture was stirred at room temperature for 1–2 hours. The reaction was monitored by TLC until complete. The pH was adjusted to weakly acidic with 1 N dilute hydrochloric acid. The mixture was extracted 3–4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 2.02 g of a pale yellow solid, in 66% yield. LC-MS (APCI): m / z = 337.3 (M+1) + .

[1227] Synthesis of compound (S)-2-(1-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)-4-hydroxypiperidin-4-yl)tert-butyl acetate in step 3

[1228] Compounds 5-(4-(2-(tert-butoxy)-2-oxoethyl)-4-hydroxypiperidin-1-yl)-2-pyridinecarboxylic acid (2.55 g, 7.6 mmol), (S)-3-amino-2,6-piperidinedione (1.5 g, 11.4 mmol), HATU (5.8 g, 15.2 mmol), and DIEA (2.9 g, 22.8 mmol) were added to a reaction flask and dissolved in 20 mL of anhydrous DMF under nitrogen protection. The mixture was stirred overnight at room temperature. After the reaction was complete, excess water was added for dilution, and the mixture was extracted 3-4 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 1.73 g of a yellow solid, in 51% yield. LC-MS (APCI): m / z = 447.4 (M+1) + .

[1229] Synthesis of intermediate B-13 in step 4

[1230] Compound (S)-2-(1-(6-((2,6-dioxadiazin-3-yl)carbamoyl)pyridin-3-yl)-4-hydroxypiperidin-4-yl)tert-butyl acetate (1.66 g, 3.7 mmol) and 4M 1,4-dioxane hydrochloride solution (10 mL, 40 mmol) were added to the reaction flask. The mixture was stirred at room temperature for 1–2 hours. After the reaction was complete, the solvent was removed by TLC. The solution was then concentrated and added directly to the next reaction step without purification. LC-MS (APCI): m / z = 391.2 (M+1) + .

[1231] Preparation of intermediate B-14 compound 2-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)-4-hydroxypiperidin-4-yl)acetic acid

[1232] The synthesis is performed using the following route:

[1233] Step 1: Synthesis of compound tert-butyl 2-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)-4-hydroxypiperidin-4-yl)acetate

[1234] 2-(4-hydroxypiperidin-4-yl)tert-butyl acetate (2.15 g, 10.0 mmol), 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione (3.23 g, 11.0 mmol), and DIEA (2.58 g, 20.0 mmol) were added to a reaction flask and dissolved in 20 mL of anhydrous DMF. The mixture was heated to 80 °C under nitrogen protection and stirred overnight. The reaction was monitored by TLC until completion. Excess water was added to quench the reaction. The mixture was extracted 3-4 times with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 3.47 g of a yellow solid, yield 71%. LC-MS (APCI): m / z = 490.6 (M+1) + .

[1235] Synthesis of intermediate B-14 in step 2

[1236] Add 1.81 g (3.7 mmol) of 2-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)-4-hydroxypiperidin-4-yl)tert-butyl acetate and 10 mL (40 mmol) of 4 M 1,4-dioxane hydrochloride solution to the reaction flask. Stir the mixture at room temperature for 1–2 hours. After the reaction is complete, monitor the reaction by TLC. Concentrate the mixture to remove the solvent. No purification is required; the mixture can be directly added to the next reaction step. LC-MS (APCI): m / z = 434.1 (M+1) + .

[1237] Preparation of intermediate B-15 compound (S)-2-(1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)-4-hydroxypiperidin-4-yl)acetic acid

[1238] The synthesis is performed using the following route:

[1239] Step 1: Synthesis of compound methyl 4-(4-(2-(tert-butoxy)-2-oxoethyl)-4-hydroxypiperidin-1-yl)-2-cyanobenzoate

[1240] 2-(4-hydroxypiperidin-4-yl)tert-butyl acetate (2.15 g, 10.0 mmol), methyl 2-cyano-4-fluorobenzoate (1.97 g, 11.0 mmol), and DIEA (2.58 g, 20.0 mmol) were added to a reaction flask and dissolved in 20 mL of anhydrous DMSO. The mixture was heated to 60 °C under nitrogen protection and stirred overnight. The reaction was monitored by TLC until complete. Excess water was added to quench the reaction. The mixture was extracted 3-4 times with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated to remove the solvent, and purified by silica gel column chromatography to give 3.37 g of an off-white solid, 90% yield. LC-MS (APCI): m / z = 375.4 (M+1) + .

[1241] Step 2: Synthesis of methyl 4-(4-(2-(tert-butoxy)-2-oxoethyl)-4-hydroxypiperidin-1-yl)-2-carboxybenzoate

[1242] Methyl 4-(4-(2-(tert-butoxy)-2-oxoethyl)-4-hydroxypiperidin-1-yl)-2-cyanobenzoate (1.87 g, 5.0 mmol), sodium dihydrogen phosphate (2.40 g, 20.0 mmol), 20 mL pyridine, 2 mL acetic acid, 1 mL purified water, and a catalytic amount of Raney nickel were added to a reaction flask. The mixture was heated to 50 °C and stirred overnight. The reaction was monitored by TLC until completion. The catalyst was removed by filtration, and the filtrate was concentrated and purified by silica gel column chromatography to give 0.77 g of a pale yellow solid, with a yield of 41%. LC-MS (APCI): m / z = 378.4 (M+1) + .

[1243] Synthesis of tert-butyl acetate (S)-2-(1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)-4-hydroxypiperidin-4-yl)acetate in step 3

[1244] Methyl 4-(4-(2-(tert-butoxy)-2-oxoethyl)-4-hydroxypiperidin-1-yl)-2-carboxybenzoate (0.77 g, 2.05 mmol), (S)-3-amino-2,6-piperidinedione (394 mg, 3.07 mmol), 8 mL of methanol, and 0.5 mL of acetic acid were added to a reaction flask. Sodium cyanoborohydride (258 mg, 4.1 mmol) was added in portions. After the addition was complete, the mixture was stirred at room temperature for 3–4 hours. After the reaction was complete as monitored by TLC, the solvent was removed by concentration. The residue was purified by silica gel column chromatography to give 675 mg of a pale yellow solid, with a yield of 72%. LC-MS (APCI): m / z = 458.4 (M+1) + .

[1245] Synthesis of intermediate B-15 in step 4

[1246] Compound (S)-2-(1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)-4-hydroxypiperidin-4-yl)tert-butyl acetate (675 mg, 1.48 mmol) and 4 M 1,4-dioxane hydrochloride solution (4 mL, 16.0 mmol) were added to the reaction flask. The mixture was stirred at room temperature for 1–2 hours. After the reaction was complete, the solvent was removed by TLC. The solution was then concentrated and added directly to the next reaction step without purification. LC-MS (APCI): m / z = 402.3 (M+1) + .

[1247] Preparation of intermediate B-16 compound 2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidin-4-yl)acetic acid

[1248] The synthesis is performed using the following route:

[1249] Step 1: Synthesis of compound 6-bromo-5-fluoro-1-methyl-1H-indazole-3-amine

[1250] 4-Bromo-2,5-difluorobenzonitrile (30.0 g, 137.6 mmol), methylhydrazine sulfate (59.4 g, 412.8 mmol), triethylamine (55.6 g, 550.4 mmol), and 100 mL of anhydrous ethanol were added to a reaction flask. The mixture was heated to 80 °C and reacted overnight. The reaction was monitored by TLC until complete. After cooling to room temperature, 300 mL of purified water was added, and a white solid precipitated. The solid was filtered, and the filter cake was then slurried with 1 L of water for 1 hour. The filtrate was removed by filtration, and the filter cake was dried under vacuum to obtain 25.2 g of a pale yellow solid, with a yield of 75%. LC-MS (APCI): m / z = 243.9 (M+1) + .

[1251] Step 2: Synthesis of compound 3-((6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)amino)propionic acid

[1252] 6-Bromo-5-fluoro-1-methyl-1H-indazole-3-amine (25.2 g, 103.7 mmol), acrylic acid (11.2 g, 155.5 mmol), 250 mL of 2M dilute hydrochloric acid aqueous solution, and TBAB (3.4 g, 10.4 mmol) were added to a reaction flask. The mixture was heated to 100 °C under nitrogen protection and stirred overnight. The reaction was monitored by TLC until complete. The mixture was cooled to room temperature, diluted with excess water, and the pH was adjusted to 8-9 with sodium bicarbonate. A pale yellow solid precipitated. The solid was filtered, and the filter cake was dried under vacuum to obtain 12.3 g of solid. The filtrate was extracted 2-3 times with ethyl acetate. The organic phases were combined, concentrated to remove the solvent, and purified by silica gel column chromatography to obtain 4.0 g of pale yellow solid. A total of 16.3 g of product was obtained. The yield was 50%. LC-MS (APCI): m / z = 316.1 (M+1) + .

[1253] Step 3: Synthesis of compound 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[1254] Compound 3-((6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)amino)propionic acid (12.3 g, 39.0 mmol), sodium cyanate (5.1 g, 78.1 mmol), 123 mL of acetic acid, and 40 mL of concentrated hydrochloric acid were added to a reaction flask. The mixture was heated to 60 °C and stirred for 16 hours under nitrogen protection. The reaction was complete as detected by TLC. After cooling to room temperature, excess water was added for dilution, resulting in the precipitation of a white solid. The solid was filtered, and the filter cake was dried under vacuum to obtain 12.5 g of a white solid, with a yield of 94%. LC-MS (APCI): m / z = 341.3 (M+1) + .

[1255] Step 4: Synthesis of compound tert-butyl 2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidin-4-yl)acetate

[1256] Compounds 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (6.0 g, 17.6 mmol), 2-(4-hydroxypiperidin-4-yl)tert-butyl acetate (5.7 g, 26.5 mmol), Ruphos Pd-G3 (2.9 g, 3.52 mmol), and cesium carbonate (17.2 g, 52.8 mmol) were added to a reaction flask. Under nitrogen protection, 70 mL of 1,4-dioxane was added, and the mixture was heated to 130 °C and stirred overnight. The reaction was completed by TLC. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 2.5 g of a pale yellow solid, in 30% yield. LC-MS (APCI): m / z = 476.6 (M+1) + .

[1257] Synthesis of intermediate B-16 in step 5

[1258] Add 100 mg (0.21 mmol) of tert-butyl 2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidin-4-yl)acetate and 3 mL (12.0 mmol) of 4 M 1,4-dioxane hydrochloride solution to the reaction flask. Stir the mixture at room temperature for 1–2 hours. After the reaction is complete, monitor the reaction by TLC. Concentrate the mixture to remove the solvent. No purification is required; the mixture can be directly added to the next reaction step. LC-MS (APCI): m / z = 420.3 (M+1) + .

[1259] Preparation of intermediates B-17-A and B-17-B compounds (S)-2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetic acid and (R)-2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetic acid

[1260] The synthesis is performed using the following route:

[1261] The racemic compound B-11 was separated by supercritical fluid chromatography to obtain the target products B-17-A (retention time: 2.03 min, relative content: 49.1%) and B-17-B (retention time: 1.89 min, relative content: 50.9%).

[1262] Chromatographic separation conditions:

[1263] Column: CHIRALCEL, OJ-3, 50×4.6mm ID, 3μm

[1264] Column temperature: 35℃

[1265] Flow rate: 3.0 mL / min

[1266] UV detection wavelength: 220nm

[1267] Mobile phase: Carbon dioxide: Methanol (0.05% diethylamine) = 60:40

[1268] Preparation of intermediate B-18 compound 2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidin-4-yl)acetic acid

[1269] The synthesis is performed using the following route:

[1270] Step 1: Synthesis of 6-bromo-1-methyl-1H-indazole-3-amine

[1271] 4-Bromo-2-fluorobenzonitrile (27.4 g, 137.6 mmol), methylhydrazine sulfate (59.4 g, 412.8 mmol), triethylamine (55.6 g, 550.4 mmol), and 100 mL of anhydrous ethanol were added to a reaction flask. The mixture was heated to 80 °C and reacted overnight. The reaction was monitored by TLC until complete. After cooling to room temperature, 300 mL of purified water was added, and a white solid precipitated. The solid was filtered, and the filter cake was then slurried with 1 L of water for 1 hour. The filtrate was removed by filtration, and the filter cake was dried under vacuum to obtain 24.4 g of a pale yellow solid, with a yield of 79%. LC-MS (APCI): m / z = 226.4 (M+1) + .

[1272] Step 2: Synthesis of 3-((6-bromo-1-methyl-1H-indazol-3-yl)amino)propionic acid

[1273] 6-Bromo-1-methyl-1H-indazole-3-amine (24.4 g, 108.7 mmol), acrylic acid (11.2 g, 155.5 mmol), 250 mL of 2M dilute hydrochloric acid aqueous solution, and TBAB (3.4 g, 10.4 mmol) were added to a reaction flask. The mixture was heated to 100 °C under nitrogen protection and stirred overnight. The reaction was monitored by TLC until complete. The mixture was cooled to room temperature, diluted with excess water, and the pH was adjusted to 8-9 with sodium bicarbonate. A pale yellow solid precipitated. The solid was filtered, and the filter cake was dried under vacuum to obtain 14.4 g of solid. The filtrate was extracted 2-3 times with ethyl acetate. The organic phases were combined, concentrated to remove the solvent, and purified by silica gel column chromatography to obtain 3.3 g of pale yellow solid. A total of 17.7 g of product was obtained. The yield was 55%. LC-MS (APCI): m / z = 298.3 (M+1). + .

[1274] Step 3: Synthesis of 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[1275] 3-((6-bromo-1-methyl-1H-indazol-3-yl)amino)propionic acid (11.6 g, 39.0 mmol), sodium cyanate (5.1 g, 78.1 mmol), 123 mL of acetic acid, and 40 mL of concentrated hydrochloric acid were added to a reaction flask. The mixture was heated to 60 °C and stirred for 16 hours under nitrogen protection. The reaction was complete as detected by TLC. After cooling to room temperature, excess water was added for dilution, resulting in the precipitation of a white solid. The solid was filtered, and the filter cake was dried under vacuum to obtain 11.1 g of a white solid, with a yield of 88%. LC-MS (APCI): m / z = 323.3 (M+1) + .

[1276] Step 4: Synthesis of tert-butyl 2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidin-4-yl)acetate

[1277] 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (5.67 g, 17.6 mmol), 2-(4-hydroxypiperidin-4-yl)tert-butyl acetate (5.7 g, 26.5 mmol), Ruphos Pd-G3 (2.9 g, 3.52 mmol), and cesium carbonate (17.2 g, 52.8 mmol) were added to a reaction flask. Under nitrogen protection, 70 mL of 1,4-dioxane was added, and the mixture was heated to 130 °C and stirred overnight. The reaction was completed by TLC. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 2.1 g of a pale yellow solid, with a yield of 26.7%. LC-MS (APCI): m / z = 458.6 (M+1) + .

[1278] Synthesis of intermediate B-18 in step 5

[1279] Add 96 mg (0.21 mmol) of 2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidin-4-yl)tert-butyl acetate and 3 mL (12.0 mmol) of 4 M 1,4-dioxane hydrochloride solution to the reaction flask. Stir the mixture at room temperature for 1–2 hours. After the reaction is complete as monitored by TLC, concentrate the solution to remove the solvent. No purification is required; the solution can be directly added to the next reaction step. LC-MS (APCI): m / z = 402.3 (M+1) + .

[1280] Preparation of intermediate B-19 compound 2-(1-(3-(2,6-dioxopiperidin-3-yl)benzofuran-6-yl)-4-hydroxypiperidin-4-yl)acetic acid

[1281] The synthesis is performed using the following route:

[1282] Step 1: Synthesis of 7-bromo-4-(chloromethyl)-2H-benzopyran-2-one

[1283] Add 19 mL of purified water to the reaction flask, cool to 0 °C, slowly add concentrated sulfuric acid (103 g, 1.03 mol), stir for 10 minutes, then raise to room temperature, add 3-bromophenol (10.0 g, 57.8 mmol), cool again to 0 °C, add ethyl 4-chloroacetoacetate (12.4 g, 75.1 mmol), slowly raise to room temperature and stir overnight. Monitor the reaction by TLC until complete. Slowly pour the reaction solution into 300 mL of purified water, precipitating a white solid. Filter, and then slurry the filter cake with 500 mL of water for 1 hour. Filter to remove the filtrate, and vacuum dry the filter cake to obtain 10.0 g of white solid, yield 62.8%. LC-MS (APCI): m / z = 274.9 (M+1) + .

[1284] Step 2: Synthesis of 2-(6-bromobenzofuran-3-yl)acetic acid

[1285] 10.0 g (36.3 mmol) of 7-bromo-4-(chloromethyl)-2H-benzopyran-2-one and 100 mL of purified water were added to a reaction flask. Sodium hydroxide (4.79 g, 120 mmol) was added in portions. The mixture was heated to 80 °C and stirred for 5–7 hours under nitrogen protection. The reaction was monitored by TLC until completion. The mixture was then cooled to room temperature, and the pH was adjusted to 5–6 with 1 N dilute hydrochloric acid in an ice bath. A white solid precipitated. The precipitate was filtered, and the filter cake was dried under vacuum to obtain 6.0 g of white solid. The yield was 64.8%. LC-MS (APCI): m / z = 255.0 (M+1) + .

[1286] Step 3: Synthesis of ethyl 2-(6-bromobenzofuran-3-yl)ethyl acetate

[1287] 2-(6-bromobenzofuran-3-yl)acetic acid (6.0 g, 23.5 mmol) and 60 mL of anhydrous ethanol were added to a reaction flask. Concentrated sulfuric acid (1.2 g, 11.8 mmol) was added dropwise under ice bath. The mixture was heated to 80 °C and stirred for 2 hours under nitrogen protection. The reaction was monitored by TLC until complete. The solvent was removed by concentration. The residue was dissolved in 200 mL of ethyl acetate, followed by 200 mL of purified water. The organic phase was separated, and the aqueous phase was extracted 3-4 times with ethyl acetate. The organic phases were combined, washed with saturated brine, and concentrated. The residue was purified by silica gel column chromatography to give 6.1 g of a colorless oily liquid, with a yield of 90.1%. LC-MS (APCI): m / z = 283.1 (M+1) + .

[1288] Step 4: Synthesis of tert-butyl 2-(1-(3-(2-ethoxy-2-oxoethyl)benzofuran-6-yl)-4-hydroxypiperidin-4-yl)acetate

[1289] Ethyl 2-(6-bromobenzofuran-3-yl)acetate (4.96 g, 17.6 mmol), tert-butyl 2-(4-hydroxypiperidin-4-yl)acetate (5.7 g, 26.5 mmol), Ruphos Pd-G3 (2.9 g, 3.52 mmol), and cesium carbonate (17.2 g, 52.8 mmol) were added to a reaction flask under nitrogen protection. The mixture was heated to 100 °C and stirred overnight. The reaction was monitored by TLC until complete. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 2.5 g of a pale yellow solid, in 33.7% yield. LC-MS (APCI): m / z = 418.6 (M+1) + .

[1290] Step 5: Synthesis of tert-butyl 2-(1-(3-(2,6-dioxopiperidin-3-yl)benzofuran-6-yl)-4-hydroxypiperidin-4-yl)acetate

[1291] 2-(1-(3-(2-ethoxy-2-oxoethyl)benzofuran-6-yl)-4-hydroxypiperidin-4-yl)tert-butyl acetate (2.5 g, 5.93 mmol), potassium tert-butoxide (732 mg, 6.52 mmol), and 30 mL of anhydrous tetrahydrofuran were added to a reaction flask. Acrylamide (421 mg, 5.93 mmol) was slowly added dropwise under ice bath conditions. After the addition was complete, the mixture was brought to room temperature and stirred for 3–5 hours. The reaction was monitored by TLC until completion. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 1.27 g of a pale yellow solid, with a yield of 48.6%. LC-MS (APCI): m / z = 443.3 (M+1) + .

[1292] Step 6: Synthesis of 2-(1-(3-(2,6-dioxopiperidin-3-yl)benzofuran-6-yl)-4-hydroxypiperidin-4-yl)acetic acid

[1293] Add 93 mg (0.21 mmol) of 2-(1-(3-(2,6-dioxadiazin-3-yl)benzofuran-6-yl)-4-hydroxypiperidin-4-yl)tert-butyl acetate and 3 mL (12.0 mmol) of 4N 1,4-dioxane hydrochloride solution to the reaction flask. Stir the mixture at room temperature for 1–2 hours. After the reaction is complete, monitor the reaction by TLC. Concentrate the solution to remove the solvent. No purification is required; the solution can be directly added to the next reaction step. LC-MS (APCI): m / z = 387.5 (M+1) + .

[1294] Preparation of intermediate B-20 compound 2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)imidazo[1,2-a]pyridin-7-yl)-4-hydroxypiperidin-4-yl)acetic acid

[1295] The synthesis is performed using the following route:

[1296] Step 1: Synthesis of compound 7-bromo-3-iodoimidazole[1,2-a]pyridine

[1297] 7-Bromoimidazole[1,2-a]pyridine (1.96 g, 10.0 mmol) was added to a reaction flask and dissolved in 30 mL of acetonitrile. Under nitrogen protection, N-iodosuccinimide (2.7 g, 12.0 mmol) was added in portions. The mixture was stirred overnight at room temperature. The reaction was monitored by TLC until complete. The reaction solution was slowly poured into 50 mL of purified water, and 10 mL of saturated sodium thiosulfate aqueous solution was added. The mixture was stirred for half an hour, and a pale yellow solid precipitated. The solid was filtered, and the filter cake was slurried with 100 mL of water for 1 hour. The filtrate was removed by filtration, and the filter cake was dried under vacuum to obtain 2.51 g of a pale yellow solid, with a yield of 77.8%. LC-MS (APCI): m / z = 322.8 (M+1) + .

[1298] Step 2: Synthesis of compound 1-(7-bromoimidazolo[1,2-a]pyridin-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione

[1299] 7-Bromo-3-iodoimidazolo[1,2-a]pyridine (2.51 g, 7.78 mmol), 3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (2.7 g, 11.7 mmol), cuprous iodide (149 mg, 0.78 mmol), trans-cyclohexanediamine (178 mg, 1.56 mmol), and cesium carbonate (6.3 g, 19.5 mmol) were added to a reaction flask. Under nitrogen protection, 30 mL of 1,4-dioxane was added, and the mixture was heated to 70 °C and stirred overnight. The reaction was monitored by TLC until complete. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 1.7 g of a pale yellow solid, in 51.7% yield. LC-MS (APCI): m / z = 429.1 (M+1) + .

[1300] Step 3: Synthesis of compound 1-(7-bromoimidazolo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[1301] 1-(7-bromoimidazolo[1,2-a]pyridin-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (1.7 g, 4.0 mmol), 10 mL trifluoroacetic acid, and 5 mL trifluoromethanesulfonic acid were added to a reaction flask. The mixture was heated to 80 °C and stirred for 2–4 hours under nitrogen protection. The reaction was monitored by TLC until complete. The solvent was removed by concentration, and the residue was dissolved in 50 mL of dichloromethane. The residue was washed twice, successively with saturated sodium bicarbonate aqueous solution and saturated brine. After concentration, the residue was purified by silica gel column chromatography to give 469 mg of a pale yellow solid, with a yield of 38.1%. LC-MS (APCI): m / z = 309.7 (M+1) + .

[1302] Step 4: Synthesis of compound 2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)imidazo[1,2-a]pyridin-7-yl)-4-hydroxypiperidin-4-yl)tert-butyl acetate

[1303] 1-(7-bromoimidazolo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (469 mg, 1.5 mmol), 2-(4-hydroxypiperidin-4-yl) tert-butyl acetate (570 mg, 2.7 mmol), Xphos Pd-G3 (127 mg, 0.15 mmol), and cesium carbonate (1.48 g, 4.5 mmol) were added to a reaction flask. Under nitrogen protection, 10 mL of 1,4-dioxane was added, and the mixture was heated to 120 °C and stirred overnight. The reaction was monitored by TLC until complete. The solvent was removed by concentration, and the mixture was purified by silica gel column chromatography to give 299 mg of a pale yellow solid, with a yield of 45.1%. LC-MS (APCI): m / z = 444.3 (M+1) + .

[1304] Synthesis of intermediate B-20 in step 5

[1305] Add 93 mg (0.21 mmol) of 2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)imidazo[1,2-a]pyridin-7-yl)-4-hydroxypiperidin-4-yl)tert-butyl acetate and 3 mL (12.0 mmol) of 4N 1,4-dioxane hydrochloride solution to the reaction flask. Stir the mixture at room temperature for 1-2 hours. After the reaction is complete as monitored by TLC, concentrate the solution to remove the solvent. No purification is required; the solution is directly added to the next reaction step. LC-MS (APCI): m / z = 388.5 (M+1) + .

[1306] Preparation of intermediate B-21 compound 2-(1-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)pyrazolo[1,5-a]pyridin-6-yl)-4-hydroxypiperidin-4-yl)acetic acid

[1307] Following the preparation method of intermediate B-20, 7-bromoimidazolo[1,2-a]pyridine (1.96 g, 10.0 mmol) was replaced with 6-bromopyrazolo[1,5-a]pyridine (1.96 g, 10.0 mmol) to obtain intermediate B-21, which was directly added to the next reaction without purification. LC-MS (APCI): m / z = 388.4 (M+1) + .

[1308] Preparation of intermediate B-22 compound 2-(1-(1-(2,6-dioxopiperidin-3-yl)-6-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-4-hydroxypiperidin-4-yl)acetic acid

[1309] The synthesis is performed using the following route:

[1310] Step 1: Synthesis of compound 5-bromo-4-fluoro-N-methyl-2-nitroaniline

[1311] 1-Bromo-2,5-difluoro-4-nitrobenzene (2.37 g, 10.0 mmol) was added to a reaction flask and dissolved with 20 mL of ethanol by stirring. An ethanol solution of methylamine (620 mg, 20.0 mmol) was then added, and the mixture was stirred overnight at room temperature. The reaction was monitored by TLC until complete. The reaction solution was slowly poured into 100 mL of purified water, resulting in the precipitation of a yellow solid. The solid was filtered, and the filter cake was further slurried with 100 mL of water for 1 hour. The filtrate was removed by filtration, and the filter cake was vacuum dried to obtain 2.26 g of a yellow solid, with a yield of 91.2%. LC-MS (APCI): m / z = 248.9 (M+1) + .

[1312] Step 2: Synthesis of compound 2-(1-(2-fluoro-5-(methylamino)-4-nitrophenyl)-4-hydroxypiperidin-4-yl)tert-butyl acetate

[1313] 5-Bromo-4-fluoro-N-methyl-2-nitroaniline (2.26 g, 9.1 mmol), 2-(4-hydroxypiperidin-4-yl)tert-butyl acetate (2.95 g, 13.7 mmol), Xphos Pd-G3 (770 mg, 0.9 mmol), and cesium carbonate (5.9 g, 18.2 mmol) were added to a reaction flask under nitrogen protection. 50 mL of 1,4-dioxane was added, and the mixture was heated to 120 °C and stirred overnight. The reaction was complete by TLC. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 1.6 g of a pale yellow solid, with a yield of 45.8%. LC-MS (APCI): m / z = 384.6 (M+1) + .

[1314] Step 3: Synthesis of compound 2-(1-(4-amino-2-fluoro-5-(methylamino)phenyl)-4-hydroxypiperidin-4-yl)tert-butyl acetate

[1315] 1.6 g (4.2 mmol) of 2-(1-(2-fluoro-5-(methylamino)-4-nitrophenyl)-4-hydroxypiperidin-4-yl)tert-butyl acetate and 30 mL of tetrahydrofuran were added to a reaction flask. Under nitrogen protection, a catalytic amount of palladium on carbon was added. The mixture was purged with hydrogen three times, and the mixture was stirred at room temperature for 2–4 hours using a hydrogen balloon. The reaction was monitored by TLC until completion. The catalyst was removed by diatomaceous earth filtration. The filtrate was concentrated and purified by silica gel column chromatography to obtain 1.4 g of a pale yellow solid, with a yield of 93.6%. LC-MS (APCI): m / z = 354.1 (M+1) + .

[1316] Step 4: Synthesis of compound tert-butyl 2-(1-(6-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-4-hydroxypiperidin-4-yl)acetate

[1317] 1.4 g (3.9 mmol) of 2-(1-(4-amino-2-fluoro-5-(methylamino)phenyl)-4-hydroxypiperidin-4-yl)tert-butyl acetate and 389 mg (1.3 mmol) of triphosgene were added to a reaction flask. Under nitrogen protection, 20 mL of anhydrous dichloromethane was added, and DIEA (1.01 g, 7.8 mmol) was slowly added dropwise in an ice bath. After the addition was complete, the mixture was brought to room temperature and stirred overnight. The reaction was monitored by TLC until complete. The solvent was removed by concentration, and the product was purified by silica gel column chromatography to give 0.94 g of a pale yellow solid, with a yield of 63.7%. LC-MS (APCI): m / z = 380.3 (M+1) + .

[1318] Step 5: Synthesis of compound 2-(5-(4-(2-(tert-butoxy)-2-oxoethyl)-4-hydroxypiperidin-1-yl)-6-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)dimethyl glutarate

[1319] 2-(1-(6-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-4-hydroxypiperidin-4-yl)tert-butyl acetate (0.94 g, 2.48 mmol), dimethyl 2-bromoglutarate (709 mg, 2.98 mmol), cesium carbonate (1.61 g, 4.96 mmol), and 30 mL of anhydrous DMF were added to a reaction flask. The mixture was heated to 60 °C under nitrogen protection and stirred for 3–5 hours. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature and diluted with excess water. The mixture was extracted 3–4 times with ethyl acetate. The organic phases were combined, washed with saturated brine, and concentrated. The residue was purified by silica gel column chromatography to give 1.06 g of a yellow oily liquid, with a yield of 79.6%. LC-MS (APCI): m / z = 538.3 (M+1) + .

[1320] Step 6: Synthesis of compound 2-(5-(4-(2-(tert-butoxy)-2-oxoethyl)-4-hydroxypiperidin-1-yl)-6-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)glutaric acid

[1321] To a reaction flask, add 1.06 g (1.97 mmol) of dimethyl 2-(5-(4-(2-(tert-butoxy)-2-oxoethyl)-4-hydroxypiperidin-1-yl)-6-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)glutarate, 8 mL of tetrahydrofuran, and 8 mL of purified water. Add sodium hydroxide (473 mg, 11.82 mmol) under ice bath cond...

Claims

1. A compound of formula (IA) or (IB), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof: in, A1is N or CR A1 ; A2is N or CR A2 ; A3 is N or CR A3 ; A4 is N or CR A4 ; R A1 , R A2 , R A3 and R A4 are independently H, D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; B1is N or CR B1 ; B2 is N or CR B2 ; B3 is N or CR B3 ; B4 is N or CR B4 ; B5 is N or CR B5 ; B6is N or CR B6 ; R B1 , R B2 , R B3 , R B4 , R B5 and R B6 are independently H, D, halogen, -OH, -CN, C 1-6 alkyl, C 1- 6haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; o is 1, 2, or 3; each X is independently O, NR X , C(R X )2, C(O), or S(O)2; each R is independently H, D, or C1-6alkyl; X independently H, D, or C1-6alkyl; 1-6 independently H, D, or C1-6alkyl; B1 with one R X together with the atom to which they are attached form a C3-8cycloalkyl or 5-7 membered heterocyclyl; 5-6 C3-8cycloalkyl or 5-7 membered heterocyclyl; R N For H or C 1-6 alkyl; R is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 5-10 membered heteroaryl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl, or NR1R2; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 5-10 membered heteroaryl, C 3-6 cycloalkyl and 4-7 membered heterocyclyl are optionally substituted with one or more groups selected from D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; R1and R2are independently C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclyl, or R1and R2together with the N atom to which they are attached form a 4-7 membered monocyclic heterocyclic ring, a 6-10 membered fused heterocyclic ring, a 6-10 membered bridged heterocyclic ring or a 6-9 membered spirocyclic heterocyclic ring; wherein the above groups are optionally substituted with one or more groups selected from D, halogen, -OH, -CN, C 1- 6alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; L is -SO- (L1) i -S1- (L2) j -S2- (L3) m -S3- (L4) n -S4-; wherein S0, S1, S2, S3and S4are independently a bond, -0-, -NR S -, -S-, -S(O)2-, -C(O)-, -C(O)-NR S -, -NR S -C(O)-, -NR S -C(O)-NR S -, -C(O)O-, -OC(O)-, -(CH2CH2O) k -, C 1-6 alkylene, C 1-6 alkenylene or C 1-6 alkynylene; wherein each R S is independently H or C 1-6 alkyl; k is 1, 2, 3, 4 or 5; i is 0 or 1; j is 0 or 1; m is 0 or 1; n is 0 or 1; L1 is a divalent group selected from a benzene ring or a 5-6 membered heteroaromatic ring; wherein the above group is optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups; each L2, L3and L4is independently a bivalent radical selected from C 1-6 alkynyl, 3-6 membered monocyclic carbocyclic ring, 4-7 membered monocyclic heterocyclic ring, 6-10 membered fused carbocyclic ring, 6-10 membered fused heterocyclic ring, 6-10 membered bridged carbocyclic ring, 6-10 membered bridged heterocyclic ring, 6-9 membered spiro carbocyclic ring, or 6-9 membered spiro heterocyclic ring; wherein the above radicals are optionally substituted with one or more radicals selected from D, halo, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy; U1 and U2 are each independently selected from the following formula (U A ), formula (U B ), formula (U C ), formula (U D ), formula (U E ), formula (U F ) or formula (U G ): in, It can be a single bond or a double bond; Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2; Each W is independently a chemical bond, NH, O, C(O)NH, NHC(O), CH2 or CD2; Each Q1 is independently C(O) or C(R5)2; Each Q2 is independently either N or CH; Each Q3 is independently either N or CR5; Each P1, P2, P3, and P4 is independently N or CR6; P5 and P6 are either N or C; H1 is N, C, or CR7; H2 and H3 are independently N, O, S, NR7, CR7, C(R7)2 or C(O); each R3is independently H or C 1-6 alkyl; q can be 0, 1, 2, 3, 4, or 5; d is 0 or 1; each R4is independently D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, or two R4on the same atom or two R4on adjacent atoms, together with the atom(s) to which they are attached, form a C 3-7 carbocycle or 4-7 membered heterocycle; each R5is independently H, D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy, or two R5on the same atom together with the atom to which they are attached form a C 3-7 carbocycle or 4-7 membered heterocycle; each R6is independently H, D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy, or two R6on adjacent atoms together with the atoms to which they are attached form a C 3-7 carbocycle, 4-7 membered heterocycle, phenyl ring, or 5-6 membered heteroaromatic ring; each R7is independently H, D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclyl, or two R7on the same atom or two R7on adjacent atoms, together with the atom(s) to which they are attached, form a C 3-7 carbocyclic ring, 4-7 membered heterocyclic ring, phenyl ring, or 5-6 membered heteroaromatic ring; The premise is that when o is 1, X is an O atom, R1 is a methyl group and R2 is an ethyl group, U1 and U2 are not... Preferably, U2 is selected from the following formula (U A ), formula (U B ), formula (U F ), formula (U G ), formula (U H ) or formula (U J ): with the proviso that when o is 1, X is an O atom, R1is methyl and R2is ethyl, U1is of formula (U A ), formula (U B ) or formula (U F ).

2. The compound according to claim 1, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, wherein it is a compound of formula (IIA) or (IIB). in, R, R A1 , R A2 , R B1 , X, L, U1 and U2 are as defined in claim 1.

3. The compound according to claim 1 or 2, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, wherein, X is O.

4. The compound according to claim 1 or 2, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, wherein, X is NH.

5. The compound according to any one of claims 1-4, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R is C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl or NR1R2; wherein the C 1-6 alkyl, C 3-6 cycloalkyl and 4-7 membered heterocyclyl are optionally substituted with one or more groups selected from D, halo, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; R1and R2are independently C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclyl, or R1and R2together with the N atom to which they are attached form a 4-7 membered monocyclic heterocyclic ring, a 6-10 membered fused heterocyclic ring, a 6-10 membered bridged heterocyclic ring or a 6-9 membered spirocyclic heterocyclic ring; wherein the above groups are optionally substituted with one or more groups selected from D, halogen, -OH, -CN, C 1- 6alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy.

6. The compound according to claim 5, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R is -N(Me)(Et).

7. The compound according to claim 5, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R is NR1R2; R1and R2together with the N atom to which they are attached form a 4-7 membered monocyclic heterocycle, a 6-10 membered fused heterocycle, a 6-10 membered bridged heterocycle or a 6-9 membered spirocyclic heterocycle; wherein the above is optionally substituted with one or more groups selected from D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy.

8. The compound according to claim 7, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R is 9. The compound according to claim 8, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R is 10. The compound according to claim 9, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R is 11. The compound according to any one of claims 1-10, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L is -(L1) i -(L2)-S2-S3-(L4) - ; wherein S2is a chemical bond, -C(O)-, -C(O)-NR S - or -NR S - C(O)-; wherein each R S independently is H or C 1-6 alkyl; S3 is -C 1-6 alkylene-; i is 0 or 1; L1is a divalent group selected from a phenyl ring or a 5-6 membered heteroaromatic ring; wherein the above mentioned group is optionally substituted with one or more groups selected from D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; L2is a bivalent radical selected from 3-6 membered monocyclic carbocyclic ring, 4-7 membered monocyclic heterocyclic ring, 6-10 membered fused carbocyclic ring, 6-10 membered fused heterocyclic ring, 6-10 membered bridged carbocyclic ring, 6-10 membered bridged heterocyclic ring, 6-9 membered spiro carbocyclic ring or 6-9 membered spiro heterocyclic ring; wherein the above radicals are optionally substituted with one or more radicals selected from D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; L4is a bivalent radical selected from C 1-6 alkyne, 3-6 membered monocyclic carbocyclic ring, 4-7 membered monocyclic heterocyclic ring, 6-10 membered fused carbocyclic ring, 6-10 membered fused heterocyclic ring, 6-10 membered bridged carbocyclic ring, 6-10 membered bridged heterocyclic ring, 6-9 membered spiro carbocyclic ring, or 6-9 membered spiro heterocyclic ring; wherein the above radicals are optionally substituted with one or more radicals selected from D, halo, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy.

12. The compound according to claim 11, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, S2 is a chemical bond.

13. The compound according to claim 11, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, S2 is -C(O)-.

14. The compound according to claim 11, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, S2is -C(O)-NR S - or -NR S - C(O)-.

15. The compound according to any one of claims 11-14, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, S3 is a methylene group.

16. The compound according to any one of claims 11-15, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, i is 0.

17. The compound according to any one of claims 11-15, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, i is 1.

18. The compound according to any one of claims 11-17, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L1 is a divalent group selected from benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, pyrrole ring, furan ring, thiophene ring, imidazole ring, pyrazole ring, oxazole ring, isoxazole ring, thiazole ring, or isothiazole ring.

19. The compound according to any one of claims 11-17, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L1 is a divalent group selected from a benzene ring or a 5-6 membered heteroaromatic ring having 1 or 2 N atoms.

20. The compound according to any one of claims 11-19, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L2is a divalent radical selected from 4-7 membered monocyclic heterocyclyl, 6-10 membered fused heterocycle, 6-10 membered bridged heterocycle or 6-9 membered spirocyclic heterocycle; wherein the above radicals are optionally substituted with one or more radicals selected from D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1- 6haloalkoxy.

21. The compound according to any one of claims 11-20, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L2 is The above-mentioned groups are optionally surrounded by one or more elements selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substitution of halogenated alkoxy groups.

22. The compound according to any one of claims 11-21, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L4is a divalent group selected from C 1-6 alkynyl, 3-6 membered monocyclic carbocyclic ring, 4-7 membered monocyclic heterocyclic ring, 6-10 membered bridged carbocyclic ring, or 6-10 membered bridged heterocyclic ring; wherein the above groups are optionally substituted with one or more groups selected from D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy.

23. The compound according to any one of claims 11-22, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L4 is The above-mentioned groups are optionally surrounded by one or more elements selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substitution of halogenated alkoxy groups.

24. The compound according to any one of claims 1-23, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U1 and U2 are independently selected from the following formula (U A ) or formula (U B ): in, Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2; Each Q1 is independently C(O) or C(R5)2; Each P1, P2, and P3 is independently N or CR6; each R3is independently H or C 1-6 alkyl; q can be 0, 1, 2, 3, 4, or 5; d is 0 or 1; each R4is independently D, halo, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, or two R4on the same atom or two R4on adjacent atoms, together with the atom(s) to which they are attached, form a C 3-7 carbocycle or 4-7 membered heterocycle; each R5is independently H, D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy, or two R5on the same atom together with the atom to which they are attached form a C 3-7 carbocycle or 4-7 membered heterocycle; each R6is independently H, D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy, or two R6on adjacent atoms together with the atoms to which they are attached form a C 3-7 carbocycle, 4-7 membered heterocycle, phenyl ring, or 5-6 membered heteroaromatic ring.

25. The compound according to any one of claims 1-24, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U1 and U2 are independently selected from the following formula (U A1 ) or formula (U B1 ): in, Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2; Each Q1 is independently C(O) or C(R5)2; Each R3 is independently H or C. 1-6 alkyl; p is 0, 1, or 2; q can be 0, 1, 2, 3, 4, or 5; each R4is independently D, halo, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy, or two R4on the same atom or two R4on adjacent atoms, together with the atom(s) to which they are attached, form a C 3-7 carbocycle or 4-7 membered heterocycle; each R5is independently H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1- 6haloalkoxy, or two R5on the same atom together with the atom to which they are attached form a C 3-7 carbocycle or 4-7 membered heterocycle; each R6is independently D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, or two R6on adjacent atoms together with the atoms to which they are attached form a C 3-7 carbocyclic, 4-7 membered heterocyclic, phenyl, or 5-6 membered heteroaryl ring.

26. The compound according to any one of claims 1-25, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U1 and U2 are independently selected from the following formula (U A1 ) or formula (U B1 ): in, Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2; Each Q1 is independently C(O) or C(R5)2; Each R3 is independently H or methyl; p is 0, 1, or 2; q is 0, 1, or 2; each R4is independently D, halo, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, or two R4on the same atom or two R4on adjacent atoms, together with the atom(s) to which they are attached, form a C 3-7 carbocycle or 4-7 membered heterocycle; Each R5 is independently H, D, or halogen; Each R6 is independently either D or halogen.

27. The compound according to any one of claims 1-26, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U1 and U2 are independently selected from the following formula (U A2 ) or formula (U B2 ): Each Q1 is independently C(O) or CH2; p is 0, 1, or 2; Each R6 is independently either D or halogen.

28. The compound according to any one of claims 1-27, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U1 and U2 are independently selected from the following formula (U C ) or formula (U D ): in, Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2; Each W is independently a chemical bond, NH, O, C(O)NH, NHC(O), CH2 or CD2; Each Q2 is independently either N or CH; Each P1, P2, P3, and P4 is independently N or CR6; each R3is independently H or C 1-6 alkyl; q can be 0, 1, 2, 3, 4, or 5; d is 0 or 1; each R4is independently D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, or two R4on the same atom or two R4on adjacent atoms, together with the atom(s) to which they are attached, form a C 3-7 carbocycle or 4-7 membered heterocycle; each R6is independently H, D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy, or two R6on adjacent atoms together with the atoms to which they are attached form a C 3-7 carbocycle, 4-7 membered heterocycle, phenyl ring, or 5-6 membered heteroaromatic ring.

29. The compound according to any one of claims 1-28, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U1 and U2 are independently selected from the following formula (U C1 ) or formula (U D1 ): in, Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2; Each W is independently a chemical bond, NH, O, C(O)NH, NHC(O), CH2 or CD2; Each Q2 is independently either N or CH; Each P1 is independently either N or CR6; each R3is independently H or C 1-6 alkyl; q can be 0, 1, 2, 3, 4, or 5; each R4is independently D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy, or two R4on the same atom or two R4on adjacent atoms, together with the atom(s) to which they are attached, form a C 3-7 carbocycle or 4-7 membered heterocycle; p is 0, 1, or 2; each R6is independently H, D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy, or two R6on adjacent atoms together with the atoms to which they are attached form a C 3-7 carbocycle, 4-7 membered heterocycle, phenyl ring, or 5-6 membered heteroaromatic ring.

30. The compound according to any one of claims 1-29, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U1 and U2 are independently defined by the following formula (U C1 ) or formula (U D1 ): in, Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2; Each W is independently a chemical bond, NH, O, C(O)NH, NHC(O), CH2 or CD2; Each Q2 is independently either N or CH; Each P1 is independently either N or CR6; Each R3 is independently H or methyl; p is 0, 1, or 2; q is 0, 1, or 2; each R4is independently D, halo, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy, or two R4on the same atom or two R4on adjacent atoms, together with the atom(s) to which they are attached, form a C 3-7 carbocycle or 4-7 membered heterocycle; Each R6 is independently H, D, or halogen.

31. The compound according to any one of claims 1-30, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U1 and U2 are independently defined by the following formula (U C2 ) or formula (U D2 ): in, Each W is independently a chemical bond, NH, C(O)NH or NHC(O); Each Q2 is independently either N or CH; Each P1 is independently either N or CR6; p is 0, 1, or 2; Each R6 is independently H, D, or halogen.

32. The compound according to any one of claims 1-31, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U1 and U2 are independently selected from the following formula (U E ): in, It can be a single bond or a double bond; Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2; Each Q2 is independently either N or CH; Each P1, P2, P3, and P4 is independently N or CR6; P5 and P6 are either N or C; H1 is N, C, or CR7; H2 and H3 are independently N, O, S, NR7, CR7, C(R7)2 or C(O); R3is H or C 1-6 alkyl; q can be 0, 1, 2, 3, 4, or 5; d is 0 or 1; each R4is independently D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, or two R4on the same atom or two R4on adjacent atoms, together with the atom(s) to which they are attached, form a C 3-7 carbocycle or 4-7 membered heterocycle; each R6is independently H, D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy, or two R6on adjacent atoms together with the atoms to which they are attached form a C 3-7 carbocycle, 4-7 membered heterocycle, phenyl ring, or 5-6 membered heteroaromatic ring; each R7is independently H, D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclyl, or two R7on the same atom or two R7on adjacent atoms, together with the atom(s) to which they are attached, form a C 3-7 carbocyclic ring, 4-7 membered heterocyclic ring, phenyl ring, or 5-6 membered heteroaromatic ring.

33. The compound according to any one of claims 1-32, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U1 and U2 are independently selected from the following formula (U E1 ), formula (U E2 ), formula (U E3 ), formula (U E4 ), formula (U E5 ), formula (U E6 ), formula (U E7 ), formula (U E15 ) or formula (U E16 ): in, Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2; Each Q2 is independently either N or CH; Each P1, P2, P3, and P4 is independently N or CR6; each R3is independently H or C 1-6 alkyl; q can be 0, 1, 2, 3, 4, or 5; d is 0 or 1; each R4is independently D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, or two R4on the same atom or two R4on adjacent atoms, together with the atom(s) to which they are attached, form a C 3-7 carbocycle or 4-7 membered heterocycle; each R6is independently H, D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy, or two R6on adjacent atoms together with the atoms to which they are attached form a C 3-7 carbocycle, 4-7 membered heterocycle, phenyl ring, or 5-6 membered heteroaromatic ring; each R7is independently H, D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclyl.

34. The compound according to any one of claims 1-33, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U1 and U2 are independently selected from the following formula (U E1 ), formula (U E2 ), formula (U E3 ), formula (U E4 ), formula (U E5 ), formula (U E6 ), formula (U E7 ), formula (U E15 ) or formula (U E16 ): in, Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2; Each Q2 is independently either N or CH; Each P1, P2, P3, and P4 is independently N or CR6; Each R3 is independently H or methyl; q is 0, 1, or 2; each R4is independently D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, or two R4on the same atom or two R4on adjacent atoms, together with the atom(s) to which they are attached, form a C 3-7 carbocycle or 4-7 membered heterocycle; Each R6 is independently H, D, or halogen; each R7is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclyl.

35. The compound according to any one of claims 1-34, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U1 and U2 are independently selected from the following formula (U E8 ), formula (U E9 ), formula (U E10 ), formula (U E11 ), formula (U E12 ), formula (U E13 ), formula (U E14 ), formula (U E17 ) or formula (U E18 ): in, Each Q2 is independently either N or CH; p is 0, 1, or 2; Each R6 is independently either D or halogen; each R7is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclyl.

36. The compound according to any one of claims 1-35, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U1 and U2 are independently selected from the following formula ((U F ): in, V represents a chemical bond, such as C(O), NH, O, S, S(O)2, CH2, or CD2; Each Q3 is independently either N or CR5; Each P1, P2, and P3 is independently N or CR6; R3is H or C 1-6 alkyl; q can be 0, 1, 2, 3, 4, or 5; d is 0 or 1; each R4is independently D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, or two R4on the same atom or two R4on adjacent atoms, together with the atom(s) to which they are attached, form a C 3-7 carbocycle or 4-7 membered heterocycle; each R5is independently H, D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; each R6is independently H, D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy, or two R6on adjacent atoms together with the atoms to which they are attached form a C 3-7 carbocycle, 4-7 membered heterocycle, phenyl ring, or 5-6 membered heteroaromatic ring.

37. The compound according to any one of claims 1-36, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U1 and U2 are independently selected from the following formula ((U F1 ): in, V represents a chemical bond, such as C(O), NH, O, S, S(O)2, CH2, or CD2; Each Q3 is independently either N or CR5; R3 is H or methyl; p is 0, 1, or 2; q is 0, 1, or 2; each R4is independently D, halo, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, or two R4on the same atom or two R4on adjacent atoms, together with the atom(s) to which they are attached, form a C 3-7 carbocycle or 4-7 membered heterocycle; Each R5 is independently H, D, or halogen; Each R6 is independently either D or halogen.

38. The compound according to any one of claims 1-37, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U1 and U2 are independently selected from the following formula ((U F2 ): in, Each Q3 is independently either N or CR5; Each R5 is independently H, D, or halogen; p is 0, 1, or 2; Each R6 is independently either D or halogen.

39. The compound according to any one of claims 1-38, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U1 and U2 are independently selected from the following formula (U G ): in, V represents a chemical bond, such as C(O), NH, O, S, S(O)2, CH2, or CD2; Each P1, P2, P3, and P4 is independently N or CR6; each R6is independently H, D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy, or two R6on adjacent atoms together with the atoms to which they are attached form a C 3-7 carbocycle, 4-7 membered heterocycle, phenyl ring, or 5-6 membered heteroaromatic ring.

40. The compound according to any one of claims 1-39, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U1 and U2 are independently selected from the following formula (U G1 ): in, V represents a chemical bond, such as C(O), NH, O, S, S(O)2, CH2, or CD2; p is 0, 1, or 2; Each R6 is independently either D or halogen.

41. The compound according to any one of claims 1-40, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U1 and U2 are independently selected from the following formula (U G2 ):

42. The compound according to any one of claims 1-41, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U2 is the following formula (U H ) or formula (U J ): in, Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2; Each P1, P2, P3, and P4 is independently N or CR6; each R3is independently H or C 1-6 alkyl; q can be 0, 1, 2, 3, 4, or 5; d is 0 or 1; each R4is independently D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, or two R4on the same atom or two R4on adjacent atoms, together with the atom(s) to which they are attached, form a C 3-7 carbocycle or 4-7 membered heterocycle; each R6is independently H, D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy, or two R6on adjacent atoms together with the atoms to which they are attached form a C 3-7 carbocycle, 4-7 membered heterocycle, phenyl ring, or 5-6 membered heteroaromatic ring.

43. The compound according to any one of claims 1-42, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U2 is the following formula (U H1 ) or formula (U J1 ): in, Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2; Each P1 is independently either N or CR6; each R3is independently H or C 1-6 alkyl; q can be 0, 1, 2, 3, 4, or 5; each R4is independently D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, or two R4on the same atom or two R4on adjacent atoms, together with the atom(s) to which they are attached, form a C 3-7 carbocycle or 4-7 membered heterocycle; p is 0, 1, or 2; each R6is independently H, D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy, or two R6on adjacent atoms together with the atoms to which they are attached form a C 3-7 carbocycle, 4-7 membered heterocycle, phenyl ring, or 5-6 membered heteroaromatic ring.

44. The compound according to any one of claims 1-43, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U2 is the following formula (U H1 ) and formula (U J1 ): in, Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2; Each P1 is independently either N or CR6; Each R3 is independently H or methyl; p is 0, 1, or 2; q is 0, 1, or 2; each R4is independently D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy, or two R4on the same atom or two R4on adjacent atoms, together with the atom(s) to which they are attached, form a C 3-7 carbocycle or 4-7 membered heterocycle; Each R6 is independently H, D, or halogen.

45. The compound according to any one of claims 1-44, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U2 is the following formula (U H2 ) or formula (U J2 ): in, Each P1 is independently either N or CR6; p is 0, 1, or 2; Each R6 is independently H, D, or halogen.

46. ​​The compound according to any one of claims 1-23, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U1 and U2 are independently selected from the following formula (U A1 ), formula (U B1 ), formula (U C1 ), formula (U D1 ), formula (U E1 ), formula (U E2 ), formula (U E3 ), formula (U E4 ), formula (U E5 ), formula (U E6 ), formula (U E7 ), formula (U E15 ), formula (U E16 ), formula (U F1 ) or formula (U G1 ): in, Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2; Each W is independently a chemical bond, NH, O, C(O)NH, NHC(O), CH2 or CD2; Each Q1 is independently C(O) or C(R5)2; Each Q2 is independently either N or CH; Each Q3 is independently either N or CR5; Each P1, P2, P3, and P4 is independently N or CR6; P5 and P6 are either N or C; each R3is independently H or C 1-6 alkyl; p is 0, 1, or 2; q can be 0, 1, 2, 3, 4, or 5; d is 0 or 1; each R4is independently D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, or two R4on the same atom or two R4on adjacent atoms, together with the atom(s) to which they are attached, form a C 3-7 carbocycle or 4-7 membered heterocycle; each R5is independently H, D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy, or two R5on the same atom together with the atom to which they are attached form a C 3-7 carbocycle or 4-7 membered heterocycle; each R6is independently H, D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy, or two R6on adjacent atoms together with the atoms to which they are attached form a C 3-7 carbocycle, 4-7 membered heterocycle, phenyl ring, or 5-6 membered heteroaromatic ring; each R7is independently H, D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclyl, or two R7on the same atom or two R7on adjacent atoms, together with the atom(s) to which they are attached, form a C 3-7 carbocyclic ring, 4-7 membered heterocyclic ring, phenyl ring, or 5-6 membered heteroaromatic ring.

47. The compound according to any one of claims 1-23, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U1 and U2 are independently selected from the following formula (U A1 ), formula (U B1 ), formula (U C1 ), formula (U D1 ), formula (U E1 ), formula (U E2 ), formula (U E3 ), formula (U E4 ), formula (U E5 ), formula (U E6 ), formula (U E7 ), formula (U E15 ), formula (U E16 ), formula (U F1 ) or formula (U G1 ): in, Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2; Each W is independently a chemical bond, NH, O, C(O)NH, NHC(O), CH2 or CD2; Each Q1 is independently C(O) or C(R5)2; Each Q2 is independently either N or CH; Each Q3 is independently either N or CR5; Each P1, P2, P3, and P4 is independently N or CR6; Each R3 is independently H or methyl; p is 0 or 1; q is 0, 1, or 2; each R4is independently D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, or two R4on the same atom or two R4on adjacent atoms, together with the atom(s) to which they are attached, form a C 3-7 carbocycle or 4-7 membered heterocycle; Each R5 is independently H, D, or halogen; Each R6 is independently H, D, or halogen; each R7is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclyl.

48. The compound according to any one of claims 1-23, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U1 and U2 are independently selected from the following formula (U A1 ), formula (U B1 ), formula (U D1 ), formula (U E1 ), formula (U E5 ), formula (U E7 ), formula (U E15 ), formula (U E16 ), or formula (U) G1 ): in, Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2; Each W is independently a chemical bond, NH, O, C(O)NH, NHC(O), CH2 or CD2; Each Q1 is independently C(O) or C(R5)2; Each Q2 is independently either N or CH; Each P1, P2, and P3 is independently N or CR6; Each R3 is independently H or methyl; p is 0, 1, or 2; q is 0, 1, or 2; each R4is independently D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy, or two R4on the same atom or two R4on adjacent atoms, together with the atom(s) to which they are attached, form a C 3-7 carbocycle or 4-7 membered heterocycle; Each R5 is independently H, D, or halogen; Each R6 is independently H, D, or halogen; each R7is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclyl.

49. The compound according to any one of claims 1-23, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U1 and U2 are independently selected from the following formula (U A2 ), formula (U B2 ), formula (U C2 ), formula (U D2 ), formula (U E8 ), formula (U E9 ), formula (U E10 ), formula (U E11 ), formula (U E12 ), formula (U E13 ), formula (U E14 ), formula (U E17 ), formula (U E18 ), formula (U F2 ) or formula (U G2 ): in, Each W is independently a chemical bond, NH, C(O)NH or NHC(O); Each Q1 is independently C(O) or CH2; Each Q2 is independently either N or CH; Each Q3 is independently either N or CR5; Each P1 is independently either N or CR6; Each R5 is independently H, D, or halogen; p is 0, 1, or 2; Each R6 is independently H, D, or halogen; each R7is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclyl.

50. The compound according to any one of claims 1-23, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U1 and U2 are independently selected from the following formula (U A2 ), formula (U B2 ), formula (U D2 ), formula (U E8 ), formula (U E12 ), formula (U E14 ), formula (U E17 ), formula (U E18 ) or formula (U G2 ): in, Each W is independently a chemical bond, NH, C(O)NH or NHC(O); Each Q1 is independently C(O) or CH2; Each Q2 is independently either N or CH; Each P1 is independently either N or CR6; p is 0, 1, 2 or 3; Each R6 is independently H, D, or halogen; each R7is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclyl.

51. The compound according to any one of claims 1-23, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U2 is selected from the following formula (U A1 ), formula (U B1 ), formula (U F1 ), formula (U G1 ), formula (U H1 ) or formula (U J1 ): in, Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2; Each Q1 is independently C(O) or C(R5)2; Each Q3 is independently either N or CR5; Each P1 is independently either N or CR6; each R3is independently H or C 1-6 alkyl; p is 0, 1, or 2; q can be 0, 1, 2, 3, 4, or 5; each R4is independently D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, or two R4on the same atom or two R4on adjacent atoms, together with the atom(s) to which they are attached, form a C 3-7 carbocycle or 4-7 membered heterocycle; each R5is independently H, D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy, or two R5on the same atom together with the atom to which they are attached form a C 3-7 carbocycle or 4-7 membered heterocycle; Each R6 is independently H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups, or two R6 atoms on adjacent atoms together with the atoms they are attached to, form C. 3-7 Carbon ring, 4-7 membered heterocyclic ring, benzene ring or 5-6 membered heteroaromatic ring.

52. The compound according to any one of claims 1-23, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U2 is selected from the following formula (U A1 ), formula (U B1 ), formula (U F1 ), formula (U G1 ), formula (U H1 ) or formula (U J1 ): in, Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2; Each Q1 is independently C(O) or C(R5)2; Each Q3 is independently either N or CR5; Each P1 is independently either N or CR6; Each R3 is independently H or methyl; p is 0, 1, or 2; q is 0, 1, or 2; Each R4 is independently D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups, or two R4 atoms on the same atom or two R4 atoms on adjacent atoms, together with the atoms they are attached to, form C. 3-7 Carbon rings or 4-7 membered heterocycles; R5 is H, D, or a halogen; Each R6 is independently H, D, or halogen.

53. The compound according to any one of claims 1-23, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U2 is selected from the following formula (U A1 ), formula (U B1 ), formula (U G1 ), formula (U H1 ) or formula (U J1 ): in, Each V is independently a chemical bond, C(O), NH, O, S, S(O)2, CH2 or CD2; Each Q1 is independently C(O) or C(R5)2; Each P1 is independently either N or CR6; Each R3 is independently H or methyl; p is 0, 1, or 2; q is 0, 1, or 2; Each R4 is independently D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy groups, or two R4 atoms on the same atom or two R4 atoms on adjacent atoms, together with the atoms they are attached to, form C. 3-7 Carbon rings or 4-7 membered heterocycles; Each R5 is independently H, D, or halogen; Each R6 is independently H, D, or halogen; Each R7 is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups.

54. The compound according to any one of claims 1-23, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U2 is selected from the following formula (U A2 ), formula (U B2 ), formula (U F2 ), formula (U G2 ) formula (U H2 ) and formula (U J2 ): in, Each Q1 is independently C(O) or CH2; Each Q3 is independently either N or CR5; Each P1 is independently either N or CR6; Each R5 is independently H, D, or halogen; p is 0, 1, or 2; Each R6 is independently H, D, or halogen.

55. The compound according to any one of claims 1-23, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U2 is selected from the following formula (U A2 ), formula (U B2 ), formula (U G2 ) formula (U H2 ) and formula (U J2 ): in, Each Q1 is independently C(O) or CH2; Each P1 is independently either N or CR6; p is 0, 1, or 2; Each R6 is independently H, D, or halogen.

56. The compound according to claim 2, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein it is a compound of formula (IIIA) or formula (IIIB), in, X is either O or NH; R A1 and R A2 Independently, it can be H, D, halogen, -OH, -CN, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; R B1 For H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; R1 and R2 are independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups, where R1 and R2 together with the N atom to which they are attached form a 4-7 membered monocyclic heterocycle, a 6-10 membered fused heterocycle, a 6-10 membered bridged heterocycle, or a 6-9 membered spirocyclic heterocycle; wherein the above groups are optionally surrounded by one or more atoms selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups; i is 0 or 1; L1 is a divalent group selected from a benzene ring or a 5-6 membered heteroaromatic ring; wherein the above group is optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups; L2 is a divalent group selected from 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered fused carbon rings, 6-10 membered fused heterocyclic rings, 6-10 membered bridged carbon rings, 6-10 membered bridged heterocyclic rings, 6-9 membered spirocyclic carbon rings, or 6-9 membered spirocyclic heterocyclic rings; wherein the above groups are optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups; L4 is a divalent group selected from 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered fused carbon rings, 6-10 membered fused heterocyclic rings, 6-10 membered bridged carbon rings, 6-10 membered bridged heterocyclic rings, 6-9 membered spirocyclic carbon rings, or 6-9 membered spirocyclic heterocyclic rings; wherein the above groups are optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups; U1 is selected from the following formula (U A1 ), formula (U B1 ), formula (U D1 ) or formula (U E1 ): U2 is selected from the following formula (U A1 ), formula (U B1 ), formula (U H1 ) or formula (U J1 ): in, Each V is an independent chemical bond; Each W is independently a chemical bond, NH, O, C(O)NH, NHC(O), CH2 or CD2; Each Q1 is independently C(O) or C(R5)2; Each Q2 is independently either N or CH; Each P1, P2, and P3 is independently N or CR6; Each R3 is independently H or methyl; p is 0, 1, or 2; q is 0, 1, or 2; Each R4 is independently D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups, or two R4 atoms on the same atom or two R4 atoms on adjacent atoms, together with the atoms they are attached to, form C. 3-7 Carbon rings or 4-7 membered heterocycles; Each R5 is independently H, D, or halogen; Each R6 is independently H, D, or halogen; Each R7 is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups.

57. The compound according to claim 56, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, X is either O or NH; R A1 and R A2 Independently H, D, halogen, -CN, methyl, halomethyl, methoxy or halomethoxy; R B1 H, D, halogen, -CN, methyl, halomethyl, methoxy or halomethoxy; R1 and R2 are independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups, or R1 and R2 together with the N atom to which they are attached to form a 4-7 membered monocyclic heterocycle, a 6-10 membered fused heterocycle, a 6-10 membered bridged heterocycle, or a 6-9 membered spirocyclic heterocycle; wherein the above groups are optionally surrounded by one or more atoms selected from D, halogen, -OH, -CN, C. 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups; i is 0 or 1; L1 is a divalent group selected from a benzene ring or a 5-6 membered heteroaromatic ring having 1 or 2 N atoms, optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups; L2 is a divalent group selected from 4-7 membered monocyclic heterocycles, 6-10 membered fused heterocycles, 6-10 membered bridged heterocycles, or 6-9 membered spirocyclic heterocycles; wherein the above groups are optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups; L4 is a divalent group selected from 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered bridged carbon rings, or 6-10 membered bridged heterocyclic rings; wherein the above group is optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups; U1 is selected from the following formula (U A2 ), formula (U B2 ), formula (U D2 ) or formula (U E8 ): U2 is selected from the following formula (U A2 ), formula (U B2 ), formula (U H2 ) and formula (U J2 ): in, Each W is independently a chemical bond, NH, C(O)NH or NHC(O); Each Q1 is independently C(O) or CH2; Each Q2 is independently either N or CH; P1 is either N or CR6; p is 0, 1, 2 or 3; Each R6 is independently H, D, or halogen; Each R7 is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups.

58. The compound according to claim 55 or 56, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R1 is methyl, and R2 is ethyl.

59. The compound according to claim 55 or 56, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R1 and R2, together with the N atom they are attached to, form the following groups:

60. The compound according to claim 55 or 56, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R1 and R2, together with the N atoms they are attached to, form the following ring:

61. The compound according to claim 55 or 56, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R1 and R2, together with the N atoms they are attached to, form 62. The compound according to any one of claims 55-61, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L2 is The above-mentioned groups are optionally surrounded by one or more elements selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substitution of halogenated alkoxy groups.

63. The compound according to any one of claims 55-61, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L2 is Preferably, L2 is More preferably, L2 is 64. The compound according to any one of claims 55-63, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L4 is The above-mentioned groups are optionally surrounded by one or more elements selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substitution of halogenated alkoxy groups.

65. The compound according to any one of claims 55-63, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L4 is The aforementioned groups are optionally substituted by one or more groups selected from D, halogens, or -OH.

66. The compound according to any one of claims 55-63, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L4 is 67. The compound according to any one of claims 55-66, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, i is 1.

68. The compound according to any one of claims 55-67, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R A1 and R A2 Independently H, D, halogen, or -CN; R B1 It can be H, D, halogen, or -CN.

69. The compound according to any one of claims 55-68, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, X is O, R A1 For CN, R A2 For F, R B1 For H.

70. The compound according to claim 69, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L1 is a divalent group of the benzene ring.

71. The compound according to any one of claims 55-68, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, X is NH, R A1 For Cl, R A2 For F, R B1 For H.

72. The compound according to claim 71, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L1 is a divalent group of pyrazole.

73. The compound according to any one of claims 55-68, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U1 is 74. The compound according to claim 70 or 72, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U1 is 75. The compound according to any one of claims 55-68, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U2 is 76. The compound according to claim 2, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein it is a compound of formula (VIA) or (VIB). in, X is either O or NH; R A1 and R A2 Independently, it can be H, D, halogen, -OH, -CN, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; R B1 For H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; R1 and R2 are independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups, where R1 and R2 together with the N atom to which they are attached form a 4-7 membered monocyclic heterocycle, a 6-10 membered fused heterocycle, a 6-10 membered bridged heterocycle, or a 6-9 membered spirocyclic heterocycle; wherein the above groups are optionally surrounded by one or more atoms selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups; L1 is a divalent group selected from a benzene ring or a 5-6 membered heteroaromatic ring; wherein the above group is optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups; L4 is a divalent group selected from 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered fused carbon rings, 6-10 membered fused heterocyclic rings, 6-10 membered bridged carbon rings, 6-10 membered bridged heterocyclic rings, 6-9 membered spirocyclic carbon rings, or 6-9 membered spirocyclic heterocyclic rings; wherein the above groups are optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substitution of halogenated alkoxy groups.

77. The compound according to claim 76, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, in, X is either O or NH; R A1 and R A2 Independently H, D, halogen, -CN, methyl, halomethyl, methoxy or halomethoxy; R B1 H, D, halogen, -CN, methyl, halomethyl, methoxy or halomethoxy; R1 and R2 are independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups, or R1 and R2 together with the N atom to which they are attached to form a 4-7 membered monocyclic heterocycle, a 6-10 membered fused heterocycle, a 6-10 membered bridged heterocycle, or a 6-9 membered spirocyclic heterocycle; wherein the above groups are optionally surrounded by one or more atoms selected from D, halogen, -OH, -CN, C. 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups; L1 is a divalent group selected from a benzene ring or a 5-6 membered heteroaromatic ring having 1 or 2 N atoms, optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups; L4 is a divalent group selected from 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered bridged carbon rings, or 6-10 membered bridged heterocyclic rings; wherein the above group is optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy and C 1-6 Substitution of halogenated alkoxy groups.

78. The compound according to claim 76 or 77, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R1 is methyl, and R2 is ethyl.

79. The compound according to claim 76 or 77, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R1 and R2, together with the N atoms they are attached to, form the following ring:

80. The compound according to claim 76 or 77, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R1 and R2, together with the N atoms they are attached to, form the following ring:

81. The compound according to claim 76 or 77, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R1 and R2, together with the N atoms they are attached to, form 82. The compound according to any one of claims 76-81, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L4 is The above-mentioned groups are optionally surrounded by one or more elements selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substitution of halogenated alkoxy groups.

83. The compound according to any one of claims 76-81, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L4 is The aforementioned groups are optionally substituted by one or more groups selected from D, halogens, or -OH.

84. The compound according to any one of claims 76-81, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L4 is 85. The compound according to any one of claims 76-84, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R A1 and R A2 Independently H, D, halogen, or -CN; R B1 It can be H, D, halogen, or -CN.

86. The compound according to any one of claims 76-85, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, X is O, R A1 For CN, R A2 For F, R B1 For H.

87. The compound according to any one of claims 73-82, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, X is NH, R A1 For Cl, R A2 For F, R B1 For H.

88. The compound according to claim 2, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the compound is of formula (VA). in, R A1 and R A2 Independently, it can be H, D, halogen, -OH, -CN, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; R B1 For H, D, halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; R1 and R2, together with the N atom they are attached to, form a 4-7 membered monocyclic heterocycle, a 6-10 membered fused heterocycle, a 6-10 membered bridged heterocycle, or a 6-9 membered spirocyclic heterocycle; wherein the above groups are optionally surrounded by one or more atoms selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups; i is 0 or 1; L1 is a divalent group selected from a 5-6 membered heteroaromatic ring having 1 or 2 N atoms, optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups; L2 is a divalent group selected from 4-7 membered monocyclic heterocycles, 6-10 membered fused heterocycles, 6-10 membered bridged heterocycles, or 6-9 membered spirocyclic heterocycles; wherein the above groups are optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups; L4 is a divalent group selected from 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered bridged carbon rings, or 6-10 membered bridged heterocyclic rings; wherein the above group is optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups; U1 is selected from the following formula (U A1 ), formula (U B1 ), formula (U D1 ), formula (U E1 ), formula (U E2 ), formula (U E3 ), formula (U E4 ), formula (U E5 ), formula (U E6 ), formula (U E7 ), formula (U E15 ) or formula (U E16 ): in, Each V is an independent chemical bond; Each W is independently a chemical bond, NH, O, C(O)NH, NHC(O), CH2 or CD2; Each Q1 is independently C(O) or C(R5)2; Each Q2 is independently either N or CH; Each P1, P2, and P3 is independently N or CR6; Each R3 is independently H or methyl; p is 0, 1, or 2; q is 0, 1, or 2; Each R4 is independently D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups, or two R4 atoms on the same atom or two R4 atoms on adjacent atoms, together with the atoms they are attached to, form C. 3-7 Carbon rings or 4-7 membered heterocycles; Each R5 is independently H, D, or halogen; Each R6 is independently H, D, or halogen; Each R7 is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups.

89. The compound according to claim 88, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U1 is selected from the following formula (U A1 ), formula (U B1 ), formula (U D1 ) or formula (U E1 ).

90. The compound according to claim 88, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R A1 and R A2 Independently H, D, halogen, -CN, methyl, halomethyl, methoxy or halomethoxy; R B1 H, D, halogen, -CN, methyl, halomethyl, methoxy or halomethoxy; R1 and R2, together with the N atom they are attached to, form a 4-7 membered monocyclic heterocycle, a 6-10 membered fused heterocycle, a 6-10 membered bridged heterocycle, or a 6-9 membered spirocyclic heterocycle; wherein the above groups are optionally surrounded by one or more atoms selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups; i is 0 or 1; L1 is a divalent group selected from a 5-6 membered heteroaromatic ring having 1 or 2 N atoms, optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups; L2 is a divalent group selected from 4-7 membered monocyclic heterocycles, 6-10 membered fused heterocycles, 6-10 membered bridged heterocycles, or 6-9 membered spirocyclic heterocycles; wherein the above groups are optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups; L4 is a divalent group selected from 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered bridged carbon rings, or 6-10 membered bridged heterocyclic rings; wherein the above group is optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups; U1 is selected from the following formula (U A2 ), formula (U B2 ), (U D2 ), formula (U E8 ), formula (U E9 ), formula (U E10 ), formula (U E11 ), formula (U E12 ), formula (U E13 ), formula (U E14 ), formula (U E17 ) or formula (U E18 ): in, Each W is independently a chemical bond, NH, C(O)NH or NHC(O); Each Q1 is independently C(O) or CH2; Each Q2 is independently either N or CH; P1 is either N or CR6; p is 0, 1, 2 or 3; Each R6 is independently H, D, or halogen; Each R7 is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups.

91. The compound according to claim 90, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U1 is selected from the following formula (U A2 ), formula (U B2 ), formula (U D2 ) or formula (U E8 ).

92. The compound according to any one of claims 88-91, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L1 is a divalent group selected from a 5-membered heteroaromatic ring having 1 or 2 N atoms, optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substitution of halogenated alkoxy groups.

93. The compound according to any one of claims 88-92, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L2 is The above-mentioned groups are optionally surrounded by one or more elements selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substitution of halogenated alkoxy groups.

94. The compound according to claim 90, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein it is a compound of formula (VA-1) or formula (VA-2). in, R A1 and R A2 Independently H, D, halogen, -CN, methyl, halomethyl, methoxy or halomethoxy; R B1 H, D, halogen, -CN, methyl, halomethyl, methoxy or halomethoxy; R1 and R2, together with the N atom they are attached to, form a 4-7 membered monocyclic heterocycle, a 6-10 membered fused heterocycle, a 6-10 membered bridged heterocycle, or a 6-9 membered spirocyclic heterocycle; wherein the above groups are optionally surrounded by one or more atoms selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups; L4 is a divalent group selected from 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered bridged carbon rings, or 6-10 membered bridged heterocyclic rings; wherein the above group is optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups; U1 is selected from the following formula (U A2 ), formula (U B2 ), (U D2 ), formula (U E8 ), formula (U E9 ), formula (U E10 ), formula (U E11 ), formula (U E12 ), formula (U E13 ), formula (U E14 ), formula (U E17 ) or formula (U E18 ): in, Each W is independently a chemical bond, NH, C(O)NH or NHC(O); Each Q1 is independently C(O) or CH2; Each Q2 is independently either N or CH; P1 is either N or CR6; p is 0, 1, or 2; Each R6 is independently H, D, or halogen; Each R7 is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups.

95. The compound according to claim 94, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U1 is selected from the following formula (U A2 ), formula (U B2 ), formula (U D2 ) or formula (U E8 ).

96. The compound according to any one of claims 88-95, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R1 and R2, together with the N atoms they are attached to, form the following ring:

97. The compound according to any one of claims 88-95, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R1 and R2, together with the N atoms they are attached to, form the following ring:

98. The compound according to any one of claims 88-95, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R1 and R2, together with the N atoms they are attached to, form 99. The compound according to any one of claims 88-98, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L4 is The above-mentioned groups are optionally surrounded by one or more elements selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substitution of halogenated alkoxy groups.

100. The compound according to any one of claims 88-99, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L4 is The aforementioned groups are optionally substituted by one or more groups selected from D, halogens, or -OH.

101. The compound according to any one of claims 88-99, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L4 is 102. The compound according to any one of claims 88-101, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R A1 and R A2 Independently H, D, halogen, or -CN; R B1 It can be H, D, halogen, or -CN.

103. The compound according to any one of claims 88-102, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R A1 For Cl, R A2 For F, R B1 For H.

104. The compound according to any one of claims 88-103, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U1 is 105. The compound according to any one of claims 88-103, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U1 is 106. The compound according to any one of claims 88-103, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U1 is selected from:

107. The compound according to claim 2, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the compound is of formula (VIA). in, R1 and R2, together with the N atom they are attached to, form a 4-7 membered monocyclic heterocycle, a 6-10 membered fused heterocycle, a 6-10 membered bridged heterocycle, or a 6-9 membered spirocyclic heterocycle; wherein the above groups are optionally surrounded by one or more atoms selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups; i is 0 or 1; L1 is a divalent group selected from a 5-6 membered heteroaromatic ring having 1 or 2 N atoms, optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups; L2 is a divalent group selected from 4-7 membered monocyclic heterocycles, 6-10 membered fused heterocycles, 6-10 membered bridged heterocycles, or 6-9 membered spirocyclic heterocycles; wherein the above groups are optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups; S2 is a chemical bond or -C(O)-; L4 is a divalent group selected from 3-6 membered monocyclic carbon rings, 4-7 membered monocyclic heterocyclic rings, 6-10 membered bridged carbon rings, or 6-10 membered bridged heterocyclic rings; wherein the above group is optionally surrounded by one or more groups selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy and C 1-6 Group substitution of halogenated alkoxy groups; U1 is selected from the following formula (U A1 ), formula (U B1 ), formula (U D1 ), formula (U E1 ), formula (U E2 ), formula (U E3 ), formula (U E4 ), formula (U E5 ), formula (U E6 ), formula (U E7 ), formula (U E15 ) or formula (U E16 ): in, Each V is an independent chemical bond; Each W is independently a chemical bond, NH, O, C(O)NH, NHC(O), CH2 or CD2; Each Q1 is independently C(O) or C(R5)2; Each Q2 is independently either N or CH; Each P1, P2, and P3 is independently N or CR6; Each R3 is independently H or methyl; p is 0, 1, or 2; q is 0, 1, or 2; Each R4 is independently D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups, or two R4 atoms on the same atom or two R4 atoms on adjacent atoms, together with the atoms they are attached to, form C. 3-7 Carbon rings or 4-7 membered heterocycles; Each R5 is independently H, D, or halogen; Each R6 is independently H, D, or halogen; Each R7 is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups.

108. The compound according to claim 107, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U1 is selected from the following formula (U A2 ), formula (U B2 ), (U D2 ), formula (U E8 ), formula (U E9 ), formula (U E10 ), formula (U E11 ), formula (U E12 ), formula (U E13 ), formula (U E14 ), formula (U E17 ) or formula (U E18 ): in, Each W is independently a chemical bond, NH, C(O)NH or NHC(O); Each Q1 is independently C(O) or CH2; Each Q2 is independently either N or CH; P1 is either N or CR6; p is 0, 1, or 2; Each R6 is independently H, D, or halogen; Each R7 is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups.

109. The compound according to claim 108, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, S2 is a chemical bond, and U1 is selected from the following formula (U A2 ), formula (U B2 ) or (U D2 ): in, Each W is independently C(O)NH or NHC(O); Each Q1 is independently C(O) or CH2; Each Q2 is independently either N or CH; P1 is either N or CR6; p is 0, 1, or 2; Each R6 is independently H, D, or halogen.

110. The compound according to claim 108, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, S2 is -C(O)-, and U1 is selected from the following (U D2 ), formula (U E8 ), formula (U E9 ), formula (U E10 ), formula (U E11 ), formula (U E12 ), formula (U E13 ), formula (U E14 ), formula (U E17 ) or formula (U E18 ): in, Each W is independently a chemical bond or NH; Each Q2 is independently either N or CH; P1 is either N or CR6; p is 0, 1, 2 or 3; Each R6 is independently H, D, or halogen; Each R7 is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups.

111. The compound according to any one of claims 107-110, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R1 and R2, together with the N atoms they are attached to, form the following ring:

112. The compound according to any one of claims 107-110, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R1 and R2, together with the N atoms they are attached to, form the following ring:

113. The compound according to any one of claims 107-110, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R1 and R2, together with the N atoms they are attached to, form 114. The compound according to any one of claims 107-113, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, i is 1, and L1 is a divalent group of the benzene ring.

115. The compound according to any one of claims 107-113, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, i is 1, and L1 is a divalent group of the pyrazole ring.

116. The compound according to any one of claims 107-113, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, i is 0.

117. The compound according to any one of claims 107-116, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L2 is The above-mentioned groups are optionally surrounded by one or more elements selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substitution of halogenated alkoxy groups.

118. The compound according to any one of claims 107-116, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L2 is Preferably, L2 is More preferably, L2 is 119. The compound according to any one of claims 107-118, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L4 is The above-mentioned groups are optionally surrounded by one or more elements selected from D, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substitution of halogenated alkoxy groups.

120. The compound according to any one of claims 107-119, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L4 is The aforementioned groups are optionally substituted by one or more groups selected from D, halogens, or -OH.

121. The compound according to any one of claims 107-119, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L4 is 122. A compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, isotopic variant, hydrate, or solvate thereof, wherein, The compounds were selected from Table 1.

123. A pharmaceutical composition comprising a compound of any one of claims 1-122, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable excipient.

124. The pharmaceutical composition according to claim 123, further comprising other therapeutic agents.

125. The pharmaceutical composition of claim 124, wherein the other therapeutic agent is another BRAF inhibitor, MEK inhibitor, immune checkpoint inhibitor, or EGFR antibody; Preferably, another BRAF inhibitor is sorafenib, vemurafenib, dabrafenib, or cannefenib; Preferably, the MEK inhibitor is trametinib or selmetinib; Preferably, the immune checkpoint inhibitor is nivolumab, pembrolizumab, simipelimab, ipilimumab, relatlimab, atezolizumab, avelumab, or durvalumab; Preferably, the EGFR antibody is cetuximab or panitumumab.

126. Use of any compound of claims 1-122, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or any pharmaceutical composition of claims 123-125 in the preparation of a medicament for treating diseases mediated by mutant BRAF. Preferably, the mutant BRAF is V600E, V600K, V600R, V600D or V600N; Preferably, the mutated BRAF is G469A, G469V, G469L, G469R, G469S, L597Q, L597R, L597S, L597V, K601E, K601N, G464E, G464V, G464R, R462I, I463S, E586K, F595L, A598V, T599I, or K301T; Preferably, the mutated BRAF is G466A, G466E, G466R, G466V, S467L, G469E, N581I, D594E, D594G, D594N, S467A, S467E, N581S, K483M, D594A, D594H, D594V, G596A, G596C, G596D, or G596R; Preferably, the mutant BRAF is G464I, N581T, L584F, E586K, G593D, G596C, S605I, S607F, N694T, E26A, V130M, L745L or D284E. Preferably, the mutated BRAF is p61-BRAF V600E; Preferably, the mutated BRAF is a BRAF V600E / NRAS Q61K double mutation.

127. A method of treating a disease mediated by a mutant BRAF in a subject, the method comprising administering to the subject a compound of any one of claims 1-122 or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or a pharmaceutical composition of any one of claims 123-125. Preferably, the mutant BRAF is V600E, V600K, V600R, V600D or V600N; Preferably, the mutated BRAF is G469A, G469V, G469L, G469R, G469S, L597Q, L597R, L597S, L597V, K601E, K601N, G464E, G464V, G464R, R462I, I463S, E586K, F595L, A598V, T599I, or K301T; Preferably, the mutated BRAF is G466A, G466E, G466R, G466V, S467L, G469E, N581I, D594E, D594G, D594N, S467A, S467E, N581S, K483M, D594A, D594H, D594V, G596A, G596C, G596D, or G596R; Preferably, the mutant BRAF is G464I, N581T, L584F, E586K, G593D, G596C, S605I, S607F, N694T, E26A, V130M, L745L or D284E. Preferably, the mutated BRAF is p61-BRAF V600E; Preferably, the mutated BRAF is a BRAF V600E / NRAS Q61K double mutation.

128. A compound of any one of claims 1-122, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of any one of claims 123-125, for the treatment of diseases mediated by mutant BRAF. Preferably, the mutant BRAF is V600E, V600K, V600R, V600D or V600N; Preferably, the mutated BRAF is G469A, G469V, G469L, G469R, G469S, L597Q, L597R, L597S, L597V, K601E, K601N, G464E, G464V, G464R, R462I, I463S, E586K, F595L, A598V, T599I, or K301T; Preferably, the mutated BRAF is G466A, G466E, G466R, G466V, S467L, G469E, N581I, D594E, D594G, D594N, S467A, S467E, N581S, K483M, D594A, D594H, D594V, G596A, G596C, G596D, or G596R; Preferably, the mutant BRAF is G464I, N581T, L584F, E586K, G593D, G596C, S605I, S607F, N694T, E26A, V130M, L745L or D284E. Preferably, the mutated BRAF is p61-BRAF V600E; Preferably, the mutated BRAF is a BRAF V600E / NRAS Q61K double mutation.

129. The use of claim 126, the method of claim 127, or the use of the compound or composition of claim 128, wherein the mutated BRAF-mediated disease is melanoma, triple-negative breast cancer, non-small cell lung cancer, colorectal cancer, microsatellite-stabilized colorectal cancer, thyroid cancer, ovarian cancer, cholangiocarcinoma, Eldheim-Chester disease, Langerhans histiocytosis, ganglioglioma, glioma, glioblastoma, piloblastic leukemia, multiple myeloma, pilocytic myxoid astrocytoma, anaplastic multiline xanthoastrocytoma, astrocytoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, pancreatic cancer, clear cell sarcoma of the chest, or salivary gland carcinoma.

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