C-kit or pdgfrα-targeted proteolysis targeting chimera compound, and composition and use thereof

Abstract

The present invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or a solvate thereof, and a pharmaceutical composition thereof and the use thereof in the treatment of c-Kit or PDGFRα-related diseases.

Description

Targeting c-kit or pdgfra protein degradation targeting chimera compounds, and compositions and uses thereof

[0001] Reference to Related Applications

[0002] This application claims priority to Chinese Patent Application No. 2024113985039, filed September 30, 2024, Chinese Patent Application No. 2024117598730, filed December 03, 2024, Chinese Patent Application No. 2025109845463, filed July 16, 2025, Chinese Patent Application No. 2025113736420, filed September 23, 2025, and incorporates the entirety of the above applications by reference as part of the specification. TECHNICAL FIELD

[0003] The present application belongs to the field of medicine, and in particular relates to protein degradation targeting chimera compounds for treating c-Kit or PDGFRa related diseases, pharmaceutical compositions containing them, and their preparation methods and uses. BACKGROUND

[0004] Receptor tyrosine kinases (RTKs) are involved in different steps of tumor development and progression. Their signaling affects cell growth, differentiation, adhesion, motility, and death. RTKs are divided into 20 subfamilies, including class III RTKs. Class III RTKs include c-Kit, Colony Stimulating Factor 1 Receptor (CSF1R), fms Like Tyrosine Kinase 3 (FLT3), and Platelet-Derived Growth Factor Receptors a / b (PDGFRa / b). These molecular receptors are membrane-bound enzymes composed of an extracellular ligand-binding domain (ED), a juxtamembrane domain (JMD), a highly conserved intracellular tyrosine kinase domain (TKD), and a C-terminal tail. In the non-activated state, class III RTKs exist as self-inhibited monomers in the cell membrane, and in some cases as preformed dimers. They are activated by dimerization of short-chain a-helical bundles of cytokines and induce signals necessary for hematopoietic cell development and homeostasis upon activation.

[0005] Under physiological conditions, RTKs prevent dysregulated proliferation and influence cell sensitivity to apoptotic signals. In cancer cells, genetic and epigenetic modifications of RTKs induce a selective advantage of variant cells, leading to rapid and uncontrolled proliferation. Oncogenic activation of RTKs is caused by mutations in the ED and activation loop or by abnormal chromosomal translocations leading to gain-of-function. Chromosomal breakpoints to RTKs result in fusion proteins. Chaperone proteins associate with the entire catalytic domain, leading to constitutive activation of the RTK portion.

[0006] c-Kit (also known as CD117) is a receptor tyrosine kinase expressed on numerous cell types. c-Kit contains a long extracellular domain, a transmembrane segment, and an intracellular portion. The ligand for c-Kit is Stem Cell Factor (SCF), which binds to the extracellular domain of c-Kit inducing receptor dimerization and activating downstream signaling pathways. Mutations in c-Kit typically occur in the DNA encoding the juxtamembrane domain (exon 11). They also occur at lower frequency in exons 7, 8, 9, 13, 14, 17, and 18. The mutations render c-Kit function independent of activation by SCF, leading to high cell division rates and possible genomic instability. Mutant c-Kit has been implicated in the pathogenesis of several disorders and conditions, including systemic mastocytosis, gastrointestinal stromal tumors (GIST), acute myeloid leukemia (AML), melanoma, and seminomas. Thus, there is a need for therapeutic agents that inhibit c-Kit, and in particular agents that inhibit mutant c-Kit.

[0007] Mutations in the ED, TM domain, JMD, and TK 2 domains were detected in c-Kit. The point mutations were primarily D419, V530, and D816, among others, except for the JMD. Insertions / deletions and internal tandem duplications (ITD) between amino acids 550-561 were also detected in this domain. Mutations in the JMD and TK domains were detected in FLT3. The mutations in the JMD were mostly ITD between amino acids 587-600. In the TK domain, only point mutations K663, N676, D835, I836, N841, Y842, among others, were reported.

[0008] PDGFR is a cell surface tyrosine kinase receptor of the Platelet-Derived Growth Factor (PDGF) family members. PDGF subunits PDGF-A and PDGF-B are important factors in regulating cell proliferation, cell differentiation, cell growth, development, and many diseases including cancer. In PDGFRa, mutations at amino acid V536 were detected in JMD. PDGFRa D842V mutations have been found in different GIST subsets, usually from the stomach. D842V mutations are known to be associated with tyrosine kinase inhibitor resistance. Therefore, there is a need for agents that target this mutation.

[0009] Proteolysis targeting chimera (PROTAC) is a targeted protein degradation technology that uses small molecule compounds to regulate protein levels. PROTAC has a different mode of action than traditional small molecule drugs and can use unique targets to send proteins to proteasomes for the purpose of chemically degrading proteins. Its core concept is to use artificial small molecule compounds to recruit a specific ubiquitin ligase and degrade the protein by ubiquitination of the target protein. This technology has better tolerance than traditional drugs in the case of target protein mutations, etc. due to the iterative mode of degradation.

[0010] PROTAC can overcome some drug resistance mechanisms faced by small molecule inhibitors, such as mutations in target proteins, upregulation of expression, changes in active sites, etc., because PROTAC does not need to tightly bind to the target protein or inhibit its enzyme activity, only needs to recruit it to the vicinity of the E3 ligase, so that it is ubiquitinated and degraded.

[0011] c-Kit and PDGFRa inhibitors are widely used in cancer treatment, but they also have some shortcomings and defects.

[0012] Many c-Kit inhibitors lack selectivity for other RTKs, which can lead to off-target effects and cause unintended side effects. Tumor cells can develop resistance to c-Kit inhibitors through mutations, etc., leading to drug failure. For example, activating mutations of the c-Kit gene (such as the D816V mutation) can make the c-Kit inhibitor imatinib lose its inhibitory effect. c-Kit is not only expressed in tumor cells, but also plays an important role in normal cells, such as the hematopoietic system and gastrointestinal function, so inhibiting c-Kit can cause gastrointestinal discomfort, anemia, and other side effects. The downstream signaling pathway of c-Kit is complex, and single inhibition of c-Kit may not completely stop tumor progression and may induce compensatory activation of other signaling pathways.

[0013] Many PDGFRa inhibitors also target other receptor tyrosine kinases, particularly vascular endothelial growth factor receptors (VEGFR), which can lead to vascular-related side effects such as hypertension and risk of bleeding. Similar to c-Kit, PDGFRa inhibitors also face the problem of drug resistance. Tumor cells can escape the effect of inhibitors through mutations of PDGFRa or activation of other growth factor pathways. PDGFRa also plays a key role in normal cell functions, particularly in angiogenesis and tissue repair, so PDGFRa inhibitors can cause cardiovascular problems, delayed wound healing, and other angiogenesis-related side effects. The use of PDGFR inhibitors alone has limited efficacy in certain tumor types, and is usually combined with other therapies to improve treatment efficacy.

[0014] PROTAC is a promising anticancer strategy that can overcome the limitations of traditional small molecule inhibitors, providing more target options and higher treatment efficiency. Currently, several drugs developed based on PROTAC technology have entered the clinical trial stage, showing certain antitumor activity. Therefore, it is necessary to further develop new PROTACs for the treatment of c-Kit or PDGFRa related diseases. SUMMARY

[0015] The present application provides a new type of c-Kit or PDGFRa protein degradation targeting chimera compound (also referred to as "protein degrader") and a composition comprising the same and uses thereof. The protein degrader provided by the present application has a novel structure, good drug efficacy, high bioavailability, is safer, can inhibit or degrade c-Kit and / or PDGFRa and its mutants, and can be used for treating diseases related to c-Kit or PDGFRa, such as tumors and the like.

[0016] To this end, the present application adopts the following technical solutions:

[0017] In one aspect, the present application relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:

[0018] wherein,

[0019] Y is selected from N or CH;

[0020] R1is selected from a divalent group of a 5 or 6-membered heteroarene or a phenyl ring; wherein the above divalent group is optionally substituted with one or more R;

[0021] each R is independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6haloalkoxy, C 3-6 cycloalkyl or 3- to 7-membered heterocycloalkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl or 3- to 7-membered heterocycloalkyl optionally substituted with one or more D, up to complete deuteriation;

[0022] R2and R3are independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6haloalkoxy, C 3-6 cycloalkyl or 3- to 7-membered heterocycloalkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl or 3- to 7-membered heterocycloalkyl optionally substituted with one or more D, up to complete deuteriation;

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

[0024] R a are independently selected from H, D, halogen, -NH2, -CN, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy optionally substituted with one or more D, up to complete deuteriation;

[0025] L is a divalent linking group;

[0026] U is a group that binds to an E3 ubiquitin ligase.

[0027] In another aspect, the present application relates to a pharmaceutical composition comprising a compound of the present application, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable excipient.

[0028] In another aspect, the present invention relates to a kit comprising a first container containing the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or pharmaceutical compositions thereof; and optionally, a second container containing other therapeutic agents; and optionally, a third container containing pharmaceutical excipients for diluting or suspending said compound and / or other therapeutic agents.

[0029] In another aspect, the present invention relates to the use of the compounds of the present invention, or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions of the present invention, or kits of the present invention in the preparation of medicaments for treating diseases associated with c-Kit or PDGFRα.

[0030] In another aspect, the present invention relates to a method for inducing the inhibition and / or degradation of c-Kit or PDGFRα in cells, the method comprising contacting cells with a compound of the present invention, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition of the present invention, or a kit of the present invention. In a particular embodiment, the contact may be performed in vitro or in vivo.

[0031] In another aspect, the present invention relates to a method for treating a disease associated with c-Kit or PDGFRα in a subject, the method comprising administering to the subject a compound of the present invention, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of the present invention.

[0032] In another aspect, the present invention relates to the use of the compounds of the present invention, or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions of the present invention, or kits of the present invention, in the treatment of diseases associated with c-Kit or PDGFRα.

[0033] In specific embodiments, the c-Kit involved in this invention may or may not have a mutation; in specific embodiments, the PDGFRα involved in this invention may or may not have a mutation.

[0034] In particular embodiments, c-Kit has a mutation in exon 9. In particular embodiments, c-Kit has a mutation in exon 11. In particular embodiments, c-Kit has a mutation in exon 13. In particular embodiments, c-Kit has a mutation in exon 14. In particular embodiments, c-Kit has a mutation in exon 17. In particular embodiments, c-Kit has at least one mutation selected from insAY502-503, delWK557-558, V560G, V654A, T670I, or D816V.

[0035] In particular embodiments, PDGFRa has a mutation in exon 14. In particular embodiments, PDGFRa has a mutation in exon 15. In particular embodiments, PDGFRa has a mutation in exon 18. In particular embodiments, PDGFRa has at least one mutation selected from V658A, T674I, G680R, or D824V.

[0036] In particular embodiments, the disease associated with c-Kit or PDGFRa is systemic mastocytosis, gastrointestinal stromal tumor, acute myeloid leukemia, melanoma, seminoma, intracranial germinoma, mediastinal B-cell lymphoma, Ewing's sarcoma, diffuse large B-cell lymphoma, dysgerminoma, myelodysplastic syndrome, nasal NK / T-cell lymphoma, chronic myelomonocytic leukemia, and brain cancer.

[0037] Other objects and advantages of the application will become apparent to those skilled in the art from the following detailed description, examples, and claims.

[0038] Definitions

[0039] Chemical Definitions

[0040] The definitions of specific functional groups and chemical terms are described in more detail below.

[0041] When a range of values is listed, each value and sub-range therein is intended. For example, "C 1-6 "alkyl" includes C1, C2, C3, C4, C5, C6, C 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 , C4-5 and C 5-6 alkyl.

[0042] "C 1-6 "alkyl" refers to a straight or branched chain saturated hydrocarbon group having from 1 to 6 carbon atoms, also referred to herein as "lower alkyl." In some embodiments, C 1-4 alkyl is particularly preferred. Examples of alkyl groups include, but are not limited to, methyl (Ci), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), t-butyl (C4), sec-butyl (C4), i-butyl (C4), n-pentyl (C5), 3-pentyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), t-amyl (C5), and n-hexyl (C6). Each of the alkyl groups is independently optionally substituted, e.g., with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, whether or not modified by "substituted," with appropriate substituents as defined below.

[0043] "C 2-6 "alkenyl" refers to a straight or branched chain hydrocarbon group having from 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 2-butenyl) or terminal (e.g., in 1-butenyl). In some embodiments, C 2-4 alkenyl is particularly preferred. Examples of alkenyl groups include, but are not limited to, ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Each of the alkenyl groups is independently optionally substituted, e.g., with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, whether or not modified by "substituted," with appropriate substituents as defined below.

[0044] "C 2-6 "alkynyl" refers to a straight or branched chain hydrocarbon group having from 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 2-4Alkynyl groups are particularly preferred. In some embodiments, the alkynyl group does not contain any double bonds. The one or more carbon triple bonds can be internal (for example, in 2-butynyl) or terminal (for example, 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), pentynyl (C5), hexynyl (C6), and the like. Each of the alkynyl groups is independently optionally substituted, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, as appropriate, with suitable substituents defined below, regardless of whether the alkynyl group is modified with "substituted" before it.

[0045] "C 1-6 Alkoxy" refers to the group -OR, where R is a substituted or unsubstituted C 1-6 alkyl group. In some embodiments, the C 1-4 Alkoxy groups are particularly preferred. Specific alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, t-butyloxy, sec-butyloxy, n-pentyloxy, n-hexyloxy, and 1,2-dimethylbutoxy.

[0046] "C 1-6 Alkylene" refers to a divalent group formed by removing a hydrogen from each of two C 1-6 alkyl groups, and can be a substituted or unsubstituted alkylene group. In some embodiments, the C 1-4 Alkylene groups are particularly preferred. Unsubstituted alkylene groups include, but are not limited to: methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylene groups, for example, alkylene groups substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- 2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0047] "C 0-6 Alkylene" includes a chemical bond and C 1-6 alkylene groups as defined above.

[0048] "Halo" or "halogen" means fluoro (F), chloro (CI), bromo (Br), and iodo (I). In some embodiments, the halo group is F, CI, or Br. In some embodiments, the halo group is F or CI. In some embodiments, the halo group is F.

[0049] Thus, "C 1-6 "Haloalkyl" and "C 1-6 "Haloalkoxy" means an "alkoxy" group as described above, substituted with one or more halogen groups. In some embodiments, C 1-6 "Haloalkyl" and "C 1-6 "Haloalkoxy" means an "alkoxy" group as described above, substituted with one or more halogen groups. In some embodiments, C 1-4 "Haloalkyl" and "C 1- "Haloalkyl" and "C 1-4 "Haloalkyl" and "C 1-2 "Haloalkyl" and "C

[0050] "C 3-10 "Cycloalkyl" means a non-aromatic cyclic hydrocarbon group having from three to ten ring carbon atoms and zero heteroatoms. In some embodiments, C 3-7 "Cycloalkyl" means a non-aromatic cyclic hydrocarbon group having from three to ten ring carbon atoms and zero heteroatoms. In some embodiments, C 3-6 "Cycloalkyl" means a non-aromatic cyclic hydrocarbon group having from three to ten ring carbon atoms and zero heteroatoms. In some embodiments, C 5-6 "Cycloalkyl" means a non-aromatic cyclic hydrocarbon group having from three to ten ring carbon atoms and zero heteroatoms. In some embodiments, C 10 Cycloalkyl" means a non-aromatic cyclic hydrocarbon group having from three to ten ring carbon atoms and zero heteroatoms. In some embodiments, C 10 Cycloalkyl" means a non-aromatic cyclic hydrocarbon group having from three to ten ring carbon atoms and zero heteroatoms. In some embodiments, C 10 Cycloalkyl" means a non-aromatic cyclic hydrocarbon group having from three to ten ring carbon atoms and zero heteroatoms. In some embodiments, C10 ), and the like. Whether or not preceded by the modifier "substituted", each of the cycloalkyl groups is independently optionally substituted, e.g., with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, suitable substituents being defined below.

[0051] "3 to 14 membered heterocyclyl" refers to a 3 to 14 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits. In some embodiments, 3 to 7 membered heterocyclyl groups are preferred, which are 3 to 7 membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms; in some embodiments, 3 to 6 membered heterocyclyl groups are particularly preferred, which are 3 to 6 membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms; more preferred are 5 to 6 membered heterocyclyl groups, which are 5 to 6 membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl groups also include ring systems in which the above heterocyclyl ring is fused with one or more cycloalkyl, aryl, or heteroaryl rings, wherein the point of attachment is on the heterocyclyl ring; and in such cases, the number of ring members continues to designate the number of ring members in the heterocyclyl ring system. Whether or not preceded by the modifier "substituted", each of the heterocyclyl groups is independently optionally substituted, e.g., with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, suitable substituents being defined below.

[0052] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, without limitation, hexahydrotriazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl, and thieocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6aryl ring (also referred to in the present application as 5,6-bicyclic heterocyclyl groups) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to a C6aryl ring (also referred to in the present application as 6,6-bicyclic heterocyclyl groups) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0053] "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 π electrons shared in a cyclic array) 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 ("C10 aryl"; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen ring carbon atoms ("C14 aryl"; e.g., anthryl). In some embodiments, the aryl group has twelve ring carbon atoms ("C12 aryl"; e.g., biphenyl). 10 Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) 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 ("C10 aryl"; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen ring carbon atoms ("C14 aryl"; e.g., anthryl). In some embodiments, the aryl group has twelve ring carbon atoms ("C12 aryl"; e.g., biphenyl). 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 π electrons shared in a cyclic array) 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 ("C10 aryl"; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen ring carbon atoms ("C14 aryl"; e.g., anthryl). In some embodiments, the aryl group has twelve ring carbon atoms ("C12 aryl"; e.g., biphenyl). 6-10Aryl is particularly preferred, more preferably C6 aryl. Aryl also includes ring systems in which the above-described aryl ring is fused to one or more cycloalkyl or heterocyclyl rings, with the point of attachment being on the aryl ring, in which case the number of carbon atoms designates the number of carbon atoms in the aryl ring system. Each aryl group is independently optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, as defined below, whether or not modified by "substituted."

[0054] "5- to 10-membered heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above-described heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl rings, with the point of attachment being on the heteroaryl ring, in which case the number of carbon atoms designates the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5- to 6-membered heteroaryl is particularly preferred, which is a 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. Each heteroaryl group is independently optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, as defined below, whether or not modified by "substituted."

[0055] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. 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 tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0056] Exemplary substituents on carbon 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)(NRbb )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, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

[0057] or two geminal hydrogens on a carbon atom are replaced with a group =0, =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 ;

[0058] each R aa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R aa groups are joined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

[0059] each R bb 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(Rcc )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, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R bb groups are joined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

[0060] each R cc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R cc groups are joined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

[0061] each R dd 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, -SO2R ee , -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, carbocyclyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups, or two geminal R dd substituents can be combined to form =O or =S;

[0062] each R ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;

[0063] each R ff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R ff groups combine to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg group is substituted;

[0064] R gg each independently is: 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(C 1-6 alkyl) + X - , -NH3 + X - , -N(OC 1-6 alkyl)(C 1-6 alkyl), -N(OH)(C 1-6 alkyl), -NH(OH), -SH, -SC 1-6 alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1- 6alkyl), -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), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 alkyl, -C(=NH)N(C 1-6 alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 alkyl)2, -OC(NH)NH(C 1-6alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2, -SO2NH(C 1-6 alkyl), -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 1-6 alkyl)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- alkyl, -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(=O)P(C 1-6 alkyl)2, C 1-6 alkyl, C 1-6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 carbocyclyl, C6-C 10 aryl, C3-C7 heterocyclyl, C5-C 10 heteroaryl; or two geminal R gg substituents can combine to form =O or =S; wherein X - is a counterion.

[0065] Exemplary substituents on a 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, -SO2Rcc -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, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R cc groups attached to a nitrogen atom are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd , R aa , R bb , R cc , and R dd are as described above.

[0066] “Deuterated” or“D” means that one or more hydrogens in a compound or group are replaced by deuterium; deuterated can be mono-substituted, di-substituted, poly-substituted, or per-substituted. The terms“one or more deuterated” and“one or more deuterium substitutions” are used interchangeably.

[0067] “Non-deuterated compound” means a compound having a proportion of deuterium atoms no greater than the natural isotopic content of deuterium (0.015%).

[0068] Deuterium has an isotopic content at the deuterated position that is at least greater than the natural isotopic content of deuterium by 0.015%, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, more preferably greater than 99%.

[0069] Other Definitions

[0070] The term "pharmaceutically acceptable salt" means those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. 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 application include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acid, or with organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acids, or by using standard procedures for salt formation known in the art, for example, ion exchange procedures. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, bisulfite, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts, and the like. If appropriate, further pharmaceutically acceptable salts include nontoxic ammonium, quaternary ammonium, and amine cations formed by

[0071] A "subject" for administration includes, but is not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, swine, 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.

[0072] "Disease," "disorder," and "condition" are used interchangeably herein.

[0073] Unless otherwise indicated, the term "treatment" as used herein includes actions that occur while a subject has a particular disease, disorder, or condition, that decrease 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 actions that occur before a subject has a particular disease, disorder, or condition ("prophylactic treatment").

[0074] "Combination" and related terms refer to the administration of a therapeutic agent of the present application simultaneously or sequentially with another therapeutic agent. For example, a compound of the present application can be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or administered simultaneously in a single unit dosage form with another therapeutic agent.

[0075] Generally, an "effective amount" of a compound refers to a quantity sufficient to achieve a biologic outcome. As will be understood by those of ordinary skill in the art, an effective amount of a compound of the present application can vary depending on such factors as the biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and symptoms of the subject. Effective amounts include therapeutically and prophylactically effective amounts.

[0076] Unless otherwise indicated, a "therapeutically effective amount" of a compound, as used herein, is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0077] Unless otherwise indicated, a "prophylactically effective amount" of a compound, as used herein, is an amount sufficient to prevent a disease, disorder or condition, or an amount sufficient to prevent one or more symptoms associated with the disease, disorder or condition, or to prevent the disease, disorder or condition from recurring. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the process of preventing the disease, disorder or condition. The term "prophylactically effective amount" can include an amount that improves overall prophylaxis, or enhances the prophylactic efficacy of other prophylactic agents. DETAILED DESCRIPTION

[0078] Compounds

[0079] In the present application, "a compound of the present application" refers to a compound of Formula (I) - Formula (VI) (including subsets of each formula, such as Formula (V A1 ) compounds), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0080] In one embodiment, the present application relates to a compound of Formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:

[0081] wherein,

[0082] Y is selected from N or CH;

[0083] R1is selected from a divalent group of a 5- or 6-membered heteroarene or a phenyl ring; wherein the divalent group is optionally substituted with one or more R;

[0084] each R is independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6haloalkoxy, C 3-6 cycloalkyl or 3- to 7-membered heterocycloalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more D, up to complete deuteriation;

[0085] R2and R3are independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6haloalkoxy, C 3-6cycloalkyl or 3- to 7-membered heterocycloalkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl or 3- to 7-membered heterocycloalkyl optionally substituted with one or more D, up to complete deuteriation;

[0086] n is 0, 1, 2, 3 or 4;

[0087] R a is independently selected from H, D, halogen, -NH2, -CN, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy optionally substituted with one or more D, up to complete deuteriation;

[0088] L is a bivalent linking group;

[0089] U is a group that binds to an E3 ubiquitin ligase.

[0090] In one embodiment, the compound of formula (I) can exist in tautomeric forms: .

[0091] Y

[0092] In one embodiment of formula (I), Y is N or CH; in another embodiment of formula (I), Y is N; in another embodiment of formula (I), Y is CH.

[0093] R1

[0094] In one embodiment of formula (I), R1is selected from a bivalent group of a 5- or 6- membered heteroarene or a phenyl ring; wherein the above bivalent group is optionally substituted with one or more R;

[0095] In another embodiment of formula (I), R1is a bivalent group of a 5-membered heteroarene optionally substituted with 1, 2 or 3 R;

[0096] In another embodiment of formula (I), R1is a bivalent group of a 6-membered heteroarene or a phenyl ring optionally substituted with 1, 2, 3 or 4 R.

[0097] In one particular embodiment of formula (I), R1is selected from:

[0098] represents the remaining one of L, and * represents the remaining one of the compound of formula (I).

[0099] In another embodiment of formula (I), R1is selected from:

[0100] represents the remaining one of L, and * represents the remaining one of the compound of formula (I).

[0101] In a more specific embodiment of formula (I), R1is:

[0102] represents the remaining one of L, and * represents the remaining one of the compound of formula (I).

[0103] In another more specific embodiment of formula (I), R1is selected from:

[0104] represents the remaining one of L, and * represents the remaining one of the compound of formula (I).

[0105] R

[0106] In one embodiment of formula (I), each R is independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, or 3- to 7-membered heterocycloalkyl, wherein the C 1- 6alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, or 3- to 7-membered heterocycloalkyl, optionally substituted with one or more D, up to complete deuteration;

[0107] In one specific embodiment of formula (I), each R is independently selected from H, D, F, Cl, CH3, CD3, ethyl, isopropyl, t-butyl, CF3, methoxy, trifluoromethoxy, or cyclopropyl;

[0108] In another specific embodiment of formula (I), each R is independently H or D.

[0109] R2and R3

[0110] In one embodiment of formula (I), R2and R3are independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1- 6haloalkyl, C 1-6 alkoxy, C1-6 haloalkyl, C 3-6 cycloalkyl or 3- to 7-membered heterocycloalkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl or 3- to 7-membered heterocycloalkyl optionally substituted with one or more D, up to complete deuteration;

[0111] In another embodiment of formula (I), R2and R3are independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 3-6 cycloalkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 3-6 cycloalkyl optionally substituted with one or more D, up to complete deuteration;

[0112] In one particular embodiment of formula (I), R2and R3are independently selected from H, D, F, CI, CH3, CD3, ethyl, CF3, methoxy, trifluoromethoxy or cyclopropyl;

[0113] In another particular embodiment of formula (I), R2and R3are independently CI, CH3or CD3.

[0114] n

[0115] In one embodiment of formula (I), n is 0, 1, 2, 3 or 4; in one particular embodiment of formula (I), n is 0; in another particular embodiment of formula (I), n is 1; in another particular embodiment of formula (I), n is 2; in another particular embodiment of formula (I), n is 3; in another particular embodiment of formula (I), n is 4.

[0116] R a

[0117] In one embodiment of formula (I), R a are independently selected from H, D, halogen, -NH2, -CN, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, wherein said C 1-6 alkyl, C 1-6Haloalkyl, C 1-6 alkoxy, or C 1-6 The haloalkoxy group is optionally substituted with one or more D atoms until it is fully deuterated;

[0118] In a specific implementation of formula (I), R a It is independently selected from H, D, F, Cl, CH3, CD3, ethyl, CF3, methoxy, trifluoromethoxy, or cyclopropyl;

[0119] In another specific implementation of formula (I), R a It can be Cl, CH3, or CD3 independently.

[0120] In another specific implementation of formula (I), R a Independently, it can be either H or D.

[0121] L

[0122] In one embodiment of formula (I), L is a divalent linker;

[0123] In a specific embodiment of formula (I), L is the divalent linker shown in formula (IV): -S0-(L1) i -S1-(L2) j -S2-(L3) k -S3-■(IV)

[0124] in,

[0125] i is 0 or 1, j is 0 or 1, and k is 0 or 1; provided that at least one of i, j, and k is not 0;

[0126] L1, L2, and L3 are each an independent chemical bond, or selected from C 3-7 Cycloalkanes, divalent groups of 4 to 7-membered heterocycles, wherein the divalent groups are optionally surrounded by one or more elements selected from D, halogens, OH, CN, C. 1-3 Alkyl and C 1-3 Substitution of alkyl groups;

[0127] S0, S1, S2, and S3 are each independently a chemical bond, namely -O-, -S-, -NH-, -C(O)-, -C(O)NH-, -NHC(O)-, and -C(O)NH(CH2). p -、-C(O)(CH2) p -、-NHC(O)(CH2) p -、-(CH2) p -、-(CH2CH2O) q -、C 1-6 imide or C 1-6alkynylene; wherein p is 1, 2, 3, or 4; q is 1, 2, or 3;

[0128] represents a bond to U.

[0129] In another embodiment of formula (I), L is a bivalent linking group represented by formula (IV A ) -(L1) i -(L2) j -(L3) k -■(IV A ).

[0130] In another embodiment of formula (I), L is a bivalent linking group represented by formula (IV B ) -(L1) i -S1-(L2) j -S2-(L3) k -■(IV B ).

[0131] In another embodiment of formula (I), L is a bivalent linking group represented by formula (IV C ) -S0-(L1) i (L2) j -S2-(L3) k -S3-■(IV C )

[0132] wherein (L1) i and (L2) j share one atom and / or one chemical bond.

[0133] In another embodiment of formula (I), L is a bivalent linking group represented by formula (IV D ) -S0-(L1) i -S1-(L2) j (L3) k -S3-■(IV D )

[0134] wherein (L2) j and (L3) k share one atom and / or one chemical bond.

[0135] L1, L2, and L3

[0136] In one embodiment of L, one or two of L1, L2, and L3 is a chemical bond and the remaining are each independently a bivalent group selected from 4- to 7-membered heterocyclic rings containing 1 or 2 N atoms, wherein the bivalent group is optionally substituted with one or more substituents selected from D, halogen, OH, CN, C 1-3 alkyl, and C1-3 haloalkyl groups;

[0137] In another embodiment of L, L1is a bond, each of L2and L3is independently a divalent radical selected from 4- to 7-membered heterocyclic rings containing 1 or 2 N atoms, wherein said divalent radical is optionally substituted with one or more radicals selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl groups;

[0138] In another embodiment of L, L2is a bond, each of L1and L3is independently a divalent radical selected from 4- to 7-membered heterocyclic rings containing 1 or 2 N atoms, wherein said divalent radical is optionally substituted with one or more radicals selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl groups;

[0139] In another embodiment of L, L3is a bond, each of L1and L2is independently a divalent radical selected from 4- to 7-membered heterocyclic rings containing 1 or 2 N atoms, wherein said divalent radical is optionally substituted with one or more radicals selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl groups;

[0140] In another embodiment of L, L1and L2are bonds, L3is a divalent radical selected from 4- to 7-membered heterocyclic rings containing 1 or 2 N atoms, wherein said divalent radical is optionally substituted with one or more radicals selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl groups;

[0141] In another embodiment of L, L1and L3are bonds, L2is a divalent radical selected from 4- to 7-membered heterocyclic rings containing 1 or 2 N atoms, wherein said divalent radical is optionally substituted with one or more radicals selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl groups;

[0142] In another embodiment of L, L2and L3are bonds, L1is a divalent radical selected from 4- to 7-membered heterocyclic rings containing 1 or 2 N atoms, wherein said divalent radical is optionally substituted with one or more radicals selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl groups.

[0143] In one embodiment of L, each of L1, L2and L3is independently a bond or a divalent radical selected from C 3-7a bivalent group of a cycloalkane or a 4- to 7-membered heterocycle, wherein the bivalent group is optionally substituted by one or more groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl;

[0144] In another particular embodiment of L, L1, L2and L3are each independently a bond;

[0145] In another particular embodiment of L, L1, L2and L3are each independently selected from C 3-7 a bivalent group of a cycloalkane or a 4- to 7-membered heterocycle, wherein the bivalent group is optionally substituted by one or more groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl;

[0146] In another particular embodiment of L, L1, L2and L3are each independently C 3-7 a bivalent group of a cycloalkane or a 4- to 7-membered heterocycle, wherein the bivalent group is optionally substituted by one or more groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl;

[0147] In another particular embodiment of L, L1, L2and L3are each independently a bivalent group of a 4- to 7-membered heterocycle, wherein the bivalent group is optionally substituted by one or more groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl;

[0148] In another particular embodiment of L, L1, L2and L3are each independently:

[0149] wherein the bivalent group is optionally substituted by one or more groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl.

[0150] In another particular embodiment of L, L1, L2and L3are each independently:

[0151] wherein the bivalent group is optionally substituted by one or more groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl.

[0152] In a particular embodiment of L, (L1) i and (L2)j share one atom and / or one chemical bond;

[0153] In another embodiment of L, (L2) j and (L3) k share one atom and / or one chemical bond;

[0154] In another embodiment of L, (L1) i (L2) j and (L2) j (L3) k are each independently:

[0155] wherein the above groups are optionally substituted with one or more groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl.

[0156] i, j and k

[0157] In one embodiment of L, i is 0 or 1, j is 0 or 1, k is 0 or 1, with the proviso that at least one of i, j and k is not 0; in another embodiment of L, i is 1, j is 0, k is 0; in another embodiment of L, i is 1, j is 1, k is 0; in another embodiment of L, i is 1, j is 0, k is 1; in another embodiment of L, i is 1, j is 1, k is 1; in another embodiment of L, i is 0, j is 0, k is 1; in another embodiment of L, i is 0, j is 1, k is 0; in another embodiment of L, i is 0, j is 1, k is 1.

[0158] S0, S1, S2and S3

[0159] In one embodiment of L, S0, S1, S2and S3are each independently a bond, -O-, -S-, -NH-, -C(O)-, -C(O)NH-, -NHC(O)-, -C(O)NH(CH2) p -, -C(O)(CH2) p -, -NHC(O)(CH2) p -, -(CH2) p -, -(CH2CH2O) q -, C 1-6 alkylene or C 1-6 alkynylene, wherein p is 1, 2, 3 or 4, and q is 1, 2 or 3;

[0160] In another specific implementation of L, S0, S1, S2, and S3 are each an independent chemical bond;

[0161] In another specific implementation of L, S0, S1, S2 and S3 are each independently -O-, -S-, -NH-, -C(O)-, -C(O)NH-, -NHC(O)-;

[0162] In another specific embodiment of L, S0, S1, S2 and S3 are each independently vinylidene, propenyne, ethynylidene or propynylidene;

[0163] In another specific implementation of L, S0, S1, S2 and S3 are each independently -C(O)NHCH2-, -C(O)NH(CH2)2-, -C(O)NH(CH2)3- or -C(O)NH(CH2)4-;

[0164] In another specific implementation of L, S0, S1, S2 and S3 are each independently -C(O)CH2-, -C(O)(CH2)2-, -C(O)(CH2)3- or -C(O)(CH2)4-;

[0165] In another specific implementation of L, S0, S1, S2 and S3 are each independently -NHC(O)CH2-, -NHC(O)(CH2)2-, -NHC(O)(CH2)3- or -NHC(O)(CH2)4-;

[0166] In another specific implementation of L, S0, S1, S2 and S3 are each independently -CH2-, -(CH2)2-, -(CH2)3- or -(CH2)4-;

[0167] In another specific implementation of L, S0, S1, S2 and S3 are each independently -CH2CH2O-, -(CH2CH2O)2- or -(CH2CH2O)3-.

[0168] In a more specific implementation of equation (I), L is:

[0169] The above-mentioned groups are optionally surrounded by 1-6 atoms selected from D, halogen, OH, CN, C.1-3 alkyl and C 1-3 haloalkyl groups.

[0170] In another more specific embodiment of formula (I), L is:

[0171] wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl groups.

[0172] In another more specific embodiment of formula (I), L is:

[0173] wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl groups.

[0174] In another more specific embodiment of formula (I), L is:

[0175] wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl groups.

[0176] U

[0177] In another more specific embodiment of formula (I), U is:

[0178] wherein,

[0179] represents a single or double bond;

[0180] each V is independently a bond, C(O), NH, O, S, C(O)NH, NHC(O), or CH2;

[0181] each W is independently a bond, C(O), NH, O, S, C(O)NH, NHC(O), or CH2;

[0182] each Q1 is independently C(O) or C(R9)2;

[0183] each Q2 is independently N or CH;

[0184] each Q3and Q4is independently N or CR9;

[0185] each K1, K2, and K3is independently N or CR9;

[0186] K4and K5are each independently N or C;

[0187] H1is N, C, or CR9;

[0188] H2and H3are each independently C(O), N, O, S, NR9, CR9, or C(R9)2;

[0189] H4and H8are each independently N or CR9;

[0190] H5, H6, and H7are each independently C(O), O, S, NR9, or C(R9)2;

[0191] each R7is independently H or C 1-6 alkyl;

[0192] each R8is independently D, halogen, C 1-6 alkyl, or C 1-6 haloalkyl; or two R8together with the atom to which they are attached form a C 3-7 cycloalkane or 4- to 7-membered heterocycle;

[0193] each R9is independently H, D, halogen, C 1-6 alkyl, or C 1-6 haloalkyl; or two R9together with the atom to which they are attached form a C 3-7 cycloalkane, 4- to 7-membered heterocycle, C 6-10 aromatic hydrocarbon, or 5- to 10-membered heteroaromatic hydrocarbon;

[0194] each o is independently 0, 1, or 2;

[0195] each h is independently 0, 1, 2, 3, or 4;

[0196] each z is independently 0, 1, or 2;

[0197] each r and s is independently 0, 1, 2, or 3; and r and s are not simultaneously 0;

[0198] each t and u is independently 0, 1, 2, or 3; and t and u are not simultaneously 0.

[0199] In another embodiment of Formula (I), U is:

[0200] represents a single or double bond;

[0201] each V is independently a bond, C(O), NH, O, S, C(O)NH, NHC(O), or CH2;

[0202] each W is independently a bond, C(O), NH, O, S, C(O)NH, NHC(O), or CH2;

[0203] each Q1is independently C(O) or C(R9)2;

[0204] each Q2is independently N or CH;

[0205] each Q3and Q4is independently N or CR9;

[0206] each R7is independently H or C 1-6 alkyl;

[0207] each R8is independently D, halogen, C 1-6 alkyl, or C 1-6 haloalkyl; or two R8together with the atom to which they are attached form a C 3-7 cycloalkane or 4- to 7-membered heterocycle;

[0208] each R9is independently H, D, halogen, C 1-6 alkyl, or C 1-6 haloalkyl; or two R9together with the atom to which they are attached form a C 3-7 cycloalkane, 4- to 7-membered heterocycle, C 6-10 aromatic hydrocarbon, or 5- to 10-membered heteroaromatic hydrocarbon;

[0209] each h is independently 0, 1, 2, 3, or 4;

[0210] each k is independently 0, 1, 2, 3, or 4;

[0211] each z is independently 0, 1, or 2;

[0212] each r is independently 0, 1, or 2;

[0213] each r and s is independently 1, 2, or 3;

[0214] each t and u is independently 1, 2, or 3.

[0215] In one embodiment of Formula (I), U is:

[0216] wherein,

[0217] Q3is N or CR9;

[0218] each R9is independently H, D, or halogen;

[0219] each k is independently 0, 1, or 2.

[0220] In another specific embodiment of formula (I), U is:

[0221] wherein,

[0222] Q3is N or CR9;

[0223] each R9is independently H, D, or halogen;

[0224] each k is independently 0, 1, or 2.

[0225] In another specific embodiment of formula (I), U is:

[0226] wherein,

[0227] Q3is N or CR9;

[0228] each R9is independently H, D, or halogen;

[0229] each k is independently 0, 1, or 2.

[0230] In another specific embodiment of formula (I), U is:

[0231] In another embodiment of formula (I), U is

[0232] In another embodiment of formula (I), U is:

[0233] wherein,

[0234] each V is independently a bond, C(O), NH, O, S, C(O)NH, NHC(O), or CH2;

[0235] each R 10 is independently H, CH3, OCH2CH2OH, (OCH2CH2)2OH,

[0236] each R 11 is independently H, Cl, CN, ethynyl, phenyl,

[0237] In another embodiment of formula (I), U is:

[0238] wherein,

[0239] each V is independently a bond, C(O), NH, O, S, C(O)NH, NHC(O), or CH2;

[0240] each R 10 is independently H, CH3, OCH2CH2OH, (OCH2CH2)2OH,

[0241] each R 11 is independently H, Cl, CN, ethynyl, phenyl,

[0242] each R 12 is independently -CH3,

[0243] each R 13 is independently -CH3, -CH(CH3)2, -C(CH3)3, or -OCH3.

[0244] In another embodiment of formula (I), U is:

[0245] In another embodiment of formula (I), U is:

[0246] Any of the above embodiments, or any combination thereof, can be combined with any of the other embodiments, or any combination thereof. For example, any of the embodiments of Y, or any combination thereof, can be combined with any of the embodiments of R1, R, R2, R3, n, R a , L, L1, L2, L3, i, j, k, S0, S1, S2, S3, p, q, U, V, W, Q1, Q2, Q3, Q4, K1, K2, K3, K4, K5, H1, H2, H3, H4, H5, H6, H7, H8, R7, R8, R9, o, h, k, z, r, s, t, u, R 10 , R 11 , R 12 , and R 13 . The present application is intended to include all such combinations of embodiments, which are limited only by the scope of the specification, and are not listed in their entirety.

[0247] In one embodiment, the present application relates to a compound of Formula (I), or a tautomer, stereoisomer, pro-drug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof:

[0248] wherein,

[0249] Y is selected from N or CH;

[0250] R1is selected from a divalent group of a 5- or 6-membered heteroarene or a phenyl ring; wherein said divalent group is optionally substituted with one or more R;

[0251] each R is independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6haloalkoxy, C 3-6 cycloalkyl or 3- to 7-membered heterocycloalkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl or 3- to 7-membered heterocycloalkyl optionally substituted with one or more D, up to complete deuteration;

[0252] R2and R3are independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6haloalkoxy, C 3-6 cycloalkyl or 3- to 7-membered heterocycloalkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl or 3- to 7-membered heterocycloalkyl optionally substituted with one or more D, up to complete deuteration;

[0253] n is 0, 1, 2, 3, or 4;

[0254] R a is independently selected from H, D, halogen, -NH2, -CN, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6haloalkoxy is optionally substituted with one or more D up to complete deuteration;

[0255] L is a divalent linking group;

[0256] U is a group that binds to an E3 ubiquitin ligase.

[0257] In another embodiment, the present application relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1is a divalent group of a 5-membered heteroarene, optionally substituted with 1, 2, or 3 R.

[0258] In another embodiment, the present application relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1is selected from:

[0259] ^ indicates attachment to L, and * indicates attachment to the remaining end of the compound of formula (I).

[0260] In another embodiment, the present application relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1is:

[0261] ^ indicates attachment to L, and * indicates attachment to the remaining end of the compound of formula (I).

[0262] In another embodiment, the present application relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1is a divalent group of a 6-membered heteroarene or a phenyl ring, optionally substituted with 1, 2, 3, or 4 R.

[0263] In another embodiment, the present application relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1is selected from:

[0264] ^ indicates attachment to L, and * indicates attachment to the remaining end of the compound of formula (I).

[0265] In another embodiment, the present application relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1is selected from:

[0266] ^ indicates attachment to L, and * indicates attachment to the remaining end of the compound of formula (I).

[0267] In another embodiment, the present application relates to a compound of Formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein each R is independently selected from H, D, F, CI, CH3, CD3, ethyl, isopropyl, tert-butyl, CF3, methoxy, trifluoromethoxy, or cyclopropyl.

[0268] In another embodiment, the present application relates to a compound of Formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein each R is independently H or D.

[0269] In another embodiment, the present application relates to a compound of Formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein Y is CH.

[0270] In another embodiment, the present application relates to a compound of Formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R2and R3are independently selected from H, D, F, CI, CH3, CD3, ethyl, CF3, methoxy, trifluoromethoxy, or cyclopropyl.

[0271] In another embodiment, the present application relates to a compound of Formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R2and R3are independently CI, CH3, or CD3.

[0272] In another embodiment, the present application relates to a compound of Formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein n is 0.

[0273] In one embodiment, the present application relates to a compound of Formula (II), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof:

[0274] wherein,

[0275] each R is independently selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6haloalkyl, C

[0276] R2and R3are independently selected from H, D, F, Cl, CH3, CD3, ethyl, CF3, methoxy, trifluoromethoxy, or cyclopropyl; 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 3-6 cycloalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 3-6 cycloalkyl is optionally substituted with one or more D, up to complete deuteration;

[0277] L is a divalent linking group;

[0278] U is a group that binds to an E3 ubiquitin ligase.

[0279] In another embodiment, the present application is directed to a compound of Formula (II), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein each R is independently selected from H, D, F, Cl, CH3, CD3, ethyl, isopropyl, t-butyl, CF3, methoxy, trifluoromethoxy, or cyclopropyl;

[0280] Preferably, each R is independently H or D.

[0281] In another embodiment, the present application is directed to a compound of Formula (II), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R2and R3are independently selected from H, D, F, Cl, CH3, CD3, ethyl, CF3, methoxy, trifluoromethoxy, or cyclopropyl;

[0282] Preferably, R2and R3are independently Cl, CH3, or CD3.

[0283] In one embodiment, the present application is directed to a compound of Formula (III), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:

[0284] wherein,

[0285] each R is independently selected from H, D, F, Cl, CH 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy, wherein the C 1-6 alkyl, C1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy optionally substituted with one or more D, up to complete deuteration;

[0286] R2and R3are independently selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 3-6 cycloalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 3-6 cycloalkyl optionally substituted with one or more D, up to complete deuteration;

[0287] L is a divalent linking group;

[0288] U is a group that binds to an E3 ubiquitin ligase.

[0289] In another embodiment, the present application relates to a compound of Formula (III), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein each R is independently selected from H, D, F, CI, CH3, CD3, ethyl, isopropyl, t-butyl, CF3, methoxy, trifluoromethoxy or cyclopropyl;

[0290] Preferably, each R is independently H or D.

[0291] In another embodiment, the present application relates to a compound of Formula (III), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R2and R3are independently selected from H, D, F, CI, CH3, CD3, ethyl, CF3, methoxy, trifluoromethoxy or cyclopropyl;

[0292] Preferably, R2and R3are independently CI, CH3or CD3.

[0293] In one embodiment, the present application relates to a compound of Formula (I), Formula (II) or Formula (III), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L is a divalent linking group represented by Formula (IV): i -S1-(L2) j -S2-(L3) k -S3-■(IV)

[0294] wherein,

[0295] i is 0 or 1, j is 0 or 1, k is 0 or 1; provided that at least one of i, j and k is not 0;

[0296] L1, L2and L3are each independently a bond, or selected from C 3-7 cycloalkane, 4- to 7-membered heterocyclic divalent radical, wherein the divalent radical is optionally substituted with one or more radicals selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl;

[0297] S0, S1, S2and S3are each independently a bond, -O-, -S-, -NH-, -C(O)-, -C(O)NH-, -NHC(O)-, -C(O)NH(CH2) p -, -C(O)(CH2) p -, -NHC(O)(CH2) p -, -(CH2) p -, -(CH2CH2O) q -, C 1-6 alkylene or C 1-6 alkynylene; wherein p is 1, 2, 3 or 4; q is 1, 2 or 3;

[0298] represents the attachment to U.

[0299] In another embodiment, the present application relates to a compound of Formula (I), Formula (II) or Formula (III), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L is a divalent linking group of Formula (IV A ) -(L1) i -(L2) j -(L3) k -(IV A ).

[0300] In another embodiment, the present application relates to a compound of Formula (I), Formula (II) or Formula (III), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L is a divalent linking group of Formula (IV B ) -(L1) i -S1-(L2) j -S2-(L3) k -(IV B ).

[0301] In another embodiment, the present application relates to a compound of Formula (I), Formula (II), or Formula (III), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein L is a bivalent linking group represented by Formula (IV) C ) -S0-(L1) i (L2) j -S2-(L3) k -S3-■(IV C )

[0302] wherein (L1) i and (L2) j share one atom and / or one chemical bond.

[0303] In another embodiment, the present application relates to a compound of Formula (I), Formula (II), or Formula (III), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein L is a bivalent linking group represented by Formula (IV) D ) -S0-(L1) i -S1-(L2) j (L3) k -S3-■(IV D )

[0304] wherein (L2) j and (L3) k share one atom and / or one chemical bond.

[0305] In another embodiment, the present application relates to a compound of Formula (I), Formula (II), or Formula (III), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein one or two of L1, L2, and L3is a chemical bond, and the remaining are each independently a bivalent group selected from 4- to 7-membered heterocyclic rings containing 1 or 2 N atoms; wherein the bivalent group is optionally substituted with one or more groups selected from D, halogen, OH, CN, C 1-3 alkyl, and C 1-3 haloalkyl.

[0306] In another embodiment, the present application relates to a compound of Formula (I), Formula (II), or Formula (III), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein L is:

[0307] wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl.

[0308] In another embodiment, the present application is directed to a compound of Formula (I), Formula (II), or Formula (III), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L is:

[0309] wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl.

[0310] In another embodiment, the present application is directed to a compound of Formula (I), Formula (II), or Formula (III), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L is:

[0311] wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl.

[0312] In another embodiment, the present application is directed to a compound of Formula (I), Formula (II), or Formula (III), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L is:

[0313] wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl.

[0314] In another embodiment, the present application is directed to a compound of Formula (I), Formula (II), or Formula (III), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein U is:

[0315] wherein,

[0316] represents a single or double bond;

[0317] each V is independently a bond, C(O), NH, O, S, C(O)NH, NHC(O), or CH2;

[0318] each W is independently a bond, C(O), NH, O, S, C(O)NH, NHC(O), or CH2;

[0319] each Q1is independently C(O) or C(R9)2;

[0320] each Q2is independently N or CH;

[0321] each Q3and Q4is independently N or CR9;

[0322] each K1, K2, and K3is independently N or CR9;

[0323] K4and K5are each independently N or C;

[0324] H1is N, C, or CR9;

[0325] H2and H3are each independently C(O), N, O, S, NR9, CR9, or C(R9)2;

[0326] H4and H8are each independently N or CR9;

[0327] H5, H6, and H7are each independently C(O), O, S, NR9, or C(R9)2;

[0328] each R7is independently H or C 1-6 alkyl;

[0329] each R8is independently D, halogen, C 1-6 alkyl, or C 1-6 haloalkyl; or two R8together with the atom to which they are attached form a C 3-7 cycloalkane or 4- to 7-membered heterocycle;

[0330] each R9is independently H, D, halogen, C 1-6 alkyl, or C 1-6 haloalkyl; or two R9together with the atom to which they are attached form a C 3-7 cycloalkane, 4- to 7-membered heterocycle, C 6-10 arene, or 5- to 10-membered heteroarene;

[0331] each o is independently 0, 1, or 2;

[0332] each h is independently 0, 1, 2, 3, or 4;

[0333] each z is independently 0, 1, or 2;

[0334] each r and s is each independently 0, 1, 2, or 3; and r and s are not simultaneously 0;

[0335] each t and u is each independently 0, 1, 2, or 3; and t and u are not simultaneously 0.

[0336] In another embodiment, the present application relates to a compound of Formula (I), Formula (II), or Formula (III), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein U is:

[0337] wherein,

[0338] represents a single or double bond;

[0339] each V is independently a bond, C(O), NH, O, S, C(O)NH, NHC(O), or CH2;

[0340] each W is independently a bond, C(O), NH, O, S, C(O)NH, NHC(O), or CH2;

[0341] each Q1is independently C(O) or C(R9)2;

[0342] each Q2is independently N or CH;

[0343] each Q3and Q4is independently N or CR9;

[0344] each R7is independently H or C 1-6 alkyl;

[0345] each R8is independently D, halogen, C 1-6 alkyl, or C 1-6 haloalkyl; or two R8together with the atom to which they are attached form a C 3-7 cycloalkane or 4- to 7-membered heterocycle;

[0346] each R9is independently H, D, halogen, C 1-6 alkyl, or C 1-6 haloalkyl; or two R9together with the atom to which they are attached form a C 3-7 cycloalkane, 4- to 7-membered heterocycle, C6-10 an aromatic or 5- to 10-membered heteroaromatic hydrocarbon;

[0347] each h is independently 0, 1, 2, 3, or 4;

[0348] each k is independently 0, 1, 2, 3, or 4;

[0349] each z is independently 0, 1, or 2;

[0350] each r is independently 0, 1, or 2;

[0351] each r and s is independently 1, 2, or 3;

[0352] each t and u is independently 1, 2, or 3.

[0353] In another embodiment, the present application is directed to a compound of Formula (I), Formula (II), or Formula (III), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein U is:

[0354] wherein,

[0355] Q3is N or CR9;

[0356] each R9is independently H, D, or halogen;

[0357] each k is independently 0, 1, or 2.

[0358] In another embodiment, the present application is directed to a compound of Formula (I), Formula (II), or Formula (III), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein U is:

[0359] wherein,

[0360] Q3is N or CR9;

[0361] each R9is independently H, D, or halogen;

[0362] each k is independently 0, 1, or 2.

[0363] In another embodiment, the present application is directed to a compound of Formula (I), Formula (II), or Formula (III), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein U is:

[0364] wherein,

[0365] Q3 is N or CR9;

[0366] each R9 is independently H, D, or halogen;

[0367] each k is independently 0, 1, or 2.

[0368] In another embodiment, the present application relates to a compound of Formula (I), Formula (II), or Formula (III), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein U is:

[0369] In one embodiment, the present application relates to a compound of Formula (I), Formula (II), or Formula (III), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein U is

[0370] In one embodiment, the present application relates to a compound of Formula (I), Formula (II), or Formula (III), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein U is:

[0371] wherein,

[0372] each V is independently a bond, C(O), NH, O, S, C(O)NH, NHC(O), or CH2;

[0373] each R 10 is independently H, CH3, OCH2CH2OH, (OCH2CH2)2OH,

[0374] each R 11 is independently H, Cl, CN, ethynyl, phenyl,

[0375] In another embodiment, the present application relates to a compound of Formula (I), Formula (II), or Formula (III), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein U is:

[0376] wherein,

[0377] each V is independently a bond, C(O), NH, O, S, C(O)NH, NHC(O), or CH2;

[0378] each R is independently H, CH3, OCH2CH2OH, (OCH2CH2)2OH, 10 each independently H, CH3, OCH2CH2OH, (OCH2CH2)2OH,

[0379] each R is independently H, CH3, OCH2CH2OH, (OCH2CH2)2OH, 11 each independently H, CH3, OCH2CH2OH, (OCH2CH2)2OH,

[0380] each R is independently H, CH3, OCH2CH2OH, (OCH2CH2)2OH, 12 each independently -CH3,

[0381] each R is independently H, CH3, OCH2CH2OH, (OCH2CH2)2OH, 13 each independently -CH3, -CH(CH3)2, -C(CH3)3, or -OCH3.

[0382] In one embodiment, the present application relates to a compound of Formula (I), Formula (II), or Formula (III), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein U is:

[0383] In one embodiment, the present application relates to a compound of Formula (I), Formula (II), or Formula (III), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein U is:

[0384] In one specific embodiment, the present application relates to a compound, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, isotopologue, hydrate, or solvate thereof, wherein the compound is selected from the group consisting of the following compounds:

[0385] The compounds of the present application can include one or more asymmetric centers and can thus occur as various stereoisomeric forms, such as enantiomeric and / or diastereomeric forms. For example, the compounds of the present application can be individual enantiomers, diastereomers or geometric isomers (such as cis- and trans-isomers), or can be mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be separated by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and formation and crystallization of chiral salts; or the preferred isomer can be prepared by asymmetric synthesis.

[0386] "tautomer" refers to an isomer of a compound in which a functional group is transformed into another functional group and which can rapidly interconvert with the other isomer, both isomers being in dynamic equilibrium.

[0387] Those skilled in the art will appreciate that organic compounds can form complexes with solvents, which can be present in the reaction or in the final product. These complexes are known as "solvates". When the solvent is water, the solvate is called a "hydrate". The present application encompasses all solvates of the compounds of the present application.

[0388] The term "solvate" refers to a form of a compound or salt thereof in which the compound is combined with one or more solvent molecules, typically formed by solvolysis. This physical association can include hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein can be prepared as, for example, crystalline forms, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the solid state compound. "Solvate" includes both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0389] The term "hydrate" refers to a compound in combination with water. Typically, the ratio of water molecules to compound molecules in a hydrate of a compound is defined. Thus, a hydrate of a compound can be represented, for example, by the general formula R xH20, where R is the compound, and x is a number greater than zero. A given compound can form more than one hydrate type, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than zero and less than 1, for example, hemihydrates (R 0.5H20)), and polyhydrates (x is a number greater than 1, for example, dihydrates (R 2H20) and hexahydrates (R 6H20)).

[0390] The compounds of the present application can be in amorphous or crystalline form (polymorphs). Furthermore, the compounds of the present application can exist in one or more crystalline forms. Accordingly, the present application includes within its scope all amorphous or crystalline forms of the compounds of the present application. The term "polymorph" refers to crystalline forms (or salts, hydrates or solvates thereof) of a compound in which the same elements are arranged in a different packing arrangement. Different crystalline forms often have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. The recrystallization solvent, rate of crystallization, storage temperature, and other factors can cause one crystalline form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0391] The present application also includes isotopically-labelled compounds, which are identical to those recited in Formula (I) but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be suitably substituted into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, and chlorine, such as 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. The present application also includes the prodrugs of the present application that contain the aforementioned isotopes and / or other isotopes of atoms present in the present application. The compounds of the present application, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs that contain the aforementioned isotopes and / or other isotopes of atoms are within the scope of the present application. Certain isotopically-labelled compounds of the present application, for example those into which radioactive isotopes such as 3 H, and 14 C, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Isotopically labelled compounds of Formula (I) of the present application and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes and / or in the examples and

[0392] In addition, prodrugs are also included in the context of the present application. The term "prodrug" as used in the context of the present application means a compound which is converted into its active form, which has a medical effect, in vivo, for example by hydrolytic cleavage in the blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, 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 incorporated herein by reference.

[0393] A prodrug is any covalently bonded compound which, when administered to a patient, releases the parent compound in vivo. Prodrugs are typically prepared by modifying functional groups in such a way that their solubility characteristics are improved when the prodrug is administered to a patient. Prodrugs include, for example, compounds of the present application in which hydroxy, amino, or mercapto groups are bonded to any group which, when administered to a patient, cleaves to form a hydroxy, amino, or mercapto group. Thus, representative examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of the hydroxy, mercapto, and amino functional groups of the compounds of Formula (I). In addition, in the case of carboxylic acids (-COOH), esters can be used, for example, methyl ester, ethyl ester, and the like. The esters themselves can be active and / or can be hydrolyzed under in vivo conditions of the human body. Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those that break down easily in the human body to release the parent acid or salt thereof.

[0394] Pharmaceutical compositions, formulations, and kits

[0395] In another aspect, the present application provides pharmaceutical compositions comprising a compound of the present application (also referred to as the "active ingredient") and a pharmaceutically acceptable excipient. 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 prophylactically effective amount of the active ingredient.

[0396] A pharmaceutically acceptable excipient for use in the application means a nontoxic carrier, adjuvant or vehicle which does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of this application include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene- block polymers, polyethylene glycol and wool fat.

[0397] The application also includes kits (e.g., pharmaceutical packs). The kits provided can comprise a compound of the application, other therapeutic agents, and containers (e.g., vials, ampules, bottles, syringes, and / or dispersable packs or other suitable containers) comprising the first and second containers. In some embodiments, the kits provided can also optionally include a third container comprising a pharmaceutically-acceptable carrier, which can be used to dilute or suspend the compound of the application and / or other therapeutic agents. In some embodiments, the combination of the compound of the application and other therapeutic agents provided in the first and second containers form a single unit dosage form.

[0398] The pharmaceutical compositions provided by the application can be administered by a variety of routes including, but not limited to, oral ingestion, parenteral injection, inhalation, topical application, rectal administration, nasal administration, buccal administration, vaginal administration, administration via an implant, or other means of administration. For example, parenteral injection for use in the application includes subcutaneous injections, intradermal injections, intravenous injections, intramuscular injections, intra-articular injections, intra-arterial injections, intrasynovial injections, intrasternal injections, intrathecal injections, intralesional injections, and intracranial injection or infusion techniques.

[0399] Generally, an effective amount of a compound provided by the application is administered. The amount of a compound actually to be administered can be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound to be administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0400] When used to prevent a condition described herein, a compound provided herein is administered to a subject at risk of developing the condition, typically on the advice and under the supervision of a doctor, at a dosage level as described above. Subjects at risk of developing a particular condition include, generally, those who have a family history of the condition, or those who, through genetic testing or screening, are determined to be particularly susceptible to developing the condition.

[0401] The pharmaceutical compositions provided herein can also be administered chronically ("chronic administration"). Chronic administration refers to the administration of a compound or a pharmaceutical composition thereof over an extended period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or the administration can continue indefinitely, e.g., for the remainder of the subject's life. In some embodiments, chronic administration is intended to provide a constant level of the compound in the blood, e.g., within a therapeutic window, over an extended period of time.

[0402] Various methods of administration can be used to further deliver the pharmaceutical compositions of the present application. For example, in some embodiments, the pharmaceutical composition can be administered as a bolus, e.g., 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, e.g., an intramuscular or subcutaneous bolus dose releases the active ingredient slowly, while a bolus delivered directly to the vein, e.g., by IV infusion, can deliver more rapidly, such that the concentration of the active ingredient in the blood rapidly increases to an effective level. In other embodiments, the pharmaceutical composition can be administered as a continuous infusion, e.g., by IV infusion, to provide a steady state concentration of the active ingredient in the subject's body. In still other embodiments, a bolus dose of the pharmaceutical composition can be administered first, followed by a continuous infusion.

[0403] Oral compositions can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage form, e.g., in ampoules, or in pre-measured amounts in capsules and the like. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc., in the case of solid compositions. In such compositions, the compound is typically the minor component, e.g., from about 0.1 to about 50% by weight, or preferably from about 1 to about 40% by weight, with the remainder being various carriers or excipients and processing aids useful in forming the desired dosing form.

[0404] For oral dosage forms, a representative schedule is one to five oral dosages per day, especially two to four oral dosages, typically three oral dosages. Using these dosage patterns, each dosage provides from about 0.01 to about 20 mg / kg of the compound of the application, with preferred dosages providing from about 0.1 to about 10 mg / kg, especially from about 1 to about 5 mg / kg, per dosage.

[0405] To provide blood levels similar to, or lower than, those achieved using injectable dosages, transdermal dosages are typically selected in amounts from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.

[0406] Injectable dosage levels range from about 0.1 mg / kg / hr to at least 10 mg / kg / hr for from about 1 to about 120 hours, especially 24 to 96 hours. To achieve adequate steady state levels, a preloading bolus of from about 0.1 mg / kg to about 10 mg / kg or more can also be administered. The maximum total dosage for a 40 to 80 kg human patient should not exceed about 2 g / day.

[0407] Liquid forms suitable for oral administration can include a suitable aqueous or nonaqueous vehicle with buffers, suspending agents, and dispensing agents, colorants, flavorants, and the like. Solid forms can include, for example, any of the following ingredients, or compounds of similar nature: a binder such as, for example, microcrystalline cellulose, gum tragacanth or gelatin; an excipient, such as, for example, starch or lactose, a disintegrating agent, such as, for example, alginic acid, Primogel, or corn starch; a lubricant, such as, for example, magnesium stearate; a glidant, such as, for example, colloidal silicon dioxide; a sweetening agent, such as, for example, sucrose or saccharin; or a flavoring agent, such as, for example, peppermint, methyl salicylate, or orange flavoring.

[0408] Injectable compositions are typically based upon sterile saline or phosphate buffered saline, or other injectable vehicles known in the art. As before, in such compositions the active compound is typically the minor component, often from about 0.05 to 10% by weight, with the remainder being the injectable carrier or the like.

[0409] Transdermal compositions are typically formulated to contain active ingredients in a topical ointment or cream. When formulated in an ointment, the active ingredient typically is combined with a base such as petroleum or a water miscible ointment base. Alternatively, the active ingredient can be formulated in a cream with, for example, an oil-in-water cream base. Such transdermal formulations are known in the art and typically include additional components to enhance penetration of the active ingredient or formulation through the skin. All such known transdermal formulations and components are contemplated as being within the scope of the present application.

[0410] The compounds of the present application can also be administered by transdermal devices. Transdermal administration can be achieved by means such as a reservoir secured to the skin or a porous matrix type, or a variety of solid matrix patches.

[0411] The above ingredients for compositions for oral administration, injection or topical administration are merely representative. Other materials and processing techniques can be found in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0412] The compounds of the present application can also be administered in sustained release forms or from sustained release drug delivery systems. Representative sustained release materials are described in Remington's Pharmaceutical Sciences.

[0413] The present application also relates to pharmaceutically acceptable formulations of the compounds of the present application. 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, which consist of 6, 7, and 8 α-1,4-linked glucose units, respectively, optionally including one or more substituents on the linked sugar moieties, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitutions. In some embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, e.g., U.S. 5,376,645. In some embodiments, the formulation includes hexapropyl-β-cyclodextrin (e.g., in water, 10-50%).

[0414] Indications

[0415] In one aspect, the present application provides a compound of the present application (including all individual embodiments and generic subsets disclosed herein) or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, isotopically-labeled variant, hydrate or solvate thereof, and a pharmaceutical composition or kit of the present application for use in a method of treatment and / or use in treating a disease associated with c-Kit or PDGFRa.

[0416] In one embodiment, the c-Kit or PDGFRa associated disease is selected from the group consisting of systemic mastocytosis, gastrointestinal stromal tumor, acute myeloid leukemia, melanoma, seminoma, intracranial germinoma, mediastinal B-cell lymphoma, Ewing's sarcoma, diffuse large B-cell lymphoma, dysgerminoma, myelodysplastic syndrome, nasal NK / T-cell lymphoma, chronic myelomonocytic leukemia, and brain cancer.

[0417] In some embodiments, the compounds of the application are useful in the treatment of disorders associated with c-Kit, such as diseases associated with unregulated kinase signaling, including cell proliferative diseases, fibrotic diseases, and metabolic diseases, among others. Cell proliferative diseases that can be treated by the compounds of the application include cancers and mast cell proliferative diseases. The presence of c-Kit or mutant c-Kit has also been associated with many types of cancers, diseases, and disorders. Moreover, the association between c-Kit abnormalities and disease is not limited to cancers. c-Kit has been associated with malignancies including mast cell tumors, small cell lung cancer, testicular cancer, gastrointestinal stromal tumors (GIST), metastatic GIST, glioblastoma, astrocytoma, neuroblastoma, female genital tract malignancies, sarcomas of neuroectodermal origin, colorectal cancer, carcinoma in situ, Schwann cell tumors associated with neurofibromatosis, acute myelocytic leukemia (AML), acute lymphoblastic leukemia, chronic myelocytic leukemia, mastocytosis, and melanoma, and inflammatory diseases including asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis, inflammatory bowel syndrome, graft rejection, hypereosinophilia, urticarial pigmentosa (UP), telangiectasia macularis eruptiva perstans (TMEP), systemic mastocytosis, indolent systemic mastocytosis, smoldering systemic mastocytosis, infiltrative systemic mastocytosis, mast cell leukemia, and mast cell sarcoma. The presence of mutant forms of c-Kit has been associated with a variety of diseases or disorders, such as gastrointestinal stromal tumor (GIST), mast cell leukemia, germ cell tumors, T-cell lymphoma, mastocytosis, acute lymphoblastic leukemia, and seminomas.

[0418] In some embodiments, the compounds of the application are useful in the treatment of disorders associated with PDGFRa, such as solid tumors (including benign or especially malignant types), especially sarcomas, gastrointestinal stromal tumors (GIST), colon cancer, acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), neoplasia, thyroid cancer, systemic mastocytosis, hypereosinophilic syndrome, fibrosis, lupus erythematosus, graft versus host disease, neurofibromas, pulmonary hypertension, Alzheimer's disease, seminomas, dysgerminomas, mast cell tumors, lung cancer, bronchial cancer, testicular intraepithelial neoplasia, melanoma, breast cancer, neuroblastoma, papillary / follicular thyroid cancer, malignant lymphoma, non-Hodgkin's lymphoma, multiple endocrine neoplasia type 2, pheochromocytoma, thyroid cancer, parathyroid hyperplasia / adenoma, colon cancer, colorectal adenoma, ovarian cancer, prostate cancer, glioblastoma, brain tumors, malignant glioma, pancreatic cancer, malignant pleural mesothelioma, hemangioblastoma, hemangioma, kidney cancer, liver cancer, adrenal cancer, bladder cancer, stomach cancer, rectal cancer, vaginal cancer, cervical cancer, endometrial cancer, multiple myeloma, neck and head tumors, and other hyperplastic or proliferative diseases or the like, or combinations thereof.

[0419] In some embodiments, the compounds of the application are useful in the treatment of diseases or disorders associated with c-Kit mutations in exon 9, exon 11, exon 13, exon 14, exon 17, and / or exon 18 of the c-Kit gene sequence. In some embodiments, the compounds of the application are useful in the treatment of diseases or disorders associated with PDGFRa mutations in exon 12, exon 14, exon 15, and / or exon 18 of the PDGFRa gene sequence. In some embodiments, the present application provides methods for treating diseases or disorders associated with at least one c-Kit mutation in exon 9, exon 11, exon 13, exon 14, exon 17, and / or exon 18 of the c-Kit gene sequence. In some embodiments, the present application provides methods for treating diseases or disorders associated with at least one PDGFRa mutation in exon 12, exon 14, exon 15, and / or exon 18 of the PDGFRa gene sequence.

[0420] In some embodiments, the compounds of the application can be active against one or more c-Kit protein kinases having a mutation in exon 17 of the c-Kit gene sequence (e.g., c-Kit protein mutations D816V, D816Y, D816F, D816K, D816H, D816A, D816G, D816E, D816I, D816F, D820A, D820E, D820G, D820Y, N822K, N822H, V560G, Y823D, and A829P). In some embodiments, the application provides methods for treating a disease or disorder associated with at least one c-Kit mutation (e.g., a c-Kit mutation selected from D816V, D816Y, D816F, D816K, D816H, D816A, D816G, D816E, D816I, D816F, D820A, D820E, D820G, D820Y, N822K, N822H, V560G, Y823D, and A829P). In some embodiments, the application provides methods for treating a disease or disorder associated with at least one c-Kit mutation (e.g., a c-Kit mutation selected from C809, C809G, D816H, D820A, D820G, N822H, N822K, and Y823D).

[0421] In some embodiments, the compounds of the application can be active against one or more c-Kit protein kinases having a mutation in exon 11 of the c-Kit gene sequence (e.g., c-Kit protein mutations del557-559insF and V559G / D). In some embodiments, the application provides methods for treating a disease or disorder associated with at least one c-Kit mutation (e.g., a c-Kit mutation selected from L576P, V559D, V560D, V560G, W557G, del557-559insF, delEVQWK554-558, delEVQWKVVEEINGNNYVYI554-571, delKPMYEVQWK550-558, delKPMYEVQW550-557FL, delKV558-559, delKV558-559N, delMYEVQW552-557, delPMYE551-554, delVV559-560, delWKVVE557-561, delWK557-558, delWKVV557-560C, delWKVV557-560F, delYEVQWK553-558, and K558NP).

[0422] In some embodiments, the compounds of the application can be active against one or more c-Kit protein kinases having a mutation in exon 11 / 13 of the c-Kit gene sequence (e.g., c-Kit protein mutations V559D / V654A, V560G / D816V, and V560G / D822K). In some embodiments, the application provides methods for treating a disease or disorder associated with one or more c-Kit mutations in exon 11 / 13.

[0423] In some embodiments, the compounds of the application can be active against one or more c-Kit protein kinases having a mutation in exon 9 of the c-Kit gene sequence. In some embodiments, the application provides methods for treating a disease or disorder associated with at least one c-Kit mutation in exon 9.

[0424] In some embodiments, the compounds of the application can be active against one or more PDGFRa protein kinases having a mutation. In some embodiments, the application provides methods for treating a disease or disorder associated with at least one PDGFRa mutation in exon 12 of the PDGFRa gene sequence (e.g., PDGFRa protein mutations V561D, delRV560-561, delRVIES560-564, insER561-562, SPDGHE566-571R, SPDGHE566-571K, or insYDSRW582-586). In some embodiments, the application provides methods for treating a disease or disorder associated with at least one PDGFRa mutation in exon 14 of the PDGFRa gene sequence (e.g., PDGFRa protein mutation N659K). In some embodiments, the application provides methods for treating a disease or disorder associated with at least one PDGFRa mutation in exon 18 of the PDGFRa gene sequence (e.g., PDGFRa protein mutations D842V, D842Y, D842I, DI842-843IM, D846Y, Y849C, delD842, delI843, delRD841-842, delDIM842-845, delDIMH842-845, delIMHD843-846, delMHDS844-847, RD841-842KI, DIMH842-845A, DIMH842-845V, DIMHD842-846E, DIMHD842-846S, DIMHD842-846N, DIMHD842-846G, IMHDS843-847T, IMHDS8843-847M, or HDSN845-848P).

[0425] In some embodiments, the compounds of the application can be active against one or more PDGFRa protein kinases having an exon 18 mutation in the PDGFRa gene sequence (e.g., PDGFRa protein mutation D842V, D842I, or D842Y). In some embodiments, the application provides methods for treating a disease or disorder associated with at least one PDGFRa mutation in exon 18 (e.g., PDGFRa protein mutation D842V).

[0426] In some embodiments, diseases or conditions that can be treated using the compounds of the application include, but are not limited to, multi-infarct dementia, brain injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease, seizures and epilepsy; neoplastic diseases including, but not limited to, melanoma, glioma, glioblastoma multiforme, pilocytic astrocytoma, sarcoma, carcinoma (e.g., gastrointestinal cancer, liver cancer, biliary tract cancer, cholangiocarcinoma (bile duct cancer), colorectal cancer, lung cancer, breast cancer, gallbladder cancer, pancreatic cancer, thyroid cancer, renal cancer, ovarian cancer, adrenocortical carcinoma, prostate cancer), lymphoma (e.g., histiocytic lymphoma), neurofibromatosis, gastrointestinal stromal tumor, acute myelocytic leukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis, neuroendocrine tumors (e.g., medullary thyroid carcinoma), benign tumors, small cell lung cancer, Kaposi's sarcoma, and pheochromocytoma; neuropathic or inflammatory pain including, but not limited to, acute pain, chronic pain, cancer pain, migraine; cardiovascular diseases including, but not limited to, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis (e.g., thrombotic microangiopathy syndromes), atherosclerosis, and reperfusion injury; inflammation and / or proliferation including, but not limited to, psoriasis, eczema, arthritis and autoimmune diseases and conditions, osteoarthritis, endometriosis, scarring, vascular restenosis, fibrotic diseases, rheumatoid arthritis, inflammatory bowel disease (IBD); immunodeficiency diseases including, but not limited to, organ transplant rejection, graft-versus-host disease, and HIV-associated Kaposi's sarcoma; renal, cystic, or prostatic diseases including, but not limited to, diabetic nephropathy, polycystic kidney disease, renal hardening, glomerulonephritis, prostatic hyperplasia, polycystic liver disease, tuberous sclerosis, von Hippel-Lindau disease, medullary cystic kidney disease, renal tuberculosis, and cystic fibrosis; metabolic diseases including, but not limited to, obesity; infections including, but not limited to, Helicobacter pylori, hepatitis and influenza virus, fever, HIV, and sepsis; pulmonary diseases including, but not limited to, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS); genetic developmental diseases including, but not limited to, Noonan's syndrome, Costello syndrome, (faciocutaneoskeletal syndrome), LEOPARD syndrome, cardio-facio-cutaneous syndrome (CFC), and neural crest syndrome abnormalities that cause cardiovascular disease, skeletal disease, intestinal disease, skin disease, hair disease, and endocrine disease;and diseases associated with muscle regeneration or degeneration, including but not limited to, sarcopenia, muscular dystrophy (including but not limited to Duchenne muscular dystrophy, Becker muscular dystrophy, Emery-Dreifuss muscular dystrophy, Limb-Girdle muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic muscular dystrophy, oculopharyngeal muscular dystrophy, distal muscular dystrophy, and congenital muscular dystrophy), motor neuron diseases (including but not limited to amyotrophic lateral sclerosis, infantile progressive spinal muscular atrophy, spinal and bulbar muscular atrophy, juvenile spinal muscular atrophy, spinal and bulbar muscular atrophy, and adult spinal muscular atrophy), inflammatory myopathies (including but not limited to dermatomyositis, polymyositis, and inclusion body myositis), diseases of the neuromuscular junction (including but not limited to myasthenia gravis, Lambert-Eaton syndrome, and congenital myasthenic syndromes), myopathies caused by endocrine abnormalities (including but not limited to hyperthyroid myopathy and hypothyroid myopathy), peripheral nerve diseases (including but not limited to Charcot-Marie-Tooth disease, Dejerine-Sottas disease, and Friedreich's ataxia), other myopathies (including but not limited to myotonia congenita, paramyotonia congenita, central core disease, oculopharyngeal muscular disease, myotubular myopathy, periodic paralysis), and muscle metabolic diseases (including but not limited to phosphofructokinase deficiency, acid maltase deficiency, phosphofructokinase deficiency, debbranching enzyme deficiency, mitochondrial myopathy, carnitine deficiency, carnitine palmitoyltransferase deficiency, phosphoglycokinase deficiency, phosphoglycokinase deficiency, lactate dehydrogenase deficiency, and muscle adenylate deaminase deficiency). In one embodiment, the disease or disorder is selected from the group consisting of melanoma, glioma, glioblastoma multiforme, pilocytic astrocytoma, sarcoma, hepatocarcinoma, cholangiocarcinoma, cholangiocarcinoma, colorectal carcinoma, lung carcinoma, gallbladder carcinoma, breast carcinoma, pancreatic carcinoma, thyroid carcinoma, renal carcinoma, ovarian carcinoma, adrenocortical carcinoma, prostate carcinoma, malignant lymphoma, neurofibroma, gastrointestinal stromal tumor, acute myelocytic leukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis, medullary thyroid carcinoma, benign tumors, small cell lung carcinoma, Kaposi's sarcoma, pheochromocytoma, acute pain, chronic pain, and polycystic kidney disease. In a preferred embodiment, the disease or disorder is selected from the group consisting of melanoma, glioma, glioblastoma multiforme, pilocytic astrocytoma, colorectal carcinoma, thyroid carcinoma, lung carcinoma, ovarian carcinoma, prostate carcinoma, hepatocarcinoma, gallbladder carcinoma, gastrointestinal stromal tumor, cholangiocarcinoma, cholangiocarcinoma, acute pain, chronic pain, and polycystic kidney disease.

[0427] In some embodiments, the disease or condition treatable with the compounds of the application include, but are not limited to, ischemic stroke, cerebrovascular ischemia, multi-infarct dementia, craniocerebral trauma, spinal cord injury, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, dementia, senile chorea, Huntington's disease, neoplastic disease, neoplastic disease complications, chemotherapy-induced hypoxia, gastrointestinal stromal tumor, prostatic tumor, mastocytoma, canine mastocytoma, acute myelogenous leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, multiple myeloma, melanoma, mastocytosis, glioma, glioblastoma, astrocytoma, neuroblastoma, sarcoma, sarcoma of neuroectodermal origin, leiomyosarcoma, lung cancer, breast cancer, pancreatic cancer, colon cancer, hepatocellular carcinoma, renal carcinoma, female genital tract cancer, squamous cell carcinoma, carcinoma in situ, lymphoma, histiocytic lymphoma, non-Hodgkin's lymphoma, MEN2 syndrome, neurofibroma, Schwann cell tumor, myelodysplastic syndrome, leukemia, tumor angiogenesis, thyroid cancer, liver cancer, bone cancer, skin cancer, brain cancer, central nervous system cancer, pancreatic cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, colon cancer, bladder cancer, prostate cancer, gastrointestinal tract cancer, endometrial cancer, fallopian tube cancer, testicular cancer, ovarian cancer, neuropathic pain, inflammatory pain, acute pain, chronic pain, migraine, cardiovascular disease, heart failure, cardiac hypertrophy, thrombosis, thrombotic microangiopathy syndromes, atherosclerosis, reperfusion injury, ischemia, cerebrovascular ischemia, hepatic ischemia, inflammation, polycystic kidney disease, age-related macular degeneration, rheumatoid arthritis, allergic rhinitis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, Sjogren's syndrome, Wegener's granulomatosis, psoriasis, scleroderma, chronic thyroiditis, Grave's disease, myasthenia gravis, multiple sclerosis, osteoarthritis, endometriosis, skin scarring, tissue scarring, vascular restenosis, fibrotic diseases, eosinophilia, central nervous system inflammation, pancreatitis, nephritis, atopic dermatitis, hepatitis, immunodeficiency diseases, severe combined immunodeficiency, organ transplant rejection, graft-versus-host disease, kidney disease, prostate disease, diabetic nephropathy, renal hardening, glomerulonephritis, interstitial nephritis, lupus nephritis, prostate hyperplasia, chronic renal failure, renal tubular necrosis, diabetes-related kidney complications, diabetes-related kidney hypertrophy, type I diabetes, type II diabetes, metabolic syndrome, obesity, fatty liver, insulin resistance, hyperglycemia, adipose lipolysis, infection, Helicobacter pylori infection, influenza virus infection, fever, sepsis, lung disease, chronic obstructive pulmonary disease, acute respiratory distress syndrome, asthma, allergy, bronchitis, emphysema, pulmonary fibrosis, genetic developmental diseases, Noonan's syndrome, Crouzon syndrome, Apert syndrome, type I acrocephalosyndactyly,Pfeiffer syndrome, Jackson-Weiss syndrome, Costello syndrome, faciocutaneoskeletal syndrome, leopard syndrome, cardiac fascial syndrome, cardiovascular disease, skeletal disease, enteropathy, dermatopathy, trichopathy, or endocrinopathy, bone structure or mineralization disease, osteoporosis, increased risk of bone fracture, hypercalcemia, bone metastasis, Grave's disease, Hirschsprung disease, lymphedema, selective T cell deficiency, X-linked agammaglobulinemia, diabetic retinopathy, alopecia, erectile dysfunction, and tuberous sclerosis.

[0428] Combination therapy

[0429] In another aspect, the compounds of the present application (including all individual embodiments and generic subsets of the present application disclosed) or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, isotopically-labeled variations, hydrates or solvates thereof, and the pharmaceutical compositions or kits of the present application, can be used in combination or concurrently with at least one other active agent (e.g., an anticancer agent or regimen) to treat diseases and conditions.

[0430] The terms "in combination" and "concurrently" in this context mean that the agents are administered together, including substantially simultaneously, in the same or separate dosage forms, in the same or different modes of administration, or sequentially, e.g., as part of the same treatment regimen, or by consecutive treatment regimens. Thus, if dosed sequentially, in some cases, an effective concentration of the first of the two compounds can still be detectable at the treatment site at the time administration of the second compound is initiated. The sequence and interval can be determined so that they act together (e.g., synergistically to provide greater benefit than if administered otherwise). For example, the therapeutic agents can be administered concurrently or sequentially at different points in time in any order; however, if not administered concurrently, they can be administered in close enough

[0431] In some embodiments, the other active agent is selected from alkylating agents, including but not limited to, adozelesin, altretamine, bendamustine, bizelesin, busulfan, carboplatin, carboquone, carmofur, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, ethyleneimine, fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven, lomustine, mannosulfan, mechlorethamine, melphalan, mitobronitol, nedaplatin, nimustine, oxaliplatin, piposulfan, prednimustine, procarbazine, ranimustine, satraplatin, semustine, streptozocin, temozolomide, thiotepa, treosulfan, triethylenimelophenol, triethylenemelamine, triplatin tetranitrate, trofosphamide, and uramustine; antibiotics, including but not limited to, aclarubicin, amrubicin, bleomycin, dactinomycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, idarubicin, menogaril, mitomycin, neocarzinostatin, pentostatin, pirarubicin, plicamycin, valrubicin, and zorubicin;antimetabolites, including but not limited to aminopterin, azacitidine, azathioprine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed, tegafur-uracil, thioguanine, trimetrexate, and vidarabine; immunotherapies, antibody therapies, including but not limited to alemtuzumab, bevacizumab, cetuximab, galiximab, gemtuzumab, panitumumab, pertuzumab, rituximab, brentuximab, tositumomab, trastuzumab, 90Y ibritumomab tiuxetan, ipilimumab, tremelimumab, and anti-CTLA-4 antibodies; hormones or hormone antagonists, including but not limited to anastrozole, androgens, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprolide, magestrol, raloxifene, tamoxifen, and toremifene; taxanes, including but not limited to DJ-927, docetaxel, TPI 287, Larotaxel, ortataxel, paclitaxel, DHA-paclitaxel, and tesetaxel;retinoids, including but not limited to, alitretinoin, bexarotene, fenretinide, isotretinoin, and tretinoin; alkaloids, including but not limited to, demecolcine, homoharringtonine, vinblastine, vincristine, vindesine, vinflunine, and vinorelbine; anti-angiogenic agents, including but not limited to, AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide, and thalidomide; topoisomerase inhibitors, including but not limited to, amsacrine, belotecan, edotecarin, etoposide, etoposide phosphate, exatecan, irinotecan (and active metabolite SN-38 (7-ethyl-10-hydroxy-camptothecin)), lurtotecan, mitoxantrone, pixantrone, rubitecan, teniposide, topotecan, and 9-aminocamptothecan; kinase inhibitors, including but not limited to, axitinib (AG013736), dasatinib (BMS354825), erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib, motesanib diphosphate (AMG706), nilotinib (AMN107), seliciclib, sorafenib, sunitinib malate, AEE-788, BMS-599626, UCN-01 (7-hydroxystaurosporine), vemurafenib, dabrafenib, PLX3397, selumetinib, and vatalanib; targeted signaling inhibitors, including but not limited to, bortezomib, geldanamycin, and rapamycin; biological response modifiers, including but not limited to, imiquimod, interferon-alpha, interleukin-2;and other chemotherapeutic agents, including but not limited to 3-AP (3-amino-2- carboxymethylform hydrothiozone), altrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, elesclomol, eribulin mesylate (E7389), ixabepilone, lonidamine, masoprocol, mitoguanazone, oblimersen, sulindac, testolactone, tiazofurin, mTOR inhibitors (such as sirolimus, temsirolimus, everolimus, deforolimus), PI3K inhibitors (such as BEZ235, GDC-0941, XL147, XL765), Cdk4 inhibitors (such as PD-332991), Akt inhibitors, Hsp90 inhibitors (such as geldanamycin, radicicol, tanespimycin), farnesyl transferase inhibitors (such as tipifarnib), and aromatase inhibitors (letrozole, anastrozole, exemestane).

[0432] In some embodiments, the method of treating cancer comprises administering to the subject an effective amount of a composition comprising a compound of the present application (including all individual embodiments and generic subsets disclosed herein) or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, isotopically enriched variant, hydrate or solvate thereof, and a pharmaceutical composition or kit of the present application, and a chemotherapeutic agent selected from the group consisting of capecitabine, 5-fluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin, docetaxel, SN-38, temozolomide, vinblastine, bevacizumab, cetuximab, interferon-alpha, interleukin 2, and erlotinib.

[0433] In some embodiments, the chemotherapeutic agent is a Mek inhibitor. Exemplary Mek inhibitors include, but are not limited to, AS703026, AZD6244 (Selumetinib), AZD8330, BIX02188, CI-1040 (PD184352), GSK1120212 (JTP-74057), PD0325901, PD318088, PD98059, RDEA119 (BAY869766), TAK-733, and U0126-EtOH. In another embodiment, the chemotherapeutic agent is a tyrosine kinase inhibitor.Exemplary tyrosine kinase inhibitors include, but are not limited to, AEE788, AG- 1478 (Tyrphostin AG-1478), AG-490, apatinib (YN968D1), AV-412, AV-951 (Tivozanib), axitinib, AZD8931, BIBF1120 (Vargatef), BIBW2992 (afatinib), BMS794833, BMS-599626, brivanib (BMS-540215), alanine brivanib (BMS-582664), cediranib (AZD2171), chrysophanol (rheum emodin), Crenolanib (CP-868569), CUDC-101, CYC116, dolasitinib (TKI258 di-lactate), E7080, erlotinib hydrochloride (Tarceva, CP-358774, OSI-774, NSC-718781), foretinib (GSK1363089, XL880), gefitinib (ZD-1839 or Iressa), imatinib (Gleevec), imatinib mesylate, Ki8751, KRN633, lapatinib (Tykerb), linifanib (ABT-869), masitinib (Masivet, AB1010), MGCD-265, motesanib (AMG-706), MP-470, mulitinib (TAK165), neratinib (HKI-272), NVP-BHG712, OSI-420 (demethyl erlotinib, CP-473420), OSI-930, pazopanib hydrochloride, PD-153035 HCl, PD173074, pelitinib (EKB-569), PF299804, ponatinib (AP24534), PP121, RAF265 (CHIR-265), Raf265 derivatives, regorafenib (BAY73-4506), sorafenib tosylate (Nexavar), sunitinib malate (Sutent), tiranabine (BAY57-9352), TSU-68 (SU6668), vandetanib (Zactima), vatalanib (PTK787) dihydrochloride, WZ3146, WZ4002, WZ8040, XL-184 free base (cabozantinib), XL647, EGFR siRNA, FLT4 siRNA, KDR siRNA, anti-diabetic agents (e.g., metformin), PPAR agonists (rosiglitazone, pioglitazone, bezafibrate, ciprofibrate, clofibrate, gemfibrozil, fenofibrate, indeglitazar), and DPP4 inhibitors (sitagliptin, vildagliptin, saxagliptin, dutogliptin, gemigliptin, anagliptin).In some embodiments, the chemotherapeutic agent is an EGFR inhibitor. Exemplary EGFR inhibitors include, but are not limited to: AEE-788, AP-26113, BIBW-2992 (Tovok), CI-1033, GW-572016, Iressa, LY2874455, RO-5323441, Tarceva (erlotinib, OSI-774), CUDC-101, and WZ4002. In some embodiments, the chemotherapeutic agent is selected from the group consisting of: capecitabine, 5-fluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin, docetaxel, SN-38, temozolomide, vinblastine, bevacizumab, cetuximab, interferon-alpha, interleukin 2, or erlotinib.

[0434] In some embodiments, the compounds of the application (including all individual embodiments and generic subsets disclosed herein) or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, isotopic variants, hydrates, or solvates thereof, and the pharmaceutical compositions or kits of the application can be administered to a patient who has received another therapy, such as chemotherapy, radioimmunotherapy, surgical therapy, immunotherapy, radiation therapy, targeted therapy, or any combination thereof.

[0435] In some embodiments, the treatment regimen can include administration of the compounds of the application (including all individual embodiments and generic subsets disclosed herein) or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, isotopic variants, hydrates, or solvates thereof, and the pharmaceutical compositions or kits of the application in combination with one or more additional therapeutic agents known to treat a disease or condition, such as cancer. The dosage of the additional anticancer therapeutic agent can be the same as or even lower than the known or recommended dosage. Representative examples of other active agents and treatment regimens include radiation therapy, chemotherapeutic agents (such as mitotic inhibitors, angiogenesis inhibitors, anti-hormones, autophagy inhibitors, alkylating agents, intercalating antibiotics, growth factor inhibitors, anti-androgens, signal transduction pathway inhibitors, anti-microtubule agents, platinum coordination complexes, HDAC inhibitors, proteasome inhibitors, and topoisomerase inhibitors), immunomodulatory agents, therapeutic antibodies (such as monospecific and bispecific antibodies), and CAR-T therapies.

[0436] In some embodiments, the compound of the application (including all individual embodiments and generic subsets disclosed herein) or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, isotopic variant, hydrate, or solvate thereof, and the pharmaceutical composition or kit of the application, and an additional anti-cancer therapeutic agent can be administered within less than 5 minutes of each other, less than 30 minutes of each other, less than 1 hour of each other, about 1 hour of each other, about 1 to about 2 hours of each other, about 2 to about 3 hours of each other, about 3 to about 4 hours of each other, about 4 to about 5 hours of each other, about 5 to about 6 hours of each other, about 6 to about 7 hours of each other, about 7 to about 8 hours of each other, about 8 to about 9 hours of each other, about 9 to about 10 hours of each other, about 10 to about 11 hours of each other, about 11 to about 12 hours of each other, about 12 to 18 hours of each other, 18 to 24 hours of each other, 24 to 36 hours of each other, 36 to 48 hours of each other, 48 to 52 hours of each other, 52 to 60 hours of each other, 60 to 72 hours of each other, 72 to 84 hours of each other, 84 to 96 hours of each other, or 96 to 120 hours of each other. The two or more anti-cancer therapeutic agents can be administered during the same patient visit.

[0437] In some embodiments, the compound of the application (including all individual embodiments and generic subsets disclosed herein) or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, isotopic variant, hydrate, or solvate thereof, and the pharmaceutical composition or kit of the application, and an additional agent or therapeutic agent (e.g., an anti-cancer therapeutic agent) are administered periodically. For example, in the context of cancer treatment, a cycling therapy involves administering one anti-cancer therapeutic agent for a period of time, followed by administering a second anti-cancer therapeutic agent for a period of time and repeating this sequential administration, i.e., cycling, to reduce the development of resistance to one or both of the anti-cancer therapeutic agents, to avoid or reduce the side effects of one or both of the anti-cancer therapeutic agents, and / or to improve the efficacy of the treatment. In one embodiment, a cycling therapy involves administering a first anti-cancer therapeutic agent for a period of time, followed by administering a second anti-cancer therapeutic agent for a period of time, optionally, followed by administering a third anti-cancer therapeutic agent for a period of time, and so on, and repeating this sequential administration, i.e., cycling, to reduce the development of resistance to one of the anti-cancer therapeutic agents, to avoid or reduce the side effects of one of the anti-cancer therapeutic agents, and / or to improve the efficacy of the anti-cancer therapeutic agents.

[0438] In some embodiments, the compound of the application (including all individual embodiments and generic subsets disclosed herein) or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, isotopic variant, hydrate, or solvate thereof, and the pharmaceutical composition or kit of the application, can be used in combination with other anti-cancer agents.

[0439] Examples

[0440] The application will be further described in conjunction with specific examples. It should be understood that these examples are only intended to illustrate the application and are not intended to limit the scope of the application. The experimental methods in the following examples, unless otherwise specified, are generally carried out under conventional conditions or under the conditions recommended by the manufacturer. Unless otherwise specified, parts and percentages are parts by weight and percentages by weight.

[0441] Generally, 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 generally 0.1-60 hours, preferably 0.5-24 hours.

[0442] The abbreviations used in the application have the following meanings:

[0443] Synthesis of related intermediate compounds

[0444] Preparation of intermediate A-1 3-ethynyl-5-nitropyridin-2-amine

[0445] Synthesis using the following route:

[0446] Step 1 Synthesis of compound 5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine

[0447] 3-iodo-5-nitropyridin-2-amine (40.00 g, 150.94 mmol, 1.00 equiv.), ethynyltrimethylsilane (42.57 mL, 301.88 mmol, 2.00 equiv.), PdCl2(PPh3)2 (1.06 g, 1.51 mmol, 0.01 equiv.), CuI (0.87 g, 4.53 mmol, 0.03 equiv.) and DIPEA (78.73 mL, 452.82 mmol, 3.00 equiv.) were dissolved in anhydrous DMF (300 mL), and the reaction was stirred at room temperature for 2 hours after being replaced with nitrogen 3 times. The reaction was monitored by TLC. Water (300 mL) was added, and the mixture was extracted with EtOAc (300 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The yellow solid was separated by silica gel column chromatography to give 32.74 g, with a yield of 92.30%. LC-MS (ESI): m / z = 236.1 [M+H] + .

[0448] Step 2 Synthesis of intermediate A-1

[0449] Dissolve 5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine (32.74 g, 139.32 mmol, 1.00 equiv.) and TBAF (45.96 mL, 167.18 mmol, 1.20 equiv.) in anhydrous THF (300 mL), stir the reaction at room temperature for 1 hour, monitor the reaction completion by TLC. Add water (300 mL), filter to get the filter cake, wash with water, dry under suction, separate by silica gel column to get yellow solid 18.49 g, yield 81.40%. LC-MS (ESI): m / z = 164.0 [M+H] + .

[0450] Preparation of intermediate A-2 4-(1'-(4-iodophenyl)-[1,3'-biazetidinyl]-3-yl)benzyl piperazine-1-carboxylate

[0451] Synthesis by the following route:

[0452] Step 1 Synthesis of compound 4-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperazine-1-carboxylate

[0453] Dissolve benzyl-1-piperazinecarboxylate (10.00 g, 45.45 mmol, 1.00 equiv.), tert-butyl 3-oxoazetidine-1-carboxylate (10.10 g, 59.09 mmol, 1.30 equiv.), AcOH (13.00 mL, 227.25 mmol, 5.00 equiv.) and NaBH(OAc)3 (28.91 g, 136.35 mmol, 3.00 equiv.) in anhydrous DCM (150 mL), replace nitrogen 3 times, stir the reaction at room temperature for 3 hours, monitor the reaction completion by TLC. Add water (150 mL), and drop saturated sodium bicarbonate solution to adjust pH to neutral, extract with DCM (150 mL x 3), dry the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, separate by silica gel column to get colorless oil 15.82 g, yield 92.80%. LC-MS (ESI): m / z = 376.2 [M+H] + .

[0454] Step 2 Synthesis of compound 4-(azetidin-3-yl)piperazine-1-carboxylate

[0455] Benzyl 4-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperazine-1-carboxylate (5.00 g, 13.33 mmol, 1.00 equiv.) was dissolved in anhydrous DCM (20 mL), TFA (5.10 mL, 66.65 mmol, 5.00 equiv.) was added, the reaction was stirred at room temperature for 1 h, TLC monitoring reaction was completed. Added water (20 mL), and dropwise saturated sodium bicarbonate solution, the pH was adjusted to 8-9, extracted with DCM (20 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated by silica gel column to give colorless oil 3.12 g, yield 85.22%. LC-MS (ESI): m / z = 276.2 [M+H] + .

[0456] Step 3 Synthesis of compound tert-butyl 3-(4-((benzyloxy)carbonyl)piperazin-1-yl)-[1,3'- azetidinyl]-1'-carboxylate

[0457] Benzyl 4-(azetidin-3-yl)piperazine-1-carboxylate (3.10 g, 11.27 mmol, 1.00 equiv.), tert-butyl 3-oxoazetidine-1-carboxylate (2.89 g, 16.91 mmol, 1.50 equiv.), AcOH (3.22 mL, 56.35 mmol, 5.00 equiv.) and NaBH3CN (1.42 g, 22.54 mmol, 2.00 equiv.) were dissolved in anhydrous mixed solvent MeOH / DMF (100 mL / 10 mL), nitrogen was replaced 3 times, the reaction was stirred at 50 °C for 2 h, TLC monitoring reaction was completed. Lowered to room temperature, added water (100 mL), and dropwise saturated sodium bicarbonate solution, the pH was adjusted to 8-9, extracted with EtOAc (100 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated by silica gel column to give colorless oil 3.01 g, yield 62.20%. LC-MS (ESI): m / z = 431.3 [M+H] + .

[0458] Step 4 Synthesis of compound benzyl 4-([1,3'-azetidinyl]-3-yl)piperazine-1-carboxylate

[0459] Tert-butyl 3-(4-((benzyloxy)carbonyl)piperazin-1-yl)-[1,3'-azetidinyl]-1'- carboxylate (3.00 g, 6.98 mmol, 1.00 equiv.) was dissolved in anhydrous DCM (20 mL), TFA (2.67 mL, 34.90 mmol, 5.00 equiv.) was added, the reaction was stirred at room temperature for 1 h, TLC monitoring reaction was completed. Water (20 mL) was added, and the pH was adjusted to neutral by adding a saturated sodium bicarbonate solution, extracted with DCM (20 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column to give 1.80 g of colorless oil, with a yield of 78.30%. LC-MS (ESI): m / z = 331.2 [M+H] + .

[0460] Synthesis of intermediate A-2 in step 5

[0461] Benzyl 4-([1,3'-azetidinyl]-3-yl)piperazine-1-carboxylate (1.50 g, 4.55 mmol, 1.00 equiv.), 1,4-diiodobenzene (2.25 g, 6.83 mmol, 1.50 equiv.), Pd2(dba)3 (210.70 mg, 0.23 mmol, 0.05 equiv.), XantPhos (266.30 mg, 0.46 mmol, 0.10 equiv.) and NaO t Bu (1.31 g, 13.65 mmol, 3.00 equiv.) was dissolved in anhydrous 1,4-dioxane (50 mL), and the reaction was stirred at 110°C for 2 h after being replaced with nitrogen 3 times. TLC monitoring reaction was completed. The temperature was lowered to room temperature, water (50 mL) was added, and the mixture was extracted with EtOAc (50 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column to give 1.23 g of yellow solid, with a yield of 51.02%. LC-MS (ESI): m / z = 533.1 [M+H] + .

[0462] Preparation of intermediate A-3 benzyl 3-(4-(1-(4-iodophenyl)azetidin-3-yl)piperazin-1- yl)azetidine-1-carboxylate

[0463] The following route was used for synthesis:

[0464] Step 1 Synthesis of compound tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate

[0465] Benzyl 3-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperazin-1-yl)azetidine-1- carboxylate (5.00 g, 13.33 mmol, 1.00 equiv.) was dissolved in MeOH (20 mL), 10% palladium on carbon (wetted with 55% H2O, 1.58 g, 0.67 mmol, 0.05 equiv.) was added, the reaction was purged with hydrogen gas 3 times, stirred at room temperature for 3 hours under 1 atmosphere of hydrogen gas, TLC monitoring showed the reaction was complete. The palladium on carbon was filtered off, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column to give 2.97 g of colorless oil, with a yield of 92.51%. LC-MS (ESI): m / z = 242.2 [M+H] + .

[0466] Step 2 Synthesis of compound benzyl 3-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperazin-1- yl)azetidine-1-carboxylate

[0467] Benzyl 3-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperazin-1-yl)azetidine-1-carboxylate (5.00 g, 13.33 mmol, 1.00 equiv.) was dissolved in MeOH (20 mL), 10% palladium on carbon (wetted with 55% H2O, 1.58 g, 0.67 mmol, 0.05 equiv.) was added, the reaction was purged with hydrogen gas 3 times, stirred at room temperature for 3 hours under 1 atmosphere of hydrogen gas, TLC monitoring showed the reaction was complete. The palladium on carbon was filtered off, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column to give 2.97 g of colorless oil, with a yield of 92.51%. LC-MS (ESI): m / z = 242.2 [M+H] + .

[0468] Step 3 Synthesis of compound benzyl 3-(4-(azetidin-3-yl)piperazin-1-yl)azetidine-1-carboxylate

[0469] Benzyl 3-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperazin-1-yl)azetidine-1- carboxylate (4.50 g, 10.47 mmol, 1.00 equiv.) was dissolved in anhydrous DCM (30 mL), TFA (4.01 mL, 52.35 mmol, 5.00 equiv.) was added, the reaction was stirred at room temperature for 1 h, TLC monitoring showed that the reaction was completed. Water (30 mL) was added, and a saturated sodium bicarbonate solution was added dropwise to adjust the pH to 8-9, extracted with DCM (30 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated on a silica gel column to give 2.95 g of yellow solid, with a yield of 85.30%. LC-MS (ESI): m / z = 331.2 [M+H] + .

[0470] Synthesis of intermediate A-3

[0471] Benzyl 3-(4-(azetidin-3-yl)piperazin-1-yl)azetidine-1-carboxylate (2.90 g, 8.79 mmol, 1.00 equiv.), 1,4-diiodobenzene (4.35 g, 13.19 mmol, 1.50 equiv.), Pd2(dba)3 (403.00 mg, 0.44 mmol, 0.05 equiv.), XantPhos (509.50 mg, 0.88 mmol, 0.10 equiv.) and NaO t Bu (2.53 g, 26.37 mmol, 3.00 equiv.) was dissolved in anhydrous 1,4-dioxane (50 mL), and the reaction was stirred at 120°C for 2 h after being replaced with nitrogen 3 times. TLC monitoring showed that the reaction was completed. The temperature was lowered to room temperature, water (50 mL) was added, and the mixture was extracted with EtOAc (50 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated on a silica gel column to give 2.49 g of yellow solid, with a yield of 53.14%. LC-MS (ESI): m / z = 533.1 [M+H] + .

[0472] Preparation of intermediate A-4 tert-butyl [3,3'-azetidinium]-1-carboxylate

[0473] The following route was used for synthesis:

[0474] Step 1 Synthesis of compound 1-benzhydrylazetidin-3-yl methanesulfonate

[0475] Dissolve 1-benzhydrylazetidin-3-ol (15.00 g, 62.76 mmol, 1.00 equiv.) and TEA (13.06 mL, 94.14 mmol, 1.50 equiv.) in anhydrous DCM (150 mL), replace nitrogen 3 times, cool to -20 °C, and stir the reaction. Add MsCl (5.85 mL, 75.31 mmol, 1.20 equiv.) dropwise using a syringe, and allow the reaction to proceed for 30 min, monitoring by TLC. Allow the reaction to warm to room temperature, add water (50 mL), and dropwise add saturated sodium bicarbonate solution to adjust the pH to neutral. Extract with DCM (150 mL x 3), wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Separate the yellow solid by silica gel column chromatography to obtain 18.92 g of a yellow solid at a yield of 95.12%. LC-MS (ESI): m / z = 318.1 [M+H] + .

[0476] Step 2 Synthesis of compound 2-(1-benzhydrylazetidin-3-yl)propane-1,3-diol

[0477] Dissolve diethyl malonate (17.70 mL, 116.72 mmol, 2.00 equiv.) and NaH (2.80 g, 116.72 mmol, 2.00 equiv.) in anhydrous DMF (100 mL), replace nitrogen 3 times, and stir at room temperature for 20 min. Then, slowly inject 1-benzhydrylazetidin-3-yl methanesulfonate (18.50 g, 58.36 mmol, 1.00 equiv.) dissolved in anhydrous DMF (20 mL) into the bottle and stir the reaction for 2 h. Then, allow the reaction to warm to 70 °C and stir overnight, monitoring by TLC. Allow the reaction to cool to room temperature, add water (100 mL), and extract with EtOAc (100 mL x 3). Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Separate the yellow oil by silica gel column chromatography to obtain 20.31 g of a yellow oil at a yield of 91.32%. LC-MS (ESI): m / z = 382.2 [M+H] + .

[0478] Step 3 Synthesis of compound 2-(1-benzhydrylazetidin-3-yl)propane-1,3-diol

[0479] Diethyl 2-(1-benzhydrylazetidin-3-yl)propanedioate (20.00 g, 52.49 mmol, 1.00 equiv.) was dissolved in anhydrous THF (200 mL), purged with nitrogen 3 times, LiAIH4(50.39 mL, 125.98 mmol, 2.5 M in THF, 2.40 equiv.) was added dropwise by syringe, the reaction was stirred at room temperature overnight, TLC monitored the reaction was complete. Sodium sulfate decahydrate was added at 0 °C to quench, after no obvious gas was released, a small amount of water was added, stirred at room temperature for 15 minutes, the solid was removed by filtration, water (100 mL) was added, extracted with EtOAc (200 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column to give colorless oil 12.30 g, yield 78.90%. LC-MS (ESI): m / z = 298.2 [M+H] + .

[0480] Step 4 Synthesis of compound tert-butyl 3-(1,3-dihydroxypropan-2-yl)azetidine-1-carboxylate

[0481] 2-(1-Benzhydrylazetidin-3-yl)propane-1,3-diol (12.00 g, 40.40 mmol, 1.00 equiv.) was dissolved in MeOH (150 mL), 20% palladium hydroxide on carbon (wetted with 50% H2O, 1.13 g, 0.81 mmol, 0.02 equiv.) was added, purged with hydrogen 3 times, after stirring at room temperature for 16 hours under 1 atmosphere of hydrogen atmosphere, Boc2O (10.57 g, 48.48 mmol, 1.20 equiv.) was added, continue to stir at room temperature for 3 hours, TLC monitored the reaction was complete. The palladium hydroxide on carbon was filtered off, the filtrate was concentrated under reduced pressure, and separated by silica gel column to give colorless oil 8.80 g, yield 94.29%. LC-MS (ESI): m / z = 232.2 [M+H] + .

[0482] Step 5 Synthesis of compound tert-butyl 3-(1,3-dibromopropan-2-yl)azetidine-1-carboxylate

[0483] PPh3(28.93 g, 110.40 mmol, 3.00 equiv.) and Br2(5.66 mL, 110.40 mmol, 3.00 equiv.) were dissolved in anhydrous DCM (150 mL), and the solution was stirred at 0 °C for 1 h after being replaced with nitrogen for 3 times. TEA (15.32 mL, 110.40 mmol, 3.00 equiv.) was added, and 3-(1,3-dihydroxypropan-2-yl)azetidine-1-carboxylic acid tert-butyl ester (8.50 g, 36.80 mmol, 1.00 equiv.) dissolved in anhydrous DCM (20 mL) was slowly injected into the bottle. The reaction was stirred at room temperature for 5 h, and TLC monitoring showed that the reaction was complete. Saturated sodium sulfite solution (150 mL) was added, and the organic phase was extracted with DCM (150 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The white solid was obtained by silica gel column separation, and the yield was 11.05 g (84.57%). LC-MS (ESI): m / z = 356.0 [M+H] + .

[0484] Step 6 Synthesis of compound 1'-benzyl-[3,3'-azetidine]-1-carboxylic acid tert-butyl ester

[0485] 3-(1,3-dibromopropan-2-yl)azetidine-1-carboxylic acid tert-butyl ester (11.00 g, 30.99 mmol, 1.00 equiv.), BnNH2(6.63 g, 61.98 mmol, 2.00 equiv.) and DIPEA (26.94 mL, 154.95 mmol, 5.00 equiv.) were dissolved in anhydrous MeCN (150 mL), and the solution was stirred at 82 °C for overnight after being replaced with nitrogen for 3 times. TLC monitoring showed that the reaction was complete. The reaction was cooled to room temperature, water (150 mL) was added, and the organic phase was extracted with EtOAc (150 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The yellow oil was obtained by silica gel column separation, and the yield was 9.06 g (96.76%). LC-MS (ESI): m / z = 303.2 [M+H] + .

[0486] Step 7 Synthesis of intermediate A-4 oxalate salt

[0487] Dissolve 1 '-benzyl-[3,3'-aziridine]-1 -carboxylic acid tert-butyl ester (9.00 g, 29.80 mmol, 1.00 equiv.) and oxalic acid (1.34 g, 14.90 mmol, 0.50 equiv.) in MeOH (150 mL), add 10% palladium on carbon (wetted with 55% H2O, 3.51 g, 1.49 mmol, 0.05 equiv.), charge with hydrogen gas 3 times, stir at room temperature for 36 hours under 6 atmospheres of hydrogen gas, monitor the reaction completion by TLC. Filter off the palladium on carbon, concentrate the filtrate under reduced pressure, slurry in a mixture of ethanol / methyl tert-butyl ether (20 / 1) to get white solid 5.78 g, yield 75.50%. LC-MS (ESI): m / z = 213.2 [M+H] + .

[0488] Preparation of intermediate A-5 1 -(4-iodophenyl)-[3, 1':3',3"- triaziridine]-1 "-carboxylic acid tert-butyl ester

[0489] Synthesis is carried out using the following route:

[0490] Step 1 Synthesis of compound 1 -(4-iodophenyl)aziridine-3-ol

[0491] Dissolve 1,4-diiodobenzene (6.60 g, 20.00 mmol, 1.00 equiv.), 3-hydroxyaziridine hydrochloride (2.64 g, 24.00 mmol, 1.20 equiv.), Pd2(dba)3(916.00 mg, 1.00 mmol, 0.05 equiv.), XantPhos (1.16 g, 2.00 mmol, 0.10 equiv.) and Cs2CO3(19.56 g, 60.00 mmol, 3.00 equiv.) in anhydrous 1,4-dioxane (100 mL), charge with nitrogen gas 3 times, warm up to 100 °C, stir the reaction for 2 hours, monitor the reaction completion by TLC. Cool down to room temperature, add water (100 mL), extract with EtOAc (100 mL x 3), dry the organic phase over anhydrous sodium sulfate, filter, concentrate under reduced pressure, separate over a silica gel column to get pale yellow solid 1.98 g, yield 35.96%. LC-MS (ESI): m / z = 276.0 [M+H] + .

[0492] Step 2 Synthesis of compound 1 -(4-iodophenyl)aziridine-3-one

[0493] 1-(4-iodophenyl)azacyclobutane-3-ol (1.90 g, 6.91 mmol, 1.00 equiv.) and DMP (3.52 g, 8.29 mmol, 1.20 equiv.) were dissolved in anhydrous DCM (60 mL). The mixture was stirred at 0 °C for 2 hours, and the reaction was monitored by TLC until completion. Water (60 mL) was added, followed by dropwise addition of saturated sodium thiosulfate solution and saturated sodium bicarbonate solution. The mixture was extracted with DCM (60 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography to give 1.10 g of a pale yellow solid, yield 58.26%. LC-MS (ESI): m / z = 274.0 [M + H] + .

[0494] Step 3 Synthesis of intermediate A-5

[0495] 1-(4-iodophenyl)azacyclobut-3-one (1.00 g, 3.66 mmol, 1.00 equiv.), intermediate A-4 oxalate (1.88 g, 7.32 mmol, 2.00 equiv.), AcOH (0.63 mL, 10.98 mmol, 3.00 equiv.), and DIPEA (1.27 mL, 7.32 mmol, 2.00 equiv.) were dissolved in anhydrous MeOH (50 mL). The mixture was purged with nitrogen three times. NaBH3CN (461.20 mg, 7.32 mmol, 2.00 equiv.) dissolved in anhydrous MeOH (5 mL) was slowly injected into the flask. The mixture was heated to 50 °C and stirred for 3 hours. The reaction was monitored by TLC until it was complete. Add water (50 mL), extract with EtOAc (50 mL × 3), wash the organic phase with saturated brine, dry to anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate by silica gel column chromatography to give 845.70 mg of white solid, yield 49.27%. LC-MS (ESI): m / z = 470.1 [M + H] + .

[0496] Preparation of intermediate A-6 2-(4-bromophenyl)-5-nitro-1H-pyrrolo[2,3-b]pyridine

[0497] Synthesized using the following route:

[0498] Step 1: Synthesis of compound 3-((4-bromophenyl)ethynyl)-5-nitropyridine-2-amine

[0499] To a solution of 3-iodo-5-nitropyridin-2-amine (10.00 g, 37.74 mmol, 1.00 equiv.), (4-bromophenyl)ethynyl (7.51 g, 41.51 mmol, 1.10 equiv.), PdCl2(PPh3)2 (533.50 mg, 0.76 mmol, 0.02 equiv.), Cul (431.70 mg, 2.26 mmol, 0.06 equiv.) and TEA (15.71 mL, 113.22 mmol, 3.00 equiv.) in anhydrous DMF (100 mL) was purged with nitrogen for 3 times, the reaction was stirred at room temperature for 4 hours, TLC monitoring reaction was completed. Added water (100 mL), extracted with EtOAc (100 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated by silica gel column to get yellow solid 10.82 g, yield 90.45%. LC-MS (ESI): m / z = 318.0 [M+H] + .

[0500] Synthesis of intermediate A-6 in Step 2

[0501] To a solution of 3-((4-bromophenyl)ethynyl)-5-nitropyridin-2-amine (10.80 g, 34.07 mmol, 1.00 equiv.) and KO t Bu (7.63 g, 68.14 mmol, 2.00 equiv.) in anhydrous DMF (100 mL) was purged with nitrogen for 3 times, the reaction was stirred at 80 °C for 30 minutes, TLC monitoring reaction was completed. Lowered to room temperature, added water (100 mL), filtered, the filter cake was washed with water, dried, separated by silica gel column to get yellow solid 9.80 g, yield 90.77%. LC-MS (ESI): m / z = 318.0 [M+H] + .

[0502] Preparation of intermediate A-7 tert-butyl 2-(4-hydroxypiperidin-4-yl)acetate

[0503] The following synthetic route was used:

[0504] Step 1 Synthesis of compound benzyl 4-(2-(tert-butoxy)-2-oxoethyl)-4- hydroxypiperidine-1-carboxylate

[0505] tert-Butyl acetate (5.97 g, 51.50 mmol, 1.20 equiv.) was dissolved in anhydrous THF (100 mL), purged with nitrogen gas for 3 times, cooled to -78 °C and stirred, LDA (2 M in THF, 42.92 mL, 85.84 mmol, 2.00 equiv.) was added dropwise by syringe, the reaction was continued for 30 min, 4-oxopiperidine-1-carboxylic acid benzyl ester (10.00 g, 42.92 mmol, 1.00 equiv.) dissolved in anhydrous THF (10 mL) was added dropwise, the reaction was continued for 2 h, TLC monitoring showed that the reaction was completed. Saturated ammonium chloride solution (50 mL) was added, the temperature was raised to room temperature, extracted with EtOAc (100 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated on a silica gel column to obtain 12.01 g of yellow oil, with a yield of 80.15%. LC-MS (ESI): m / z = 350.2 [M+H] + .

[0506] Synthesis of intermediate A-7 in step 2

[0507] Benzyl 4-(2-(tert-butoxy)-2-oxoethyl)-4-hydroxypiperidine-1-carboxylate (12.00 g, 34.36 mmol, 1.00 equiv.) was dissolved in MeOH (150 mL), 10% Pd / C (wetted with 55% H2O, 4.05 g, 1.72 mmol, 0.05 equiv.) was added, purged with hydrogen gas for 3 times, stirred at room temperature under 1 atm of hydrogen gas overnight, TLC monitoring showed that the reaction was completed. The palladium carbon was filtered off, the filtrate was concentrated under reduced pressure, and separated on a silica gel column to obtain 6.29 g of white solid, with a yield of 85.10%. LC-MS (ESI): m / z = 216.2 [M+H] + .

[0508] Preparation of intermediate A-8 tert-butyl 4-((1-(4-iodophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate

[0509] The following synthesis route was used:

[0510] tert-Butyl 4-(piperidin-4-ylmethyl)piperazine-1 -carboxylate (1.60 g, 5.65 mmol, 1.00 equiv.), 4-iodobenzenboronic acid (2.80 g, 11.30 mmol, 2.00 equiv.), Cu(OAc)2(1.23 g, 6.78 mmol, 1.20 equiv.) and pyridine (0.91 mL, 11.30 mmol, 2.00 equiv.) were dissolved in anhydrous DCM (50 mL), purged with oxygen for 3 times, stirred at room temperature for 48 hours, TLC monitored that the reaction was completed. Water (50 mL) was added, extracted with EtOAc (50 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated by silica gel column to get yellow solid 479.50 mg, yield 17.50%. LC-MS (ESI): m / z = 486.2 [M+H] + .

[0511] Preparation of intermediate A-9 (1-(4-iodophenyl)piperidin-4-yl)methanol

[0512] The following synthetic route was used:

[0513] Step 1 Synthesis of compound (1-(4-nitrophenyl)piperidin-4-yl)methanol

[0514] p-Fluoronitrobenzene (5.00 g, 35.46 mmol, 1.00 equiv.), 4-hydroxymethylpiperidine (5.30 g, 46.10 mmol, 1.30 equiv.) and DIPEA (18.50 mL, 106.38 mmol, 3.00 equiv.) were dissolved in anhydrous DMSO (100 mL), purged with nitrogen for 3 times, stirred at 120 °C for 2 hours, TLC monitored that the reaction was completed. Lowered to room temperature, added water (200 mL), filtered to get the filter cake, washed with water, dried, separated by silica gel column to get yellow solid 8.30 g, yield 99.35%. LC-MS (ESI): m / z = 237.1 [M+H] + .

[0515] Step 2 Synthesis of compound (1-(4-aminophenyl)piperidin-4-yl)methanol

[0516] (1-(4-nitrophenyl)piperidin-4-yl)methanol (8.20 g, 34.75 mmol, 1.00 equiv.) was dissolved in MeOH (100 mL), 10% Pd / C (wetted with 55% H2O, 4.10 g, 1.74 mmol, 0.05 equiv.) was added, and the reaction was stirred at room temperature under 1 atm of hydrogen overnight with TLC monitoring. The palladium carbon was filtered off, and the filtrate was concentrated under reduced pressure. The red-brown solid was separated on a silica gel column to give 6.45 g in 90.10% yield. LC-MS (ESI): m / z = 207.1 [M+H] + .

[0517] Synthesis of intermediate A-9 in Step 3

[0518] (1-(4-aminophenyl)piperidin-4-yl)methanol (6.40 g, 31.07 mmol, 1.00 equiv.) was dissolved in concentrated hydrochloric acid (50 mL, 12 M) at 0 °C, NaNO2(2.36 g, 34.18 mmol, 1.10 equiv.) was added, and the reaction was stirred at 0 °C for 30 min. An aqueous solution (100 mL) of KI (20.63 g, 124.28 mmol, 4.00 equiv.) was added, the reaction was purged with nitrogen three times, the temperature was raised to 90 °C, and the reaction was stirred for 1 h with TLC monitoring. The reaction was cooled to room temperature, water (100 mL) was added, and the pH was adjusted to neutral by dropwise addition of saturated sodium bicarbonate solution. The organic phase was extracted with DCM (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The yellow solid was separated on a silica gel column to give 7.22 g in 73.30% yield. LC-MS (ESI): m / z = 318.0 [M+H] + .

[0519] Preparation of intermediate A-10 4-(1,3-dioxolan-2-yl)-1-(4-iodophenyl)piperidine

[0520] The following synthetic route was used:

[0521] Synthesis of compound 1-(4-iodophenyl)piperidine-4-carbaldehyde in Step 1

[0522] Intermediate A-9 (7.00 g, 22.08 mmol, 1.00 equiv.) and DMP (14.04 g, 33.12 mmol, 1.50 equiv.) were dissolved in anhydrous DCM (100 mL), the reaction was stirred at room temperature for 1 h, TLC monitoring reaction was completed. Added water (100 mL), dropwise saturated sodium thiosulfate solution, then dropwise saturated sodium bicarbonate solution, extracted with DCM (100 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated by silica gel column to get white solid 5.25 g, yield 75.50%. LC-MS (ESI): m / z = 316.0 [M+H] + .

[0523] Synthesis of intermediate A-10 in step 2

[0524] 1-(4-iodophenyl)piperidine-4-carbaldehyde (5.20 g, 16.51 mmol, 1.00 equiv.), ethylene glycol (4.60 mL, 82.55 mmol, 5.00 equiv.) and TsOH H2O (313.50 mg, 1.65 mmol, 0.10 equiv.) were dissolved in toluene (100 mL), heated to 100 °C and stirred overnight, TLC monitoring reaction was completed. Lowered to room temperature, added water (100 mL), extracted with EtOAc (100 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated by silica gel column to get yellow solid 5.42 g, yield 91.40%. LC-MS (ESI): m / z = 360.0 [M+H] + .

[0525] Preparation of intermediate A-11 (1-(4-ethynylphenyl)piperidin-4-yl)methyl methanesulfonate

[0526] The following synthetic route was used:

[0527] Step 1 Synthesis of compound (1-(4-((trimethylsilyl)ethynyl)phenyl)piperidin-4-yl)methanol

[0528] Intermediate A-9 (2.00 g, 6.31 mmol, 1.00 equiv.), ethynyltrimethylsilane (1.78 mL, 12.62 mmol, 2.00 equiv.), PdCl2(PPh3)2 (224.60 mg, 0.32 mmol, 0.05 equiv.), CuI (181.50 mg, 0.95 mmol, 0.15 equiv.) and TEA (2.63 mL, 18.93 mmol, 3.00 equiv.) were dissolved in anhydrous DMF (20 mL), the reaction was stirred at 50 °C for 2 h after 3 times of nitrogen replacement. The reaction was monitored by TLC. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was separated by silica gel column to give brown oil 1.54 g in 84.84% yield. LC-MS (ESI): m / z = 288.2 [M+H] + .

[0529] Step 2 Synthesis of compound (1-(4-ethynylphenyl)piperidin-4-yl)methanol

[0530] (1-(4-((trimethylsilyl)ethynyl)phenyl)piperidin-4-yl)methanol (1.50 g, 5.23 mmol, 1.00 equiv.) and TBAF (1.73 mL, 6.28 mmol, 1.20 equiv.) were dissolved in anhydrous THF (20 mL) and stirred at room temperature for 1 h. The reaction was monitored by TLC. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was separated by silica gel column to give yellow solid 1.03 g in 91.46% yield. LC-MS (ESI): m / z = 216.1 [M+H] + .

[0531] Step 3 Synthesis of intermediate A-11

[0532] Intermediate A-12 Preparation of tert-butyl 7-((l-(4-ethynylphenyl)piperidin-4- yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate + .

[0533] Intermediate A-12 Preparation of tert-butyl 7-((l-(4-ethynylphenyl)piperidin-4- yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0534] The following synthetic route was employed:

[0535] Intermediate A-12 Preparation of tert-butyl 7-((l-(4-ethynylphenyl)piperidin-4- yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate + .

[0536] Intermediate A-12 Preparation of tert-butyl 7-((l-(4-ethynylphenyl)piperidin-4- yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0537] The following synthetic route was employed:

[0538] Intermediate A-11 (1.00 g, 3.41 mmol, 1.00 equiv.), tert-butyl 2,6-diazaspiro[3,3]heptane-2- carboxylate oxalate (1.83 g, 3.75 mmol, 1.10 equiv.) and K2CO3 (1.88 g, 13.64 mmol, 4.00 equiv.) were dissolved in anhydrous MeCN (20 mL), and the reaction was stirred at 100 °C for 2 h after being purged with nitrogen for 3 times. The reaction was monitored by TLC. After cooling to room temperature, water (20 mL) was added, and the mixture was extracted with EtOAc (20 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give yellow solid 1.11 g in 82.61% yield. LC-MS (ESI): m / z = 396.3 [M+H] + .

[0539] Preparation of intermediate A-14 1-(4-iodophenyl)piperidin-4-one

[0540] The following synthetic route was used:

[0541] Step 1 Synthesis of compound 1-(4-nitrophenyl)piperidin-4-ol

[0542] p-Fluoronitrobenzene (4.00 g, 28.37 mmol, 1.00 equiv.), piperidin-4-ol (3.73 g, 36.88 mmol, 1.30 equiv.) and DIPEA (14.80 mL, 85.11 mmol, 3.00 equiv.) were dissolved in anhydrous DMSO (100 mL), and the reaction was stirred at 120 °C for 2 h after being purged with nitrogen for 3 times. The reaction was monitored by TLC. After cooling to room temperature, water (200 mL) was added, and the mixture was filtered to give a filter cake, which was washed with water, dried, and separated by silica gel column chromatography to give yellow solid 6.06 g in 96.24% yield. LC-MS (ESI): m / z = 223.1 [M+H] + .

[0543] Step 2 Synthesis of compound 1-(4-aminophenyl)piperidin-4-ol

[0544] Dissolve 1-(4-nitrophenyl)piperidin-4-ol (6.00 g, 27.03 mmol, 1.00 equiv.) in MeOH (100 mL), add 10% Pd / C (wetted with 55% H2O, 3.18 g, 1.35 mmol, 0.05 equiv.), stir at room temperature under 1 atm of hydrogen overnight, monitor the reaction by TLC. Filter off the palladium carbon, concentrate the filtrate under reduced pressure, separate by silica gel column to get 4.72 g of brown solid, yield 91.03%. LC-MS (ESI): m / z = 193.1 [M+H] + .

[0545] Step 3 Synthesis of compound 1-(4-iodophenyl)piperidin-4-ol

[0546] Dissolve 1-(4-aminophenyl)piperidin-4-ol (4.70 g, 24.48 mmol, 1.00 equiv.) in concentrated hydrochloric acid (50 mL, 12 M) at 0 °C, add NaNO2(1.86 g, 26.93 mmol, 1.10 equiv.) and stir the reaction at 0 °C for 30 min, add a solution of KI (16.25 g, 97.92 mmol, 4.00 equiv.) in H2O (100 mL), replace with nitrogen 3 times, warm to 90 °C and stir the reaction for 1 h, monitor the reaction by TLC. Cool to room temperature, add water (100 mL) and dropwise saturated sodium bicarbonate solution to adjust the pH to neutral, extract with DCM (100 mL x 3), dry the organic phase over anhydrous sodium sulfate, filter, concentrate under reduced pressure and separate by silica gel column to get 5.28 g of yellow solid, yield 71.22%. LC-MS (ESI): m / z = 304.0 [M+H] + .

[0547] Step 4 Synthesis of intermediate A-14

[0548] Dissolve 1-(4-iodophenyl)piperidin-4-ol (5.20 g, 17.16 mmol, 1.00 equiv.) and DMP (10.91 g, 25.74 mmol, 1.50 equiv.) in anhydrous DCM (100 mL), stir the reaction at room temperature for 1 h, monitor the reaction by TLC. Add water (100 mL), dropwise saturated sodium thiosulfate solution, dropwise saturated sodium bicarbonate solution, extract with DCM (100 mL x 3), dry the organic phase over anhydrous sodium sulfate, filter, concentrate under reduced pressure and separate by silica gel column to get 3.34 g of yellow solid, yield 64.70%. LC-MS (ESI): m / z = 302.0 [M+H] + .

[0549] Preparation of Intermediate A-15 8-(4-iodophenyl)-1,4-dioxa-8-azaspiro[4.5]decane

[0550] The following synthetic route was employed:

[0551] Intermediate A-14 (3.30 g, 10.96 mmol, 1.00 equiv.), ethylene glycol (3.05 mL, 54.80 mmol, 5.00 equiv.) and TsOH H2O (209.00 mg, 1.10 mmol, 0.10 equiv.) were dissolved in toluene (100 mL), warmed to 100 °C and stirred overnight, TLC monitored the reaction was completed. Cooled to room temperature, added water (100 mL), extracted with EtOAc (100 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated by silica gel column to give 3.33 g of colorless solid, yield 88.00%. LC-MS (ESI): m / z = 346.0 [M+H] + .

[0552] Preparation of Intermediate A-16 tert-butyl 6-(1-(4-iodophenyl)piperidin-4-yl)-2,6- diazaspiro[3.3]heptane-2-carboxylate

[0553] The following synthetic route was employed:

[0554] Intermediate A-14 (1.00 g, 3.32 mmol, 1.00 equiv.), tert-butyl 2,6-diazaspiro[3,3]heptane-2- carboxylate oxalate (1.62 g, 3.32 mmol, 1.00 equiv.), DIPEA (1.15 mL, 6.64 mmol, 2.00 equiv.), AcOH (0.95 mL, 16.60 mmol, 5.00 equiv.) and NaBH3CN (418.30 mg, 6.64 mmol, 2.00 equiv.) were dissolved in anhydrous mixed solvent MeOH / DMF (15 mL / 5 mL), replaced with nitrogen for 3 times, warmed to 50 °C and stirred overnight, TLC monitored the reaction was completed. Cooled to room temperature, added water (20 mL), and added dropwise saturated sodium bicarbonate solution, adjusted the pH to neutral, extracted with EtOAc (20 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated by silica gel column to give 1.20 g of yellow solid, yield 74.83%. LC-MS (ESI): m / z = 484.1 [M+H] + .

[0555] Preparation of intermediate A-17 tert-butyl 3-((1-(4-iodophenyl)piperidin-4- yl)oxy)azetidine-1-carboxylate

[0556] The following synthetic route was employed:

[0557] Step 1 Synthesis of tert-butyl 3-(pyridin-4-yloxy)azetidine-1-carboxylate

[0558] N-Boc-3-hydroxyazetidine (2.00 g, 11.56 mmol, 1.00 equiv.) and NaH (60% wt, 1.39 g, 34.68 mmol, 3.00 equiv.) were dissolved in anhydrous DMSO (20 mL), purged with nitrogen gas for 3 times, stirred at room temperature for 5 minutes, then 4-chloropyridine hydrochloride (1.73 g, 11.56 mmol, 1.00 equiv.) was added into the bottle, stirred at room temperature overnight, TLC monitored that the reaction was completed. Water (20 mL) was added, extracted with EtOAc (20 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated by silica gel column to get yellow oil 1.48 g, yield 51.13%. LC-MS (ESI): m / z = 251.1 [M+H] + .

[0559] Step 2 Synthesis of tert-butyl 3-(piperidin-4-yloxy)azetidine-1-carboxylate

[0560] Tert-butyl 3-(pyridin-4-yloxy)azetidine-1-carboxylate (1.40 g, 5.60 mmol, 1.00 equiv.) and TsOH (963.20 mg, 5.60 mmol, 1.00 equiv.) were dissolved in anhydrous EtOH (15 mL), PtO2(63.60 mg, 0.28 mmol, 0.05 equiv.) was added, purged with hydrogen gas for 3 times, stirred at room temperature for 48 hours under the atmosphere of 1 atmosphere of hydrogen gas, TLC monitored that the reaction was completed. The solid was filtered off, the filtrate was concentrated under reduced pressure, separated by silica gel column to get yellow oil 1.32 g, yield 91.91%. LC-MS (ESI): m / z = 257.2 [M+H] + .

[0561] Step 3 Synthesis of intermediate A-17

[0562] tert-Butyl 3-(piperidin-4-yloxy)azetidine-1 -carboxylate (1.30 g, 5.08 mmol, 1.00 equiv.), 1,4-diiodobenzene (1.68 g, 5.08 mmol, 1.00 equiv.), Pd2(dba)3(229.00 mg, 0.25 mmol, 0.05 equiv.), XantPhos (295.30 mg, 0.51 mmol, 0.10 equiv.) and NaO t Bu (1.46 g, 15.24 mmol, 3.00 equiv.) was dissolved in anhydrous 1,4-dioxane (20 mL), purged with nitrogen for 3 times, and stirred at 100 °C for 2 h after warming up. The reaction was monitored by TLC. After cooling down to room temperature, water (20 mL) was added, and the mixture was extracted with EtOAc (20 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The yellow solid (1.36 g) was obtained by silica gel column separation with a yield of 58.64%. LC-MS (ESI): m / z = 459.1 [M+H] + .

[0563] Preparation of intermediate A-18 tert-butyl 6-((1-(4-iodophenyl)piperidin-4-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate

[0564] The following synthetic route was used:

[0565] Step 1 Synthesis of tert-butyl 6-(pyridin-4-yloxy)-2-azaspiro[3.3]heptane-2-carboxylate

[0566] tert-Butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (2.80 g, 13.15 mmol, 1.00 equiv.) and NaH (60% wt, 1.58 g, 39.45 mmol, 3.00 equiv.) were dissolved in anhydrous DMSO (20 mL), purged with nitrogen for 3 times, and stirred at room temperature for 5 min. Then 4-chloropyridine hydrochloride (1.97 g, 13.15 mmol, 1.00 equiv.) was added to the bottle, and the reaction was stirred at room temperature overnight. The reaction was monitored by TLC. After adding water (20 mL), the mixture was extracted with EtOAc (20 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The yellow solid (3.55 g) was obtained by silica gel column separation with a yield of 93.14%. LC-MS (ESI): m / z = 291.2 [M+H] + .

[0567] Step 2 Synthesis of compound 1 -benzyl-4-((2-(tert-butoxycarbonyl)-2- azaspiro[3.3]heptan-6-yl)oxy)pyridin-1-ium

[0568] Dissolve 6-(pyridin-4-yloxy)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (2.00 g, 6.90 mmol, 1.00 equiv.) and BnBr (0.90 mL, 7.59 mmol, 1.10 equiv.) in anhydrous MeCN (15 mL), purge with nitrogen for 3 times, warm up to 80 °C, stir the reaction overnight, monitor the reaction by TLC. Concentrate under reduced pressure to get 2.20 g of brown oil, yield 69.20%. LC-MS (ESI): m / z = 382.2 [M+H] + .

[0569] Step 3 Synthesis of compound 6-((1 -benzyl-1,2,3,6-tetrahydropyridin-4-yl)oxy)-2- azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0570] Dissolve 1 -benzyl-4-((2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)oxy)pyridin- 1 -ium (2.20 g, 4.77 mmol, 1.00 equiv.) in anhydrous MeOH (20 mL), slowly add NaBH4 (1.09 g, 28.62 mmol, 6.00 equiv.) in batches, stir the reaction at room temperature for 1 hour, monitor the reaction by TLC. Add water (20 mL), and drop saturated sodium bicarbonate solution to adjust the pH to neutral, extract with EtOAc (20 mL x 3), dry the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, separate by silica gel column to get 1.80 g of white solid, yield 98.27%. LC-MS (ESI): m / z = 385.2 [M+H] + .

[0571] Step 4 Synthesis of compound 6-(piperidin-4-yloxy)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0572] tert-Butyl 6-((l-benzyl-l,2,3,6-tetrahydropyridin-4-yl)oxy)-2-azaspiro[3.3]heptane-2- carboxylate (1.80 g, 4.69 mmol, 1.00 equiv.) was dissolved in MeOH (15 mL), 10% Pd / C (wetted with 55% H2O, 565.30 mg, 0.24 mmol, 0.05 equiv.) was added, the reaction was stirred at room temperature under 6 atm of hydrogen overnight, TLC monitored the reaction was complete. The palladium carbon was filtered off, the filtrate was concentrated under reduced pressure, and the yellow oil was separated by silica gel column to give 1.10 g, 79.24% yield. LC-MS (ESI): m / z = 297.2 [M+H] + .

[0573] Synthesis of intermediate A-18

[0574] tert-Butyl 6-(piperidin-4-yloxy)-2-azaspiro[3.3]heptane-2-carboxylate (500.00 mg, 1.69 mmol, 1.00 equiv.), 1,4-diiodobenzene (838.20 mg, 2.54 mmol, 1.50 equiv.), Pd2(dba)3 (82.40 mg, 0.09 mmol, 0.05 equiv.), XantPhos (98.40 mg, 0.17 mmol, 0.10 equiv.) and NaO t Bu (486.70 mg, 5.07 mmol, 3.00 equiv.) was dissolved in anhydrous 1,4-dioxane (15 mL), purged with nitrogen 3 times, and stirred at 120 °C for 2 hours. The reaction was monitored by TLC. The temperature was lowered to room temperature, water (15 mL) was added, and the mixture was extracted with EtOAc (15 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The yellow solid was separated by silica gel column to give 620.00 mg, 73.67% yield. LC-MS (ESI): m / z = 499.1 [M+H] + .

[0575] Preparation of intermediate A-19 tert-Butyl 7-((l-(4-iodophenyl)piperidin-4-yl)oxy)-2-azaspiro[3.5]nonane-2-carboxylate

[0576] The following synthetic route was used:

[0577] Step 1 Synthesis of compound tert-Butyl 7-(pyridin-4-yloxy)-2-azaspiro[3.5]nonane-2-carboxylate

[0578] tert-Butyl 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate (2.00 g, 8.30 mmol, 1.00 equiv.) and NaH (60% wt, 1.00 g, 24.90 mmol, 3.00 equiv.) were dissolved in anhydrous DMSO (20 mL), stirred for 5 min at room temperature, then 4-chloropyridine hydrochloride (1.25 g, 8.30 mmol, 1.00 equiv.) was added to the bottle, stirred at room temperature overnight, TLC monitored the reaction was completed. Added water (20 mL), extracted with EtOAc (20 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated by silica gel column to get yellow oil 2.49 g, yield 94.33%. LC-MS (ESI): m / z = 319.2 [M+H] + .

[0579] Step 2 Synthesis of compound 1-benzyl-4-((2-(tert-butoxycarbonyl)-2- azaspiro[3.5]nonan-7-yl)oxy)pyridin-1-ium

[0580] tert-Butyl 7-(pyridin-4-yloxy)-2-azaspiro[3.5]nonane-2-carboxylate (2.40 g, 7.55 mmol, 1.00 equiv.) and BnBr (0.90 mL, 7.55 mmol, 1.00 equiv.) were dissolved in anhydrous MeCN (15 mL), stirred at 80 °C for 3 times, the reaction was completed. TLC monitored, concentrated under reduced pressure to get brown oil 3.06 g, yield 99.00%. LC-MS (ESI): m / z = 410.3 [M+H] + .

[0581] Step 3 Synthesis of compound tert-butyl 7-((1-benzyl-1,2,3,6-tetrahydropyridin-4- yl)oxy)-2-azaspiro[3.5]nonane-2-carboxylate

[0582] To a solution of 7-((1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)oxy)-2- azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (2.70 g, 6.55 mmol, 1.00 equiv.) in MeOH (15 mL) was added 10% Pd / C (wetted with 55% H2O, 777.30 mg, 0.33 mmol, 0.05 equiv.) and the reaction mixture was stirred under a hydrogen atmosphere at 6 atm for 18 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give 7-((1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)oxy)-2- azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (854.40 mg, 40.26% yield) as a yellow oil. LC-MS (ESI): m / z = 325.2 [M+H] + .

[0583] Step 4. Synthesis of compound 7-(piperidin-4-yloxy)-2-azaspiro[3.5]nonane-2- carboxylic acid tert-butyl ester

[0584] To a solution of 7-((1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)oxy)-2- azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (2.70 g, 6.55 mmol, 1.00 equiv.) in MeOH (15 mL) was added 10% Pd / C (wetted with 55% H2O, 777.30 mg, 0.33 mmol, 0.05 equiv.) and the reaction mixture was stirred under a hydrogen atmosphere at 6 atm for 18 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give 7-((1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)oxy)-2- azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (854.40 mg, 40.26% yield) as a yellow oil. LC-MS (ESI): m / z = 325.2 [M+H] + .

[0585] Step 5. Synthesis of intermediate A-19

[0586] To a solution of 7-(piperidin-4-yloxy)-2-azaspiro[3.5]nonane-2-carboxylic acid tert- butyl ester (840.00 mg, 2.59 mmol, 1.00 equiv.), 1,4-diiodobenzene (854.70 mg, 2.59 mmol, 1.00 equiv.), Pd2(dba)3 (119.10 mg, 0.13 mmol, 0.05 equiv.), XantPhos (150.50 mg, 0.26 mmol, 0.10 equiv.) and NaO tBu (745.90 mg, 7.77 mmol, 3.00 equiv.) was dissolved in anhydrous 1,4-dioxane (15 mL), and the reaction was stirred at 120 °C for 2 h after being purged with nitrogen for 3 times. TLC was used to monitor the completion of the reaction. The reaction was cooled to room temperature, water (15 mL) was added, and the mixture was extracted with EtOAc (15 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give 770.00 mg of a yellow solid in a yield of 56.52%. LC-MS (ESI): m / z = 527.2 [M+H] + .

[0587] Preparation of intermediate A-19a tert-butyl 3-(pyridin-4-ylmethyl)azetidine-1-carboxylate

[0588] The following synthetic route was used:

[0589] Step 1. Synthesis of tert-butyl 3-((9-borabicyclo[3.3.1]nonan-9-yl)methyl)azetidine-1-carboxylate

[0590] 1-Boc-3-methyleneazetidine (2.00 g, 11.83 mmol, 1.00 equiv.) and 9-BBN (0.5 M in THF, 23.66 mL, 11.83 mmol, 1.00 equiv.) were dissolved in anhydrous THF (5 mL), and the reaction was stirred at 65 °C for 2 h after being purged with nitrogen for 3 times. The reaction was cooled to room temperature, and the next step was directly added.

[0591] Step 2. Synthesis of intermediate A-19a

[0592] To the reaction solution of the previous step, 4-bromopyridine hydrochloride (2.31 g, 11.83 mmol, 1.00 equiv.), PdCl2(dppf)·DCM (482.00 mg, 0.59 mmol, 0.05 equiv.), and K3PO4 (7.52 g, 35.49 mmol, 3.00 equiv.) were added, and the mixture was supplemented with mixed solvents THF / H2O (15 mL / 5 mL). The reaction was stirred at 65 °C for 2 h after being purged with nitrogen for 3 times. The reaction was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with EtOAc (30 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give 1.50 g of a brown oil in a two-step yield of 51.26%. LC-MS (ESI): m / z = 249.2 [M+H] + .

[0593] Preparation of intermediate A-20 tert-butyl 3-((1-(4-iodophenyl)piperidin-4-yl)methyl)azetidine-1-carboxylate

[0594] The following synthetic route was employed:

[0595] Step 1 Synthesis of tert-butyl 3-(piperidin-4-ylmethyl)azetidine-1-carboxylate

[0596] Intermediate A-19a (500.00 mg, 2.02 mmol, 1.00 equiv.) and PtO2(45.40 mg, 0.20 mmol, 0.10 equiv.) were dissolved in AcOH (5 mL), purged with hydrogen gas for 3 times, stirred at room temperature for 16 hours under 1 atmosphere of hydrogen gas, TLC monitored that the reaction was completed. The solid was filtered off, the filtrate was concentrated under reduced pressure, separated by silica gel column to get 473.11 mg of yellow oil, yield 92.21%. LC-MS (ESI): m / z = 255.2 [M+H] + .

[0597] Step 2 Synthesis of intermediate A-20

[0598] Tert-butyl 3-(piperidin-4-ylmethyl)azetidine-1-carboxylate (450.00 mg, 1.77 mmol, 1.00 equiv.), 1,4-diiodobenzene (584.10 mg, 1.77 mmol, 1.00 equiv.), Pd2(dba)3(82.40 mg, 0.09 mmol, 0.05 equiv.), XantPhos (104.22 mg, 0.18 mmol, 0.10 equiv.) and NaO t Bu (509.80 mg, 5.31 mmol, 3.00 equiv.) were dissolved in anhydrous 1,4-dioxane (10 mL), purged with nitrogen gas for 3 times, stirred at 100°C for 2 hours, TLC monitored that the reaction was completed. Cooled to room temperature, added water (10 mL), extracted with EtOAc (10 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated by silica gel column to get 323.40 mg of yellow solid, yield 40.07%. LC-MS (ESI): m / z = 457.1 [M+H] + .

[0599] Preparation of intermediate A-21 tert-butyl 3-((1-(4-iodophenyl)-1,2,3,6-tetrahydropyridin-4-yl)methyl)azetidine-1-carboxylate

[0600] The following synthetic route was employed:

[0601] Step 1 Synthesis of compound 1-benzyl-4-((1-(tert-butoxycarbonyl)azetidin-3- yl)methyl)pyridin-1-ium

[0602] Intermediate A-19a (700.00 mg, 2.82 mmol, 1.00 equiv.) and BnBr (0.37 mL, 3.10 mmol, 1.10 equiv.) were dissolved in anhydrous MeCN (15 mL), and the reaction was stirred at 80 °C for 16 h after being purged with nitrogen for 3 times. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed under reduced pressure, and methyl tert-butyl ether was added and stirred, filtered to obtain a yellow solid 867.90 mg, with a yield of 73.63%. LC-MS (ESI): m / z = 340.2 [M+H] + .

[0603] Step 2 Synthesis of compound tert-butyl 3-((1-benzyl-1,2,3,6-tetrahydropyridin-4- yl)methyl)azetidine-1-carboxylate

[0604] 1-benzyl-4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)pyridin-1-ium (850.00 mg, 2.03 mmol, 1.00 equiv.) was dissolved in anhydrous MeOH (10 mL), and NaBH4 (462.84 mg, 12.18 mmol, 6.00 equiv.) was added slowly in portions. The reaction was stirred at room temperature for 1 h, and the reaction was monitored by TLC. Water (10 mL) was added, and a saturated sodium bicarbonate solution was added dropwise to adjust the pH to neutral. The mixture was extracted with EtOAc (10 mL x 3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The white solid was separated by silica gel column chromatography to obtain 548.10 mg with a yield of 78.95%. LC-MS (ESI): m / z = 343.2 [M+H] + .

[0605] Step 3 Synthesis of compound tert-butyl 3-((1,2,3,6-tetrahydropyridin-4- yl)methyl)azetidine-1-carboxylate

[0606] tert-Butyl 3-((1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methyl)azetidine-1- carboxylate (500.00 mg, 1.46 mmol, 1.00 equiv.) was dissolved in anhydrous DCM (10 mL), 1-chloroethyl chloroformate (0.32 mL, 2.92 mmol, 2.00 equiv.) was added at 0 °C, the reaction was warmed to room temperature and stirred for 16 h, MeOH (2 mL) was added and stirred for 2 h, TLC monitoring showed that the reaction was completed. Water (10 mL) was added, and saturated sodium bicarbonate solution was added dropwise, extracted with DCM (10 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated on a silica gel column to give white solid 161.10 mg, with a yield of 43.79%. LC-MS (ESI): m / z = 253.2 [M+H] + .

[0607] Synthesis of intermediate A-21

[0608] tert-Butyl 3-((1,2,3,6-tetrahydropyridin-4-yl)methyl)azetidine-1-carboxylate (160.00 mg, 0.64 mmol, 1.00 equiv.), 1,4-diiodobenzene (211.20 mg, 0.64 mmol, 1.00 equiv.), Pd2(dba)3 (27.50 mg, 0.03 mmol, 0.05 equiv.), XantPhos (34.70 mg, 0.06 mmol, 0.10 equiv.) and NaO t Bu (184.30 mg, 1.92 mmol, 3.00 equiv.) was dissolved in anhydrous 1,4-dioxane (10 mL), and the reaction was stirred at 100 °C for 2 h after being replaced with nitrogen for 3 times. TLC monitoring showed that the reaction was completed. The reaction was cooled to room temperature, water (10 mL) was added, and the organic phase was extracted with EtOAc (10 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated on a silica gel column to give yellow solid 142.20 mg, with a yield of 48.95%. LC-MS (ESI): m / z = 455.1 [M+H] + .

[0609] Preparation of intermediate A-22 tert-butyl 6-(4-iodophenoxy)-2-azaspiro[3.3]heptane-2-carboxylate

[0610] The following synthetic route was used:

[0611] tert-Butyl 6-hydroxy-2-azaspiro[3.3]octane-2-carboxylate (388.00 mg, 1.82 mmol, 1.00 equiv.), 4-iodophenol (502.00 mg, 2.28 mmol, 1.25 equiv.), PPh3 (715.30 mg, 2.73 mmol, 1.50 equiv.) and DIAD (551.50 mg, 2.73 mmol, 1.50 equiv.) were dissolved in anhydrous THF (10 mL), and the reaction was stirred at room temperature for 12 hours after being replaced with nitrogen for 3 times. The reaction was monitored by TLC. Water (10 mL) was added, and the mixture was extracted with EtOAc (10 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain 700.00 mg of a yellow solid with a yield of 92.68%. LC-MS (ESI): m / z = 416.1 [M+H] + .

[0612] Preparation of intermediate A-23 tert-butyl 9-(4-iodophenoxy)-3-azaspiro[5.5]undecane-3-carboxylate

[0613] The following synthetic route was used:

[0614] According to the preparation method of intermediate A-22, tert-butyl 9-hydroxy-3- azaspiro[5.5]undecane-3-carboxylate was used to replace tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate as the raw material to prepare intermediate A-23.

[0615] Preparation of intermediate A-24 tert-butyl 4-(4-iodophenoxy)piperidine-1-carboxylate

[0616] The following synthetic route was used:

[0617] According to the preparation method of intermediate A-22, N-Boc-4-hydroxypiperidine was used to replace tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate as the raw material to prepare intermediate A-24.

[0618] Preparation of intermediate A-25 tert-butyl 4-((4-iodo-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate

[0619] The following synthetic route was used:

[0620] Step 1 Synthesis of compound tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate

[0621] N-Boc-4-piperidinemethanol (1.00 g, 4.65 mmol, 1.00 equiv.) and TEA (0.97 mL, 6.98 mmol, 1.50 equiv.) were dissolved in anhydrous DCM (15 mL), and the solution was purged with nitrogen for 3 times. MsCl (0.43 mL, 5.58 mmol, 1.20 equiv.) was added dropwise at 0 °C with a syringe, and the solution was allowed to warm to room temperature. The reaction was stirred for 3 hours, and TLC was used to monitor the completion of the reaction. Water (10 mL) was added, and the pH was adjusted to neutral by dropwise addition of saturated sodium bicarbonate solution. The solution was extracted with DCM (10 mL x 3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column to obtain 1.24 g of yellow solid with a yield of 90.82%. LC-MS (ESI): m / z = 294.1 [M+H] + .

[0622] Synthesis of intermediate A-25

[0623] tert-Butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (1.20 g, 4.10 mmol, 1.00 equiv.), 4-iodopyrazole (1.19 g, 6.15 mmol, 1.50 equiv.), and KO t Bu (688.80 mg, 6.15 mmol, 1.50 equiv.) were dissolved in anhydrous DMA (10 mL), and the solution was purged with nitrogen for 3 times. The solution was allowed to warm to 70 °C and stirred for 12 hours. The reaction was monitored by TLC. The solution was allowed to cool to room temperature, water (10 mL) was added, and the solution was extracted with EtOAc (10 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column to obtain 1.53 g of yellow solid with a yield of 95.64%. LC-MS (ESI): m / z = 392.1 [M+H] + .

[0624] Preparation of intermediate A-26 tert-butyl 4-(4-iodo-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0625] The following synthetic route was used:

[0626] According to the preparation method of intermediate A-25, N-Boc-4-hydroxypiperidine was used to replace N-Boc-4-piperidinemethanol as the raw material to prepare intermediate A-26.

[0627] Preparation of intermediate A-27 tert-butyl 3-(4-iodo-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate

[0628] The following synthetic route was adopted:

[0629] 1-Boc-3-iodopyrrolidine (1.00 g, 3.37 mmol, 1.00 equiv.), 4-iodopyrazole (981.60 mg, 5.06 mmol, 1.50 equiv.) and Cs2CO3 (1.65 g, 5.06 mmol, 1.50 equiv.) were dissolved in anhydrous DMF (10 mL), and the reaction was stirred at 100 °C for 5 h after being replaced with nitrogen for 3 times. TLC monitoring showed that the reaction was completed. After cooling to room temperature, water (10 mL) was added, and the organic phase was extracted with EtOAc (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The white solid was separated by silica gel column chromatography, and 982.90 mg was obtained in a yield of 80.35%. LC-MS (ESI): m / z = 364.0 [M+H] + .

[0630] Preparation of Intermediate A-28 tert-butyl 3-(4-iodo-1H-pyrazol-1-yl)azetidine-1-carboxylate

[0631] The following synthetic route was adopted:

[0632] According to the preparation method of Intermediate A-27, 1-Boc-3-iodoazetidine was used to replace 1-Boc-3-iodopyrrolidine as the raw material to prepare Intermediate A-28.

[0633] Preparation of Intermediate A-29 tert-butyl 6-(4-iodo-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0634] The following synthetic route was adopted:

[0635] According to the preparation method of Intermediate A-25, 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester was used to replace N-Boc-4-piperidinemethanol as the raw material to prepare Intermediate A-29.

[0636] Preparation of Intermediate A-30 tert-butyl 7-(4-iodophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0637] The following synthetic route was adopted:

[0638] tert-Butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (1.00 g, 4.43 mmol, 1.00 equiv.), 1,4-diiodobenzene (1.46 g, 4.43 mmol, 1.00 equiv.), Pd2(dba)3 (201.50 mg, 0.22 mmol, 0.05 equiv.), XantPhos (254.80 mg, 0.44 mmol, 0.10 equiv.) and NaO t Bu (1.28 g, 13.29 mmol, 3.00 equiv.) was dissolved in anhydrous 1,4-dioxane (15 mL), purged with nitrogen for 3 times, warmed to 100 °C and stirred for 2 hours, TLC monitoring reaction was completed. Lowered to room temperature, added water (15 mL), extracted with EtOAc (15 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated by silica gel column to give yellow solid 1.13 g, yield 59.47%. LC-MS (ESI): m / z = 429.1 [M+H] + .

[0639] Preparation of intermediate A-30a 7-(4-iodophenyl)-2,7-diazaspiro[3.5]nonane

[0640] The following synthetic route was adopted:

[0641] According to the synthetic method of step 2 in the preparation method of intermediate B-2, intermediate A-30a was prepared by replacing 3-(4-(4-(5-(4,5-dimethyl-1H-pyrazole-3-carboxamido)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)piperazin-1-yl)azetidine-1-carboxylic acid tert-butyl ester as the raw material.

[0642] Preparation of intermediate A-31 tert-butyl 3-(7-(4-iodophenyl)-2,7-diazaspiro[3.5]nonan-2-yl)azetidine-1-carboxylate

[0643] The following synthetic route was adopted:

[0644] According to the synthetic method of step 1 in the preparation method of intermediate B-2, intermediate A-31 was prepared by replacing intermediate B-1 with intermediate A-30a as the raw material.

[0645] Preparation of intermediate A-32 tert-butyl 9-(4-iodophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

[0646] The following synthetic route was employed:

[0647] According to the method for preparing intermediate A-30, 2-Boc-2,8-diazaspiro[4.5]decane was used to replace 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester as the raw material to prepare intermediate A-33.

[0648] Preparation of intermediate A-33 tert-butyl 8-(4-iodophenyl)-2,8-diazaspiro[4.5]decane-2-carboxylate

[0649] The following synthetic route was employed:

[0650] According to the method for preparing intermediate A-30, 2-Boc-2,8-diazaspiro[4.5]decane was used to replace 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester as the raw material to prepare intermediate A-33.

[0651] Preparation of intermediate A-34 tert-butyl 2-(4-iodophenyl)-2,8-diazaspiro[4.5]decane-8-carboxylate

[0652] The following synthetic route was employed:

[0653] According to the method for preparing intermediate A-30, 2-Boc-2,8-diazaspiro[4.5]decane was used to replace 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester as the raw material to prepare intermediate A-33.

[0654] Preparation of intermediate A-35 tert-butyl 2-(4-iodophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

[0655] The following synthetic route was employed:

[0656] According to the method for preparing intermediate A-30, 2-Boc-2,8-diazaspiro[4.5]decane was used to replace 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester as the raw material to prepare intermediate A-33.

[0657] Preparation of intermediate A-36 tert-butyl 6-(4-iodophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0658] The following synthetic route was employed:

[0659] According to the preparation method of intermediate A-30, 2,6-diazaspiro[3.3]heptane-2- carboxylic acid tert-butyl ester was replaced with 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester as raw material to prepare intermediate A-36.

[0660] Preparation of intermediate B-1 4,5-dimethyl-N-(2-(4-(piperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-carboxamide

[0661] The following route was adopted for synthesis:

[0662] Step 1 Synthesis of compound 4-(4-((trimethylsilyl)ethynyl)phenyl)piperazine-1-carboxylate

[0663] 4-(4-iodophenyl)piperazine-1-carboxylic acid tert-butyl ester (49.00 g, 126.00 mmol, 1.00 equiv.), ethynyltrimethylsilane (35.54 mL, 252.00 mmol, 2.00 equiv.), PdCl2(PPh3)2 (4.42 g, 6.30 mmol, 0.05 equiv.), CuI (2.41 g, 12.60 mmol, 0.10 equiv.) and TEA (87.40 mL, 630.00 mmol, 5.00 equiv.) were dissolved in anhydrous DMF (250 mL), and the mixture was stirred at room temperature for 5 h after being replaced with nitrogen for 3 times. Water (250 mL) was added, and the mixture was extracted with EtOAc (250 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column to obtain 43.50 g of yellow solid, with a yield of 96.44%. LC-MS (ESI): m / z = 359.2 [M+H] + .

[0664] Step 2 Synthesis of compound 4-(4-ethynylphenyl)piperazine-1-carboxylate

[0665] Tert-butyl 4-(4-((trimethylsilyl)ethynyl)phenyl)piperazine-1 -carboxylate (43.50 g, 121.51 mmol, 1.00 equiv.) and K2CO3(50.31 g, 364.53 mmol, 3.00 equiv.) were dissolved in anhydrous MeOH (850 mL), the reaction was stirred at room temperature for 2 hours, TLC monitoring reaction was completed. Added water (500 mL), extracted with EtOAc (500 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated by silica gel column to get yellow solid 32.50 g, yield 93.52%. LC-MS (ESI): m / z = 287.2 [M+H] + .

[0666] Step 3 Synthesis of tert-butyl 4-(4-((2-amino-5-nitropyridin-3-yl)ethynyl)phenyl)piperazine-1- carboxylate

[0667] Tert-butyl 4-(4-ethynylphenyl)piperazine-1 -carboxylate (32.50 g, 113.64 mmol, 1.10 equiv.), 3-bromo-5-nitropyridin-2-amine (22.52 g, 103.31 mmol, 1.00 equiv.), PdCl2(PPh3)2(3.63 g, 5.17 mmol, 0.05 equiv.), CuI (1.97 g, 10.33 mmol, 0.10 equiv.) and TEA (71.66 mL, 516.55 mmol, 5.00 equiv.) were dissolved in anhydrous DMF (200 mL), nitrogen was replaced 3 times, the temperature was raised to 80°C, the reaction was stirred for 16 hours, TLC monitoring reaction was completed. Lowered to room temperature, added water (200 mL), extracted with EtOAc (200 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated by silica gel column to get yellow solid 39.55 g, yield 90.50%. LC-MS (ESI): m / z = 424.2 [M+H] + .

[0668] Step 4 Synthesis of tert-butyl 4-(4-(5-nitro-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)piperazine-1- carboxylate

[0669] Tert-butyl 4-(4-((2-amino-5-nitropyridin-3-yl)ethynyl)phenyl)piperazine-1 -carboxylate (39.55 g, 93.50 mmol, 1.00 equiv.) and KO tBu (31.42 g, 280.50 mmol, 3.00 equiv.) was dissolved in anhydrous DMF (300 mL), and the reaction was stirred at 100 °C for 30 min after being purged with nitrogen three times. The reaction was monitored by TLC. After cooling to room temperature, water (300 mL) was added, and the mixture was extracted with EtOAc (300 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give 35.28 g of a yellow solid in a yield of 89.20%. LC-MS (ESI): m / z = 424.2 [M+H] + .

[0670] Step 5 Synthesis of compound tert-butyl 4-(4-(5-amino-1H-pyrrolo[2,3-b]pyridin-2- yl)phenyl)piperazine-1-carboxylate

[0671] tert-Butyl 4-(4-(5-nitro-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)piperazine-1-carboxylate (35.28 g, 83.40 mmol, 1.00 equiv.), B2(OH)4 (22.52 g, 250.20 mmol, 3.00 equiv.), and 4,4'-Bipyridine (0.26 g, 1.67 mmol, 0.02 equiv.) were dissolved in anhydrous DMF (200 mL), and the reaction was stirred at room temperature for 2 h after being purged with nitrogen three times. The reaction was monitored by TLC. Water (200 mL) was added, and the mixture was extracted with EtOAc (200 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give 29.96 g of a yellow solid in a yield of 91.40%. LC-MS (ESI): m / z = 394.2 [M+H] + .

[0672] Step 6 Synthesis of compound tert-butyl 4-(4-(5-(4,5-dimethyl-1H-pyrazole-3-carboxamido)- 1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)piperazine-1-carboxylate

[0673] Tert-butyl 4-(4-(5-amino-lH-pyrrolo[2,3-b]pyridin-2-yl)phenyl)piperazine-l- carboxylate (29.96 g, 76.23 mmol, 1.00 equiv.), 4,5-dimethyl-lH-pyrazole-3- carboxylic acid (16.01 g, 114.35 mmol, 1.50 equiv.), PyBOP (59.46 g, 114.35 mmol, 1.50 equiv.) and DIPEA (26.51 mL, 152.46 mmol, 2.00 equiv.) were dissolved in anhydrous DMF (200 mL), and the reaction was stirred at room temperature for 2 hours after being replaced with nitrogen for 3 times. The reaction was monitored by TLC. Water (200 mL) was added, and the mixture was extracted with EtOAc (200 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain 34.19 g of yellow solid with a yield of 87.10%. LC-MS (ESI): m / z = 516.3 [M+H] + .

[0674] Synthesis of intermediate B-1 in step 7

[0675] Tert-butyl 4-(4-(5-(4,5-dimethyl-lH-pyrazole-3-carboxamido)-lH-pyrrolo[2,3- b]pyridin-2-yl)phenyl)piperazine-l-carboxylate (34.19 g, 66.40 mmol, 1.00 equiv.) was dissolved in anhydrous DCM (200 mL), and TFA (25.42 mL, 332.00 mmol, 5.00 equiv.) was added. The reaction was stirred at room temperature for 1 hour, and the reaction was monitored by TLC. Water (200 mL) was added, and the pH was adjusted to 8-9 by dropwise addition of a saturated sodium bicarbonate solution. The mixture was extracted with EtOAc (200 mL x 3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain 23.42 g of yellow solid with a yield of 85.00%. LC-MS (ESI): m / z = 416.2 [M+H] + .

[0676] Preparation of intermediate B-2 N-(2-(4-(4-(azetidin-3-yl)piperazin-l-yl)phenyl)-lH- pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-lH-pyrazole-3-carboxamide

[0677] Synthesis using the following route:

[0678] Step 1. Synthesis of tert-butyl 3-(4-(4-(5-(4,5-dimethyl-1H-pyrazole-3-carboxamido)- 1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)piperazin-1-yl)azetidine-1-carboxylate

[0679] Intermediate B-1 (2.00 g, 4.82 mmol, 1.00 equiv.), tert-butyl 3-oxoazetidine-1-carboxylate (2.47 g, 14.46 mmol, 3.00 equiv.), AcOH (0.83 mL, 14.46 mmol, 3.00 equiv.) and NaBH3CN (607.30 mg, 9.64 mmol, 2.00 equiv.) were dissolved in anhydrous mixed solvent MeOH / DMF (150 mL / 50 mL), and the reaction was stirred at room temperature overnight after being replaced with nitrogen for 3 times. TLC monitoring showed that the reaction was completed. Water (200 mL) was added, and the pH was adjusted to neutral by dropwise addition of saturated sodium bicarbonate solution. The product was extracted with EtOAc (200 mL x 3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain 2.30 g of a gray solid with a yield of 83.92%. LC-MS (ESI): m / z = 571.3 [M+H] + .

[0680] Step 2. Synthesis of intermediate B-2

[0681] Tert-butyl 3-(4-(4-(5-(4,5-dimethyl-1H-pyrazole-3-carboxamido)-1H-pyrrolo[2,3-b]pyridin-2- yl)phenyl)piperazin-1-yl)azetidine-1-carboxylate (2.30 g, 4.04 mmol, 1.00 equiv.) was dissolved in anhydrous DCM (20 mL), and TFA (1.55 mL, 20.20 mmol, 5.00 equiv.) was added. The reaction was stirred at room temperature for 1 hour, and TLC monitoring showed that the reaction was completed. Water (20 mL) was added, and the pH was adjusted to 8-9 by dropwise addition of saturated sodium bicarbonate solution. The product was extracted with EtOAc (20 mL x 3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain 1.73 g of a gray solid with a yield of 91.30%. LC-MS (ESI): m / z = 471.3 [M+H] + .

[0682] Preparation of intermediate B-3 N-(2-(4-(4-([1,3'-azetazetidine]-3-yl)piperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide

[0683] The following route was used for the synthesis:

[0684] Step 1 Synthesis of compound 3-(4-(4-(5-(4,5-dimethyl-1H-pyrazole-3-carboxamido)- 1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)piperazin-1-yl)-[1,3'-azetidin]-1'-carboxylic acid tert-butyl ester

[0685] Intermediate B-2 (2.00 g, 4.26 mmol, 1.00 equiv.), 3-oxoazetidine-1-carboxylic acid tert-butyl ester (2.19 g, 12.78 mmol, 3.00 equiv.), AcOH (0.73 mL, 12.78 mmol, 3.00 equiv.) and NaBH3CN (536.80 mg, 8.52 mmol, 2.00 equiv.) were dissolved in anhydrous mixed solvent MeOH / DMF (150 mL / 50 mL), and the reaction was stirred at room temperature overnight after being replaced with nitrogen for 3 times. The reaction was monitored by TLC. Water (200 mL) was added, and the pH was adjusted to neutral by adding a saturated sodium bicarbonate solution dropwise. The organic phase was extracted with EtOAc (200 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting product was separated by silica gel column chromatography to obtain 1.74 g of a gray solid, with a yield of 65.40%. LC-MS (ESI): m / z = 626.4 [M+H] + .

[0686] Step 2 Synthesis of intermediate B-3

[0687] Intermediate B-2 (2.00 g, 4.26 mmol, 1.00 equiv.), 3-oxoazetidine-1-carboxylic acid tert-butyl ester (2.19 g, 12.78 mmol, 3.00 equiv.), AcOH (0.73 mL, 12.78 mmol, 3.00 equiv.) and NaBH3CN (536.80 mg, 8.52 mmol, 2.00 equiv.) were dissolved in anhydrous mixed solvent MeOH / DMF (150 mL / 50 mL), and the reaction was stirred at room temperature overnight after being replaced with nitrogen for 3 times. The reaction was monitored by TLC. Water (200 mL) was added, and the pH was adjusted to neutral by adding a saturated sodium bicarbonate solution dropwise. The organic phase was extracted with EtOAc (200 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting product was separated by silica gel column chromatography to obtain 1.74 g of a gray solid, with a yield of 65.40%. LC-MS (ESI): m / z = 626.4 [M+H] + .

[0688] Preparation of intermediate B-4 4,5-dimethyl-N-(2-(4-(3-(piperazin-1-yl)-[1,3'-biazetidin]-1'-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-carboxamide

[0689] Synthesis was performed using the following route:

[0690] Step 1 Synthesis of compound 4-(1'-(4-((2-amino-5-nitropyridin-3-yl)ethynyl)phenyl)-[1,3'-biazetidin]-3-yl)piperazine-1-carboxylate benzyl ester

[0691] Intermediate A-1 (368.40 mg, 2.26 mmol, 1.00 equiv.), intermediate A-2 (1.20 g, 2.26 mmol, 1.00 equiv.), PdCl2(PPh3)2 (77.20 mg, 0.11 mmol, 0.05 equiv.), CuI (64.90 mg, 0.34 mmol, 0.15 equiv.) and TEA (0.94 mL, 6.78 mmol, 3.00 equiv.) were dissolved in anhydrous DMF (20 mL), and the reaction was stirred at 70 °C for 2 h after being replaced with nitrogen 3 times. The reaction was monitored by TLC. After cooling to room temperature, water (20 mL) was added, and the mixture was extracted with EtOAc (20 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give 955.90 mg of a yellow solid, with a yield of 74.60%. LC-MS (ESI): m / z = 568.3 [M+H] + .

[0692] Step 2 Synthesis of compound 4-(1'-(4-(5-nitro-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-[1,3'-biazetidin]-3-yl)piperazine-1-carboxylate benzyl ester

[0693] Benzyl 4-(1'-(4-((2-amino-5-nitropyridin-3-yl)ethynyl)phenyl)-[1,3'-biazetidin]-3-yl)piperazine-1-carboxylate (950.00 mg, 1.68 mmol, 1.00 equiv.) and KO tBu (376.30 mg, 3.36 mmol, 2.00 equiv.) was dissolved in anhydrous DMF (10 mL), and the reaction was stirred at 100 °C for 1 h after being replaced with nitrogen for 3 times. TLC was used to monitor the completion of the reaction. The reaction was cooled to room temperature, and water (10 mL) was added. The mixture was filtered, and the filter cake was washed with water and dried. The yellow solid was obtained by silica gel column separation. The yield was 850.50 mg, and the yield was 89.29%. LC-MS (ESI): m / z = 568.3 [M+H] + .

[0694] Step 3 Synthesis of compound 4-(1'-(4-(5-amino-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)- [1,3'-azetidinyl]-3-yl)benzyl piperazine-1-carboxylate

[0695] Benzyl 4-(1'-(4-(5-nitro-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-[1,3'-azetidinyl]-3- yl)piperazine-1-carboxylate (840.00 mg, 1.48 mmol, 1.00 equiv.), B2(OH)4 (399.60 mg, 4.44 mmol, 3.00 equiv.), and 4,4'-Bipyridine (10.90 mg, 0.07 mmol, 0.05 equiv.) were dissolved in anhydrous DMF (10 mL), and the reaction was stirred at room temperature for 30 min after being replaced with nitrogen for 3 times. TLC was used to monitor the completion of the reaction. Water (10 mL) was added, and the mixture was filtered, and the filter cake was washed with water and dried. The yellow solid was obtained by silica gel column separation. The yield was 609.60 mg, and the yield was 76.70%. LC-MS (ESI): m / z = 538.3 [M+H] + .

[0696] Step 4 Synthesis of compound 4-(1'-(4-(5-(4,5-dimethyl-1H-pyrazole-3-carboxamido)-1H- pyrrolo[2,3-b]pyridin-2-yl)phenyl)-[1,3'-azetidinyl]-3-yl)benzyl piperazine-1-carboxylate

[0697] Benzyl 4-(1'-(4-(5-amino-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-[1,3'- azetidin]-3-yl)piperazine-1-carboxylate (600.00 mg, 1.12 mmol, 1.00 equiv.), 4,5- dimethyl-1H-pyrazole-3-carboxylic acid (156.80 mg, 1.12 mmol, 1.00 equiv.), PyBOP (696.80 mg, 1.34 mmol, 1.20 equiv.) and DIPEA (0.58 mL, 3.36 mmol, 3.00 equiv.) were dissolved in anhydrous DMF (10 mL), and the reaction was stirred at room temperature for 2 hours after being replaced with nitrogen for 3 times. The reaction was monitored by TLC. Water (10 mL) was added, and the mixture was filtered to obtain a filter cake, which was washed with water and dried. The yellow solid was separated by silica gel column to obtain 597.9 mg in 81.00% yield. LC-MS (ESI): m / z = 660.3 [M+H] + .

[0698] Synthesis of intermediate B-4

[0699] Benzyl 4-(1'-(4-(5-(4,5-dimethyl-1H-pyrazole-3-carboxamido)-1H-pyrrolo[2,3- b]pyridin-2-yl)phenyl)-[1,3'-azetidin]-3-yl)piperazine-1-carboxylate (590.00 g, 0.90 mmol, 1.00 equiv.) was dissolved in anhydrous DCM (10 mL), and MsOH (1.17 mL, 18.00 mmol, 20.00 equiv.) was added. The reaction was stirred at room temperature for 30 minutes, and the reaction was monitored by TLC. Water (10 mL) was added, and the pH was adjusted to neutral by dropwise addition of saturated sodium bicarbonate solution. The mixture was filtered to obtain a filter cake, which was washed with water and dried. The yellow solid was separated by silica gel column to obtain 430.00 mg in 91.00% yield. LC-MS (ESI): m / z = 526.3 [M+H] + .

[0700] Preparation of intermediate B-5 N-(2-(4-(3-(4-(azetidin-3-yl)piperazin-1-yl)azetidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide

[0701] Synthesis of intermediate B-5 N-(2-(4-(3-(4-(azetidin-3-yl)piperazin-1-yl)azetidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide

[0702] Synthesis of compound 3-(4-(1-(4-((2-amino-5-nitropyridin-3-yl)ethynyl)phenyl)azetidin-3-yl)piperazin-1-yl)azetidine-1-carboxylate

[0703] Intermediate A-1 (735.10 mg, 4.51 mmol, 1.00 equiv.), intermediate A-3 (2.40 g, 4.51 mmol, 1.00 equiv.), PdCl2(PPh3)2 (161.50 mg, 0.23 mmol, 0.05 equiv.), CuI (129.90 mg, 0.68 mmol, 0.15 equiv.), and TEA (1.88 mL, 13.53 mmol, 3.00 equiv.) were dissolved in anhydrous DMF (20 mL). The mixture was purged with nitrogen three times, heated to 70 °C, and stirred for 2 hours. The reaction was monitored by TLC until completion. After cooling to room temperature, water (20 mL) was added, and the mixture was extracted with EtOAc (20 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain 1.84 g of a yellow solid, with a yield of 71.80%. LC-MS (ESI): m / z = 568.3 [M+H] + .

[0704] Step 2: Synthesis of compound 3-(4-(1-(4-(5-nitro-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)azacyclobutane-3-yl)piperazin-1-yl)azacyclobutane-1-carboxylic acid benzyl ester

[0705] 3-(4-(1-(4-(((2-amino-5-nitropyridin-3-yl)ethynyl)phenyl)azacyclobutane-3-yl)piperazin-1-yl)azacyclobutane-1-carboxylic acid benzyl ester (1.80 g, 3.18 mmol, 1.00 equiv.) and KO t Bu (712.30 mg, 6.36 mmol, 2.00 equiv.) was dissolved in anhydrous DMF (10 mL), and the mixture was purged with nitrogen three times. The mixture was heated to 100 °C and stirred for 1 hour. The reaction was monitored by TLC until completion. The mixture was cooled to room temperature, water (10 mL) was added, and the mixture was filtered to obtain a filter cake. The cake was washed with water, dried under vacuum, and separated by silica gel column chromatography to obtain 1.59 g of a yellow solid, yielding 88.00%. LC-MS (ESI): m / z = 568.3 [M+H] + .

[0706] Step 3: Synthesis of compound 3-(4-(1-(4-(5-amino-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)azacyclobutane-3-yl)piperazin-1-yl)azacyclobutane-1-carboxylic acid benzyl ester

[0707] Benzyl 3-(4-(1-(4-(5-nitro-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)azetidin-3- yl)piperazin-1-yl)azetidine-1-carboxylate (1.50 g, 2.65 mmol, 1.00 equiv.), B2(OH)4 (715.50 mg, 7.95 mmol, 3.00 equiv.) and 4,4'-Bipyridine (20.30 mg, 0.13 mmol, 0.05 equiv.) were dissolved in anhydrous DMF (10 mL), stirred for 30 min at room temperature, and the reaction was monitored by TLC. Water (10 mL) was added, and the mixture was filtered to obtain a filter cake, which was washed with water, dried, and separated by silica gel column chromatography to obtain a yellow solid 1.02 g in a yield of 71.52%. LC-MS (ESI): m / z = 538.3 [M+H] + .

[0708] Step 4 Synthesis of compound Benzyl 3-(4-(1-(4-(5-(4,5-dimethyl-1H-pyrazole-3- carboxamido)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)azetidin-3-yl)piperazin-1-yl)azetidine-1- carboxylate

[0709] Benzyl 3-(4-(1-(4-(5-amino-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)azetidin-3-yl)piperazin-1- yl)azetidine-1-carboxylate (1.00 g, 1.86 mmol, 1.00 equiv.), 4,5-dimethyl-1H-pyrazole-3- carboxylic acid (260.40 mg, 1.86 mmol, 1.00 equiv.), PyBOP (1.16 g, 2.23 mmol, 1.20 equiv.) and DIPEA (0.97 mL, 5.58 mmol, 3.00 equiv.) were dissolved in anhydrous DMF (10 mL), stirred for 2 h at room temperature, and the reaction was monitored by TLC. Water (10 mL) was added, and the mixture was filtered to obtain a filter cake, which was washed with water, dried, and separated by silica gel column chromatography to obtain a yellow solid 1.10 g in a yield of 90.00%. LC-MS (ESI): m / z = 660.3 [M+H] + .

[0710] Step 5 Synthesis of intermediate B-5

[0711] Benzyl 3-(4-(1-(4-(5-(4,5-dimethyl-1H-pyrazole-3-carboxamido)-1H-pyrrolo[2,3- b]pyridin-2-yl)phenyl)azetidin-3-yl)piperazin-1-yl)azetidine-1-carboxylate (1.00 g, 1.52 mmol, 1.00 equiv.) was dissolved in anhydrous DCM (10 mL), MsOH (1.97 mL, 30.40 mmol, 20.00 equiv.) was added, the reaction was stirred at room temperature for 30 minutes, and the reaction was monitored by TLC. Water (10 mL) was added, and the pH was adjusted to neutral by dropwise addition of a saturated sodium bicarbonate solution. The mixture was filtered, washed with water, and dried under suction. The yellow solid was separated by silica gel column chromatography to give 794.40 mg in 99.55% yield. LC-MS (ESI): m / z = 526.3 [M+H] + .

[0712] Preparation of intermediate B-6 N-(2-(4-([3,1':3',3"-triazazetidine]-1-yl)phenyl)-1H-pyrrolo[2,3- b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide

[0713] The following route was used for the synthesis:

[0714] Step 1 Synthesis of compound tert-butyl 1-(4-((2-amino-5-nitropyridin-3-yl)ethynyl)phenyl)- [3,1':3',3"-triazazetidine]-1"-carboxylate

[0715] Intermediate A-1 (278.70 mg, 1.71 mmol, 1.00 equiv.), intermediate A-5 (800.00 mg, 1.71 mmol, 1.00 equiv.), PdCl2(PPh3)2 (63.20 mg, 0.09 mmol, 0.05 equiv.), CuI (49.66 mg, 0.26 mmol, 0.15 equiv.), and TEA (0.71 mL, 5.13 mmol, 3.00 equiv.) were dissolved in anhydrous DMF (10 mL), and the mixture was stirred at 80°C for 3 hours after being replaced with nitrogen 3 times. The reaction was monitored by TLC. The reaction was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with EtOAc (10 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography to give 584.60 mg of a yellow solid in 67.83% yield. LC-MS (ESI): m / z = 505.3 [M+H] + .

[0716] Step 2 Synthesis of compound tert-butyl 1-(4-(5-nitro-1H-pyrrolo[2,3-b]pyridin-2- yl)phenyl)-[3,1':3',3"-terphenylazetidine]-1"-carboxylate

[0717] tert-butyl 1-(4-((2-amino-5-nitropyridin-3-yl)ethynyl)phenyl)-[3,1':3',3"- terphenylazetidine]-1"-carboxylate (580.00 mg, 1.15 mmol, 1.00 equiv.) and KO t Bu (257.60 mg, 2.30 mmol, 2.00 equiv.) was dissolved in anhydrous DMF (10 mL), purged with nitrogen for 3 times, and stirred at 100 °C for 1 h. TLC monitoring showed that the reaction was completed. The temperature was lowered to room temperature, water (10 mL) was added, and the mixture was filtered to obtain a filter cake, which was washed with water, dried, and separated by silica gel column to obtain a yellow solid 499.60 mg in 86.20% yield. LC-MS (ESI): m / z = 505.3 [M+H] + .

[0718] Step 3 Synthesis of compound tert-butyl 1-(4-(5-amino-1H-pyrrolo[2,3-b]pyridin-2- yl)phenyl)-[3,1':3',3"-terphenylazetidine]-1"-carboxylate

[0719] tert-butyl 1-(4-(5-nitro-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-[3,1':3',3"- terphenylazetidine]-1"-carboxylate (490.00 mg, 0.97 mmol, 1.00 equiv.), B2(OH)4 (261.90 mg, 2.91 mmol, 3.00 equiv.), and 4,4'-Bipyridine (15.60 mg, 0.10 mmol, 0.10 equiv.) were dissolved in anhydrous DMF (10 mL), purged with nitrogen for 3 times, and stirred at room temperature for 30 min. TLC monitoring showed that the reaction was completed. Water (10 mL) was added, and the mixture was filtered to obtain a filter cake, which was washed with water, dried, and separated by silica gel column to obtain a yellow solid 337.70 mg in 73.44% yield. LC-MS (ESI): m / z = 475.3 [M+H] + .

[0720] Step 4 Synthesis of compound tert-butyl 1-(4-(5-(4,5-dimethyl-1H-pyrazole-3- carboxamido)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-[3,1':3',3"-terphenylazetidine]-1"- carboxylate

[0721] Tert-butyl 1-(4-(5-amino-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-[3,1':3',3"- triazacyclo butane]-1"-carboxylate (330.00 mg, 0.70 mmol, 1.00 equiv.), 4,5- dimethyl-1H-pyrazole-3-carboxylic acid (98.00 mg, 0.70 mmol, 1.00 equiv.), PyBOP (436.80 mg, 0.84 mmol, 1.20 equiv.) and DIPEA (0.37 mL, 2.10 mmol, 3.00 equiv.) were dissolved in dry DMF (10 mL), stirred at room temperature for 2 hours after purging nitrogen for 3 times. TLC monitoring reaction was completed. Water (10 mL) was added, filtered, and the filter cake was washed, dried and separated by silica gel column to obtain 392.30 mg of yellow solid with a yield of 94.02%. LC-MS (ESI): m / z = 597.3 [M+H] + .

[0722] Synthesis of intermediate B-6 in Step 5

[0723] Tert-butyl 1-(4-(5-(4,5-dimethyl-1H-pyrazole-3-carboxamido)-1H-pyrrolo[2,3- b]pyridin-2-yl)phenyl)-[3,1':3',3"-triazacyclo butane]-1"-carboxylate (380.00 mg, 0.64 mmol, 1.00 equiv.) was dissolved in dry DCM (5 mL), TFA (0.25 mL, 3.20 mmol, 5.00 equiv.) was added, and the reaction was stirred at room temperature for 30 minutes. TLC monitoring reaction was completed. Water (5 mL) was added, and the pH was adjusted to neutral by adding saturated sodium bicarbonate solution dropwise. The mixture was filtered, the filter cake was washed with water, dried and separated by silica gel column to obtain 293.60 mg of yellow solid with a yield of 92.48%. LC-MS (ESI): m / z = 497.3 [M+H] + .

[0724] Preparation of intermediate B-7 4,5-dimethyl-N-(2-(4-(piperidin-4-yl)phenyl)-1H- pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-carboxamide

[0725] The following route was used for the synthesis:

[0726] Step 1 Synthesis of compound 2-(4-bromophenyl)-1H-pyrrolo[2,3-b]pyridin-5-amine

[0727] Intermediate A-6 (9.50 g, 29.97 mmol, 1.00 equiv.), B2(OH)4(8.09 g, 89.91 mmol, 3.00 equiv.) and 4,4'-Bipyridine (234.00 mg, 1.50 mmol, 0.05 equiv.) were dissolved in anhydrous DMF (100 mL), and the reaction was stirred at room temperature for 30 min after being purged with nitrogen for 3 times. Water (100 mL) was added, and the mixture was filtered to obtain a filter cake, which was washed with water and dried. The yellow solid (7.13 g) was obtained by silica gel column separation, with a yield of 82.84%. LC-MS (ESI): m / z = 288.0 [M+H] + .

[0728] Step 2 Synthesis of compound N-(2-(4-bromophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5- dimethyl-1H-pyrazole-3-carboxamide

[0729] 2-(4-bromophenyl)-1H-pyrrolo[2,3-b]pyridin-5-amine (7.10 g, 24.74 mmol, 1.00 equiv.), 4,5-dimethyl-1H-pyrazole-3-carboxylic acid (3.46 g, 24.74 mmol, 1.00 equiv.), PyBOP (15.44 g, 29.69 mmol, 1.20 equiv.) and DIPEA (12.90 mL, 74.22 mmol, 3.00 equiv.) were dissolved in anhydrous DMF (100 mL), and the reaction was stirred at room temperature for 2 h after being purged with nitrogen for 3 times. Water (100 mL) was added, and the mixture was filtered to obtain a filter cake, which was washed with water and dried. The yellow solid (7.69 g) was obtained by silica gel column separation, with a yield of 76.04%. LC-MS (ESI): m / z = 410.1 [M+H] + .

[0730] Step 3 Synthesis of compound tert-butyl 4-(4-(5-(4,5-dimethyl-1H-pyrazole-3-carboxamido)-1H- pyrrolo[2,3-b]pyridin-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0731] N-(2-(4-bromophenyl)-lH-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-lH-pyrazole-3- carboxamide (3.00 g, 7.34 mmol, 1.00 equiv.), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 3,6-dihydropyridine-l(2H)-carboxylic acid tert-butyl ester (4.54 g, 14.68 mmol, 2.00 equiv.), Pd(DtBPF)Cl2(471.60 mg, 0.73 mmol, 0.10 equiv.) and K2CO3(4.05 g, 29.36 mmol, 4.00 equiv.) were dissolved in mixed solvents 1,4-dioxane / water (40 mL / 10 mL), purged with nitrogen gas for 3 times, warmed up to 120 °C and stirred for 16 hours. TLC monitoring showed the reaction was completed. Cooled down to room temperature, added water (50 mL), extracted with EtOAc (50 mL x 3), washed the organic phase with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated on a silica gel column to give 3.50 g of yellow solid with a yield of 93.07%. LC-MS (ESI): m / z = 513.3 [M+H] + .

[0732] Step 4 Synthesis of compound 4-(4-(5-(4,5-dimethyl-lH-pyrazole-3-carboxamido)-lH- pyrrolo[2,3-b]pyridin-2-yl)phenyl)piperidine-l-carboxylic acid tert-butyl ester

[0733] 4-(4-(5-(4,5-dimethyl-lH-pyrazole-3-carboxamido)-lH-pyrrolo[2,3-b]pyridin-2-yl)phenyl)- 3,6-dihydropyridine-l(2H)-carboxylic acid tert-butyl ester (3.40 g, 6.64 mmol, 1.00 equiv.) was dissolved in mixed solvents DCM / MeOH / DMF (50 mL / 50 mL / 50 mL), added 10% Pd / C (wetted with 55% H2O, 777.30 mg, 0.33 mmol, 0.05 equiv.), purged with hydrogen gas for 3 times, stirred at room temperature under 1 atmosphere of hydrogen gas overnight, TLC monitoring showed the reaction was completed. Filtered off the palladium carbon, concentrated the filtrate under reduced pressure, and separated on a silica gel column to give 2.82 g of red-brown solid with a yield of 82.68%. LC-MS (ESI): m / z = 515.3 [M+H] + .

[0734] Step 5 Synthesis of intermediate B-7

[0735] tert-Butyl 4-(4-(5-(4,5-dimethyl-1H-pyrazole-3-carboxamido)-1H-pyrrolo[2,3- b]pyridin-2-yl)phenyl)piperidine-1-carboxylate (2.80 g, 5.45 mmol, 1.00 equiv.) was dissolved in anhydrous DCM (30 mL), TFA (2.09 mL, 27.25 mmol, 5.00 equiv.) was added, the reaction was stirred at room temperature for 1 h, TLC monitoring showed the reaction was completed. Water (30 mL) was added, and the pH was adjusted to 8-9 by dropwise addition of saturated sodium bicarbonate solution, extracted with EtOAc (30 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated on a silica gel column to give 1.93 g of a gray solid, with a yield of 85.57%. LC-MS (ESI): m / z = 415.2 [M+H] + .

[0736] Preparation of intermediate B-8 N-(2-(4-(azetidin-3-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5- yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide

[0737] The following route was used for the synthesis:

[0738] Step 1 Synthesis of compound tert-butyl 2-(4-bromophenyl)-5-nitro-1H-pyrrolo[2,3-b]pyridine-1- carboxylate

[0739] Intermediate A-6 (10.00 g, 31.55 mmol, 1.00 equiv.), DMAP (1.93 g, 15.78 mmol, 0.50 equiv.) and DIPEA (16.46 mL, 94.65 mmol, 3.00 equiv.) were dissolved in anhydrous THF (100 mL), the bottle was purged with nitrogen 3 times, and Boc2O (13.76 g, 63.10 mmol, 2.00 equiv.) dissolved in anhydrous THF (20 mL) was slowly injected into the bottle, the reaction was stirred at room temperature overnight, TLC monitoring showed the reaction was completed. Water (100 mL) was added, extracted with EtOAc (100 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated on a silica gel column to give 4.99 g of a yellow solid, with a yield of 37.81%. LC-MS (ESI): m / z = 418.0 [M+H] + .

[0740] Step 2 Synthesis of compound tert-butyl 2-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)phenyl)-5- nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

[0741] tert-Butyl 3-iodazetidine-l-carboxylate (9.98 g, 35.25 mmol, 3.00 equiv.), Zn dust (2.67 g, 41.13 mmol, 3.50 equiv.) and I2(1.04 g, 4.11 mmol, 0.35 equiv.) were dissolved in anhydrous DMA (100 mL), the reaction was stirred at room temperature for 4 hours, under nitrogen atmosphere, tert-butyl 2-(4-bromophenyl)-5-nitro-lH-pyrrolo[2,3-b]pyridine-l-carboxylate (4.90 g, 11.75 mmol, 1.00 equiv.), Pd2(dba)3-CHCl3(838.90 mg, 0.82 mmol, 0.07 equiv.) and S-Phos (485.00 mg, 1.18 mmol, 0.10 equiv.) were added, the reaction was stirred at 50 °C for 16 hours, TLC monitoring showed that the reaction was completed. The temperature was lowered to room temperature, water (200 mL) was added, and the mixture was extracted with EtOAc (200 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give 1.59 g of yellow solid, with a yield of 27.39%. LC-MS (ESI): m / z = 495.2 [M+H] + .

[0742] Step 3 Synthesis of compound tert-butyl 5-amino-2-(4-(l-(tert-butoxycarbonyl)azetidin-3- yl)phenyl)-lH-pyrrolo[2,3-b]pyridine-l-carboxylate

[0743] tert-Butyl 2-(4-(l-(tert-butoxycarbonyl)azetidin-3-yl)phenyl)-5-nitro-lH-pyrrolo[2,3- b]pyridine-l-carboxylate (1.55 g, 3.14 mmol, 1.00 equiv.), B2(OH)4(847.80 mg, 9.42 mmol, 3.00 equiv.) and 4,4'-Bipyridine (25.00 mg, 0.16 mmol, 0.05 equiv.) were dissolved in anhydrous DMF (30 mL), the reaction was stirred at room temperature for 30 minutes, TLC monitoring showed that the reaction was completed. Water (30 mL) was added, and the mixture was extracted with EtOAc (30 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give 1.31 g of yellow solid, with a yield of 90.21%. LC-MS (ESI): m / z = 465.2 [M+H] + .

[0744] Step 4. Synthesis of compound tert-butyl 2-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)phenyl)-5-(4,5-dimethyl-1H-pyrazole-3-carboxamido)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

[0745] tert-butyl 5-amino-2-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (1.30 g, 2.80 mmol, 1.00 equiv.), 4,5-dimethyl-1H-pyrazole-3-carboxylic acid (470.40 mg, 3.36 mmol, 1.20 equiv.), PyBOP (1.75 g, 3.36 mmol, 1.20 equiv.) and DIPEA (0.97 mL, 5.60 mmol, 2.00 equiv.) were dissolved in anhydrous DMF (30 mL), and the reaction was stirred at room temperature for 2 hours after being purged with nitrogen for 3 times. The reaction was monitored by TLC. Water (30 mL) was added, and the mixture was extracted with EtOAc (30 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain 1.41 g of yellow solid with a yield of 86.07%. LC-MS (ESI): m / z = 587.3 [M+H] + .

[0746] Step 5. Synthesis of intermediate B-8

[0747] tert-butyl 2-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)phenyl)-5-(4,5-dimethyl-1H-pyrazole-3-carboxamido)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (1.40 g, 2.39 mmol, 1.00 equiv.) was dissolved in anhydrous DCM (20 mL), and TFA (0.92 mL, 11.95 mmol, 5.00 equiv.) was added. The reaction was stirred at room temperature for 1 hour, and the reaction was monitored by TLC. Water (30 mL) was added, and a saturated sodium bicarbonate solution was added dropwise to adjust the pH to 8-9. The mixture was extracted with EtOAc (20 mL x 3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain 746.90 mg of white solid with a yield of 80.96%. LC-MS (ESI): m / z = 387.2 [M+H] + .

[0748] Preparation of intermediate B-9 4,5-dimethyl-N-(2-(4-(4-(piperazin-1-ylmethyl)piperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-carboxamide Preparation of intermediate B-9 4,5-dimethyl-N-(2-(4-(4-(piperazin-1-ylmethyl)piperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-carboxamide

[0749] The following synthetic route was employed:

[0750] Step 1 Synthesis of tert-butyl 4-((l-(4-((2-amino-5-nitropyridin-3-yl)ethynyl)phenyl)piperidin-4- yl)methyl)piperazine-l-carboxylate

[0751] Intermediate A-1 (135.30 mg, 0.83 mmol, 1.00 equiv.), Intermediate A-8 (400.00 mg, 0.83 mmol, 1.00 equiv.), PdCl2(PPh3)2 (28.10 mg, 0.04 mmol, 0.05 equiv.), Cul (24.80 mg, 0.13 mmol, 0.15 equiv.) and TEA (0.35 mL, 2.49 mmol, 3.00 equiv.) were dissolved in anhydrous DMF (10 mL), purged with nitrogen for 3 times, stirred at 80 °C for 1 h, TLC monitored that the reaction was completed. Cooled to room temperature, added water (10 mL), extracted with EtOAc (10 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated on silica gel column to get yellow solid 402.30 mg, yield 93.20%. LC-MS (ESI): m / z = 521.3 [M+H] + .

[0752] Step 2 Synthesis of tert-butyl 4-((l-(4-(5-nitro-lH-pyrrolo[2,3-b]pyridin-2-yl)phenyl)piperidin-4- yl)methyl)piperazine-l-carboxylate

[0753] Tert-butyl 4-((l-(4-((2-amino-5-nitropyridin-3-yl)ethynyl)phenyl)piperidin-4-yl)methyl)piperazine-l- carboxylate (400.00 mg, 0.77 mmol, 1.00 equiv.) and KO t Bu (172.50 mg, 1.54 mmol, 2.00 equiv.) were dissolved in anhydrous DMF (10 mL), purged with nitrogen for 3 times, stirred at 80 °C for 1 h, TLC monitored that the reaction was completed. Cooled to room temperature, added water (10 mL), filtered to get the filter cake, washed with water, dried, separated on silica gel column to get yellow solid 336.70 mg, yield 84.10%. LC-MS (ESI): m / z = 521.3 [M+H] + .

[0754] Step 3 Synthesis of tert-butyl 4-((l-(4-(5-amino-lH-pyrrolo[2,3-b]pyridin-2-yl)phenyl)piperidin-4- yl)methyl)piperazine-l-carboxylate

[0755] tert-Butyl 4-((l-(4-(5-nitro-lH-pyrrolo[2,3-b]pyridin-2-yl)phenyl)piperidin-4- yl)methyl)piperazine-l-carboxylate (330.00 mg, 0.64 mmol, 1.00 equiv.), B2(OH)4 (172.80 mg, 1.92 mmol, 3.00 equiv.) and 4,4'-Bipyridine (4.70 mg, 0.03 mmol, 0.05 equiv.) were dissolved in anhydrous DMF (10 mL), stirred for 30 min at room temperature, TLC monitored the reaction was completed. Added water (10 mL), filtered, the filter cake was washed with water, and dried, separated by silica gel column to get yellow solid 214.20 mg, yield 68.31%. LC-MS (ESI): m / z = 491.3 [M+H] + .

[0756] Step 4 Synthesis of compound tert-butyl 4-((l-(4-(5-(4,5-dimethyl-lH-pyrazole-3- carboxamido)-lH-pyrrolo[2,3-b]pyridin-2-yl)phenyl)piperidin-4-yl)methyl)piperazine-l- carboxylate

[0757] tert-Butyl 4-((l-(4-(5-amino-lH-pyrrolo[2,3-b]pyridin-2-yl)phenyl)piperidin-4- yl)methyl)piperazine-l-carboxylate (210.00 mg, 0.43 mmol, 1.00 equiv.), 4,5-dimethyl- lH-pyrazole-3-carboxylic acid (60.20 mg, 0.43 mmol, 1.00 equiv.), PyBOP (270.40 mg, 0.52 mmol, 1.20 equiv.) and DIPEA (0.22 mL, 1.29 mmol, 3.00 equiv.) were dissolved in anhydrous DMF (10 mL), stirred for 2 h at room temperature, TLC monitored the reaction was completed. Added water (10 mL), filtered, the filter cake was washed with water, and dried, separated by silica gel column to get yellow solid 257.90 mg, yield 98.00%. LC-MS (ESI): m / z = 613.4 [M+H] + .

[0758] Step 5 Synthesis of intermediate B-9

[0759] Tert-butyl 4-((l-(4-(5-(4,5-dimethyl-lH-pyrazole-3-carboxamido)-lH- pyrrolo[2,3-b]pyridin-2-yl)phenyl)piperidin-4-yl)methyl)piperazine-l-carboxylate (250.00 mg, 0.41 mmol, 1.00 equiv.) was dissolved in anhydrous DCM (5 mL), TFA (0.16 mL, 2.05 mmol, 5.00 equiv.) was added, the reaction was stirred at room temperature for 30 minutes, TLC monitoring reaction was completed. Add water (5 mL), and drop saturated sodium bicarbonate solution, adjust the pH to neutral, filter, get filter cake, water washing, dry, separated by silica gel column to get yellow solid 201.70 mg, yield 96.10%. LC-MS (ESI): m / z = 513.3 [M+H] + .

[0760] Preparation of intermediate B-10 N-(2-(4-(4-formylpiperidin-l-yl)phenyl)-lH- pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-lH-pyrazole-3-carboxamide

[0761] The following synthetic route was used:

[0762] Step 1 Synthesis of compound 3-((4-(4-(l,3-dioxolan-2-yl)piperidin-l-yl)phenyl)ethynyl)-5- nitropyridin-2-amine

[0763] Intermediate A-l (226.60 mg, 1.39 mmol, 1.00 equiv.), intermediate A-10 (500.00 mg, 1.39 mmol, 1.00 equiv.), PdCl2(PPh3)2 (49.10 mg, 0.07 mmol, 0.05 equiv.), CuI (40.10 mg, 0.21 mmol, 0.15 equiv.) and TEA (0.58 mL, 4.17 mmol, 3.00 equiv.) were dissolved in anhydrous DMF (10 mL), nitrogen was replaced 3 times, the temperature was raised to 60°C, the reaction was stirred for 2 hours, TLC monitoring reaction was completed. Lower to room temperature, add water (10 mL), extracted with EtOAc (10 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated by silica gel column to get yellow solid 375.10 mg, yield 68.49%. LC-MS (ESI): m / z = 395.2 [M+H] + .

[0764] Step 2 Synthesis of compound 2-(4-(4-(l,3-dioxolan-2-yl)piperidin-l- yl)phenyl)-5-nitro-lH-pyrrolo[2,3-b]pyridine

[0765] To a solution of 3-((4-(4-(l,3-dioxolan-2-yl)piperidin-l-yl)phenyl)ethynyl)-5- nitropyridin-2-amine (370.00 mg, 0.94 mmol, 1.00 equiv.) and KO t Bu (210.60 mg, 1.88 mmol, 2.00 equiv.) was dissolved in anhydrous DMF (10 mL), purged with nitrogen for 3 times, and stirred at 80 °C for 1 h. TLC monitoring showed that the reaction was completed. The temperature was lowered to room temperature, water (10 mL) was added, and the mixture was filtered to obtain a filter cake, which was washed with water and dried. The yellow solid was obtained by silica gel column separation, and the yield was 324.10 mg, 87.52%. LC-MS (ESI): m / z = 395.2 [M+H] + .

[0766] Step 3 Synthesis of compound 2-(4-(4-(l,3-dioxolan-2-yl)piperidin-l- yl)phenyl)-lH-pyrrolo[2,3-b]pyridine-5-amine

[0767] To a solution of 2-(4-(4-(l,3-dioxolan-2-yl)piperidin-l-yl)phenyl)-5-nitro-lH- pyrrolo[2,3-b]pyridine (320.00 mg, 0.81 mmol, 1.00 equiv.), B2(OH)4 (218.70 mg, 2.43 mmol, 3.00 equiv.) and 4,4'-Bipyridine (6.20 mg, 0.04 mmol, 0.05 equiv.) in anhydrous DMF (10 mL), nitrogen was purged for 3 times, and the mixture was stirred at room temperature for 30 min. TLC monitoring showed that the reaction was completed. Water (10 mL) was added, and the mixture was filtered to obtain a filter cake, which was washed with water and dried. The yellow solid was obtained by silica gel column separation, and the yield was 182.50 mg, 61.91%. LC-MS (ESI): m / z = 365.2 [M+H] + .

[0768] Step 4 Synthesis of compound N-(2-(4-(4-(l,3-dioxolan-2-yl)piperidin-l- yl)phenyl)-lH-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-lH-pyrazole-3-carboxamide

[0769] To a stirred solution of 2-(4-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)phenyl)-1H- pyrrolo[2,3-b]pyridine-5-carboxylic acid (180.00 mg, 0.50 mmol, 1.00 equiv.) in DMF (10 mL) was added 4,5-dimethyl-1H-pyrazole-3-carboxylic acid (70.00 mg, 0.50 mmol, 1.00 equiv.), PyBOP (312.00 mg, 0.60 mmol, 1.20 equiv.) and DIPEA (0.26 mL, 1.50 mmol, 3.00 equiv.). The reaction mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC. The reaction mixture was diluted with water (10 mL) and the solid was filtered. The solid was washed with water and dried under vacuum to get 215.90 mg of the product as a light grey solid in 88.85% yield. LC-MS (ESI): m / z = 487.2 [M+H] + .

[0770] Synthesis of intermediate B-10

[0771] To a stirred solution of N-(2-(4-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)phenyl)-1H- pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide (210.00 mg, 0.43 mmol, 1.00 equiv.) in 1,4-dioxane / H2O (4 mL / 1 mL) was added hydrogen chloride 1,4-dioxane solution (1.10 mL, 4.30 mmol, 4 M, 10.00 equiv.). The reaction mixture was stirred at 50 °C for 3 h. The reaction was monitored by TLC. The reaction mixture was diluted with water (5 mL) and the solid was filtered. The solid was washed with water and dried under vacuum to get 173.60 mg of the product as a yellow solid in 91.33% yield. LC-MS (ESI): m / z = 443.2 [M+H] + .

[0772] Preparation of intermediate B-11 N-(2-(4-(4-((2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide

[0773] The following synthetic route was employed:

[0774] Step 1 Synthesis of tert-butyl 7-((1-(4-((2-amino-5-nitropyridin-3-yl)ethynyl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0775] Intermediate A-12 (1.50 g, 3.55 mmol, 1.00 equiv.), PdCl2(PPh3)2 (126.40 mg, 0.18 mmol, 0.05 equiv.), Cul (101.20 mg, 0.53 mmol, 0.15 equiv.) and DIPEA (1.85 mL, 10.65 mmol, 3.00 equiv.) were dissolved in anhydrous DMF (20 mL), the reaction was stirred at room temperature for 1 hour after the reaction was completed by TLC. Add water (20 mL), extracted with EtOAc (20 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated by silica gel column to get yellow solid 1.69 g, yield 85.20%. LC-MS (ESI): m / z = 561.3 [M+H] + .

[0776] Step 2 Synthesis of compound tert-butyl 7-((1-(4-(5-nitro-1H-pyrrolo[2,3-b]pyridin-2- yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0777] tert-butyl 7-((1-(4-((2-amino-5-nitropyridin-3-yl)ethynyl)phenyl)piperidin-4-yl)methyl)- 2,7-diazaspiro[3.5]nonane-2-carboxylate (1.65 g, 2.95 mmol, 1.00 equiv.) and KO t Bu (660.80 mg, 5.90 mmol, 2.00 equiv.) were dissolved in anhydrous DMF (30 mL), the reaction was stirred at 80 °C for 30 minutes after the reaction was completed by TLC. Lowered to room temperature, added water (30 mL), filtered to get the filter cake, washed with water, dried, separated by silica gel column to get yellow solid 1.45 g, yield 87.90%. LC-MS (ESI): m / z = 561.3 [M+H] + .

[0778] Step 3 Synthesis of compound tert-butyl 7-((1-(4-(5-amino-1H-pyrrolo[2,3-b]pyridin-2- yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0779] tert-Butyl 7-((l-(4-(5-nitro-lH-pyrrolo[2,3-b]pyridin-2-yl)phenyl)piperidin-4- yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (1.40 g, 2.50 mmol, 1.00 equiv.), B2(OH)4 (675.00 mg, 7.50 mmol, 3.00 equiv.) and 4,4'-Bipyridine (20.30 mg, 0.13 mmol, 0.05 equiv.) were dissolved in anhydrous DMF (20 mL), and the reaction was stirred at room temperature for 30 min after being purged with nitrogen for 3 times. The reaction was monitored by TLC. Water (20 mL) was added, and the mixture was filtered to obtain a filter cake, which was washed with water and dried. The yellow solid (1.02 g) was obtained by silica gel column separation with a yield of 76.98%. LC-MS (ESI): m / z = 531.3 [M+H] + .

[0780] Step 4 Synthesis of compound tert-butyl 7-((l-(4-(5-(4,5-dimethyl-lH-pyrazole-3- carboxamido)-lH-pyrrolo[2,3-b]pyridin-2-yl)phenyl)piperidin-4-yl)methyl)-2,7- diazaspiro[3.5]nonane-2-carboxylate

[0781] tert-Butyl 7-((l-(4-(5-nitro-lH-pyrrolo[2,3-b]pyridin-2-yl)phenyl)piperidin-4- yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (1.00 g, 1.88 mmol, 1.00 equiv.), 4,5-dimethyl-lH-pyrazole-3-carboxylic acid (263.20 mg, 1.88 mmol, 1.00 equiv.), PyBOP (1.18 g, 2.26 mmol, 1.20 equiv.) and DIPEA (0.98 mL, 5.64 mmol, 3.00 equiv.) were dissolved in anhydrous DMF (20 mL), and the reaction was stirred at room temperature for 2 h after being purged with nitrogen for 3 times. The reaction was monitored by TLC. Water (20 mL) was added, and the mixture was filtered to obtain a filter cake, which was washed with water and dried. The yellow solid (1.04 g) was obtained by silica gel column separation with a yield of 85.20%. LC-MS (ESI): m / z = 653.4 [M+H] + .

[0782] Step 5 Synthesis of intermediate B-11

[0783] Tert-butyl 7-((l-(4-(5-(4,5-dimethyl-lH-pyrazole-3-carboxamido)-lH- pyrrolo[2,3-b]pyridin-2-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane- 2-carboxylate (1.00 g, 1.53 mmol, 1.00 equiv.) was dissolved in anhydrous DCM (15 mL), TFA (0.59 mL, 7.65 mmol, 5.00 equiv.) was added, the reaction was stirred at room temperature for 30 minutes, TLC monitoring showed that the reaction was completed. Water (15 mL) was added, and the pH was adjusted to neutral by adding a saturated sodium bicarbonate solution. The mixture was filtered, washed with water, and dried under vacuum. The yellow solid was separated by silica gel column chromatography to give 728.90 mg, with a yield of 86.30%. LC-MS (ESI): m / z = 553.3 [M+H] + .

[0784] Preparation of intermediate B-12 N-(2-(4-(4-((2,6-diazaspiro[3.3]heptan-2-yl)methyl)piperidin- 1-yl)phenyl)-lH-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-lH-pyrazole-3-carboxamide

[0785] The following synthetic route was used:

[0786] Step 1 Synthesis of tert-butyl 6-((l-(4-((2-amino-5-nitropyridin-3-yl)ethynyl)phenyl)piperidin- 4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0787] 3-Iodo-5-nitropyridin-2-amine (670.50 mg, 2.53 mmol, 1.00 equiv.), intermediate A-13 (1.00 g, 2.53 mmol, 1.00 equiv.), PdCl2(PPh3)2 (91.30 mg, 0.13 mmol, 0.05 equiv.), CuI (72.60 mg, 0.38 mmol, 0.15 equiv.), and DIPEA (1.32 mL, 7.59 mmol, 3.00 equiv.) were dissolved in anhydrous DMF (20 mL), and the reaction was stirred at room temperature for 1 hour. TLC monitoring showed that the reaction was completed. Water (20 mL) was added, and the organic phase was extracted with EtOAc (20 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography to give a yellow solid 1.24 g, with a yield of 92.00%. LC-MS (ESI): m / z = 533.3 [M+H] + .

[0788] Step 2 Synthesis of compound tert-butyl 6-((l-(4-(5-nitro-lH-pyrrolo[2,3- b]pyridin-2-yl)phenyl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0789] tert-butyl 6-((l-(4-((2-amino-5-nitropyridin-3-yl)ethynyl)phenyl)piperidin-4- yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (1.20 g, 2.26 mmol, 1.00 equiv.) and KO t Bu (506.20 mg, 4.52 mmol, 2.00 equiv.) was dissolved in anhydrous DMF (30 mL), purged with nitrogen for 3 times, and stirred at 80 °C for 30 min. TLC monitoring showed that the reaction was completed. After cooling to room temperature, water (30 mL) was added, and the mixture was filtered to obtain a filter cake, which was washed with water and dried. The yellow solid (927.20 mg) was obtained by silica gel column separation in a yield of 77.12%. LC-MS (ESI): m / z = 533.3 [M+H] + .

[0790] Step 3 Synthesis of compound tert-butyl 6-((l-(4-(5-amino-lH-pyrrolo[2,3- b]pyridin-2-yl)phenyl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0791] tert-butyl 6-((l-(4-(5-nitro-lH-pyrrolo[2,3- b]pyridin-2-yl)phenyl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (0.92 g, 1.73 mmol, 1.00 equiv.), B2(OH)4(467.10 mg, 5.19 mmol, 3.00 equiv.) and 4,4'-Bipyridine (14.00 mg, 0.09 mmol, 0.05 equiv.) were dissolved in anhydrous DMF (20 mL), purged with nitrogen for 3 times, and stirred at room temperature for 30 min. TLC monitoring showed that the reaction was completed. Water (20 mL) was added, and the mixture was filtered to obtain a filter cake, which was washed with water and dried. The yellow solid (695.60 mg) was obtained by silica gel column separation in a yield of 80.10%. LC-MS (ESI): m / z = 503.3 [M+H] + .

[0792] Step 4 Synthesis of compound tert-butyl 6-((l-(4-(5-(4,5-dimethyl-lH-pyrazole-3- carboxamido)-lH-pyrrolo[2,3-b]pyridin-2-yl)phenyl)piperidin-4-yl)methyl)-2,6- diazaspiro[3.3]heptane-2-carboxylate

[0793] tert-Butyl 6-((1-(4-(5-(4,5-dimethyl-1H-pyrazole-3-carboxamido)-1H-pyrrolo[2,3- b]pyridin-2-yl)phenyl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]octane-2-carboxylate (0.56 g, 0.90 mmol, 1.00 equiv.) was dissolved in anhydrous DCM (10 mL), TFA (0.35 mL, 4.50 mmol, 5.00 equiv.) was added, the reaction was stirred at room temperature for 30 minutes, TLC monitoring showed that the reaction was completed. Water (10 mL) was added, and a saturated sodium bicarbonate solution was added dropwise to adjust the pH to neutral, filtered to obtain the filter cake, washed with water, and dried, and separated by silica gel column to obtain a yellow solid 393.10 mg, with a yield of 83.30%. LC-MS (ESI): m / z = 525.3 [M+H] + .

[0794] Synthesis of intermediate B-12 in Step 5

[0795] tert-Butyl 6-((1-(4-(5-(4,5-dimethyl-1H-pyrazole-3-carboxamido)-1H-pyrrolo[2,3- b]pyridin-2-yl)phenyl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]octane-2-carboxylate (0.56 g, 0.90 mmol, 1.00 equiv.) was dissolved in anhydrous DCM (10 mL), TFA (0.35 mL, 4.50 mmol, 5.00 equiv.) was added, the reaction was stirred at room temperature for 30 minutes, TLC monitoring showed that the reaction was completed. Water (10 mL) was added, and a saturated sodium bicarbonate solution was added dropwise to adjust the pH to neutral, filtered to obtain the filter cake, washed with water, and dried, and separated by silica gel column to obtain a yellow solid 393.10 mg, with a yield of 83.30%. LC-MS (ESI): m / z = 525.3 [M+H] + .

[0796] Preparation of intermediate B-13 4,5-dimethyl-N-(2-(4-(4-oxopiperidin-1-yl)phenyl)-1H- pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-carboxamide

[0797] The following synthetic route was used:

[0798] Synthesis of compound 3-((4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl)ethynyl)-5- nitropyridin-2-amine in Step 1

[0799] Intermediate A-1 (1.42 g, 8.70 mmol, 1.00 equiv.), intermediate A-15 (3.00 g, 8.70 mmol, 1.00 equiv.), PdCl2(PPh3)2 (308.88 mg, 0.44 mmol, 0.05 equiv.), CuI (250.20 mg, 1.31 mmol, 0.15 equiv.), and DIPEA (4.54 mL, 26.10 mmol, 3.00 equiv.) were dissolved in anhydrous DMF (50 mL). The mixture was purged with nitrogen three times, heated to 60 °C, and stirred for 2 hours. The reaction was monitored by TLC until completion. After cooling to room temperature, water (50 mL) was added, and the mixture was extracted with EtOAc (50 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain 2.68 g of a yellow solid, yield 81.16%. LC-MS (ESI): m / z = 381.2 [M+H] + .

[0800] Step 2: Synthesis of compound 8-(4-(5-nitro-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-1,4-dioxa-8-azaspiro[4.5]decane

[0801] 3-((4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)phenyl)ethynyl)-5-nitropyridine-2-amine (2.60 g, 6.84 mmol, 1.00 equiv.) and KO t Bu (1.53 g, 13.68 mmol, 2.00 equiv.) was dissolved in anhydrous DMF (50 mL), and the mixture was purged with nitrogen three times. The mixture was heated to 80 °C and stirred for 1 hour. The reaction was monitored by TLC until completion. The mixture was cooled to room temperature, water (50 mL) was added, and the mixture was filtered to obtain a filter cake. The cake was washed with water, dried under vacuum, and separated by silica gel column chromatography to obtain 2.24 g of a yellow solid, with a yield of 86.20%. LC-MS (ESI): m / z = 381.2 [M+H] + .

[0802] Step 3: Synthesis of compound 2-(4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-amine

[0803] To a solution of 8-(4-(5-nitro-lH-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-l,4-dioxa-8- azaspiro[4.5]decane (2.20 g, 5.79 mmol, 1.00 equiv.) and B2(OH)4(1.56 g, 17.37 mmol, 3.00 equiv.) in anhydrous DMF (50 mL) was added 4,4'-Bipyridine (45.20 mg, 0.29 mmol, 0.05 equiv.). The reaction mixture was stirred at room temperature for 30 min. The reaction was monitored by TLC. The reaction mixture was diluted with water (50 mL) and filtered to give a filter cake, which was washed with water and dried under vacuum. The filter cake was separated on a silica gel column to give 1.32 g of a yellow solid in 65.01% yield. LC-MS (ESI): m / z = 351.2 [M+H] + .

[0804] Step 4 Synthesis of compound N-(2-(4-(l,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl)-lH- pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-lH-pyrazole-3-carboxamide

[0805] To a solution of 2-(4-(l,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl)-lH-pyrrolo[2,3-b]pyridin-5- amine (1.30 g, 3.71 mmol, 1.00 equiv.) and 4,5-dimethyl-lH-pyrazole-3-carboxylic acid (519.40 mg, 3.71 mmol, 1.00 equiv.) in anhydrous DMF (50 mL) was added PyBOP (2.31 g, 4.45 mmol, 1.20 equiv.) and DIPEA (1.94 mL, 11.13 mmol, 3.00 equiv.). The reaction mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC. The reaction mixture was diluted with water (50 mL) and filtered to give a filter cake, which was washed with water and dried under vacuum. The filter cake was separated on a silica gel column to give 1.26 g of a light gray solid in 71.92% yield. LC-MS (ESI): m / z = 473.2 [M+H] + .

[0806] Step 5 Synthesis of intermediate B-13

[0807] N-(2-(4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide (1.20 g, 2.54 mmol, 1.00 equiv.) was dissolved in mixed solvent 1,4-dioxane / H2O (20 mL / 5 mL), hydrogen chloride 1,4-dioxane solution (6.35 mL, 25.40 mmol, 4 M, 10.00 equiv.) was added, and the reaction was stirred at 50 °C for 3 h after 3 times of nitrogen replacement. Water (30 mL) was added, and the mixture was filtered to obtain a filter cake, which was washed with water and dried to obtain a yellow solid 981.70 mg in a yield of 90.30%. LC-MS (ESI): m / z = 429.2 [M+H] + .

[0808] Preparation of intermediate B-14 N-(2-(4-(4-(2-azaspiro[3.3]heptan-6-yl)piperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide

[0809] The following synthetic route was used:

[0810] Step 1 Synthesis of compound tert-butyl 6-(1-(4-((2-amino-5-nitropyridin-3-yl)ethynyl)phenyl)piperidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0811] Intermediate A-1 (371.60 mg, 2.28 mmol, 1.00 equiv.), intermediate A-16 (1.10 g, 2.28 mmol, 1.00 equiv.), PdCl2(PPh3)2 (77.20 mg, 0.11 mmol, 0.05 equiv.), CuI (64.90 mg, 0.34 mmol, 0.15 equiv.) and TEA (0.95 mL, 6.84 mmol, 3.00 equiv.) were dissolved in anhydrous DMF (20 mL), and the reaction was stirred at 60 °C for 1 h after 3 times of nitrogen replacement. After the reaction was completed as monitored by TLC, the reaction was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with EtOAc (20 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain a yellow solid 1.00 g in a yield of 84.88%. LC-MS (ESI): m / z = 519.3 [M+H] + .

[0812] Step 2 Synthesis of compound tert-butyl 6-(l-(4-(5-nitro-lH-pyrrolo[2,3- b]pyridin-2-yl)phenyl)piperidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0813] tert-butyl 6-(l-(4-((2-amino-5-nitropyridin-3-yl)ethynyl)phenyl)piperidin-4-yl)-2,6- diazaspiro[3.3]heptane-2-carboxylate (1.00 g, 1.93 mmol, 1.00 equiv.) and KO t Bu (432.30 mg, 3.86 mmol, 2.00 equiv.) was dissolved in anhydrous DMF (20 mL), purged with nitrogen for 3 times, and stirred at 80 °C for 1 h. TLC monitoring showed that the reaction was completed. The temperature was lowered to room temperature, water (20 mL) was added, and the mixture was filtered to obtain a filter cake, which was washed with water, dried, and separated by silica gel column to obtain a yellow solid 916.20 mg in a yield of 91.64%. LC-MS (ESI): m / z = 519.3 [M+H] + .

[0814] Step 3 Synthesis of compound tert-butyl 6-(l-(4-(5-amino-lH-pyrrolo[2,3-b]pyridin-2- yl)phenyl)piperidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0815] tert-butyl 6-(l-(4-(5-nitro-lH-pyrrolo[2,3-b]pyridin-2-yl)phenyl)piperidin-4-yl)-2,6- diazaspiro[3.3]heptane-2-carboxylate (900.00 mg, 1.74 mmol, 1.00 equiv.), B2(OH)4 (469.80 mg, 5.22 mmol, 3.00 equiv.), and 4,4'-Bipyridine (14.00 mg, 0.09 mmol, 0.05 equiv.) were dissolved in anhydrous DMF (20 mL), purged with nitrogen for 3 times, and stirred at room temperature for 30 min. TLC monitoring showed that the reaction was completed. Water (20 mL) was added, and the mixture was filtered to obtain a filter cake, which was washed with water, dried, and separated by silica gel column to obtain a yellow solid 782.70 mg in a yield of 92.18%. LC-MS (ESI): m / z = 489.3 [M+H] + .

[0816] Step 4 Synthesis of compound tert-butyl 6-(l-(4-(5-(4,5-dimethyl-lH-pyrazole-3- carboxamido)-lH-pyrrolo[2,3-b]pyridin-2-yl)phenyl)piperidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0817] tert-Butyl 6-(1-(4-(5-amino-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)piperidin-4-yl)- 2,6-diazaspiro[3.3]octane-2-carboxylate (750.00 mg, 1.54 mmol, 1.00 equiv.), 4,5-dimethyl-1H-pyrazole-3-carboxylic acid (215.60 mg, 1.54 mmol, 1.00 equiv.), PyBOP (962.00 mg, 1.85 mmol, 1.20 equiv.) and DIPEA (0.80 mL, 4.62 mmol, 3.00 equiv.) were dissolved in dry DMF (15 mL), and the reaction was stirred at room temperature for 2 hours after being purged with nitrogen for 3 times. The reaction was monitored by TLC. Water (15 mL) was added, and the mixture was filtered to obtain a filter cake, which was washed with water and dried. The product was separated by silica gel column to obtain 463.10 mg of a gray-white solid with a yield of 49.30%. LC-MS (ESI): m / z = 611.3 [M+H] + .

[0818] Synthesis of intermediate B-14

[0819] tert-Butyl 6-(1-(4-(5-(4,5-dimethyl-1H-pyrazole-3-carboxamido)-1H-pyrrolo[2,3-b]pyridin- 2-yl)phenyl)piperidin-4-yl)-2,6-diazaspiro[3.3]octane-2-carboxylate (450.00 mg, 0.74 mmol, 1.00 equiv.) was dissolved in dry DCM (10 mL), and TFA (0.28 mL, 3.70 mmol, 5.00 equiv.) was added. The reaction was stirred at room temperature for 30 minutes, and the reaction was monitored by TLC. Water (10 mL) was added, and the pH was adjusted to neutral by dropwise addition of a saturated sodium bicarbonate solution. The mixture was filtered to obtain a filter cake, which was washed with water and dried. The product was separated by silica gel column to obtain 359.30 mg of a yellow solid with a yield of 95.20%. LC-MS (ESI): m / z = 511.3 [M+H] + .

[0820] Preparation of intermediate B-14a tert-Butyl 3-((1-(4-(5-(4,5-dimethyl-1H-pyrazole-3-carboxamido)-1H-pyrrolo[2,3-b]pyridin- 2-yl)phenyl)piperidin-4-yl)oxy)azetidine-1-carboxylate

[0821] The following synthetic route was used:

[0822] Synthesis of compound tert-Butyl 3-((1-(4-((2-amino-5-nitropyridin-3-yl)ethynyl)phenyl)piperidin-4- yl)oxy)azetidine-1-carboxylate

[0823] Intermediate A-1 (462.90 mg, 2.84 mmol, 1.00 equiv.), intermediate A-17 (1.30 g, 2.84 mmol, 1.00 equiv.), PdCl2(PPh3)2 (98.30 mg, 0.14 mmol, 0.05 equiv.), CuI (82.10 mg, 0.43 mmol, 0.15 equiv.), and TEA (1.18 mL, 8.52 mmol, 3.00 equiv.) were dissolved in anhydrous DMF (20 mL). The mixture was purged with nitrogen three times, heated to 60 °C, and stirred for 1 hour. The reaction was monitored by TLC until completion. After cooling to room temperature, water (20 mL) was added, and the mixture was extracted with EtOAc (20 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain a yellow solid of 928.10 mg, with a yield of 66.29%. LC-MS (ESI): m / z = 494.2 [M+H] + .

[0824] Step 2: Synthesis of compound 3-((1-(4-(5-nitro-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)piperidin-4-yl)oxy)azacyclobutane-1-carboxylic acid tert-butyl ester

[0825] 3-((1-(4-((2-amino-5-nitropyridin-3-yl)ethynyl)phenyl)piperidin-4-yl)oxy)azacyclobutane-1-carboxylic acid tert-butyl ester (920.00 mg, 1.87 mmol, 1.00 equiv.) and KO t Bu (418.90 mg, 3.74 mmol, 2.00 equiv.) was dissolved in anhydrous DMF (10 mL), and the mixture was purged with nitrogen three times. The mixture was heated to 80 °C and stirred for 1 hour. The reaction was monitored by TLC until completion. The mixture was cooled to room temperature, water (10 mL) was added, and the mixture was filtered to obtain a filter cake. The cake was washed with water, dried under vacuum, and separated by silica gel column chromatography to obtain 833.10 mg of a yellow solid, with a yield of 90.37%. LC-MS (ESI): m / z = 494.2 [M+H] + .

[0826] Step 3: Synthesis of compound 3-((1-(4-(5-amino-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)piperidin-4-yl)oxy)azacyclobutane-1-carboxylic acid tert-butyl ester

[0827] Tert-butyl 3-((l-(4-(5-nitro-lH-pyrrolo[2,3-b]pyridin-2-yl)phenyl)piperidin-4- yl)oxy)azetidine-l-carboxylate (820.00 mg, 1.66 mmol, 1.00 equiv.), B2(OH)4 (448.20 mg, 4.98 mmol, 3.00 equiv.) and 4,4'-Bipyridine (12.50 mg, 0.08 mmol, 0.05 equiv.) were dissolved in anhydrous DMF (15 mL), stirred for 30 min at room temperature, TLC monitored the reaction was completed. Added water (15 mL), filtered, the filter cake was washed with water, and dried, separated by silica gel column to get yellow solid 686.80 mg, yield 89.36%. LC-MS (ESI): m / z = 464.3 [M+H] + .

[0828] Synthesis of intermediate B-14a in Step 4

[0829] Tert-butyl 3-((l-(4-(5-nitro-lH-pyrrolo[2,3-b]pyridin-2-yl)phenyl)piperidin-4- yl)oxy)azetidine-l-carboxylate (820.00 mg, 1.66 mmol, 1.00 equiv.), B2(OH)4 (448.20 mg, 4.98 mmol, 3.00 equiv.) and 4,4'-Bipyridine (12.50 mg, 0.08 mmol, 0.05 equiv.) were dissolved in anhydrous DMF (15 mL), stirred for 30 min at room temperature, TLC monitored the reaction was completed. Added water (15 mL), filtered, the filter cake was washed with water, and dried, separated by silica gel column to get yellow solid 686.80 mg, yield 89.36%. LC-MS (ESI): m / z = 464.3 [M+H] + .

[0830] Preparation of intermediate B-15 N-(2-(4-(4-(azetidin-3-yloxy)piperidin-l-yl)phenyl)- lH-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-lH-pyrazole-3-carboxamide

[0831] The following synthetic route was employed:

[0832] Intermediate B-14a (590.00 mg, 1.01 mmol, 1.00 equiv.) was dissolved in anhydrous DCM (10 mL), TFA (0.39 mL, 5.05 mmol, 5.00 equiv.) was added, the reaction was stirred at room temperature for 30 minutes, TLC monitoring showed that the reaction was completed. Water (10 mL) was added, and the pH was adjusted to neutral by adding saturated sodium bicarbonate solution dropwise, filtered, the filter cake was washed with water, and dried, and separated on a silica gel column to obtain a yellow solid 444.90 mg, with a yield of 90.83%. LC-MS (ESI): m / z = 486.3 [M+H] + .

[0833] Preparation of Intermediate B-16 N-(2-(4-(4-((2-azaspiro[3.3]heptan-6-yl)oxy)piperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide

[0834] The following synthetic route was used:

[0835] According to the preparation method of Intermediate B-14, Intermediate B-16 was prepared by replacing Intermediate A-16 with Intermediate A-18 as the raw material.

[0836] Preparation of Intermediate B-17 N-(2-(4-(4-((2-azaspiro[3.5]nonan-7-yl)oxy)piperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide

[0837] The following synthetic route was used:

[0838] According to the preparation method of Intermediate B-14, Intermediate B-17 was prepared by replacing Intermediate A-16 with Intermediate A-19 as the raw material.

[0839] Preparation of Intermediate B-18 N-(2-(4-(4-(azetidin-3-ylmethyl)piperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide

[0840] The following synthetic route was used:

[0841] According to the preparation method of Intermediate B-14, Intermediate B-18 was prepared by replacing Intermediate A-16 with Intermediate A-20 as the raw material.

[0842] Preparation of Intermediate B-19, N-(2-(4-(4-(azetidin-3-ylmethyl)-3,6- dihydropyridin-l(2H)-yl)phenyl)-lH-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-lH- pyrazole-3-carboxamide

[0843] The following synthetic route was employed:

[0844] Prepared according to the procedure described in the preparation of Intermediate B-14, replacing Intermediate A-16 with Intermediate A-21 as starting material.

[0845] Preparation of Intermediate B-20, 4,5-dimethyl-N-(2-(4-(l-(pyrrolidin-3- ylmethyl)piperidin-4-yl)phenyl)-lH-pyrrolo[2,3-b]pyridin-5-yl)-lH-pyrazole-3- carboxamide

[0846] The following synthetic route was employed:

[0847] Prepared according to the procedure described in Example 2, Steps 1 to 2, replacing Intermediate B-1 with Intermediate B-7 as starting material.

[0848] Preparation of Intermediate B-21, N-(2-(4-(l-(azetidin-3-ylmethyl)piperidin-4- yl)phenyl)-lH-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-lH-pyrazole-3-carboxamide

[0849] The following synthetic route was employed:

[0850] Prepared according to the procedure described in Example 3, Steps 1 to 2, replacing Intermediate B-1 with Intermediate B-7 as starting material.

[0851] Preparation of Intermediate B-21a, 4,5-dimethyl-N-(2-(4-(l,2,3,6-tetrahydropyridin-4- yl)phenyl)-lH-pyrrolo[2,3-b]pyridin-5-yl)-lH-pyrazole-3-carboxamide

[0852] The following synthetic route was employed:

[0853] Prepared according to the procedure for the preparation of intermediate B-15 using intermediate B-7, step 3 product 4-(4-(5-(4,5-dimethyl-lH-pyrazole-3-carboxamido)-lH-pyrrolo[2,3- b]pyridin-2-yl)phenyl)-3,6-dihydropyridine-l(2H)-carboxylic acid tert-butyl ester as starting material instead of intermediate B-14a.

[0854] Preparation of intermediate B-22 N-(2-(4-(l-(azetidin-3-ylmethyl)-l,2,3,6- tetrahydropyridin-4-yl)phenyl)-lH-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-lH- pyrazole-3-carboxamide

[0855] The following synthetic route was used:

[0856] Prepared according to the procedure for the preparation of intermediate B-15 using intermediate B-7, step 3 product 4-(4-(5-(4,5-dimethyl-lH-pyrazole-3-carboxamido)-lH-pyrrolo[2,3- b]pyridin-2-yl)phenyl)-3,6-dihydropyridine-l(2H)-carboxylic acid tert-butyl ester as starting material instead of intermediate B-14a.

[0857] Preparation of intermediate B-23 4,5-dimethyl-N-(2-(4-(pyrrolidin-3-yl)phenyl)-lH- pyrrolo[2,3-b]pyridin-5-yl)-lH-pyrazole-3-carboxamide

[0858] The following synthetic route was used:

[0859] Prepared according to the procedure for the preparation of intermediate B-15 using intermediate B-7, step 3 product 4-(4-(5-(4,5-dimethyl-lH-pyrazole-3-carboxamido)-lH-pyrrolo[2,3- b]pyridin-2-yl)phenyl)-3,6-dihydropyridine-l(2H)-carboxylic acid tert-butyl ester as starting material instead of intermediate B-14a.

[0860] Preparation of intermediate B-24 4,5-dimethyl-N-(2-(4-(l-(piperidin-4- ylmethyl)azetidin-3-yl)phenyl)-lH-pyrrolo[2,3-b]pyridin-5-yl)-lH-pyrazole-3- carboxamide

[0861] The following synthetic route was used:

[0862] Prepared according to the procedure for the preparation of intermediate B-15 using intermediate B-7, step 3 product 4-(4-(5-(4,5-dimethyl-lH-pyrazole-3-carboxamido)-lH-pyrrolo[2,3- b]pyridin-2-yl)phenyl)-3,6-dihydropyridine-l(2H)-carboxylic acid tert-butyl ester as starting material instead of intermediate B-14a.

[0863] Preparation of intermediate B-25 4-(5-(4,5-dimethyl-1H-pyrazole-3-carboxamido)-1H- pyrrolo[2,3-b]pyridin-2-yl)benzoic acid

[0864] The following synthetic route was employed:

[0865] Step 1 Synthesis of methyl 4-(5-(4,5-dimethyl-1H-pyrazole-3-carboxamido)-1H- pyrrolo[2,3-b]pyridin-2-yl)benzoate

[0866] Intermediate B-7 Step 2 product N-(2-(4-bromophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5- dimethyl-1H-pyrazole-3-carboxamide (2.00 g, 4.89 mmol, 1.00 equiv.), Pd(dppf)Cl2·DCM (596.40 mg, 0.73 mmol, 0.15 equiv.) and TEA (2.04 mL, 14.67 mmol, 3.00 equiv.) were dissolved in mixed solvent MeOH / DMF (20 mL / 5 mL), CO gas was bubbled for 3 times, the reaction was stirred at 90 °C overnight, TLC monitoring reaction was completed. Lowered to room temperature, added water (25 mL), extracted with EtOAc (25 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated by silica gel column to get yellow solid 1.71 g, yield 90.06%. LC-MS (ESI): m / z = 390.2 [M+H] + .

[0867] Step 2 Synthesis of intermediate B-25

[0868] Methyl 4-(5-(4,5-dimethyl-1H-pyrazole-3-carboxamido)-1H-pyrrolo[2,3-b]pyridin-2- yl)benzoate (1.60 g, 4.11 mmol, 1.00 equiv.) and NaOH (822.00 mg, 20.55 mmol, 5.00 equiv.) were dissolved in mixed solvent DMA / H2O (10 mL / 10 mL), the reaction was stirred at 80 °C overnight, TLC monitoring reaction was completed. Lowered to room temperature, pH was adjusted to acidic, added water (20 mL), filtered, the filter cake was washed with water, dried under vacuum to get yellow solid 1.11 g, yield 71.81%. LC-MS (ESI): m / z = 376.1 [M+H] + .

[0869] Preparation of intermediate B-26 N-(2-(4-(4-(azetidin-3-yl)piperazine-1-carbonyl)phenyl)-1H- pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide

[0870] The following synthetic route was employed:

[0871] Step 1 Synthesis of compound tert-butyl 3-(4-(4-(5-(4,5-dimethyl-1H-pyrazole-3-carboxamido)-1H- pyrrolo[2,3-b]pyridin-2-yl)benzoyl)piperazin-1-yl)azetidine-1-carboxylate

[0872] Intermediate B-25 (200.00 mg, 0.53 mmol, 1.00 equiv.), tert-butyl 1- carbamoyl-3-(1-piperazinyl)azetidine-3-carboxylate (154.24 mg, 0.64 mmol, 1.20 equiv.), PyBOP (416.00 mg, 0.80 mmol, 1.50 equiv.) and DIPEA (0.28 mL, 1.59 mmol, 3.00 equiv.) were dissolved in anhydrous DMF (5 mL), and the reaction was stirred at room temperature for 3 hours after being purged with nitrogen for 3 times. Water (5 mL) was added, and the reaction was extracted with EtOAc (5 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain 238.50 mg of a brown solid with a yield of 75.25%. LC-MS (ESI): m / z = 599.3 [M+H] + .

[0873] Step 2 Synthesis of intermediate B-26

[0874] Tert-butyl 3-(4-(4-(5-(4,5-dimethyl-1H-pyrazole-3-carboxamido)-1H-pyrrolo[2,3-b]pyridin-2- yl)benzoyl)piperazin-1-yl)azetidine-1-carboxylate (220.00 mg, 0.37 mmol, 1.00 equiv.) was dissolved in anhydrous DCM (5 mL), and TFA (141.60 μL, 1.85 mmol, 5.00 equiv.) was added. The reaction was stirred at room temperature for 1 hour, and the reaction was completed by TLC monitoring. Water (5 mL) was added, and the pH was adjusted to neutral by dropwise addition of saturated sodium bicarbonate solution. The reaction was extracted with EtOAc (5 mL x 3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 151.70 mg of a white solid with a yield of 82.30%. LC-MS (ESI): m / z = 499.3 [M+H] + .

[0875] Preparation of intermediate B-27 N-(2-(4-formylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide

[0876] The following synthetic route was employed:

[0877] Step 1 Synthesis of compound N-(2-(4-(hydroxymethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide

[0878] Intermediate B-25 (200.00 mg, 0.53 mmol, 1.00 equiv.) was dissolved in anhydrous THF (8 mL), and the reaction was stirred at room temperature under a nitrogen atmosphere. BH3THF (1 M, 7.95 mL, 7.95 mmol, 15.00 equiv.) was added dropwise using a syringe, and the reaction was stirred for 1 h at room temperature. The reaction was monitored by TLC. The reaction was quenched by dropwise addition of methanol, and the reaction was stirred for 30 min at room temperature. The reaction was concentrated under reduced pressure, and the residue was separated by column chromatography on silica gel to give 53.00 mg of a white solid in a yield of 27.70%. LC-MS (ESI): m / z = 362.2 [M+H] + .

[0879] Step 2 Synthesis of intermediate B-27

[0880] N-(2-(4-(hydroxymethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide (53.00 mg, 0.15 mmol, 1.00 equiv.) and DMP (97.50 mg, 0.23 mmol, 1.20 equiv.) were dissolved in a mixed solvent of DCM / DMF (4 mL / 2 mL), and the reaction was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction was monitored by TLC. Water (6 mL) was added, and saturated sodium thiosulfate solution was added dropwise. Saturated sodium bicarbonate solution was added dropwise, and the reaction was extracted with DCM (6 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by column chromatography on silica gel to give 51.50 mg of a white solid in a yield of 95.60%. LC-MS (ESI): m / z = 360.1 [M+H] + .

[0881] Preparation of intermediate B-27a 4,5-dimethyl-N-(2-(4-(2-oxoethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-carboxamide Preparation of intermediate B-27a 4,5-dimethyl-N-(2-(4-(2-oxoethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-carboxamide

[0882] The following synthetic route was employed:

[0883] According to the synthetic method of step 3 to step 4 in the preparation method of intermediate C-1, intermediate B-27a was prepared by replacing 1-(4-bromophenyl)dihydropyrimidine-2,4(1H,3H)-dione, the product of step 2 of intermediate C-1, with N-(2-(4-bromophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide, the product of step 2 of intermediate B-7, as the raw material.

[0884] Preparation of intermediate B-28, 4,5-dimethyl-N-(2-(4-(2-(piperazin-1-yl)ethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-carboxamide

[0885] The following synthetic route was employed:

[0886] According to the synthetic method of step 1 to step 2 in the preparation method of Example 1, intermediate B-28 was prepared by replacing intermediate B-1 and 1-Boc-piperidin-4-carbaldehyde with intermediate B-27a and N-Boc-piperazine, respectively, as the raw material.

[0887] Preparation of intermediate B-29, 4,5-dimethyl-N-(2-(4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-carboxamide

[0888] The following synthetic route was employed:

[0889] Step 1 Synthesis of tert-butyl 4-((3-(4-(5-(4,5-dimethyl-1H-pyrazole-3-carboxamido)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate

[0890] Intermediate B-7, step 2 product N-(2-(4-bromophenyl)-1H-pyrrolo[2,3-b]pyridin-5- yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide (300.00 mg, 0.73 mmol, 1.00 equiv.), 4- (prop-2-yn-1-yloxy)piperidine-1-carboxylic acid tert-butyl ester (348.90 mg, 1.46 mmol, 2.00 equiv.), Pd(PPh3)4 (46.20 mg, 0.04 mmol, 0.05 equiv.), CuI (13.40 mg, 0.07 mmol, 0.10 equiv.) and TEA (0.51 mL, 3.65 mmol, 5.00 equiv.) were dissolved in anhydrous DMF (10 mL), the reaction was stirred at 80 °C for 12 h after 3 times of nitrogen replacement. TLC monitoring showed that the reaction was completed. Water (10 mL) was added, and the organic phase was extracted with EtOAc (10 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The yellow solid 317.30 mg was obtained by silica gel column separation with a yield of 76.52%. LC-MS (ESI): m / z = 569.3 [M+H] + .

[0891] Synthesis of intermediate B-29, step 2

[0892] Intermediate B-29, step 2 product 4-((3-(4-(5-(4,5-dimethyl-1H-pyrazole-3-carboxamido)- 1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (310.00 mg, 0.55 mmol, 1.00 equiv.) was dissolved in anhydrous DCM (10 mL), and TFA (0.21 mL, 2.75 mmol, 5.00 equiv.) was added. The reaction was stirred at room temperature for 30 min. TLC monitoring showed that the reaction was completed. Water (10 mL) was added, and the pH was adjusted to neutral by dropwise addition of a saturated sodium bicarbonate solution. The filter cake was obtained by filtration, washed with water, and dried under suction. The yellow solid 241.30 mg was obtained by silica gel column separation with a yield of 93.73%. LC-MS (ESI): m / z = 469.2 [M+H] + .

[0893] Preparation of intermediate B-30, 4,5-dimethyl-N-(2-(4-(3-(piperidin-4-yl)prop-1-yn-1- yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-carboxamide

[0894] The following synthetic route was used:

[0895] Intermediate B-30 was prepared according to the procedure described for the preparation of Intermediate B-29 using 1-Boc-4-ethynylpiperidine instead of 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylic acid tert-butyl ester as starting material.

[0896] Preparation of Intermediate B-31 N-(2-(4-((2-azaspiro[3.3]heptan-6-yl)oxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide

[0897] The following synthetic route was used:

[0898] Intermediate B-31 was prepared according to the procedure described for the preparation of Intermediate B-9 using Intermediate A-22 instead of Intermediate A-8 as starting material.

[0899] Preparation of Intermediate B-32 N-(2-(4-((3-azaspiro[5.5]undecan-9-yl)oxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide

[0900] The following synthetic route was used:

[0901] Intermediate B-32 was prepared according to the procedure described for the preparation of Intermediate B-9 using Intermediate A-23 instead of Intermediate A-8 as starting material.

[0902] Preparation of Intermediate B-33 4,5-Dimethyl-N-(2-(4-(piperidin-4-yloxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-carboxamide

[0903] The following synthetic route was used:

[0904] Intermediate B-33 was prepared according to the procedure described for the preparation of Intermediate B-9 using Intermediate A-24 instead of Intermediate A-8 as starting material.

[0905] Preparation of Intermediate B-34 N-(2-(4-((1-(azetidin-3-yl)piperidin-4-yl)oxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide

[0906] The following synthetic route was used:

[0907] According to the method for preparing the intermediate B-2, the intermediate B-33 was prepared by replacing the intermediate B-1 with the intermediate B-33 as a raw material.

[0908] Preparation of intermediate B-35, 4,5-dimethyl-N-(2-(l-(piperidin-4-ylmethyl)-lH- pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl)-lH-pyrazole-3-carboxamide

[0909] The following synthetic route was used:

[0910] According to the method for preparing the intermediate B-9, the intermediate B-35 was prepared by replacing the intermediate A-8 with the intermediate A-25 as a raw material.

[0911] Preparation of intermediate B-36, 4,5-dimethyl-N-(2-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)- lH-pyrrolo[2,3-b]pyridin-5-yl)-lH-pyrazole-3-carboxamide

[0912] The following synthetic route was used:

[0913] According to the method for preparing the intermediate B-9, the intermediate B-36 was prepared by replacing the intermediate A-8 with the intermediate A-26 as a raw material.

[0914] Preparation of intermediate B-37, N-(2-(l-(l-(azetidin-3-ylmethyl)piperidin-4-yl)-lH- pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-lH-pyrazole-3-carboxamide

[0915] The following synthetic route was used:

[0916] According to the method for preparing the intermediate B-9, the intermediate B-37 was prepared by replacing the intermediate B-1 with the intermediate B-36 as a raw material.

[0917] Preparation of intermediate B-38, 4,5-dimethyl-N-(2-(l-(l-(piperidin-4-ylmethyl)piperidin- 4-yl)-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl)-lH-pyrazole-3-carboxamide

[0918] The following synthetic route was used:

[0919] According to the method for synthesizing from Step 1 to Step 2 in the preparation method of Example 1, using intermediate B-36 instead of intermediate B-1 as a raw material, intermediate B-38 was prepared.

[0920] Preparation of intermediate B-39 N-(2-(1-(1-(azetidin-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide

[0921] The following synthetic route was used:

[0922] According to the method for preparing intermediate B-2, using intermediate B-36 instead of intermediate B-1 as a raw material, intermediate B-39 was prepared.

[0923] Preparation of intermediate B-40 4,5-dimethyl-N-(2-(1-(pyrrolidin-3-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-carboxamide

[0924] The following synthetic route was used:

[0925] According to the method for preparing intermediate B-9, using intermediate A-27 instead of intermediate A-8 as a raw material, intermediate B-40 was prepared.

[0926] Preparation of intermediate B-41 N-(2-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide

[0927] The following synthetic route was used:

[0928] According to the method for preparing intermediate B-9, using intermediate A-28 instead of intermediate A-8 as a raw material, intermediate B-41 was prepared.

[0929] Preparation of intermediate B-42 N-(2-(1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide

[0930] The following synthetic route was used:

[0931] According to the method for preparing intermediate B-9, intermediate B-42 was prepared by replacing intermediate A-8 with intermediate A-29 as raw material.

[0932] Preparation of intermediate B-43, 4,5-dimethyl-N-(2-(1-(2-(piperidin-4- ylmethyl)-2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)- 1H-pyrazole-3-carboxamide

[0933] The following synthetic route was used:

[0934] According to the method for preparing intermediate B-9, intermediate B-42 was prepared by replacing intermediate A-8 with intermediate A-29 as raw material.

[0935] Preparation of intermediate B-44, N-(2-(4-(2,7-diazaspiro[3.5]nonan-7-yl)phenyl)- 1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide

[0936] The following synthetic route was used:

[0937] According to the method for preparing intermediate B-9, intermediate B-44 was prepared by replacing intermediate A-8 with intermediate A-30 as raw material.

[0938] Preparation of intermediate B-45, N-(2-(4-(2-(azetidin-3-yl)-2,7- diazaspiro[3.5]nonan-7-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole- 3-carboxamide

[0939] The following synthetic route was used:

[0940] According to the method for preparing intermediate B-9, intermediate B-45 was prepared by replacing intermediate A-8 with intermediate A-31 as raw material.

[0941] Preparation of intermediate B-46, N-(2-(4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)- 1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide

[0942] The following synthetic route was used:

[0943] According to the method for preparing intermediate B-9, using intermediate A-32 to replace intermediate A-8 as raw material, intermediate B-46 was prepared.

[0944] Preparation of intermediate B-47, 4,5-dimethyl-N-(2-(4-(9-(piperidin-4-carbonyl)-3,9- diazaspiro[5.5]undecan-3-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3- carboxamide

[0945] The following synthetic route was used:

[0946] According to the method for preparing intermediate B-26, using intermediate B-46 and 1-Boc- piperidin-4-carboxaldehyde to replace intermediate B-25 and 1-tert-butoxycarbonyl-3-(1- piperazinyl)azetidine as raw material respectively, intermediate B-47 was prepared.

[0947] Preparation of intermediate B-48, N-(2-(4-(2,8-diazaspiro[4.5]decane-8-yl)phenyl)-1H- pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide

[0948] The following synthetic route was used:

[0949] According to the method for preparing intermediate B-9, using intermediate A-33 to replace intermediate A-8 as raw material, intermediate B-48 was prepared.

[0950] Preparation of intermediate B-49, N-(2-(4-(2,8-diazaspiro[4.5]decane-2-yl)phenyl)-1H- pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide

[0951] The following synthetic route was used:

[0952] According to the method for preparing intermediate B-9, using intermediate A-34 to replace intermediate A-8 as raw material, intermediate B-49 was prepared.

[0953] Preparation of intermediate B-50, N-(2-(4-(2,7-diazaspiro[3.5]nonane-2-yl)phenyl)-1H- pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide

[0954] The following synthetic route was employed:

[0955] According to the method for preparing intermediate B-9, using intermediate A-35 to replace intermediate A-8 as raw material, intermediate B-50 was prepared.

[0956] Preparation of intermediate B-51 N-(2-(4-(7-(azetidin-3-yl)-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide

[0957] The following synthetic route was employed:

[0958] According to the method for preparing intermediate B-2, using intermediate B-50 to replace intermediate B-1 as raw material, intermediate B-51 was prepared.

[0959] Preparation of intermediate B-52 4,5-dimethyl-N-(2-(4-(7-(piperidin-4-carbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-3-carboxamide

[0960] The following synthetic route was employed:

[0961] According to the method for preparing intermediate B-26, using intermediate B-50 and 1-Boc-piperidin-4-carbaldehyde to replace intermediate B-25 and 1-tert-butoxycarbonyl-3-(1-piperazinyl)azetidine as raw material respectively, intermediate B-52 was prepared.

[0962] Preparation of intermediate B-53 N-(2-(4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dimethyl-1H-pyrazole-3-carboxamide

[0963] The following synthetic route was employed:

[0964] According to the method for preparing intermediate B-9, using intermediate A-36 to replace intermediate A-8 as raw material, intermediate B-53 was prepared.

[0965] Preparation of Intermediate B-54, 4,5-dimethyl-N-(2-(4-(6-(piperidin-4-yl)-2,6- diazaspiro[3.3]heptan-2-yl)phenyl)-lH-pyrrolo[2,3-b]pyridin-5-yl)-lH-pyrazole-3- carboxamide

[0966] The following synthetic route was employed:

[0967] Intermediate B-54 was prepared according to the procedure described for the preparation of Intermediate B-26, using Intermediate B-53 and l-Boc-piperidin-4-carbaldehyde in place of Intermediate B-25 and l-tert-butoxycarbonyl-3-(l-piperazinyl)azetidine, respectively, as starting materials.

[0968] Preparation of Intermediate B-55, 4,5-dimethyl-N-(2-(4-(6-(piperidin-4-yl)-2,6- diazaspiro[3.3]heptan-2-yl)phenyl)-lH-pyrrolo[2,3-b]pyridin-5-yl)-lH-pyrazole-3- carboxamide

[0969] The following synthetic route was employed:

[0970] Intermediate B-55 was prepared according to the procedure described for the preparation of Intermediate B-2, using Intermediate B-53 and tert-butyl 4-oxopiperidine- 1-carboxylate in place of Intermediate B-l and l-Boc-3-azetidinone, respectively, as starting materials.

[0971] Preparation of Intermediate C-l, 2-(4-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)phenyl) acetaldehyde

[0972] The following route was employed for the synthesis:

[0973] Step 1 Synthesis of compound 3-((4-bromophenyl)amino)propanoic acid

[0974] To a solution of 4-bromoaniline (3.44 g, 20.00 mmol, 1.00 equiv.), TBAB (644.00 mg, 2.00 mmol, 0.10 equiv.) and acrylic acid (2.10 mL, 30.00 mmol, 1.50 equiv.) in dilute hydrochloric acid (35 mL, 2M), nitrogen was bubbled for 3 times, the temperature was raised to 100 °C and the reaction was stirred overnight, TLC monitoring reaction was completed. Lowered to room temperature, add water (35 mL), and drop saturated sodium bicarbonate solution, the pH was adjusted to 8, then drop acetic acid to adjust the pH to 5, extracted with EtOAc (35 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, to get yellow solid 4.00 g, yield 82.30%. LC-MS (ESI): m / z = 244.0 [M+H] + .

[0975] Step 2 Synthesis of compound 1-(4-bromophenyl)dihydropyrimidine-2,4(lH,3H)- dione

[0976] To a solution of 3-((4-bromophenyl)amino)propanoic acid (4.00 g, 16.46 mmol, 1.00 equiv.) and urea (1.98 g, 32.92 mmol, 2.00 equiv.) in AcOH (20 mL), the temperature was raised to 125 °C and the reaction was stirred overnight, TLC monitoring reaction was completed. Lowered to room temperature, add water (60 mL), stirred for 30 minutes, filtered, washed with water, dried, to get white solid 3.21 g, yield 72.76%. LC-MS (ESI): m / z = 269.0 [M+H] + .

[0977] Step 3 Synthesis of compound (E)-l-(4-(2-ethoxyvinyl)phenyl)dihydropyrimidine-2,4(lH,3H)-dione

[0978] Dihydropyrimidine-2,4(lH,3H)-dione (268.00 mg, 1.00 mmol, 1.00 equiv.), (E)-l-ethoxyvinyl-2-boronic acid pinacol ester (297.00 mg, 1.50 mmol, 1.50 equiv.), Pd(DtBPF)Cl2(64.60 mg, 0.10 mmol, 0.10 equiv.) and K2CO3(414.00 mg, 3.00 mmol, 3.00 equiv.) were dissolved in mixed solvents 1,4-dioxane / H2O (10 mL / 2 mL), purged with nitrogen gas for 3 times, warmed to 105 °C and stirred for 16 hours. The reaction was monitored by TLC. After cooling to room temperature, water (12 mL) was added and the mixture was extracted with EtOAc (12 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give yellow solid 120.60 mg in 46.40% yield. LC-MS (ESI): m / z = 261.1 [M+H] + .

[0979] Synthesis of intermediate C-1

[0980] (E)-l-(4-(2-ethoxyvinyl)phenyl)dihydropyrimidine-2,4(lH,3H)-dione (120.00 mg, 0.46 mmol, 1.00 equiv.) was dissolved in anhydrous DCM (5 mL), TFA (176.00 μL, 2.30 mmol, 5.00 equiv.) was added and the reaction was stirred at room temperature for 1 hour. The reaction was monitored by TLC. Water (5 mL) was added and the pH was adjusted to neutral by dropwise addition of saturated sodium bicarbonate solution. The mixture was extracted with EtOAc (5 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give grey solid 77.20 mg in 72.30% yield. LC-MS (ESI): m / z = 233.1 [M+H] + .

[0981] Preparation of intermediate C-2 2-(l-(4-((2,6-dioxopiperidin-3-yl)amino)-2- fluorophenyl)-4-hydroxypiperidin-4-yl)acetic acid

[0982] The following route was used for the synthesis:

[0983] Step 1 Synthesis of compound l-(2-fluoro-4-nitrophenyl)piperidin-4-one

[0984] Dissolve tert-butyl acetate (2.40 g, 20.68 mmol, 1.20 equiv.) in anhydrous THF (100 mL), replace nitrogen 3 times, cool to -78 °C, stir the reaction, drop LDA (11.20 mL, 22.40 mmol, 2M in THF, 1.30 equiv.) using a syringe, the reaction 30 minutes, continue to drop 1-(2-fluoro-4-nitrophenyl)piperidin-4-one (4.10 g, 17.23 mmol, 1.00 equiv.) dissolved in anhydrous THF (10 mL), the reaction 2 hours, TLC monitor the reaction is complete. Add saturated ammonium chloride solution (50 mL), rise to room temperature, extract with EtOAc (100 mL x 3), the organic phase is washed with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, separated by silica gel column to get yellow oil 5.20 g, yield 85.31%. LC-MS (ESI): m / z = 355.2 [M+H] + .

[0985] Step 3 Synthesis of compound tert-butyl 2-(1-(4-amino-2-fluorophenyl)-4- hydroxypiperidin-4-yl)acetate

[0986] Dissolve tert-butyl acetate (2.40 g, 20.68 mmol, 1.20 equiv.) in anhydrous THF (100 mL), replace nitrogen 3 times, cool to -78 °C, stir the reaction, drop LDA (11.20 mL, 22.40 mmol, 2M in THF, 1.30 equiv.) using a syringe, the reaction 30 minutes, continue to drop 1-(2-fluoro-4-nitrophenyl)piperidin-4-one (4.10 g, 17.23 mmol, 1.00 equiv.) dissolved in anhydrous THF (10 mL), the reaction 2 hours, TLC monitor the reaction is complete. Add saturated ammonium chloride solution (50 mL), rise to room temperature, extract with EtOAc (100 mL x 3), the organic phase is washed with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, separated by silica gel column to get yellow oil 5.20 g, yield 85.31%. LC-MS (ESI): m / z = 355.2 [M+H] + .

[0987] Step 3 Synthesis of compound tert-butyl 2-(1-(4-amino-2-fluorophenyl)-4- hydroxypiperidin-4-yl)acetate

[0988] Tert-butyl 2-(l-(2-fluoro-4-nitrophenyl)-4-hydroxypiperidin-4-yl)acetate (5.20 g, 14.70 mmol, 1.00 equiv.) was dissolved in MeOH (180 mL), 10% palladium on carbon (wetted with 55% H20, 1.74 g, 0.74 mmol, 0.05 equiv.) was added, and the reaction was stirred under a hydrogen atmosphere at 1 atm overnight. The reaction was monitored by TLC. The palladium on carbon was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give a yellow oil (4.29 g, 90.11% yield). LC-MS (ESI): m / z = 325.2 [M+H] + .

[0989] Step 4 Synthesis of tert-butyl 2-(l-(4-((2,6-dioxopiperidin-3-yl)amino)-2- fluorophenyl)-4-hydroxypiperidin-4-yl)acetate

[0990] Tert-butyl 2-(l-(4-amino-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetate (4.00 g, 12.35 mmol, 1.00 equiv.), 3-bromopiperidine-2,6-dione (3.56 g, 18.53 mmol, 1.50 equiv.), and NaHC03(3.11 g, 37.05 mmol, 3.00 equiv.) were dissolved in anhydrous DMF (50 mL), and the reaction was stirred at 65 °C overnight. The reaction was monitored by TLC. The reaction was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with EtOAc (50 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give a green solid (3.95 g, 73.61% yield). LC-MS (ESI): m / z = 436.2 [M+H] + .

[0991] Step 5 Synthesis of intermediate C-2

[0992] Tert-butyl 2-(l-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4- hydroxypiperidin-4-yl)acetate (3.90 g, 8.97 mmol, 1.00 equiv.) was dissolved in anhydrous 1,4-dioxane (50 mL), and hydrogen chloride 1,4-dioxane solution (22.43 mL, 89.70 mmol, 4 M, 10.00 equiv.) was added at 0 °C. The reaction was stirred at room temperature for 3 h. The reaction was monitored by TLC. The reaction was concentrated under reduced pressure to give a light green solid (2.90 g, 85.30% yield). LC-MS (ESI): m / z = 380.1 [M+H] + .

[0993] Preparation of intermediate C-3 2-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7- tetrahydropyrrolo[3,4-f]isoindol-2(lH)-yl)acetic acid

[0994] The following route was used for the synthesis:

[0995] Step 1 Synthesis of compound 2-(tert-butyl) 5,6-dimethylisoindoline-2,5,6-tricarboxylate

[0996] tert-Butyl di(prop-2-yn-l-yl)carbamate (1.45 g, 7.51 mmol, 1.00 equiv.), dimethyl butyne dicarboxylate (3.68 mL, 30.04 mmol, 4.00 equiv.) and Rh(PPh3)3Cl (138.75 mg, 0.15 mmol, 0.02 equiv.) were dissolved in anhydrous EtOH (15 mL), purged with nitrogen for 3 times, warmed to 90 °C and stirred overnight, TLC monitored the reaction was completed. Cooled to room temperature, added water (15 mL), extracted with EtOAc (15 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated by silica gel column to get 590.00 mg of yellow sticky material, yield 23.45%. LC-MS (ESI): m / z = 336.1 [M+H] + .

[0997] Step 2 Synthesis of compound tert-butyl 6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7- tetrahydropyrrolo[3,4-f]isoindoline-2(lH)-carboxylate

[0998] tert-Butyl 2-(tert-butyl) 5,6-dimethylisoindoline-2,5,6-tricarboxylate (570.00 mg, 1.70 mmol, 1.00 equiv.), 3-aminopiperidine-2,6-dione hydrochloride (364.70 mg, 2.21 mmol, 1.30 equiv.) and LiI (683.40 mg, 5.10 mmol, 3.00 equiv.) were dissolved in anhydrous pyridine (10 mL), purged with nitrogen for 3 times, warmed to 120 °C and stirred overnight, TLC monitored the reaction was completed. Cooled to room temperature, added water (10 mL), extracted with EtOAc (10 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated by silica gel column to get 270.00 mg of white solid, yield 39.81%. LC-MS (ESI): m / z = 400.1 [M+H] + .

[0999] Step 3 Synthesis of compound 2-(2,6-dioxopiperidin-3-yl)-6,7-dihydropyrrolo[3,4- f]isoindole-1,3(2H,5H)-dione

[1000] tert-Butyl 6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4- f]isoindole-2(1 H)-carboxylate (270.00 mg, 0.68 mmol, 1.00 equiv.) was dissolved in anhydrous 1,4-dioxane (5 mL), hydrogen chloride 1,4-dioxane solution (1.70 mL, 6.80 mmol, 4 M, 10.00 equiv.) was added at 0 °C, the reaction was raised to room temperature and stirred for 3 hours, TLC monitoring showed the reaction was completed. Concentrated under reduced pressure to get white solid 230.00 mg, yield 99.00%. LC-MS (ESI): m / z = 300.1 [M+H] + .

[1001] Step 4 Synthesis of compound tert-butyl 2-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo- 3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)acetate

[1002] tert-Butyl 2-(2,6-dioxopiperidin-3-yl)-6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)- dione (200.00 mg, 0.67 mmol, 1.00 equiv.), tert-butyl 2-bromoacetate (156.00 mg, 0.80 mmol, 1.20 equiv.), KI (21.60 mg, 0.13 mmol, 0.20 equiv.) and DIPEA (350.00 μL, 2.01 mmol, 3.00 equiv.) were dissolved in anhydrous DMF (10 mL), the reaction was stirred at room temperature for 5 hours after 3 times of nitrogen replacement, TLC monitoring showed the reaction was completed. Water (10 mL) was added, extracted with EtOAc (10 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column to get yellow solid 223.30 mg, yield 80.71 %. LC-MS (ESI): m / z = 414.2 [M+H] + .

[1003] Step 5 Synthesis of intermediate C-3 hydrochloride

[1004] tert-Butyl 2-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4- f]isoindol-2(lH)-yl)acetate (200.00 mg, 0.48 mmol, 1.00 equiv.) was dissolved in anhydrous 1,4-dioxane (5 mL), hydrogen chloride 1,4-dioxane solution (1.20 mL, 4.80 mmol, 4 M, 10.00 equiv.) was added at 0 °C, the reaction was warmed to room temperature and stirred for 8 hours, TLC monitoring showed that the reaction was completed. Concentrated under reduced pressure to obtain white solid 178.90 mg, yield 95.10%. LC-MS (ESI): m / z = 358.1 [M+H] + .

[1005] Preparation of intermediate C-4 3-(3-methyl-2-oxo-5-(3-oxoazetidin-l-yl)-2,3-dihydro-lH- benzo[d]imidazol-l-yl)piperidine-2,6-dione

[1006] The following synthetic route was employed:

[1007] Step 1 Synthesis of compound 1-benzyl-3,3-dimethoxyazetidine

[1008] 1,3-Dibromo-2,2-dimethoxypropane (5.24 g, 20.00 mmol, 1.00 equiv.), benzylamine (2.14 g, 20.00 mmol, 1.00 equiv.), KI (0.66 g, 4.00 mmol, 0.20 equiv.) and K2CO3 (8.28 g, 60.00 mmol, 3.00 equiv.) were dissolved in anhydrous DMF (50 mL), the nitrogen was replaced 3 times, the temperature was raised to 100 °C and the reaction was stirred overnight, TLC monitoring showed that the reaction was completed. The temperature was lowered to room temperature, water (200 mL) was added, extracted with EtOAc (50 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated on a silica gel column to obtain yellow oil 240.00 mg, yield 5.80%. LC-MS (ESI): m / z = 208.1 [M+H] + .

[1009] Step 2 Synthesis of compound 3,3-dimethylazetidine

[1010] To a stirred solution of 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)piperidine-2,6-dione (266.00 mg, 0.79 mmol, 1.00 equiv.), 3,3- dimethyloxazetidine hydrochloride (153.90 mg, 0.95 mmol, 1.20 equiv.), Ruphos Pd G3 (200.90 mg, 0.24 mmol, 0.30 equiv.) and Cs2CO3 (1.03 g, 3.16 mmol, 4.00 equiv.) in anhydrous 1,4-dioxane (15 mL) was purged with nitrogen gas for 3 times, the reaction was stirred at 120 °C overnight, TLC monitored the completion of reaction. Cooled to room temperature, water (15 mL) was added, extracted with EtOAc (15 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated on silica gel column to get yellow solid 151.00 mg in 51.11% yield. LC-MS (ESI): m / z = 3...

Claims

a compound of Formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof: wherein Y is selected from N or CH; R1is a divalent group of a 5- or 6-membered heteroarene or a phenyl ring; wherein the divalent group is optionally substituted with one or more R; each R is independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6haloalkoxy, C 3-6 cycloalkyl or 3- to 7-membered heterocycloalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1- alkoxy, C 1-6 6haloalkoxy, C 3-6 cycloalkyl or 3- to 7-membered heterocycloalkyl optionally substituted with one or more D up to complete deuteratation; R2and R3are independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- haloalkoxy, C 3-6 cycloalkyl or 3- to 7-membered heterocycloalkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 1- alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl or 3- to 7-membered heterocycloalkyl optionally substituted with one or more D up to complete deuteratation; n is 0, 1, 2, 3, or 4; R a independently selected from H, D, halogen, -NH2, -CN, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy is optionally substituted with one or more D, up to complete deuteration; L is a divalent linking group; U is a group that binds to an E3 ubiquitin ligase. The compound according to claim 1, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R1is a divalent group of a 5-membered heteroarene optionally substituted with 1, 2, or 3 R. The compound according to claim 1 or 2, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R1is selected from: ^ indicates attachment to L, and * indicates attachment to the remaining end in the compound of Formula (I). The compound according to any one of claims 1-3, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R1 is: ^ indicates attachment to L, and * indicates attachment to the remaining end in the compound of Formula (I). The compound according to claim 1, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R1is a divalent group of a 6-membered heteroarene or a phenyl ring optionally substituted with 1, 2, 3, or 4 R. The compound of claim 1 or 5, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R1is selected from: ^ indicates attachment to L, and * indicates attachment to the remaining end in the compound of Formula (I). The compound according to any one of claims 1, 5 or 6, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein, R1is selected from: ^ indicates attachment to L, and * indicates attachment to the remaining end in the compound of Formula (I). The compound according to any one of claims 1-7, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, each R is independently selected from H, D, F, Cl, CH3, CD3, ethyl, isopropyl, t-butyl, CF3, methoxy, trifluoromethoxy, or cyclopropyl. The compound according to any one of claims 1-8, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, each R is independently H or D. The compound according to any one of claims 1-9, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, Y is CH. The compound according to any one of claims 1-10, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R2and R3are independently selected from H, D, F, Cl, CH3, CD3, ethyl, CF3, methoxy, trifluoromethoxy, or cyclopropyl. The compound according to any one of claims 1-11, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R2and R3are independently Cl, CH3, or CD3. The compound according to any one of claims 1-12, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, n is 0. a compound of Formula (II), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof: wherein each R is independently selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy is optionally substituted with one or more D up to per-deuteration; R2and R3are independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 3-6 cycloalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 3-6 cycloalkyl is optionally substituted with one or more D up to complete deuteration; L is a divalent linking group; U is a group that binds to an E3 ubiquitin ligase. The compound of claim 14, or a tautomer, stereoisomer, pro-drug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, each R is independently selected from H, D, F, Cl, CH3, CD3, ethyl, isopropyl, t-butyl, CF3, methoxy, trifluoromethoxy, or cyclopropyl. Preferably, each R is independently H or D. The compound according to claim 14 or 15, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R2and R3are independently selected from H, D, F, Cl, CH3, CD3, ethyl, CF3, methoxy, trifluoromethoxy, or cyclopropyl. Preferably, R2and R3are independently Cl, CH3, or CD3. a compound of Formula (III), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof: wherein each R is independently selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy is optionally substituted with one or more D, up to per-deuteration; R2and R3are independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 3-6 cycloalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 3-6 cycloalkyl is optionally substituted with one or more D up to complete deuteration; L is a divalent linking group; U is a group that binds to an E3 ubiquitin ligase. The compound of claim 17, or a tautomer, stereoisomer, pro-drug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, each R is independently selected from H, D, F, Cl, CH3, CD3, ethyl, isopropyl, t-butyl, CF3, methoxy, trifluoromethoxy, or cyclopropyl. Preferably, each R is independently H or D. The compound according to claim 17 or 18, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R2and R3are independently selected from H, D, F, Cl, CH3, CD3, ethyl, CF3, methoxy, trifluoromethoxy, or cyclopropyl. Preferably, R2and R3are independently Cl, CH3, or CD3. The compound according to any one of claims 1-19, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L is a divalent linking group of Formula (IV): -S0-(L1) i -S1-(L2) j -S2-(L3) k -S3-■(IV) wherein i is 0 or 1, j is 0 or 1, and k is 0 or 1; provided that at least one of i, j, and k is not 0; L1, L2and L3are each independently a chemical bond, or selected from C 3-7 cycloalkane, 4- to 7-membered heterocyclic divalent radical, wherein the divalent radical is optionally substituted with one or more radicals selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl; S0, S1, S2, and S3 are each independently a bond, -0-, -S-, -NH-, -C(O)-, -C(0)NH-, -NHC(O)-, -C(0)NH(CH2) p -, p -, p -, p -, q -, 1-6 alkylene or C 1-6 alkenylene; wherein p is 1, 2, 3, or 4; q is 1, 2, or 3; ■indicates attachment to U. The compound of claim 20, or a tautomer, stereoisomer, pro-drug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L is a divalent linking group of formula (IV A ) as shown below: -(L1) i -(L2) j -(L3) k -■(IV A ). The compound of claim 20, or a tautomer, stereoisomer, pro-drug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L is a divalent linking group of formula (IV B ) as shown below: -(L1) i -S1-(L2) j -S2-(L3) k -■(IV B ). The compound of claim 20, or a tautomer, stereoisomer, pro-drug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L is a divalent linking group of formula (IV C ) as shown below: -S0-(L1) i (L2) j -S2-(L3) k -S3-■(IV C ) wherein (L1) i and (L2) j share one atom and / or one chemical bond. The compound of claim 20, or a tautomer, stereoisomer, pro-drug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L is a divalent linking group of formula (IV D ) as shown below: -S0-(L1) i -S1-(L2) j (L3) k -S3-■(IV D ) wherein (L2) j and (L3) k share one atom and / or one chemical bond. The compound according to any one of claims 20-24, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, one or two of L1, L2and L3is a bond, and the remaining are each independently a divalent radical selected from 4- to 7-membered heterocyclic rings containing 1 or 2 N atoms; wherein the divalent radical is optionally substituted with one or more radicals selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl. The compound according to any one of claims 20-25, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L is: wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl groups. The compound according to any one of claim 26, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L is: wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl groups. The compound according to any one of claims 1-25, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L is: wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl. The compound according to any one of claim 28, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L is: wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl. The compound according to any one of claims 1-29, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: wherein represents a single or double bond; each V is independently a bond, C(O), NH, O, S, C(O)NH, NHC(O), or CH2; each V is independently a bond, C(O), NH, O, S, C(O)NH, NHC(O), or CH2; each W is independently a bond, C(O), NH, O, S, C(O)NH, NHC(O), or CH2; each Q1is independently C(O) or C(R9)2; each Q2is independently N or CH; each Q3and Q4is independently N or CR9; each K1, K2, and K3is independently N or CR9; K4and K5are each independently N or C; H1is N, C, or CR9; H2and H3are each independently C(O), N, O, S, NR9, CR9, or C(R9)2; H4and H8are each independently N or CR9; H5, H6, and H7are each independently C(O), O, S, NR9, or C(R9)2; each R7is independently H or C 1-6 alkyl; each R8is independently D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; or two R8together with the atoms to which they are attached form a C 3-7 cycloalkane or 4- to 7-membered heterocycle; each R9is independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; or two R9together with the atoms to which they are attached form a C 3-7 cycloalkane, 4- to 7-membered heterocycle, C 6-10 arene or 5- to 10-membered heteroarene; each o is independently 0, 1, or 2; each h is independently 0, 1, 2, 3, or 4; each z is independently 0, 1, or 2; each r and s is independently 0, 1, 2, or 3; and r and s are not simultaneously 0; each t and u is independently 0, 1, 2, or 3; and t and u are not simultaneously 0. The compound of claim 30, or a tautomer, stereoisomer, pro-drug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: wherein, represents a single or double bond; each V is independently a bond, C(O), NH, O, S, C(O)NH, NHC(O), or CH2; each W is independently a bond, C(O), NH, O, S, C(O)NH, NHC(O), or CH2; each Q1is independently C(O) or C(R9)2; each Q2is independently N or CH; each Q3and Q4is independently N or CR9; each R7is independently H or C 1-6 alkyl; each R8is independently D, halo, C 1-6 alkyl or C 1-6 haloalkyl; or two R8together with the atoms to which they are attached form a C 3-7 cycloalkane or 4- to 7-membered heterocycle; each R9is independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; or two R9together with the atoms to which they are attached form a C 3-7 cycloalkane, 4- to 7-membered heterocycle, C 6-10 arene or 5- to 10-membered heteroarene; each h is independently 0, 1, 2, 3, or 4; each k is independently 0, 1, 2, 3, or 4; each z is independently 0, 1, or 2; each r is independently 0, 1, or 2; each r and s is independently 1, 2, or 3; each t and u is independently 1, 2, or 3. The compound of claim 31, or a tautomer, stereoisomer, pro-drug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: wherein, Q3is N or CR9; each R9is independently H, D, or halogen; each k is independently 0, 1, or 2. The compound of claim 31, or a tautomer, stereoisomer, pro-drug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: wherein, Q3is N or CR9; each R9is independently H, D, or halogen; each k is independently 0, 1, or 2. The compound of claim 31, or a tautomer, stereoisomer, pro-drug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: wherein, Q3is N or CR9; each R9is independently H, D, or halogen; each k is independently 0, 1, or 2. The compound according to any one of claims 1-31, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: The compound according to any one of claims 1-29, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is The compound according to any one of claims 1-29, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: wherein, each V is independently a bond, C(O), NH, O, S, C(O)NH, NHC(O), or CH2; each R is independently H, CH3, OCH2CH2OH, (OCH2CH2)2OH, 10 each independently H, CH3, OCH2CH2OH, (OCH2CH2)2OH, each R is independently H, Cl, CN, ethynyl, phenyl, 11 each independently H, Cl, CN, ethynyl, phenyl, The compound according to any one of claims 1-29, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: wherein, each V is independently a bond, C(O), NH, O, S, C(O)NH, NHC(O), or CH2; each R is independently H, CH3, OCH2CH2OH, (OCH2CH2)2OH, 10 each independently H, CH3, OCH2CH2OH, (OCH2CH2)2OH, each R is independently H, Cl, CN, ethynyl, phenyl, 11 each independently H, Cl, CN, ethynyl, phenyl, each R is independently -CH3, 12 each independently -CH3, Each R 13 Each can be independently -CH3, -CH(CH3)2, -C(CH3)3 or -OCH3. The compound according to any one of claims 1-29, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: The compound according to any one of claims 1-29, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: a compound, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, isotopologue, hydrate, or solvate thereof, wherein the compound is selected from the group consisting of compounds of the following formulae: a pharmaceutical composition comprising a compound of any one of claims 1-41, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutically acceptable excipient. A kit comprising a first container comprising a compound of any one of claims 1-41, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of claim 42; and optionally, a second container comprising an additional therapeutic agent; and optionally, a third container comprising a pharmaceutical excipient for diluting or suspending the compound and / or additional therapeutic agent. Use of a compound of any one of claims 1-41, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of claim 42, or a kit of claim 43, in the manufacture of a medicament for treating a disease associated with c-Kit or PDGFRa. A method of inducing c-Kit or PDGFRa inhibition and / or degradation in a cell, the method comprising contacting the cell with a compound of any one of claims 1-41, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of claim 42, or a kit of claim 43, the contacting can be performed in vitro or in vivo; Preferably, the contacting is performed in vitro; Preferably, the contacting is performed in vivo. A method of treating a disease associated with c-Kit or PDGFRa in a subject, the method comprising administering to the subject a compound of any one of claims 1-41, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of claim 42, or a kit of claim 43. Use of a compound of any one of claims 1-42, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of claim 42, or a kit of claim 43, in the treatment of a disease associated with c-Kit or PDGFRa. the use of claim 44, the method of claim 45 or 46, or the use of claim 47, wherein The c-Kit has or does not have a mutation; Preferably, the c-Kit has a mutation in exon 9; Preferably, the c-Kit has a mutation in exon 11; Preferably, the c-Kit has a mutation in exon 13; Preferably, the c-Kit has a mutation in exon 14; Preferably, the c-Kit has a mutation in exon 17; Preferably, the c-Kit has at least one mutation selected from insAY502-503, delWK557-558, V560G, V654A, T670I or D816V. the use of claim 44, the method of claim 45 or 46, or the use of claim 47, wherein The PDGFRa has or does not have a mutation; Preferably, the PDGFRa has a mutation in exon 14; Preferably, the PDGFRa has a mutation in exon 15; Preferably, the PDGFRa has a mutation in exon 18; Preferably, the PDGFRa has at least one mutation selected from V658A, T674I, G680R or D824V. the use of claim 44, the method of claim 45 or 46, or the use of claim 47, wherein The disease associated with c-Kit or PDGFRa is systemic mastocytosis, gastrointestinal stromal tumor, acute myeloid leukemia, melanoma, seminoma, mediastinal B-cell lymphoma, Ewing's sarcoma, diffuse large B-cell lymphoma, dysgerminoma, myelodysplastic syndrome, nasal NK / T-cell lymphoma, chronic myelomonocytic leukemia, and brain cancer.

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