Triazine compound and application thereof

Abstract

The present invention relates to triazine compounds of formula (I), pharmaceutical compositions containing them, and methods for their preparation and use, wherein the variables are as defined in the specification. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to triazine compounds, pharmaceutical compositions containing the same, and preparation methods and uses thereof. Background Art

[0002] The occurrence of acute leukemia is associated with genetic heterogeneity and epigenetic abnormalities (Rodríguez-Paredes M, et al. Nat Med. 2011; 17(3): 330–339), which poses a great challenge to the treatment of acute leukemia. MLL (Mixed lineage leukemia, also known as MLL1 or KMT2A) is a protein expressed in hematopoietic cells and is essential for the normal development of hematopoietic cells. It consists of two subunits, the N-terminal part and the C-terminal part formed by the cleavage of the MLL protein precursor. MLL contains two main functional domains, such as the SET (Su(var)3-9, Enhancer-of-zeste and Trithorax) domain with histone H3 lysine 4 (H3K4) methyltransferase activity at the C-terminus and the DNA binding domain (AT hook sequence) at the N-terminus. MLL usually forms a complex with chaperone proteins to regulate gene expression through epigenetic mechanisms (Krivtsov AV, et al. Nat Rev Cancer. 2007; 7: 823–33).

[0003] Studies have found that MLL gene translocation occurs in approximately 5%–10% of acute leukemia patients (including AML and ALL), and is particularly common in infant leukemia, accounting for about 80% of infant acute lymphoblastic leukemia (ALL) cases, which show strong resistance to chemotherapy (Teachey DT, et al. Br J Haematol. 2013; 162(5): 606–620). MLL translocation causes the N-terminal fragment of MLL to fuse with more than 80 partner proteins (Slany RK, et al. Haematologica. 2009; 94(7): 984–993). Analysis of whole genome gene expression in samples from MLL fusion and MLL wild-type leukemias revealed that their gene expression characteristics were significantly different. The most frequently overexpressed genes in MLL fusion leukemias are HOX (Homeobox) cluster genes (especially HOXA7-HOXA10) and the HOX gene cofactor MEIS1. HOX family genes encode transcription factors that control developmental processes, especially the development of the hematopoietic system (Li Z, et al. Cancer Res (2009) 69: 1109–16). In the hematopoietic system, HOX and MEIS1 genes are highly expressed in stem cells and early lineage progenitor cells, and the expression levels decrease with differentiation. Sustained expression of MEIS1 and HOX genes has been observed in a variety of leukemias, including MLL fusion types (Kawagoe H, et al. Leukemia (1999) 13: 687–98). Therefore, the dysregulation of the expression of HOX developmental regulators and their cofactor MEIS1 caused by MLL fusion proteins plays a key role in the stem cell-like characteristics of MLL fusion leukemias, and confers or maintains the self-renewal properties, growth and survival advantages of these cells, thereby promoting their oncogenic potential (Winters AC, et al. Front Pediatr. 2017; 5: 4). In addition to gene fusions caused by translocations, MLL partial tandem duplications (PTDs) also occur in 5–10% of childhood and adult ALL and AML. Epidemiological studies have shown that MLL-PTD predicts worse relapse-free survival in patients with acute leukemia ( K, et al. J Clin Oncol. 2002; 20: 3254–61). Therefore, there is a great medical need for leukemia caused by MLL abnormalities, and new treatments need to be developed for them.

[0004] Studies have shown that the oncogenic function of MLL fusion proteins mainly depends on their direct interaction with menin proteins (Yokoyama A, et al. Cell. 2005; 123(2): 207–218). Menin is a 67kDa protein encoded by the MEN1 (Multiple Endocrine Neoplasia I) gene located on chromosome 11q13. Menin is widely expressed and mainly localized in the cell nucleus. Although menin does not have a clear biological functional domain, menin protein can bind to a variety of functional proteins, participate in regulating gene expression, and affect cell growth and development (Balogh K, et al. Trends Endocrinol Metab. 2006; 17(9): 357-364). As one of the most important binding molecules, menin protein can directly bind to the menin binding sequence (MBM) at the N-terminus of MLL fusion protein and recruit MLL or MLL fusion protein to target genes (including HOXA9 or MEIS1) (Grembecka J, et al. J. Biol. Chem. 2010; 285(52): 40690–40698).

[0005] Studies have shown that if the MLL fusion protein loses its binding to the menin protein, it will lose its carcinogenic properties in vitro and in vivo (Caslini C, et al. Cancer. Res. 2007; 67(15):7275–7283).

[0006] In addition, if the N-terminus of the MLL-ENL fusion protein mutates, the fusion protein will be unable to bind to menin, thereby inhibiting HOX gene expression and the potential to induce mouse leukemia (Yokoyama A, et al. Cell. 2005). Using small molecule inhibitors to inhibit the interaction between MLL fusion protein and menin can significantly inhibit the proliferation of MLL fusion-related leukemia cells and promote their cell differentiation (Grembecka J, et al. Nat. Chem. Biol. 2012; 8(3): 277–284).

[0007] NPM1 is a widely expressed nucleolar phosphorylated protein that shuttles between the nucleus and the cytoplasm as a chaperone, participates in ribosome biogenesis, and maintains genomic stability (Heath EM, et al. Leukemia. 2017; 31(4): 798-807). Studies have shown that NPM1 mutations are found in 20-30% of AML patients (Papaemmanuil E, et al. NEngl J Med. 2016; 374: 2209–21.). In addition, studies have shown that in acute myeloid leukemia with mutations in the NPM1 gene, the interaction between menin and wild-type MLL1 also plays an important role. After treatment with the first-generation menin-MLL1 inhibitor, AML cells with NPM1 mutations undergo growth arrest and differentiation (Uckelmann HJ, et al. Science. 2020; 367: 586–90). These results further support the development of more effective menin-MLL1 inhibitors for leukemia patients with NPM1 mutations.

[0008] Currently, there are several small molecule inhibitors of menin for acute leukemia that are being explored in preclinical or clinical trials. However, the small molecule inhibitors of menin currently in the clinical stage still have major defects, such as the need to improve menin inhibitory activity, poor compound stability, and pharmacokinetic characteristics that make it difficult for compound exposure to reach a clinically effective dose. Therefore, the development of a new generation of more potent small molecule inhibitors of menin with good pharmacokinetic properties and lower toxic side effects is of great clinical significance.

[0009] Brief description of the invention

[0010] The present invention solves the above-mentioned needs in this field. The present invention provides novel structural inhibitor compounds with menin inhibitory activity. These compounds of the present invention have comparable or enhanced menin inhibitory activity compared to the inhibitors available in the prior art due to their improved structural patterns, and have good pharmacokinetic properties, so that they can be administered in a convenient manner and are more easily absorbed in the body, and have reduced toxic and side effects.

[0011] Thus, the present invention provides compounds of formula (I):

[0012]

[0013] or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof, wherein:

[0014] R1 is selected from hydrogen, halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C1-6 Haloalkyl, -O-(C 1-6 Alkyl) and -O-(C 1-6 haloalkyl);

[0015] R2 is selected from hydrogen, halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, -O-(C 1-6 Alkyl), -O-(C 1-6 Haloalkyl), -O-(C 3-8 Cycloalkyl), -O-(4-8 membered heterocyclic group), C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, phenyl, 5-12 membered heteroaryl, -S-(C 1-6 Alkyl), -S-(C 3-8 Cycloalkyl), -S-(4-8 membered heterocyclic group), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NHCONH2, -NHCO(C 1-6 Alkyl), -CONR a R b ,-CSNR a R b 、-COR c and-COOR e ; wherein said C 3-8 The cycloalkyl, 4-8 membered heterocyclyl, phenyl and 5-12 membered heteroaryl are each optionally substituted by one or more groups independently selected from the following: halogen, -OH, oxo, -CN, -NH2, -CONH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, -O-(C 1-6 Alkyl), -O-(C 1-6 haloalkyl), -S-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -CONH(C 1-6 alkyl) and -CON(C 1-6Alkyl)2;

[0016] R3 is selected from hydrogen, halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -O-(C 1-6 Alkyl) and -O-(C 1-6 haloalkyl);

[0017] Or R2 and R3 together with the carbon atom to which they are attached form a 5-6 membered heteroaryl or a 4-6 membered heterocyclic group; wherein the 5-6 membered heteroaryl and the 4-6 membered heterocyclic group are each optionally substituted by one or more groups independently selected from the following: halogen, -OH, oxo, -CN, -NH2, -CONH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, -O-(C 1-6 Alkyl) and -O-(C 1-6 haloalkyl);

[0018] R5 is selected from hydrogen, halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, -O-(C 1-6 Alkyl), -O-(C 1-6 Haloalkyl), C 3-8 Cyclic hydrocarbon group, 4-8 membered heterocyclic group, -S-(C 1-6 alkyl), -NHCONH2, -NHCO(C 1-6 Alkyl) and -NR a R b ;

[0019] Cy1 is a 4-12 membered heterocyclic group, which is optionally substituted by one or more groups independently selected from the following: halogen, -OH, oxo, -CN, -NH2, -CONH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, -O-(C 1-6 Alkyl) and -O-(C 1-6 haloalkyl);

[0020] Cy2 is selected from C 3-8 Cycloalkyl, 4-9 membered heterocyclyl, aryl and 5-14 membered heteroaryl;

[0021] R4 is independently selected from halogen, -CN, -OH, oxo, -SH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-(C 1-6 Alkyl), -O-(C 1-6 Haloalkyl), -O-(C 3-8 Cycloalkyl), -O-(4-8 membered heterocyclic group), -(C 1-6 alkyl) m -(C 3-8 Cycloalkyl), -(C 1-6 alkyl) m -(4-8 membered heterocyclic group), -(C 1-6 alkyl) m -phenyl, -(C 1-6 alkyl) m -(5-12 membered heteroaryl), -S-(C 1-6 Alkyl), -S-(C 3-8 Cyclic hydrocarbon group), -S-(4-8 membered heterocyclic group), -NHCONH2, -CONR a R b 、-COR c 、-COOR e 、-NR a R b 、-NR d COR c 、-NR d S(O) n R f 、-S(O) n R f and -S(O) n NR a R b ; wherein said C 1-6 Alkyl, C 3-8 The cycloalkyl, 4-8 membered heterocyclyl, phenyl and 5-12 membered heteroaryl are each optionally substituted by one or more groups independently selected from the following: halogen, -OH, oxo, -SH, -CN, -NH2, -CONH2, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, -O-(C 1-6 Alkyl), -O-(C 1-6 Haloalkyl), -O-(C 3-8 Cyclic hydrocarbon group), -O-(4-8 membered heterocyclic group), -S-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -CO(C 1-6 Alkyl), -CO(C 2-6 -alkenyl), -CO(C 2-6 Alkynyl), -CONH(C 1-6 Alkyl), -CON(C 1-6 Alkyl)2, C 3-8 Cycloalkyl and 4-8 membered heterocyclic groups;

[0022] L does not exist, or L is CH2;

[0023] R a , R b , R c , R d and R e are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(C 1-6 alkyl) m -(C 3-8 Cycloalkyl), -(C 1-6 alkyl) m -(4-8 membered heterocyclic group), -(C 1-6 alkyl) m -phenyl and -(C 1-6 alkyl) m -(5-12 membered heteroaryl); wherein the C 1-6 Alkyl, C 3-8 The cycloalkyl, 4-8 membered heterocyclyl, phenyl and 5-12 membered heteroaryl are each optionally substituted by one or more groups independently selected from the following: halogen, -OH, oxo, -SH, -CN, -NH2, -CONH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C1-6 Alkyl), -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, -O-(C 1-6 Alkyl), -O-(C 1-6 Haloalkyl), -O-(C 3-8 Cyclic hydrocarbon group), -O-(4-8 membered heterocyclic group), -S-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NH(C 3-8 Cyclic hydrocarbon group), -NH (4-8 membered heterocyclic group), -CO (C 1-6 Alkyl), -CO(C 2-6 -alkenyl), -CO(C 2-6 Alkynyl), -CO(C 3-8 Cyclic hydrocarbon group), -CO (4-8 membered heterocyclic group), -CONH (C 1-6 alkyl), -CONH(C 3-8 Cyclic hydrocarbon), -CONH (4-8 membered heterocyclic) and -CON (C 1-6 Alkyl)2;

[0024] R f is -CH3;

[0025] p is 0, 1, 2, 3, 4 or 5;

[0026] m is 0 or 1;

[0027] n is 1 or 2;

[0028] Provided that R4 is not -NH(6-membered nitrogen-containing heteroaryl) or -NH(F-substituted phenyl).

[0029] The above-mentioned compounds and the active compounds disclosed in the context of the present invention (including general compounds and specific compounds), as well as pharmaceutically acceptable salts thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers thereof, or deuterated compounds thereof, are referred to herein as "compounds of the present invention".

[0030] The present invention also provides a pharmaceutical composition comprising the compound of the present invention and optionally a pharmaceutically acceptable excipient.

[0031] The present invention also provides a method for inhibiting menin-MLL interaction in vivo or in vitro, which comprises contacting an effective amount of the compound of the present invention with menin.

[0032] The present invention also provides a method for treating or preventing a disease mediated or at least partially mediated by menin-MLL interaction, comprising administering to a subject in need thereof an effective amount of a compound of the present invention.

[0033] The present invention also provides a method for treating or preventing cancer, which comprises administering an effective amount of the compound of the present invention to a subject in need thereof.

[0034] The present invention also provides the use of a compound of the present invention in the treatment or prevention of a disease which is mediated or at least partly mediated by menin-MLL interaction.

[0035] The present invention also provides use of the compound of the present invention in treating or preventing cancer.

[0036] The present invention also provides the use of the compound of the present invention in the preparation of a medicament for treating or preventing a disease mediated or at least partially mediated by menin-MLL interaction.

[0037] The present invention also provides use of the compound of the present invention in preparing a medicament for treating or preventing cancer.

[0038] The present invention also provides compounds of the present invention for use in inhibiting menin-MLL interaction in vivo or in vitro.

[0039] The present invention also provides a compound of the invention for use as a medicament.

[0040] The present invention also provides a compound of the invention for use as a medicament in the treatment or prevention of a disease which is mediated or at least partly mediated by menin-MLL interactions, in particular for the treatment or prevention of cancer.

[0041] The present invention also provides a drug combination comprising a compound of the present invention and at least one additional therapeutic agent, wherein the additional therapeutic agent is preferably selected from: an anti-tumor agent, an anti-inflammatory agent or an immunomodulator, wherein the anti-tumor agent includes a chemotherapeutic agent, an immune checkpoint inhibitor or agonist, and a targeted therapeutic agent.

[0042] The present invention also provides a kit for treating or preventing a disease mediated or at least partially mediated by menin-MLL interaction. The kit may comprise a pharmaceutical composition of the present invention and instructions for use, wherein the pharmaceutical composition comprises a compound of the present invention.

[0043] In some embodiments of the present invention, the "disease mediated by or at least in part by menin-MLL interaction" refers to cancer, such as hematological malignancies or solid tumors, including leukemias, lymphomas and myelomas, such as acute leukemias, chronic leukemias, myeloid leukemias, myeloid leukemias, lymphocytic leukemias, lymphoblastic leukemias, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), B-cell acute lymphocytic leukemia (B-ALL), T-cell prolymphocytic leukemia (T-PLL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia, large granular lymphocytic leukemia, hairy cell leukemia (HCL), and leukemia. L), mixed lineage leukemia (MLL), MLL-related leukemia, MLL-rearranged leukemia (MLL-r), MLL-PTD leukemia, MLL-positive leukemia, NPM1 mutant leukemia, leukemias displaying the HOX / MEIS1 gene expression signature, myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), multiple myeloma (MM), Hodgkin lymphoma, non-Hodgkin lymphoma, diffuse large B-cell lymphoma (DLBCL), B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, follicular lymphoma (FL), Waldenstrom macroglobulinemia, prostate cancer, breast cancer, lung cancer, liver cancer, colon cancer, colorectal cancer, pancreatic cancer, melanoma, glioblastoma (GBM). DETAILED DESCRIPTION OF THE INVENTION

[0045] definition

[0046] The following words, phrases and symbols used in this application have the meanings described below, unless the context in which they are used indicates otherwise.

[0047] A hyphen ("-") that is not between two letters or symbols indicates the point of attachment of a substituent. For example, -O(C 1-6 Alkyl) refers to C 1-6 The alkyl group is attached to the rest of the molecule through the oxygen atom.

[0048] The term "alkyl" as used herein refers to a group having 1 to 18 carbon atoms (C 1-18 ), preferably 1 to 10 carbon atoms (C 1-10 ), particularly preferably 1 to 6 carbon atoms (C 1-6 ), more preferably 1 to 4 carbon atoms (C 1-4 ) or 1-3 carbon atoms (C 1-3 ) is a straight-chain or branched saturated hydrocarbon group. For example, "C 1-6 "Alkyl" means an alkyl group having 1 to 6 carbon atoms, "C 1-3"Alkyl" means an alkyl group having 1 to 3 carbon atoms. 1-6 Examples of alkyl include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, sec-butyl, and tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), hexyl, etc. When used as a linking group (e.g., in the definition of L) or between two dashes ("-") (e.g., -(C 1-6 alkyl)-OH), wherein the alkyl represents an alkylene group.

[0049] The term "alkenyl" as used herein refers to a group having 2 to 18 carbon atoms (C=C) containing one or more, for example 1, 2 or 3, carbon-carbon double bonds (C=C). 2-18 ), preferably 2 to 10 carbon atoms (C 2-10 ), more preferably 2 to 6 carbon atoms (C 2-6 ), more preferably 2 to 4 carbon atoms (C 2-4 ) is a straight or branched unsaturated hydrocarbon group. For example, "C 2-6 "Alkenyl" means an alkenyl group having 2 to 6 carbon atoms, "C 2-4 "Alkenyl" means an alkenyl group having 2 to 4 carbon atoms. 2-6 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl (eg, 2-propenyl), butenyl (eg, 2-butenyl), etc. The attachment point of the alkenyl group may or may not be on a double bond carbon.

[0050] The term "alkynyl" as used herein refers to a moiety having 2 to 18 carbon atoms (C≡C) that contains one or more, for example 1, 2 or 3, carbon-carbon triple bonds (C≡C). 2-18 ), preferably 2 to 10 carbon atoms (C 2-10 ), more preferably 2 to 6 carbon atoms (C 2-6 ), more preferably 2 to 4 carbon atoms (C 2-4 ) is a straight or branched unsaturated hydrocarbon group. For example, "C 2-6 "Alkynyl" means an alkynyl group having 2 to 6 carbon atoms, "C 2-4 "Alkynyl" means an alkynyl group having 2 to 4 carbon atoms. 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl (eg, 2-propynyl), butynyl (eg, 2-butynyl), etc. The point of attachment of the alkynyl group may or may not be on a triple bond carbon.

[0051] As used herein, the term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine, more preferably fluorine and chlorine.

[0052] The term "haloalkyl" as used herein refers to an alkyl group as defined herein in which one or more hydrogen atoms, for example 1, 2, 3, 4 or 5 or all hydrogen atoms are replaced by halogen atoms, and when more than one hydrogen atom is replaced by a halogen atom, the halogen atoms may be the same or different from each other. For example, "C 1-6 "Haloalkyl" means a haloalkyl group as defined above having 1 to 6 carbon atoms, "C 1-4 "Haloalkyl" means a haloalkyl group as defined above having 1 to 4 carbon atoms. 1-6 Examples of haloalkyl include, but are not limited to, -CF3, -CHF2, -CH2F, -CH2CF3, -CH(CF3)2, and the like.

[0053] The term "cycloalkyl" as used herein refers to a cyclic hydrocarbon group containing 3 to 12 ring carbon atoms (C 3-12 )(e.g. 3-8 ring carbon atoms (C 3-8 ), 5-7 ring carbon atoms (C 5-7 ), 4-7 ring carbon atoms (C 4-7 ) or 3-6 ring carbon atoms (C 3-6 )) is a saturated or partially unsaturated cyclic hydrocarbon group; it may have one or more rings, such as 1, 2 or 3, preferably 1 or 2 rings. For example, "C 3-8 "Cycloalkyl" or "3-8 membered cycloalkyl" means a cycloalkyl having 3-8 ring carbon atoms; "C 3-6 "Cycloalkyl" or "3-6 membered cycloalkyl" means a cycloalkyl having 3-6 ring carbon atoms. Cycloalkyl may include fused or bridged rings and spiro rings. The ring of the cycloalkyl may be saturated, and may contain one or more, for example one or two, double bonds (i.e., partially unsaturated), but it is not completely conjugated and is not an "aryl" as defined in the present invention. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2.2]pentyl, spiro[3.3]heptyl, bicyclo[3.1.0]hexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and the like.

[0054] As used herein, the term "heterocyclyl" or "heterocycle" is used interchangeably and refers to a saturated or partially unsaturated ring having 3-12 ring atoms (e.g., 4-12 ring atoms (4-12 membered heterocyclyl), 3-8 ring atoms (3-8 membered heterocyclyl), 4-9 ring atoms (4-9 membered heterocyclyl), 4-8 ring atoms (4-8 membered heterocyclyl), 4-6 ring atoms (4-6 membered heterocyclyl) or 4-5 ring atoms (4-5 membered heterocyclyl)), wherein the ring atoms include one or more (e.g., 1, 2 or 3, preferably 1 or 2) heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon atoms; it may have one or more rings, for example, 1, 2 or 3, preferably 1 or 2 rings. Wherein, N and S may be optionally oxidized to various oxidation states. The point of attachment of the heterocyclyl may be on the N heteroatom or on a carbon atom. For example, "4-9-membered heterocyclyl or 4-9-membered heterocycle" means a heterocyclyl having 4-9 (4, 5, 6, 7, 8 or 9) ring atoms, which contains at least one, such as 1, 2 or 3, preferably 1 or 2 heteroatoms independently selected from N, O and S; "4-8-membered heterocyclyl or 4-8-membered heterocycle" means a heterocyclyl having 4-8 (4, 5, 6, 7 or 8) ring atoms, which contains at least one, such as 1, 2 or 3, preferably 1 or 2 heteroatoms independently selected from N, O and S; "4-6-membered heterocyclyl or 4-6-membered heterocycle" means a heterocyclyl having 4-6 (4, 5 or 6) ring atoms, which contains at least one, preferably 1 or 2 heteroatoms independently selected from N, O and S (preferably N and O), which is preferably a monocyclic ring. Heterocyclyl may include a monocyclic, fused or bridged ring or spirocyclic ring. The ring of the heterocyclic group may be saturated, and may contain one or more, such as one or two, double bonds (i.e., partially unsaturated), but it is not completely conjugated, and is not a "heteroaryl" as defined in the present invention. Examples of heterocyclic groups include, but are not limited to, 4-12-membered heterocyclic groups, 4-9-membered heterocyclic groups, 4-8-membered heterocyclic groups, and 4-6-membered heterocyclic groups, such as 4-12-membered monocyclic or fused or bridged heterocyclic groups, such as oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, dioxolanyl, dioxanyl, tetrahydropyranyl, dihydropyranyl (e.g., 3,6-dihydro-2H-pyranyl and 3,4-dihydro-2H-pyranyl), morpholinyl , thiomorpholinyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyridazinyl, pyrazolidinyl, diazaspiro[3.5]nonanyl (e.g., 2,7-diazaspiro[3.5]nonanyl), azaspiro[3.5]nonanyl (e.g., 2-azaspiro[3.5]nonanyl), diazaspiro[3.4]octanyl (e.g., 2,6-diazaspiro[3.4]octanyl), and oxaspiro[3.3]heptanyl.

[0055] The term "aryl" or "aromatic ring" as used herein can be used interchangeably and refers to a carbocyclic hydrocarbon group consisting of one ring or multiple rings such as two condensed rings having 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms, wherein at least one ring is an aromatic ring. Examples of aryl include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, phenanthrenyl, indenyl, indanyl, azulenyl, preferably phenyl and naphthyl, more preferably phenyl.

[0056] As used herein, the terms "heteroaryl" and "heteroaromatic ring" are used interchangeably and refer to a mono-, bi- or tricyclic ring system having 5-15, preferably 5-14, more preferably 5-12, further preferably 5-10, most preferably 5-6 or 8-10 ring atoms, wherein at least one ring is a 5- or 6-membered aromatic ring containing one or more, for example 1 to 4, heteroatoms selected from N, O and S, wherein S and N may be optionally oxidized to various oxidation states. When the total number of S and O atoms in the heteroaryl exceeds 1, these S and O heteroatoms are not adjacent to each other. Preferably, the heteroaryl is a 5-12 membered heteroaryl. For example, the heteroaryl includes:

[0057] 5-6 membered monocyclic heteroaryl, i.e., a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, wherein the ring atoms include one or more, for example 1, 2 or 3, heteroatoms independently selected from N, O and S (preferably N), and the remaining ring atoms are carbon atoms, such as 5-membered or 6-membered heteroaryl, such as 5-membered or 6-membered nitrogen- or oxygen- or sulfur-containing heteroaryl, 5-membered or 6-membered nitrogen- and oxygen- and / or sulfur-containing heteroaryl, such as pyridyl, N-oxypyridyl, pyridone (i.e., oxopyridyl, such as 2-oxopyridyl), pyrazinyl, pyrimidinyl, triazinyl (e.g., 1,2,4-triazinyl), pyridazinyl, pyridazinonyl (i.e., oxopyridazinyl, such as 3-oxopyridazinyl), pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, triazolyl (e.g., 1,2,4-triazolyl), thienyl, furanyl, pyranyl, pyrrolyl, and

[0058] 8-10 membered bicyclic heteroaryl, i.e., a bicyclic aromatic hydrocarbon group having 8, 9 or 10 ring atoms, preferably a 9-10 membered bicyclic heteroaryl, wherein the ring atoms include one or more, for example 1, 2, 3 or 4, preferably 1, 2 or 3 heteroatoms independently selected from N, O and S (preferably N), and the remaining ring atoms are carbon atoms, wherein at least one ring is an aromatic ring, for example, an 8-10 membered nitrogen or oxygen or sulfur-containing bicyclic heteroaryl, an 8-10 membered nitrogen and oxygen and / or sulfur-containing bicyclic heteroaryl, for example, benzodioxolyl, benzoxazolyl, benzisoxazolyl, benzothiophenyl, benzothiazolyl, benzisothiazolyl oxazolyl, benzofuranyl, indolyl, indazolyl, purinyl, quinolinyl, quinolinonyl (i.e., oxoquinolinyl, e.g., 2-oxoquinolinyl), isoquinolinyl, dihydroquinolinyl, quinazolinyl, quinoxalinyl, imidazopyrimidinyl (e.g., imidazo[1,2-c]pyrimidinyl), imidazopyrazinyl (e.g., imidazo[1,2-a]pyrazinyl), imidazopyridinyl (e.g., imidazo[1,2-a]pyridinyl), imidazopyridazinyl (e.g., imidazo[1,2-b]pyridazinyl), pyrrolopyrazinyl (e.g., pyrrolo[1,2-a]pyrazinyl), pyrrolopyridinyl (e.g., 1H- pyrrolo[2,3-b]pyridinyl), pyrrolopyrimidinyl (e.g., pyrrolo[3,4-d]pyrimidinyl), pyrazolopyrazinyl (e.g., pyrazolo[1,5-a]pyrazinyl), pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4-b]pyridinyl), pyrazolopyrimidinyl (e.g., pyrazolo[1,5-a]pyrimidinyl), triazolopyrimidinyl (e.g., [1,2,4]triazolo[4,3-c]pyrimidinyl and [1,2,4]triazolo[1,5-c]pyrimidinyl), triazolopyrazinyl (e.g., [1,2,4]triazolo[1,5-a]pyrazinyl), triazolopyrimidinyl (e.g., [1,2,4]triazolo[1,5-a]pyrazinyl), pyridinyl (e.g., [1,2,4]triazolo[4,3-a]pyridinyl and [1,2,4]triazolo[1,5-a]pyridinyl), tetrazolopyridinyl (e.g., tetrazolopyridinyl), dihydro-pyrimidopyridazinyl (e.g., 3,4-dihydro-2H-pyrimidopyridazinyl), dihydro-[1,4]dioxinopyridinyl (e.g., 2,3-dihydro-[1,4]dioxinopyridinyl), dihydro-[1,4]dioxinopyridinyl (e.g., 6,7-dihydro-[1,4]dioxinopyridinyl [2,3-c]pyridazinyl).

[0059] The term "-OH" as described herein refers to a hydroxyl group.

[0060] As used herein, the term "-CN" refers to a cyano group.

[0061] The term "oxo" as used herein refers to =0.

[0062] The term "amino protecting group" as used herein is also referred to as a nitrogen protecting group, and refers to a group that can reversibly block or protect an amino and / or amide functional group so that the reaction is carried out on other functional groups of the compound. Examples of the amino protecting group include, but are not limited to, Boc (tert-butyloxycarbonyl), benzyl, Pmb (p-methoxybenzyl), alkanoyl, triphenylmethyl, benzoyl, succinyl, phthaloyl, Fmoc (9-fluorenylmethoxycarbonyl) and Cbz (benzyloxycarbonyl), etc., preferably Boc (tert-butyloxycarbonyl), benzyl, Pmb (p-methoxybenzyl) and Cbz (benzyloxycarbonyl); more preferably Boc (tert-butyloxycarbonyl).

[0063] As used herein, the terms "optional", "optional" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur. For example, "optionally substituted with one or more..." includes unsubstituted and substituted with 1, 2, 3 or more of the described substituents. It will be understood by those skilled in the art that for any group containing one or more substituents, the group does not include any sterically impractical, chemically incorrect, synthetically infeasible and / or inherently unstable substitution patterns.

[0064] As used herein, the term "substituted" or "substituted by..." means that one or more (e.g., 1, 2, 3, or 4) hydrogen atoms on a given atom or group are replaced by one or more (e.g., 1, 2, 3, or 4) substituents, preferably substituents selected from a given substituent group or group group, provided that the normal valence of the given atom is not exceeded, and the substituents may be the same or different from each other. As used herein, the term "substituted by one or more groups independently selected from..." or "substituted by one or more..." means that one or more hydrogen atoms on a given atom or group are independently replaced by one or more groups selected from a given substituent group or group group, wherein the groups may be the same or different from each other. Preferably, "substituted by one or more groups independently selected from..." or "substituted by one or more..." means that a given atom or group is replaced by 1, 2, 3, or 4 groups independently selected from a given substituent group or group group, wherein the groups may be the same or different from each other. In some embodiments, when the substituent is oxo (i.e., =O), two hydrogen atoms on a single atom are replaced. Optional substituents can be various groups, provided that the combination of substituents and / or variables produces chemically correct and stable compounds. Chemically correct and stable compounds mean that the compound is sufficiently stable to be isolated from the reaction mixture. Preferably, substituents are those implemented in the example compounds of the application.

[0065] Unless otherwise indicated, substituents are named into the core structure. For example, it is understood that when (cycloalkyl)alkyl is listed as a possible substituent, it means that the point of attachment of the substituent to the core structure is at the alkyl portion.

[0066] It will be appreciated by those skilled in the art that some compounds of formula (I) may contain one or more chiral centers, and therefore have two or more stereoisomers. Racemic mixtures of these isomers, single isomers and mixtures enriched in one enantiomer, and diastereomers and mixtures partially enriched in specific diastereomers when there are two chiral centers are all within the scope of the present invention. It will also be appreciated by those skilled in the art that the present invention includes all single stereoisomers (e.g., enantiomers, diastereomers), racemic mixtures or partially resolved mixtures of compounds of formula (I), and, where appropriate, single tautomers thereof.

[0067] The racemic mixture can be used in its own form or can be resolved into its individual isomers. Stereochemically pure compounds or mixtures enriched in one or more isomers can be obtained by resolution. Methods for separating isomers are well known (see Allinger NL and Eliel EL, "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971), including physical methods, such as chromatography using chiral adsorbents. Individual isomers in chiral form can be prepared from chiral precursors. Alternatively, the individual isomers can be chemically separated from the mixture as follows: diastereomeric salts are formed with chiral acids (e.g., individual enantiomers of 10-camphorsulfonic acid, camphoric acid, α-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), fractional crystallization of the salts, and then one or both of the resolved bases are liberated, and this process is optionally repeated to obtain one or two isomers that are substantially free of the other isomer, i.e., isomers with an optical purity of >95%. Alternatively, the racemate can be covalently linked to a chiral compound (auxiliary) to obtain diastereomers, which can be separated by chromatography or fractional crystallization, and then the chiral auxiliary is chemically removed to obtain the pure enantiomers.

[0068] The term "tautomer" refers to functional group isomers resulting from the rapid movement of an atom in a molecule between two positions. Tautomers can be interconverted, for example, the enol form and the keto form are typical tautomers.

[0069] "Pharmaceutically acceptable salt" refers to a salt of a free acid or base of a compound of formula (I) that is non-toxic, biologically tolerable or otherwise biologically suitable for administration to treat or prevent an individual. For example, acid addition salts include, for example, addition salts derived from inorganic acids and organic acids. For a general description of pharmaceutically acceptable salts, see, for example, SM Berge et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66: 1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, eds., Wiley-VCH and VHCA, Zurich, 2002.

[0070] In addition, if the compounds described herein are obtained in the form of acid addition salts, their free base forms can be obtained by basifying a solution of the acid addition salt. Conversely, if the product is in the form of a free base, its acid addition salt, especially a pharmaceutically acceptable acid addition salt, can be obtained by dissolving the free base in a suitable solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art can determine various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable acid addition salts or base addition salts without undue experimentation.

[0071] The term "solvate" means a solvent addition form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds have a tendency to entrain a fixed molar ratio of solvent molecules in the solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate. When the solvent is ethanol, the solvate formed is an ethanolate. Hydrates are formed by one or more or less than one molecule of water with one molecule of the substance, wherein the water retains its molecular state of H2O, and such a combination can form one or more hydrates, such as hemihydrates, monohydrates and dihydrates.

[0072] The term "deuterated compound" means a compound in which one or more, for example 1, 2, 3, 4, 5 or 6 hydrogen atoms in a compound are replaced by their isotope deuterium. Wherein, the content of the deuterium isotope at the deuterium element at its replacement position (deuteration degree) is at least greater than the content of the natural deuterium isotope. In some embodiments, the deuterated compound in the compound of formula (I) or its subformula (I-1), (I-2), (I-3), (I-4) has a deuteration degree of at least 50% (e.g., 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any value between these listed values). In some embodiments, the compound of formula (I) or the compounds of subformulas (I-1), (I-2), (I-3), (I-4) thereof has a degree of deuteration greater than 99.9% and up to 100%.

[0073] As used herein, the terms "group" and "radical" are synonymous and are used to indicate a functional group or a molecular fragment that can be attached to other molecular fragments.

[0074] The term "active ingredient" is used to refer to a chemical substance that has biological activity. In some embodiments, the "active ingredient" is a chemical substance that has pharmaceutical use.

[0075] The term "pharmaceutical combination" as used herein means a product obtained by mixing or combining two or more active ingredients, including fixed and non-fixed combinations of active ingredients, such as kits, pharmaceutical compositions. The term "fixed combination" means that two or more active ingredients (e.g., a compound of the invention and an additional therapeutic agent) are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that two or more active ingredients (e.g., a compound of the invention and an additional therapeutic agent) are administered to a patient simultaneously, concurrently or sequentially as separate entities, wherein the administration provides a therapeutically effective level of the compound in the patient's body.

[0076] The term "treating" or "treatment" or "preventing" a disease or disorder refers to the administration of one or more pharmaceutical substances, particularly compounds of the invention, to an individual suffering from the disease or disorder, or having symptoms of the disease or disorder, or having a predisposition to the disease or disorder, in order to cure, heal, alleviate, relieve, alter, cure, improve, ameliorate or affect the disease or disorder, symptoms of the disease or disorder, or predisposition to the disease or disorder. In some embodiments, the disease or disorder is cancer, such as a hematological malignancy or solid tumor, including leukemia, lymphoma and myeloma.

[0077] When referring to a chemical reaction, the terms "treating", "contacting" and "reacting" mean adding or mixing two or more reagents under appropriate conditions to produce the indicated and / or desired product. It should be understood that the reaction to produce the indicated and / or desired product may not necessarily come directly from the combination of the two reagents initially added, that is, there may be one or more intermediates generated in the mixture that ultimately lead to the formation of the indicated and / or desired product.

[0078] The term "effective amount" as used herein refers to an amount or dosage of a menin inhibitor that is generally sufficient to produce a beneficial effect in a patient in need of treatment or prevention of a disease or disorder mediated by or at least in part by a menin-MLL interaction. The effective amount or dosage of the active ingredient in the present invention can be determined by conventional methods (e.g., modeling, dose escalation studies, or clinical trials) in combination with conventional influencing factors (e.g., the mode or route of administration or administration, the pharmacokinetics of the drug ingredient, the severity and course of the disease or disorder, the individual's previous or ongoing treatment, the individual's health status and response to the drug, and the judgment of the attending physician).

[0079] Typical dosage range is from about 0.0001 to about 200mg active ingredient per kilogram of individual body weight every day, for example, about 0.001 to 100mg / kilogram / day, or about 0.01 to 35mg / kilogram / day, or about 0.1 to 10mg / kilogram, once a day or divided dose unit taking (for example, twice a day, three times a day, four times a day). For 70 kilograms of people, the example range of suitable dosage is about 0.05 to about 7 grams / day, or about 0.2 to about 5 grams / day. Once the patient's disease or disorder improves, the dosage can be adjusted to maintain the effect. For example, according to the change of symptoms, the dosage or the number of administrations or the dosage and the number of administrations can be reduced to the level of maintaining the desired treatment or preventive effect. Of course, if the symptoms are alleviated to an appropriate level, treatment can be stopped. However, for the recurrence of symptoms, the patient may need intermittent long-term treatment.

[0080] The term "inhibit" refers to a decrease or reduction in the baseline activity of a biological activity or process. The term "inhibits menin-MLL interaction" is the actual drug activity for the purposes of the present invention and refers to a reduction in the menin-MLL interaction that results from a direct or indirect response to the presence of a compound of the present invention, relative to the menin-MLL interaction in the absence of the compound of the present invention. The reduction in interaction can be caused by a direct interaction of the compound of the present invention with menin, or by an interaction of the compound of the present invention with one or more other factors that affect the menin-MLL interaction. For example, a compound of the present invention may reduce the menin-MLL interaction by directly binding to menin, may reduce the menin-MLL interaction by directly or indirectly affecting another factor, or may reduce the menin-MLL interaction by directly or indirectly reducing the amount of menin present in a cell or organism.

[0081] As used herein, the term "subject" or "patient" refers to mammals and non-mammals. Mammals refer to any member of the class mammals, including but not limited to: humans; non-human primates, such as chimpanzees and other apes and monkey species; farm animals, such as cattle, horses, sheep, goats and pigs; livestock, such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs; etc. Examples of non-mammals include, but are not limited to, birds, etc. The term "subject" or "patient" does not limit a particular age or gender. In some embodiments, the subject or patient is a human.

[0082] In general, the term "about" is used herein to modify a stated numerical value by 20% above or below that value.

[0083] Technical and scientific terms used herein without specific definition have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0084] All numerical ranges herein should be understood to disclose every value and subset of values ​​within the range, regardless of whether they are specifically disclosed otherwise. For example, when any numerical range is mentioned, it should be considered to mention every value within the numerical range, such as every integer within the numerical range, such as C in this article. 1-6 It means including 1, 2, 3, 4, 5 or 6 C. The present invention relates to all values ​​falling within these ranges, all smaller ranges and upper or lower limits of numerical ranges. DETAILED DESCRIPTION

[0085] Embodiment 1. Compound of formula (I):

[0086]

[0087] or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof, wherein:

[0088] R1 is selected from hydrogen, halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -O-(C 1-6 Alkyl) and -O-(C 1-6 haloalkyl);

[0089] R2 is selected from hydrogen, halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, -O-(C 1-6 Alkyl), -O-(C 1-6 Haloalkyl), -O-(C 3-8 Cycloalkyl), -O-(4-8 membered heterocyclic group), C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, phenyl, 5-12 membered heteroaryl, -S-(C 1-6 Alkyl), -S-(C 3-8 Cycloalkyl), -S-(4-8 membered heterocyclic group), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NHCONH2, -NHCO(C 1-6 Alkyl), -CONR a R b ,-CSNR a R b 、-COR c and-COOR e ; wherein said C 3-8 The cycloalkyl, 4-8 membered heterocyclyl, phenyl and 5-12 membered heteroaryl are each optionally substituted by one or more groups independently selected from the following: halogen, -OH, oxo, -CN, -NH2, -CONH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, -O-(C 1-6 Alkyl), -O-(C1-6 haloalkyl), -S-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -CONH(C 1-6 alkyl) and -CON(C 1-6 Alkyl)2;

[0090] R3 is selected from hydrogen, halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -O-(C 1-6 Alkyl) and -O-(C 1-6 haloalkyl);

[0091] Or R2 and R3 together with the carbon atom to which they are attached form a 5-6 membered heteroaryl or a 4-6 membered heterocyclic group; wherein the 5-6 membered heteroaryl and the 4-6 membered heterocyclic group are each optionally substituted by one or more groups independently selected from the following: halogen, -OH, oxo, -CN, -NH2, -CONH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, -O-(C 1-6 Alkyl) and -O-(C 1-6 haloalkyl);

[0092] R5 is selected from hydrogen, halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, -O-(C 1-6 Alkyl), -O-(C 1-6 Haloalkyl), C 3-8 Cyclic hydrocarbon group, 4-8 membered heterocyclic group, -S-(C 1-6 alkyl), -NHCONH2, -NHCO(C 1-6 Alkyl) and -NR a R b ;

[0093] Cy1 is a 4-12 membered heterocyclic group, which is optionally substituted by one or more groups independently selected from the following: halogen, -OH, oxo, -CN, -NH2, -CONH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, -O-(C 1-6 Alkyl) and -O-(C 1-6 haloalkyl);

[0094] Cy2 is selected from C 3-8 Cycloalkyl, 4-12 membered heterocyclyl, aryl and 5-14 membered heteroaryl;

[0095] R4 is independently selected from halogen, -CN, -OH, oxo, -SH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-(C 1-6 Alkyl), -O-(C 1-6 Haloalkyl), -O-(C 3-8 Cycloalkyl), -O-(4-8 membered heterocyclic group), -(C 1-6 alkyl) m -(C 3-8 Cycloalkyl), -(C 1-6 alkyl) m -(4-8 membered heterocyclic group), -(C 1-6 alkyl) m -phenyl, -(C 1-6 alkyl) m -(5-12 membered heteroaryl), -S-(C 1-6 Alkyl), -S-(C 3-8 Cyclic hydrocarbon group), -S-(4-8 membered heterocyclic group), -NHCONH2, -CONR a R b 、-COR c 、-COOR e 、-NR a R b 、-NR d COR c 、-NR d S(O) n R f 、-S(O) n R f and -S(O) n NRa R b ; wherein said C 1-6 Alkyl, C 3-8 The cycloalkyl, 4-8 membered heterocyclyl, phenyl and 5-12 membered heteroaryl are each optionally substituted by one or more groups independently selected from the following: halogen, -OH, oxo, -SH, -CN, -NH2, -CONH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, -O-(C 1-6 Alkyl), -O-(C 1-6 Haloalkyl), -O-(C 3-8 Cyclic hydrocarbon group), -O-(4-8 membered heterocyclic group), -S-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -CO(C 1-6 Alkyl), -CO(C 2-6 -alkenyl), -CO(C 2-6 Alkynyl), -CONH(C 1-6 Alkyl), -CON(C 1-6 Alkyl)2, C 3-8 Cycloalkyl and 4-8 membered heterocyclic groups;

[0096] L does not exist, or L is C 1-6 Alkyl or CO;

[0097] R a , R b , R c , R d , R e and R f are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(C 1-6 alkyl) m -(C 3-8 Cycloalkyl), -(C 1-6 alkyl) m -(4-8 membered heterocyclic group), -(C 1-6 alkyl) m -phenyl and -(C 1-6 alkyl) m -(5-12 membered heteroaryl); wherein the C1-6 Alkyl, C 3-8 The cycloalkyl, 4-8 membered heterocyclyl, phenyl and 5-12 membered heteroaryl are each optionally substituted by one or more groups independently selected from the following: halogen, -OH, oxo, -SH, -CN, -NH2, -CONH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, -O-(C 1-6 Alkyl), -O-(C 1-6 Haloalkyl), -O-(C 3-8 Cyclic hydrocarbon group), -O-(4-8 membered heterocyclic group), -S-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NH(C 3-8 Cyclic hydrocarbon group), -NH (4-8 membered heterocyclic group), -CO (C 1-6 Alkyl), -CO(C 2-6 -alkenyl), -CO(C 2-6 Alkynyl), -CO(C 3-8 Cyclic hydrocarbon group), -CO (4-8 membered heterocyclic group), -CONH (C 1-6 alkyl), -CONH(C 3-8 Cyclic hydrocarbon), -CONH (4-8 membered heterocyclic) and -CON (C 1-6 Alkyl)2;

[0098] p is 0, 1, 2, 3, 4 or 5;

[0099] m is 0 or 1;

[0100] n is 1 or 2.

[0101] Embodiment 1.1. A compound as described in Embodiment 1 or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof, wherein: Cy2 is selected from C 3-8 Cycloalkyl, 4-12 membered monocyclic or fused or bridged heterocyclic, aryl and 5-14 membered heteroaryl; preferably Cy2 is selected from C 3-8 Cycloalkyl, 4-9 membered heterocyclyl, aryl and 5-14 membered heteroaryl.

[0102] Embodiment 1.2. A compound as described in Embodiment 1 or 1.1 or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof, wherein: L is absent, or L is CH2;

[0103] Embodiment 1.3. A compound as described in any one of Embodiments 1 to 1.2, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof, wherein: R f It is -CH3.

[0104] Embodiment 1.4. A compound as described in any one of Embodiments 1 to 1.3 or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof, wherein: provided that R4 is not -NH(6-membered nitrogen-containing heteroaryl) or -NH(F-substituted phenyl), and further, R4 is not -NH(6-membered heteroaryl) or -NH(F-substituted phenyl).

[0105] Embodiment 2. A compound according to any one of Embodiments 1 to 1.4, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof, wherein:

[0106] R1 is halogen, CN or C 1-6 Haloalkyl;

[0107] R2 is selected from hydrogen, -O-(C 1-6 Alkyl), C 3-8 Cycloalkyl, 4-8 membered heterocyclic, 5-12 membered heteroaryl, -CONR a R b ,-CSNR a R b 、-COR c and-COOR e ; wherein said C 3-8 The cycloalkyl, 4-8 membered heterocyclyl and 5-12 membered heteroaryl are each optionally substituted by one or more groups independently selected from the following: halogen, -OH, oxo, -CN, -NH2, -CONH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, -O-(C 1-6 Alkyl) and -O-(C 1-6haloalkyl);

[0108] R3 is hydrogen;

[0109] Or R2 and R3 together with the carbon atom to which they are attached form a 5-6 membered heteroaryl group; wherein the 5-6 membered heteroaryl group is optionally substituted by one or more groups independently selected from the following: 1-6 alkyl;

[0110] R5 is selected from hydrogen, C 1-6 Alkyl and -NR a R b ;

[0111] Cy1 is a 4-12 membered heterocyclic group;

[0112] Cy2 is selected from C 3-8 Cycloalkyl, 4-9 membered heterocyclyl, aryl and 5-14 membered heteroaryl;

[0113] R4 is independently selected from halogen, -CN, -OH, oxo, C 1-6 Alkyl, -O-(C 1-6 Alkyl), -(C 1-6 alkyl) m -(C 3-8 Cycloalkyl), -(C 1-6 alkyl) m -(4-8 membered heterocyclic group), -(C 1-6 alkyl) m -phenyl, -(C 1-6 alkyl) m -(5-12 membered heteroaryl), -CONR a R b 、-COR c 、-COOR e 、-NR a R b 、-NR d COR c 、-NR d S(O) n R f 、-S(O) n R f and -S(O) n NR a R b ; wherein said C 1-6 Alkyl, C 3-8 The cycloalkyl, 4-8 membered heterocyclyl, phenyl and 5-12 membered heteroaryl are each optionally substituted by one or more groups independently selected from the following: halogen, -OH, oxo, -CN, -NH2, -CONH2, C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, -O-(C 1-6 Alkyl), -O-(C 1-6 Haloalkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -CONH(C 1-6 Alkyl), -CON(C 1-6 Alkyl)2, C 3-8 Cycloalkyl and 4-8 membered heterocyclic groups;

[0114] L does not exist, or L is CH2;

[0115] R a , R b , R c , R d and R e are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, -(C 1-6 alkyl) m -(C 3-8 Cycloalkyl), -(C 1-6 alkyl) m -(4-8 membered heterocyclic group), -(C 1-6 alkyl) m -phenyl and -(C 1-6 alkyl) m -(5-12 membered heteroaryl); wherein the C 1-6 Alkyl, C 3-8 The cycloalkyl, 4-8 membered heterocyclyl, phenyl and 5-12 membered heteroaryl are each optionally substituted by one or more groups independently selected from the following: halogen, -OH, -CN, -CONH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 Alkyl)-OH, -O-(C 1-6 Alkyl), -NH(C 3-8 Cyclic hydrocarbon), -CO(C 2-6 alkenyl) and -CON(C 1-6 Alkyl)2;

[0116] R f is -CH3;

[0117] p is 0, 1, 2 or 3;

[0118] m is 0 or 1;

[0119] n is 1 or 2;

[0120] Provided that R4 is not -NH(6-membered nitrogen-containing heteroaryl) or -NH(F-substituted phenyl), and further R4 is not -NH(6-membered heteroaryl) or -NH(F-substituted phenyl).

[0121] Embodiment 3. A compound as described in any one of Embodiments 1-2 or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof, wherein the compound is a compound of formula (I-1):

[0122]

[0123] in:

[0124] Z is N or CH; preferably, Z is N;

[0125] n1, n2, n3 and n4 are independently selected from 1 and 2, respectively.

[0126] Embodiment 4. A compound as described in any one of Embodiments 1-2 or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof, wherein the compound is a compound of formula (I-2):

[0127]

[0128] in:

[0129] n5 and n6 are independently selected from 1 and 2, respectively.

[0130] Embodiment 5. A compound as described in any one of Embodiments 1-4 or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof, wherein R1 is a halogen; preferably, R1 is F or Cl; more preferably, R1 is F.

[0131] Embodiment 6. A compound as described in any one of Embodiments 1-5 or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof, wherein R2 is selected from hydrogen, -O-(C 1-6 Alkyl), C 3-8 Cycloalkyl, 4-8 membered heterocyclic, 5-12 membered heteroaryl, -CONR a R b ,-CSNRa R b 、-COR c and-COOR e , where R a , R b , R c and R e are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, C 3-8 Cycloalkyl and 4-8 membered heterocyclic group; wherein said C 3-8 The cycloalkyl, 4-8 membered heterocyclyl and 5-12 membered heteroaryl are each optionally substituted by one or more groups independently selected from the following: halogen, -OH, oxo, -CN, -NH2, -CONH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, -O-(C 1-6 Alkyl) and -O-(C 1-6 Preferably, R2 is selected from hydrogen, -O-(C 1-6 Alkyl), C 3-6 Cycloalkyl, 4-6 membered heterocyclic, 5-6 membered heteroaryl, -CONR a R b ,-CSNR a R b 、-COR c and-COOR e , where R a , R b , R c and R e are independently selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and 4-6 membered heterocyclic group; wherein said C 3-6 The cycloalkyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl are each optionally substituted by one or more groups independently selected from the group consisting of halogen, -OH and C 1-6 More preferably, R2 is selected from -COO(C 1-6 alkyl) and -CON(C 1-6 Most preferably, R2 is -CON(C 1-6 Alkyl)2.

[0132] Embodiment 7. The compound as described in Embodiment 1 or its pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer, or deuterated compound thereof, wherein R3 is hydrogen.

[0133] Embodiment 8. A compound as described in any one of Embodiments 1-5 or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof, wherein R2 and R3 together with the carbon atom to which they are attached form a 5-6 membered heteroaryl group; wherein the 5-6 membered heteroaryl group is optionally substituted by one or more groups independently selected from the following: C 1-6 Preferably, R2 and R3 together with the carbon atom to which they are attached form a pyrazolyl group; wherein the pyrazolyl group is optionally substituted by one or more groups independently selected from the following: 1-6 alkyl.

[0134] Embodiment 9. A compound as described in any one of Embodiments 1-8 or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof, wherein R5 is selected from hydrogen, C 1-6 Alkyl, -NH2, -NH(C 1-6 Alkyl) and -N(C 1-6 Preferably, R5 is selected from hydrogen, C 1-6 Alkyl and -NH(C 1-6 More preferably, R5 is hydrogen.

[0135] Embodiment 10. A compound as described in any one of Embodiments 1-9 or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof, wherein L is CH2.

[0136] Embodiment 11. A compound as described in any one of Embodiments 1-10 or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof, wherein Cy2 is selected from C 3-8 Cycloalkyl, 4-8 membered heterocyclyl, phenyl and 5-12 membered heteroaryl; preferably, Cy2 is selected from C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl and 8-10 membered heteroaryl.

[0137] Embodiment 12. A compound as described in Embodiment 11 or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof, wherein Cy2 is selected from cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl, pyrrolidinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyridonyl, pyrimidinyl, indolyl, indazolyl, benzofuranyl, benzoxazolyl, imidazopyridinyl, quinolyl, quinolinonyl, quinazolinyl and dihydro-[1,4]dioxinopyridinyl.

[0138] Embodiment 13. The compound according to Embodiment 12 or its pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer, or deuterated compound thereof, wherein Cy2 is selected from

[0139]

[0140] Preferably, Cy2 is selected from

[0141] More preferably, Cy2 is Or Cy2 is Or Cy2 is

[0142] Embodiment 14. A compound as described in any one of Embodiments 1-13 or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof, wherein R4 is independently selected from halogen, -CN, -OH, oxo, C 1-6 Alkyl, -O-(C 1-6 Alkyl), -(C 1-6 alkyl) m -(C 3-8 Cycloalkyl), -(C 1-6 alkyl) m -(4-8 membered heterocyclic group), -(C 1-6 alkyl) m -phenyl, -(C 1-6 alkyl) m -(5-12 membered heteroaryl), -CONR a R b 、-COR c 、-COOR e 、-NR a R b 、-NR d COR c 、-NR d S(O) n R f and -S(O)n R f ; wherein said C 1-6 Alkyl, C 3-8 The cycloalkyl, 4-8 membered heterocyclyl, phenyl and 5-12 membered heteroaryl are each optionally substituted by one or more groups independently selected from the following: halogen, -OH, oxo, -CN, -NH2, -CONH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, -O-(C 1-6 Alkyl), -O-(C 1-6 Haloalkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -CONH(C 1-6 Alkyl), -CON(C 1-6 Alkyl)2, C 3-8 Preferably, R4 is independently selected from halogen, -CN, -OH, oxo, C 1-6 Alkyl, -O-(C 1-6 Alkyl), -(C 1-6 alkyl) m -(4-8 membered heterocyclic group), -(C 1-6 alkyl) m -phenyl, -(C 1-6 alkyl) m -(5-12 membered heteroaryl), -CONR a R b 、-COR c 、-COOR e 、-NR a R b 、-NR d COR c 、-NR d S(O) n R f and -S(O) n R f ; wherein said C 1-6 Alkyl, 4-8 membered heterocyclyl, phenyl and 5-12 membered heteroaryl are each optionally substituted by one or more groups independently selected from the following: halogen, -OH, oxo, -CN, -NH2, -CONH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 1-6 Haloalkyl, -(C 1-6 Alkyl)-OH, -O-(C 1-6 Alkyl) and C 3-8 Cycloalkyl; provided that R4 is not -NH(6-membered nitrogen-containing heteroaryl) or -NH(F-substituted phenyl), and further R4 is not -NH(6-membered heteroaryl) or -NH(F-substituted phenyl).

[0143] Embodiment 15. The compound according to Embodiment 14 or its pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer, or deuterated compound thereof, wherein R4 is independently selected from:

[0144] 1) Halogen;

[0145] 2)-CN;

[0146] 3) -OH;

[0147] 4) Oxo;

[0148] 5) C 1-6 Alkyl, optionally substituted with one or more groups independently selected from: -OH, -CN and -CONH2;

[0149] 6)-O-(C 1-6 alkyl);

[0150] 7)-(C 1-6 alkyl) m -(4-6 membered heterocyclic group); preferably, the 4-6 membered heterocyclic group is selected from oxetanyl and dihydropyranyl;

[0151] 8)-(C 1-6 alkyl) m -phenyl; wherein the phenyl is optionally substituted by one or more groups independently selected from the following: -CN;

[0152] 9)-(C 1-6 alkyl) m -(5-12 membered heteroaryl); preferably, the 5-12 membered heteroaryl is selected from 5-6 membered heteroaryl and 8-10 membered heteroaryl; more preferably, the 5-12 membered heteroaryl is selected from pyrazolyl, oxazolyl, pyridinyl, pyridonyl, pyrimidinyl, pyridazinyl, pyridazinonyl, pyrazinyl, 1,2,4-triazinyl, indolyl, imidazopyridazinyl, [1,2,4]triazolopyridinyl, pyrazolopyrimidinyl, dihydro-pyrimidopyridazinyl and dihydro-[1,4]dioxinopyridazinyl; most preferably, the 5-12 membered heteroaryl is selected from pyridinyl and pyridazinyl;

[0153] Wherein, the 5-12 membered heteroaryl is optionally substituted by one or more groups independently selected from the following: halogen, -OH, oxo, -CN, -NH2, -CONH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -(C 1-6 Alkyl)-OH, -O-(C 1-6 Alkyl) and C 3-8 Preferably, the 5-12 membered heteroaryl is optionally substituted by one or more groups independently selected from the following: halogen, -OH, -CN, -CONH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -(C 1-6 Alkyl)-OH, -O-(C 1-6 Alkyl) and C 3-8 Cycloalkyl;

[0154] 10)-CONR a R b ; Among them, R a and R b are independently selected from hydrogen, C 1-6 Alkyl, -(C 1-6 alkyl) m -(C 3-6 Cycloalkyl), -(C 1-6 alkyl) m -(4-6 membered heterocyclic group), -(C 1-6 alkyl) m -phenyl and -(C 1-6 alkyl) m -(5-6 membered heteroaryl); wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl are each optionally substituted by one or more groups independently selected from the group consisting of halogen and -O-(C 1-6 alkyl);

[0155] 11) -COR c ; Among them, R c Selected from C 1-6 Alkyl, C 2-6 Alkenyl, -(C 1-6 alkyl) m -(C 3-8 Cycloalkyl), -(C 1-6 alkyl) m -(4-6 membered heterocyclic group), -(C 1-6alkyl) m -phenyl and -(C 1-6 alkyl) m -(5-10 membered heteroaryl); wherein the C 1-6 Alkyl, C 3-8 The cycloalkyl, 4-6 membered heterocyclyl, phenyl and 5-10 membered heteroaryl are each optionally substituted by one or more groups independently selected from the following: halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -O-(C 1-6 Alkyl), -NH(C 3-6 Cyclic hydrocarbon), -CO(C 2-6 alkenyl) and -CON(C 1-6 Alkyl)2;

[0156] 12)-COOR e ; Among them, R e Selected from hydrogen and C 1-6 alkyl;

[0157] 13)-NR a R b ; Among them, R a and R b are independently selected from hydrogen, C 1-6 Alkyl and -(C 1-6 alkyl) m -(5-10 membered heteroaryl); wherein the C 1-6 The alkyl and 5-10 membered heteroaryl groups are each optionally substituted by one or more groups independently selected from the group consisting of halogen, -OH, -CN, -CONH2, C 1-6 Alkyl, -(C 1-6 Alkyl)-OH and -O-(C 1-6 alkyl), provided that R4 is not -NH(6-membered nitrogen-containing heteroaryl), further R4 is not -NH(6-membered heteroaryl);

[0158] 14)-NR d COR c ; Among them, R d Selected from hydrogen and C 1-6 Alkyl; R c C 1-6 Alkyl, which is optionally substituted by one or more groups independently selected from the group consisting of -CN and -O-(C 1-6 alkyl);

[0159] 15)-NR d S(O) n R f ; Among them, R d is hydrogen; Rf is -CH3;

[0160] 16)-S(O) n R f ; Among them, R f It is -CH3.

[0161] Embodiment 16. The compound according to Embodiment 1 or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof, wherein the compound is a compound of formula (I-3):

[0162]

[0163] in:

[0164] n1, n2, n3 and n4 are independently selected from 1 and 2; preferably, n1 and n2 are both 1, and n3 and n4 are both 2;

[0165] R1 is halogen; preferably, R1 is F or Cl; more preferably, R1 is F;

[0166] R2 is selected from hydrogen, -O-(C 1-6 Alkyl), C 3-8 Cycloalkyl, 4-8 membered heterocyclic, 5-12 membered heteroaryl, -CONR a R b ,-CSNR a R b 、-COR c and-COOR e , where R a , R b , R c and R e are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, C 3-8 Cycloalkyl and 4-8 membered heterocyclic group; wherein said C 3-8 The cycloalkyl, 4-8 membered heterocyclyl and 5-12 membered heteroaryl are each optionally substituted by one or more groups independently selected from the following: halogen, -OH, oxo, -CN, -NH2, -CONH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, -O-(C 1-6 Alkyl) and -O-(C 1-6 Preferably, R2 is selected from hydrogen, -O-(C 1-6 Alkyl), C 3-6 Cycloalkyl, 4-6 membered heterocyclic, 5-6 membered heteroaryl, -CONR a R b ,-CSNR a R b 、-COR c and-COOR e , where R a , R b , R c and R e are independently selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and 4-6 membered heterocyclic group; wherein said C 3-6 The cycloalkyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl are each optionally substituted by one or more groups independently selected from the group consisting of halogen, -OH and C 1-6 More preferably, R2 is selected from -COO(C 1-6 alkyl) and -CON(C 1-6 Most preferably, R2 is -CON(C 1-6 Alkyl)2;

[0167] R3 is hydrogen;

[0168] Or R2 and R3 together with the carbon atom to which they are attached form a 5-6 membered heteroaryl group; wherein the 5-6 membered heteroaryl group is optionally substituted by one or more groups independently selected from the following: 1-6 Preferably, R2 and R3 together with the carbon atom to which they are attached form a pyrazolyl group; wherein the pyrazolyl group is optionally substituted by one or more groups independently selected from the following: 1-6 alkyl;

[0169] R5 is selected from hydrogen, C 1-6 Alkyl, -NH2, -NH(C 1-6 Alkyl) and -N(C 1-6 Preferably, R5 is selected from hydrogen, C 1-6 Alkyl and -NH(C 1-6 More preferably, R5 is hydrogen;

[0170] Cy2 is selected from C 3-6Cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl and 8-10 membered heteroaryl; preferably, Cy2 is selected from cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl, pyrrolidinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyridonyl, pyrimidinyl, indolyl, indazolyl, benzofuranyl, benzoxazolyl, imidazopyridinyl, quinolyl, quinolinonyl, quinazolinyl and dihydro-[1,4]dioxinopyridinyl; more preferably, Cy2 is selected from

[0171] Most preferably, Cy2 is

[0172] R4 is independently selected from halogen, -CN, -OH, oxo, C 1-6 Alkyl, -O-(C 1-6 Alkyl), -(C 1-6 alkyl) m -(4-8 membered heterocyclic group), -(C 1-6 alkyl) m -phenyl, -(C 1-6 alkyl) m -(5-12 membered heteroaryl), -CONR a R b 、-COR c 、-COOR e 、-NR a R b 、-NR d COR c 、-NR d S(O) n R f and -S(O) n R f ; wherein said C 1-6 Alkyl, 4-8 membered heterocyclyl, phenyl and 5-12 membered heteroaryl are each optionally substituted by one or more groups independently selected from the following: halogen, -OH, oxo, -CN, -NH2, -CONH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -(C 1-6 Alkyl)-OH, -O-(C 1-6 Alkyl) and C 3-8 Preferably, R4 is independently selected from:

[0173] 1) Halogen;

[0174] 2)-CN;

[0175] 3) -OH;

[0176] 4) Oxo;

[0177] 5) C 1-6 Alkyl, optionally substituted with one or more groups independently selected from: -OH, -CN and -CONH2;

[0178] 6)-O-(C 1-6 alkyl);

[0179] 7)-(C 1-6 alkyl) m -(4-6 membered heterocyclic group); preferably, the 4-6 membered heterocyclic group is selected from oxetanyl and dihydropyranyl;

[0180] 8)-(C 1-6 alkyl) m -phenyl; wherein the phenyl is optionally substituted by one or more groups independently selected from the following: -CN;

[0181] 9)-(C 1-6 alkyl) m -(5-12 membered heteroaryl); preferably, the 5-12 membered heteroaryl is selected from 5-6 membered heteroaryl and 8-10 membered heteroaryl; more preferably, the 5-12 membered heteroaryl is selected from pyrazolyl, oxazolyl, pyridinyl, pyridonyl, pyrimidinyl, pyridazinyl, pyridazinonyl, pyrazinyl, 1,2,4-triazinyl, indolyl, imidazopyridazinyl, [1,2,4]triazolopyridinyl, pyrazolopyrimidinyl, dihydro-pyrimidopyridazinyl and dihydro-[1,4]dioxinopyridazinyl; most preferably, the 5-12 membered heteroaryl is selected from pyridinyl and pyridazinyl;

[0182] Wherein, the 5-12 membered heteroaryl is optionally substituted by one or more groups independently selected from the following: halogen, -OH, oxo, -CN, -NH2, -CONH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -(C 1-6 Alkyl)-OH, -O-(C 1-6 Alkyl) and C 3-8 Preferably, the 5-12 membered heteroaryl is optionally substituted by one or more groups independently selected from the following: halogen, -OH, -CN, -CONH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -(C 1-6 Alkyl)-OH, -O-(C 1-6 Alkyl) and C3-8 Cycloalkyl;

[0183] 10)-CONR a R b ; Among them, R a and R b are independently selected from hydrogen, C 1-6 Alkyl, -(C 1-6 alkyl) m -(C 3-6 Cycloalkyl), -(C 1-6 alkyl) m -(4-6 membered heterocyclic group), -(C 1-6 alkyl) m -phenyl and -(C 1-6 alkyl) m -(5-6 membered heteroaryl); wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl are each optionally substituted by one or more groups independently selected from the group consisting of halogen and -O-(C 1-6 alkyl);

[0184] 11) -COR c ; Among them, R c Selected from C 1-6 Alkyl, C 2-6 Alkenyl, -(C 1-6 alkyl) m -(C 3-8 Cycloalkyl), -(C 1-6 alkyl) m -(4-6 membered heterocyclic group), -(C 1-6 alkyl) m -phenyl and -(C 1-6 alkyl) m -(5-10 membered heteroaryl); wherein the C 1-6 Alkyl, C 3-8 The cycloalkyl, 4-6 membered heterocyclyl, phenyl and 5-10 membered heteroaryl are each optionally substituted by one or more groups independently selected from the following: halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -O-(C 1-6 Alkyl), -NH(C 3-6 Cyclic hydrocarbon), -CO(C 2-6 alkenyl) and -CON(C 1-6 Alkyl)2;

[0185] 12)-COOR e ; Among them, R e Selected from hydrogen and C 1-6alkyl;

[0186] 13)-NR a R b ; Among them, R a and R b are independently selected from hydrogen and C 1-6 Alkyl; wherein the C 1-6 The alkyl group is optionally substituted with one or more groups independently selected from: -CN and -O-(C 1-6 alkyl);

[0187] 14)-NR d COR c ; Among them, R d Selected from hydrogen and C 1-6 Alkyl; R c C 1-6 Alkyl, which is optionally substituted by one or more groups independently selected from the group consisting of -CN and -O-(C 1-6 alkyl);

[0188] 15)-NR d S(O) n R f ; Among them, R d is hydrogen; R f is -CH3;

[0189] 16)-S(O) n R f ; Among them, R f is -CH3;

[0190] L is CH2;

[0191] p is 0, 1, 2 or 3;

[0192] m is 0 or 1;

[0193] n is 1 or 2; preferably, n is 2.

[0194] Embodiment 17. The compound as described in Embodiment 1 or its pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer, or deuterated compound thereof, wherein the compound is a compound of formula (I-4):

[0195]

[0196] in:

[0197] n5 and n6 are independently selected from 1 and 2 respectively; preferably, n5 and n6 are both 1;

[0198] R1 is halogen; preferably, R1 is F;

[0199] R2 is -CON(C 1-6 Alkyl)2;

[0200] R3 is hydrogen;

[0201] R5 is hydrogen;

[0202] Cy2 is selected from C 3-8 Cycloalkyl and 4-8 membered heterocyclic groups; preferably, Cy2 is selected from cyclopropyl and pyrrolidinyl; more preferably, Cy2 is selected from Most preferably, Cy2 is

[0203] R4 is independently selected from -(C 1-6 alkyl) m -(5-12 membered heteroaryl) and -NR a R b wherein the 5-12 membered heteroaryl groups are each optionally substituted by one or more groups independently selected from the following: -CN and C 1-6 Alkyl; preferably, R4 is independently selected from:

[0204] 1)-(C 1-6 wherein the indolyl group is optionally substituted by one or more groups independently selected from the following: -CN and C 1-6 alkyl;

[0205] 2)-NR a R b ; Among them, R a and R b are independently selected from hydrogen, C 1-6 Alkyl and -(C 1-6 alkyl) m -(5-10 membered heteroaryl); wherein the C 1-6 The alkyl and 5-10 membered heteroaryl groups are each optionally substituted with one or more groups independently selected from: -OH, -CN, C 1-6 Alkyl and -(C 1-6 Alkyl)-OH, provided that R4 is not -NH(6-membered nitrogen-containing heteroaryl), further R4 is not -NH(6-membered heteroaryl);

[0206] p is 0, 1 or 2; preferably, p is 1;

[0207] m is 0 or 1.

[0208] Embodiment 18. A compound or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof, selected from:

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220] Embodiment 19. A pharmaceutical composition comprising a compound according to any one of Embodiments 1-18 and / or a pharmaceutically acceptable salt thereof, and optionally comprising a pharmaceutically acceptable excipient.

[0221] Embodiment 20. A method for inhibiting menin-MLL interaction in vivo or in vitro, comprising contacting an effective amount of a compound according to any one of Embodiments 1-18 and / or a pharmaceutically acceptable salt thereof with menin.

[0222] Embodiment 21. Use of a compound and / or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 18 in the preparation of a medicament for treating or preventing a disease mediated by or at least partially mediated by menin-MLL interaction, wherein the disease mediated by or at least partially mediated by menin-MLL interaction is preferably cancer; the cancer is preferably a hematological malignancy or a solid tumor, including leukemia, lymphoma and myeloma; the cancer is more preferably selected from acute leukemia, chronic leukemia, myeloid leukemia, myeloid leukemia, lymphocytic leukemia, lymphoblastic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), B-cell acute lymphocytic leukemia (B-ALL), T-cell prolymphocytic leukemia (T-ALL), and the like. -PLL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia, large granular lymphocytic leukemia, hairy cell leukemia (HCL), mixed lineage leukemia (MLL), MLL-related leukemia, MLL-rearranged leukemia (MLL-r), MLL-PTD leukemia, MLL-positive leukemia, NPM1 mutant leukemia, leukemias displaying the HOX / MEIS1 gene expression signature, myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), multiple myeloma (MM), Hodgkin lymphoma, non-Hodgkin lymphoma, diffuse large B-cell lymphoma (DLBCL), B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, follicular lymphoma (FL), Waldenstrom's macroglobulinemia, prostate cancer, breast cancer, lung cancer, liver cancer, colon cancer, colorectal cancer, pancreatic cancer, melanoma, glioblastoma (GBM).

[0223] Embodiment 22. A method for treating or preventing a disease in an individual, comprising administering to an individual in need thereof an effective amount of a compound and / or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-18, wherein the disease is mediated by menin-MLL interaction or at least partially mediated by menin-MLL interaction; the disease is preferably cancer; the cancer is preferably a hematological malignancy or a solid tumor, including leukemia, lymphoma and myeloma; the cancer is more preferably selected from acute leukemia, chronic leukemia, myeloid leukemia, myeloid leukemia, lymphocytic leukemia, lymphoblastic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), B-cell acute lymphocytic leukemia (B-ALL), T-cell prolymphocytic leukemia (T-PLL), chronic lymphocytic ... The following are the clinical diagnosis and treatment of leukemia: CLL, chronic myeloid leukemia, large granular lymphocytic leukemia, hairy cell leukemia (HCL), mixed lineage leukemia (MLL), MLL-related leukemia, MLL-rearranged leukemia (MLL-r), MLL-PTD leukemia, MLL-positive leukemia, NPM1 mutant leukemia, leukemias displaying the HOX / MEIS1 gene expression signature, myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), multiple myeloma (MM), Hodgkin lymphoma, non-Hodgkin lymphoma, diffuse large B-cell lymphoma (DLBCL), B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, follicular lymphoma (FL), Waldenstrom macroglobulinemia, prostate cancer, breast cancer, lung cancer, liver cancer, colon cancer, colorectal cancer, pancreatic cancer, melanoma, glioblastoma (GBM).

[0224] Embodiment 23. A compound according to any one of Embodiments 1-18 and / or a pharmaceutically acceptable salt thereof for use as a medicament.

[0225] Embodiment 24. A compound and / or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 18, for use in treating or preventing a disease mediated by or at least partially mediated by menin-MLL interaction, wherein the disease is preferably cancer; the cancer is preferably a hematological malignancy or a solid tumor, including leukemia, lymphoma and myeloma; the cancer is more preferably selected from acute leukemia, chronic leukemia, myeloid leukemia, myeloid leukemia, lymphocytic leukemia, lymphoblastic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), B-cell acute lymphocytic leukemia (B-ALL), T-cell prolymphocytic leukemia (T-PLL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), leukemia, large granular lymphocytic leukemia, hairy cell leukemia (HCL), mixed lineage leukemia (MLL), MLL-related leukemia, MLL-rearranged leukemia (MLL-r), MLL-PTD leukemia, MLL-positive leukemia, NPM1 mutant leukemia, leukemias displaying the HOX / MEIS1 gene expression signature, myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), multiple myeloma (MM), Hodgkin lymphoma, non-Hodgkin lymphoma, diffuse large B-cell lymphoma (DLBCL), B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, follicular lymphoma (FL), Waldenstrom macroglobulinemia, prostate cancer, breast cancer, lung cancer, liver cancer, colon cancer, colorectal cancer, pancreatic cancer, melanoma, glioblastoma (GBM).

[0226] Embodiment 25. A drug combination comprising a compound and / or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1-18, and at least one additional therapeutic agent, wherein the additional therapeutic agent is preferably selected from: an anti-tumor agent, an anti-inflammatory agent or an immunomodulatory agent, wherein the anti-tumor agent includes a chemotherapeutic agent, an immune checkpoint inhibitor or agonist, and a targeted therapeutic agent.

[0227] Embodiment 26. Compound of formula (II):

[0228]

[0229] or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof, wherein:

[0230] R6 is an amino protecting group; preferably, R6 is an amino protecting group selected from the group consisting of Boc (tert-butyloxycarbonyl), benzyl, Pmb (p-methoxybenzyl) and Cbz (benzyloxycarbonyl); more preferably, R6 is Boc (tert-butyloxycarbonyl); X1 is halogen; preferably, X1 is chlorine;

[0231] X2 is hydrogen or halogen; preferably, X2 is hydrogen or chlorine; more preferably, X2 is chlorine.

[0232] Embodiment 27. The compound according to Embodiment 26, which is:

[0233]

[0234] or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof.

[0235] Embodiment 28. Compound of formula (III):

[0236]

[0237] or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof, wherein:

[0238] R1, R2, R3 and R5 are as defined in any one of Embodiments 1-17;

[0239] R7 is hydrogen or an amino protecting group; preferably, R7 is hydrogen or an amino protecting group selected from the group consisting of Boc (tert-butyloxycarbonyl), benzyl, Pmb (p-methoxybenzyl) and Cbz (benzyloxycarbonyl); more preferably, R7 is hydrogen or Boc (tert-butyloxycarbonyl).

[0240] Embodiment 28.1. A compound as described in Embodiment 28, wherein when R5 is H or chloro, R2 is not -C(O)N(CH(CH3)2)2, -C(O)N(CH(CH3)2)(CH3), -C(O)N(CH(CH3)2)(CH2CH3), -C(O)N(CH(CH3)2)(CH2CHF2), -C(O)N(CH(CH3)2)(CH2CF3), -C(O)N(CH(CH3)2)(CH2CH2OH), -C(O)N(cyclopropyl)2, -C(O)N(CH(CH3)2)(cyclopropyl), -C(O)N(CH2CH3)(cyclopropyl), -C(O)N(CH(CH3)2)(cyclobutyl), pyrimidinyl substituted with isopropyl, and pyrazolyl substituted with isopropyl and / or chloro.

[0241] Embodiment 29. The compound according to embodiment 28, which is selected from:

[0242]

[0243]

[0244] or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof.

[0245] The various embodiments described in the present invention (including the examples below) and the features in the various embodiments should be understood to be able to be combined with each other arbitrarily, and the various schemes obtained by these combinations are included in the scope of the present invention, just as the schemes obtained by these combinations are specifically and one by one listed in this document, unless the context clearly shows otherwise.

[0246] Advantageous Effects of the Invention

[0247] As mentioned above, it is known that the binding and interaction between MLL fusion protein and menin protein is very important for MLL protein to exert its oncogenic function. Inhibiting or interfering with the interaction between MLL-menin can significantly inhibit the proliferation of cells in MLL fusion protein-related cancer diseases. We have surprisingly found that the compounds of the present invention having the above-mentioned structural characteristics can significantly inhibit the binding activity of menin and MLL protein, and can strongly inhibit cell proliferation in cell lines carrying mutations, thereby having potential value as anti-proliferation, pro-apoptosis and / or anti-invasive drugs in preventing, curbing and / or treating diseases mediated by menin-MLL interaction or at least partially mediated by menin-MLL interaction, such as cancer or tumors defined herein.

[0248] Specifically, it has been found that the compounds of the present invention can achieve one or more of the following technical effects: ● Potent MLL-menin binding inhibitory activity: The compounds of the present invention, especially the compounds of the examples herein, show inhibitory activity on the binding of the proteins in a molecular level MLL and menin protein binding assay (fluorescence polarization method), and the IC50 value is generally in the range of 0.1nM to 10μM, such as 0.1nM to 5μM, preferably 0.1nM to 1μM, more preferably 0.1nM to 100nM, and most preferably 0.1nM to 50nM, as verified in Example 3;

[0249] ● Potent cell proliferation inhibition activity: The compounds of the present invention, especially the compounds of the examples herein, show potent proliferation inhibition activity in a human acute myeloid leukemia cell MV-4-11 proliferation inhibition assay, with a GI50 value generally in the range of 0.1 nM to 10 μM, such as 0.1 nM to 5 μM, preferably 0.1 nM to 1 μM, more preferably 1 nM to 100 nM, most preferably 1 nM to 50 nM, as verified in Example 4;

[0250] ●Expected to have good pharmacokinetic properties;

[0251] ●It is expected to have satisfactory safety and fewer toxic side effects.

[0252] General synthetic method

[0253] The compounds of formula (I) described herein and / or their pharmaceutically acceptable salts can be synthesized using commercially available starting materials, by methods known in the art or by methods disclosed in this patent application. The synthetic routes shown in Schemes 1-3 illustrate the general synthetic methods of the compounds of the present invention.

[0254] Method 1:

[0255]

[0256] Solution 1

[0257] As shown in Scheme 1, under alkaline conditions (such as but not limited to triethylamine), the compound of formula (1-1) undergoes a substitution reaction with the compound of formula (1-2) to obtain a compound of formula (1-3). The compound of formula (1-3) undergoes a substitution reaction with the compound of formula (1-4) under alkaline conditions (such as but not limited to DBU) to obtain a compound of formula (1-5). The compound of formula (1-5) undergoes a reduction dechlorination reaction under a catalyst (such as but not limited to Pd / C) to generate a compound of formula (1-6), and then continues to remove Boc under acidic conditions (such as but not limited to HCl) to convert it into a compound of formula (1-7). Then, under the action of a reducing agent (such as but not limited to sodium acetate borohydride, sodium cyanoborohydride, etc.), the compound of formula (1-7) and the compound of formula (1-8) undergo a reductive amination reaction to obtain a compound of formula (I-3) (wherein R5=H, L=CH2). Alternatively, under the action of a condensing agent (such as but not limited to HATU), the compound of formula (1-7) and the compound of formula (1-9) undergo a condensation reaction to obtain a compound of formula (I-3) (wherein R5 = H, L = CO). Wherein, R1, R2, R3, R4, Cy2, n1, n2, n3, n4 and p are as defined herein.

[0258] Method 2:

[0259]

[0260] Solution 2

[0261] As shown in Scheme 2, under alkaline conditions (such as but not limited to triethylamine), the compound of formula (1-5) undergoes a substitution reaction with the compound of formula (2-1) to generate a compound of formula (2-3) (wherein R5 = -NR a R b Alternatively, the compound of formula (1-5) and the compound of formula (2-2) undergo coupling reaction under the catalysis of a palladium reagent (such as but not limited to Pd(PPh3)4) to obtain a compound of formula (2-3) (wherein R5 = C 1-6 Alkyl). The compound of formula (2-3) (wherein R5 = -NR a R b Or R5=C 1-6 alkyl), remove Boc under acidic conditions (such as but not limited to HCl) to obtain a compound of formula (2-4). Then, under the action of a reducing agent (such as but not limited to sodium acetate borohydride, sodium cyanoborohydride, etc.), the compound of formula (2-4) and the compound of formula (2-5) undergo a reductive amination reaction to obtain a compound of formula (I-3) (wherein L = CH2, R5 = -NR a R b Or R5=C 1-6 alkyl). Among them, R1, R2, R3, R4, R a , R b , Cy2, n1, n2, n3, n4 and p are as defined herein; M is boronic anhydride, boronic ester or boronic acid.

[0262] Method 3:

[0263]

[0264] Solution 3

[0265] As shown in Scheme 3, under alkaline conditions (such as but not limited to triethylamine), the compound of formula (1-1) undergoes a substitution reaction with the compound of formula (3-1) to obtain a compound of formula (3-2). The compound of formula (3-2) undergoes a substitution reaction with the compound of formula (3-3) under alkaline conditions (such as but not limited to DBU) to obtain a compound of formula (3-4). The compound of formula (3-4) undergoes a reduction dechlorination under the action of a catalyst (such as but not limited to Pd / C) to produce a compound of formula (3-5). The compound of formula (3-5) undergoes a Boc removal under acidic conditions (such as but not limited to HCl) to obtain a compound of formula (3-6). Then, under the action of a reducing agent (such as but not limited to sodium acetate borohydride, sodium cyanoborohydride, etc.), the compound of formula (3-6) and the compound of formula (3-7) undergo a reductive amination reaction to obtain a compound of formula (I-4) (wherein R5 = H). wherein R1, R2, R3, R4, Cy2, n5, n6 and p are as defined herein.

[0266] The substituents of the compounds obtained by the above methods can be further modified to obtain other desired compounds. Synthetic chemical transformation methods can be referenced, for example, in: R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent versions thereof.

[0267] Before use, the compounds of the present invention may be purified by column chromatography, high performance liquid chromatography, crystallization or other appropriate methods.

[0268] Pharmaceutical compositions and uses

[0269] The compounds of the present invention (e.g., any of the compounds of the embodiments herein) can be formulated into pharmaceutical compositions alone or in combination with one or more additional therapeutic agents. The pharmaceutical compositions include: (a) an effective amount of a compound of the present invention; (b) a pharmaceutically acceptable excipient (e.g., one or more pharmaceutically acceptable carriers); and optionally (c) at least one additional therapeutic agent.

[0270] A pharmaceutically acceptable excipient is an excipient that is compatible with the active ingredient in the composition (in some embodiments, stabilizes the active ingredient) and is not harmful to the individual being treated. For example, solubilizers such as cyclodextrins (which can form specific, more soluble complexes with the compounds of the invention) can be used as pharmaceutical excipients to deliver the active ingredient. Examples of other excipients include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments such as D&C Yellow #10. Suitable pharmaceutically acceptable excipients are disclosed in a standard reference book in the art (Remington's Pharmaceutical Sciences, A. Osol).

[0271] The pharmaceutical composition containing the compound of the present invention can be administered in various known ways, such as oral, topical, rectal, parenteral, inhalation or implantation, etc. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intraspinal, intralesional and intracranial injection or infusion.

[0272] The pharmaceutical compositions described herein can be prepared in the form of tablets, capsules, bagged granules, dragees, powders, granules, lozenges, powder injections, liquid preparations or suppositories. In some embodiments, the pharmaceutical compositions comprising the compounds of the present invention can be formulated for intravenous infusion, topical administration or oral administration.

[0273] The composition for oral administration can be in any oral acceptable dosage form, including but not limited to: tablets, capsules, emulsions and aqueous suspensions, dispersants and solutions. Commonly used tablet carriers include lactose and corn starch. Lubricants such as magnesium stearate are also often added to tablets. When administered orally in capsule form, useful diluents include lactose and dry corn starch. When administered orally in the form of an aqueous suspension or emulsion, an emulsifier or suspending agent can be used to suspend or dissolve the active ingredient in the oil phase. If necessary, certain sweeteners, flavoring agents or pigments can also be added.

[0274] In some embodiments, the amount of the compound of the present invention in tablets can be 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, 100, 125, 150, 200, 250, 300, 400 and 500 mg. In some embodiments, the amount of the compound of the present invention in capsules can be 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, 100, 125, 150, 200, 250, 300, 400 and 500 mg.

[0275] Sterile injectable compositions (such as aqueous or oily suspensions) can be prepared according to techniques known in the art using suitable dispersants or wetting agents (e.g., Tween 80) and suspending agents. Sterile injectable compositions can also be sterile injectable solutions or suspensions in nontoxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Pharmaceutically acceptable carriers and solvents can be used, in particular, mannitol, water, Ringer's solution, and saline. In addition, sterile, nonvolatile oils such as synthetic mono- or diglycerides are commonly used as solvents or suspending media. Fatty acids such as oleic acid and its glyceride derivatives and natural pharmaceutically acceptable oils such as olive oil or castor oil (especially its polyoxyethylated form) are commonly used as injectable media. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, or carboxymethyl cellulose or similar dispersants.

[0276] The inhalation composition may be prepared according to techniques well known in the art of pharmaceutical formulation using benzyl alcohol or other suitable preservatives, using absorption promoters to improve bioavailability, using fluorocarbons and / or other solubilizing or dispersing agents known in the art, or it may be prepared as a solution in saline.

[0277] Topical compositions can be formulated in the form of oils, creams, lotions, ointments, etc. Suitable carriers for the compositions include vegetable oils or mineral oils, white vaseline (white soft paraffin), branched chain fats or oils, animal fats, and high molecular weight alcohols (i.e., alcohols with carbon atoms greater than 12). In some embodiments, a pharmaceutically acceptable carrier is a carrier in which the active ingredient can be dissolved. If necessary, the composition may also include an emulsifier, a stabilizer, a wetting agent, and an antioxidant, as well as a substance that imparts color or fragrance to it. In addition, a transdermal penetration enhancer may also be added to the topical preparation. Examples of such enhancers are found in U.S. Patent Nos. 3,989,816 and 4,444,762.

[0278] Creams can be prepared from a mixture of mineral oil, self-emulsifying beeswax and water, with the active ingredient dissolved in a small amount of fat, such as almond oil, mixed therein. An example of a cream comprises about 40 parts of water, about 20 parts of beeswax, about 40 parts of mineral oil, and about 1 part of almond oil by weight. Ointments can be prepared by mixing a solution of the active ingredient in a vegetable oil, such as almond oil, with warm soft paraffin and cooling the mixture. An example of an ointment comprises about 30% almond oil and about 70% white soft paraffin by weight.

[0279] Suitable in vitro experiments can be used to evaluate the effect of the compounds of the present invention in inhibiting the menin-MLL interaction. The effect of the compounds of the present invention in preventing or treating cancer can be further tested by in vivo experiments. For example, the compounds of the present invention can be administered to animals (such as mouse models) suffering from cancer, and then their therapeutic effects can be evaluated. If the results of the preclinical test are successful, the dosage range and administration route for animals such as humans can also be predicted.

[0280] The compounds of the invention show sufficient preclinical utility to warrant clinical trials and are expected to show beneficial therapeutic or prophylactic effects, for example, in individuals suffering from cancer.

[0281] As used herein, the term "cancer" refers to a cellular disorder characterized by uncontrolled or dysregulated cell proliferation, reduced cell differentiation, inappropriate ability to invade surrounding tissues, and / or the ability to establish new growth foci at other sites. The term "cancer" includes, but is not limited to, solid tumors and hematological malignancies (e.g., leukemias, lymphomas, or myelomas). The term "cancer" includes cancers of the skin, tissues, organs, bones, cartilage, blood, and blood vessels. The term "cancer" includes both primary cancers and metastatic cancers, recurrent cancers, and refractory cancers.

[0282] Non-limiting examples of solid tumors include pancreatic cancer; bladder cancer; colorectal cancer; colon cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; testicular cancer; kidney cancer, including, for example, metastatic renal cell carcinoma; urothelial carcinoma; liver cancer; hepatocellular carcinoma; lung cancer, including, for example, non-small cell lung cancer (NSCLC), small cell lung cancer, bronchioloalveolar carcinoma (BAC), and lung adenocarcinoma; ovarian cancer, including, for example, progressive epithelial cancer or primary peritoneal cancer; cervical cancer; endometrial cancer; gastric cancer; esophageal cancer ; bile duct cancer; head and neck cancer, including, for example, squamous cell carcinoma of the head and neck; skin cancer, including, for example, melanoma and basal carcinoma; neuroendocrine cancer, including metastatic neuroendocrine tumors; brain tumors, including, for example, glioma, glioblastoma (GBM), anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma; bone cancer; sarcoma, including, for example, Kaposi's sarcoma; adrenal cancer; mesothelioma; mesothelial carcinoma; choriocarcinoma; muscle cancer; connective tissue cancer; and thyroid cancer.

[0283] Non-limiting examples of hematological malignancies include acute leukemias; chronic leukemias; myeloid leukemias; myeloid leukemias; lymphocytic leukemias; chronic lymphoid leukemias; lymphoblastic leukemias; acute lymphoblastic leukemias; acute myeloid leukemias (AML); juvenile acute myeloid leukemias; chronic myeloid leukemias (CML), including accelerated phase CML and CML blast phase (CML-BP); acute lymphocytic leukemias (ALL); acute T-cell lymphocytic leukemias; B-cell acute lymphocytic leukemias (B-ALL); T-cell prolymphocytic leukemias (T-PLL); chronic lymphocytic leukemias (CLL), including high-risk CLL; chronic myeloid leukemias; large granular lymphocytic leukemias; human acute monocytic leukemia (M(5)); hairy cell leukemias (HCL); mixed MLL-related leukemia; MLL-rearranged leukemia (MLL-r); MLL-PTD leukemia; MLL-positive leukemia; NPM1-mutated leukemia; leukemias displaying the HOX / MEIS1 gene expression signature; small lymphocytic lymphoma (SLL); lymphoblastic lymphoma; Hodgkin lymphoma; non-Hodgkin lymphoma (NHL); mantle cell lymphoma (MCL); B-cell lymphoma; T-cell lymphoma; diffuse large B-cell lymphoma (DLBCL); large B-cell lymphoma (LBCL); follicular lymphoma (FL); marginal zone lymphoma; Burkitt's lymphoma; non-Burkitt's high-grade B-cell lymphoma; extranodal marginal zone B-cell lymphoma; multiple myeloma (MM); Waldenstrom's macroglobulinemia (Waldenstrom's myeloproliferative syndrome (MDS)

[0284] In some embodiments, the solid tumor is prostate cancer, breast cancer, lung cancer, liver cancer, colon cancer, colorectal cancer, pancreatic cancer, melanoma, glioblastoma (GBM).

[0285] In some embodiments, the hematological malignancy is an acute leukemia, a chronic leukemia, a myeloid leukemia, a myeloid leukemia, a lymphocytic leukemia, a lymphoblastic leukemia, an acute myeloid leukemia (AML), a chronic myeloid leukemia (CML), an acute lymphocytic leukemia (ALL), a B-cell acute lymphocytic leukemia (B-ALL), a T-cell prolymphocytic leukemia (T-PLL), a chronic lymphocytic leukemia (CLL), a chronic myeloid leukemia, a large granular lymphocytic leukemia, a hairy cell leukemia (HCL), a mixed lineage leukemia (MLL) , MLL-related leukemia, MLL-rearranged leukemia (MLL-r), MLL-PTD leukemia, MLL-positive leukemia, NPM1 mutant leukemia, leukemias displaying the HOX / MEIS1 gene expression signature, myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), multiple myeloma (MM), Hodgkin lymphoma, non-Hodgkin lymphoma, diffuse large B-cell lymphoma (DLBCL), B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, follicular lymphoma (FL), Waldenstrom macroglobulinemia.

[0286] The compounds of the invention can be used to achieve a beneficial therapeutic or prophylactic effect, for example, in an individual suffering from cancer.

[0287] In addition, the compounds of the present invention (e.g., any of the example compounds herein) can be used in combination with additional therapeutic agents for the treatment of diseases or conditions described herein, such as cancer. The additional therapeutic agent can be administered separately from the compounds of the present invention, or it can be included in a pharmaceutical composition according to the present disclosure, such as a fixed-dose combination drug. In some embodiments, the additional therapeutic agent is an ingredient that is known or has been found to be effective in treating diseases mediated by menin-MLL interactions or at least partially mediated by menin-MLL interactions, such as other menin inhibitors or compounds that can effectively antagonize other targets associated with the specific disease. Combination therapy can be used to improve the efficacy (e.g., by including a compound that can enhance the efficacy or effectiveness of the compounds of the present invention in the combination therapy), reduce one or more side effects, or reduce the required dose of the compounds of the present invention.

[0288] In some embodiments, the compounds of the present invention (e.g., any of the example compounds herein) may be used in combination with other therapeutic agents, such as anti-tumor agents, anti-inflammatory agents, or immunomodulators, including chemotherapeutic agents, immune checkpoint inhibitors or agonists, and targeted therapeutic agents. The term "anti-tumor agent" used herein refers to any agent given to a subject with cancer for the purpose of treating cancer, including but not limited to chemotherapeutic agents, immune checkpoint inhibitors or agonists, and targeted therapeutic agents, etc.

[0289] Non-limiting examples of chemotherapeutic agents include topoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecin and its analogs or metabolites, and doxorubicin); topoisomerase II inhibitors (e.g., etoposide, teniposide, mitoxantrone, desmethoxydaunorubicin, and daunomycin); alkylating agents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, nitrosocarbamide, lomustine, methyllomustine, streptozotocin, decarbazine, methotrexate, mitoflasha, nitrosocarbamide ... The invention also includes but is not limited to sedative agents such as chloramphenicol, ...

[0290] Non-limiting examples of immune checkpoint inhibitors or agonists include PD-1 inhibitors, such as anti-PD-1 antibodies, for example, pembrolizumab, nivolumab, and spartalizumab; PD-L1 inhibitors, such as anti-PD-L1 antibodies, for example, atezolizumab, durvalumab, and avelumab; CTLA-4 inhibitors, such as anti-CTLA-4 antibodies, for example, ipilimumab; and BTLA inhibitors, LAG-3 inhibitors, TIM3 inhibitors, TIGIT inhibitors, VISTA inhibitors, OX-40 agonists, and the like.

[0291] Targeted therapeutic agents include various small molecule or macromolecular targeted therapeutic agents, non-limiting examples of which include: protein tyrosine kinase inhibitors (e.g., imatinib mesylate and gefitinib); proteasome inhibitors (e.g., bortezomib); NF-κB inhibitors, including IκB kinase inhibitors; KRAS G12C inhibitors; KRAS G12D inhibitors; ERK inhibitors; CDK4 / 6 inhibitors; PI3Kδ inhibitors; SYK inhibitors; Bcl-2 inhibitors; BTK inhibitors; EZH1 / 2 inhibitors; BRAF inhibitors (e.g., dabrafenib); MEK inhibitors (e.g., trametinib); mTOR inhibitors (e.g., rapamycin); anti-CD40 antibodies (e.g., APX005M, RO7009789); antibodies that bind to proteins overexpressed in cancer and thereby downregulate cell replication, such as anti-CD20 antibodies (e.g., rituximab, ibritumomab tiuxetan, tositumomab), anti-Her2 monoclonal antibodies (e.g., trastuzumab), anti-EGFR antibodies (e.g., cetuximab), and anti-VEGF antibodies (e.g., bevacizumab); anti-angiogenic drugs, such as lenalidomide, etc.; and other protein or enzyme inhibitors, which are known to be upregulated, overexpressed, or activated in cancer, and whose inhibition can downregulate cell replication.

[0292] Example

[0293] The following examples are illustrative of the present invention and are not intended to limit the present invention in any way. The data given (e.g., amounts, temperatures, etc.) strive to ensure their accuracy, but those skilled in the art will understand that there will be some experimental errors and offsets. Unless otherwise stated, all parts are parts by weight, temperatures are degrees Celsius, and pressures are atmospheric pressure or near atmospheric pressure. All mass spectrometry data were provided by Agilent.

[0294] 6120 and 1100. All nuclear magnetic resonance data were measured by Varian 400MHz NMR. Except for the specifically synthesized intermediates, all reagents used in the present invention were obtained from commercial channels. The names of all compounds except the reagents were generated by Chemdraw 19.0. Rapid column chromatography was performed using a conventional silica gel column, unless otherwise specified or contradicted by the context.

[0295] In any structural formula herein, if there are vacant valencies on any atom, the vacant valencies are actually hydrogen atoms which are not specifically depicted for the sake of simplicity.

[0296] In this application, if both the name and structural formula of a compound are given, in the event of inconsistency between the two, the structure of the compound shall prevail unless the context indicates that the structure of the compound is incorrect and the name is correct.

[0297] The following is a list of abbreviations used in the examples:

[0298]

[0299]

[0300]

[0301] Example 1

[0302] Preparation of intermediates Intermediate 1-1: tert-butyl 2-(3,6-dichloro-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

[0303]

[0304] In a reaction flask, 3,5,6-trichloro-1,2,4-triazine (5.0 g, 27.0 mmol) and triethylamine (5.46 g, 54 mmol) were dissolved in dichloromethane (30 ml). Under an ice bath, tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (5.52 g, 24.0 mmol) dissolved in 20 ml of dichloromethane was slowly added to the flask. The mixture was heated to room temperature and stirred for 1 hour. After the reaction was completed, the reaction solution was washed with water and saturated sodium chloride solution in turn. The organic phase was dried with sodium sulfate, concentrated, and purified by flash column chromatography (petroleum ether / ethyl acetate = 100:0-0:100 gradient elution) to obtain 7.07 g of yellow solid. MS (m / z): 374.2, 376.2 [M+H] +

[0305] The following intermediates were prepared by referring to the preparation process of intermediate 1-1, using corresponding raw materials and reagents under appropriate conditions recognized by those skilled in the art.

[0306]

[0307]

[0308] Intermediate 2-1: N-ethyl-5-fluoro-2-hydroxy-N-isopropylbenzamide

[0309]

[0310] (A) N-ethyl-5-fluoro-N-isopropyl-2-methoxybenzamide

[0311] In the reaction flask, add thionyl chloride (20ml), then add 5-fluoro-2-methoxybenzoic acid (5.1g, 30.0mmol), stir and heat to 80℃ and react for 2 hours. After concentrating to remove the solvent, the residue is dissolved in dichloromethane (100ml). The solution is cooled to 0℃, triethylamine (4.55g, 45.0mmol) and N-ethylpropane-2-amine (3.14g, 36.0mmol) are added, and the reaction is stirred for 2 hours after warming to room temperature. After the reaction is completed, the solvent is concentrated and purified by flash column chromatography (petroleum ether / ethyl acetate = 100:0-0:100 gradient elution) to obtain 6.6g of yellow solid. MS (m / z): 240.0 [M+H]+

[0312] (B) N-ethyl-5-fluoro-2-hydroxy-N-isopropylbenzamide

[0313] In a reaction flask, dissolve N-ethyl-5-fluoro-N-isopropyl-2-methoxybenzamide (6.6 g, 27.58 mmol) in dichloromethane (150 ml), cool to 0°C, add boron tribromide (33 ml, 36.0 mmol), warm to room temperature, and stir to react for 48 hours. After concentrating and removing the solvent, 5.4 g of yellow solid was obtained. MS (m / z): 226.0 [M+H]+

[0314] The following intermediates were prepared by referring to the preparation process of intermediate 2-1, using corresponding raw materials and reagents under appropriate conditions recognized by those skilled in the art.

[0315]

[0316] Intermediate 3: Isopropyl 5-fluoro-2-hydroxybenzoate

[0317]

[0318] (A) 5-Fluoro-2-hydroxybenzoic acid

[0319] In a reaction flask, add methyl 5-fluoro-2-hydroxybenzoate (3.0 g, 17.63 mmol), sodium hydroxide (2.12 g, 52.90 mmol), methanol (30 ml) and water (10 ml), heat to 60°C for 15 hours, cool to room temperature, adjust pH to 2.0 with 1 mol / L dilute hydrochloric acid, filter, and dry the filter cake to obtain 2.6 g of a white solid. MS (m / z): 157.1 [M+H] +

[0320] (B) Isopropyl 5-fluoro-2-hydroxybenzoate

[0321] In a reaction flask, add 5-fluoro-2-hydroxybenzoic acid (2.6g, 16.65mmol), N,N'-carbonyldiimidazole (2.7g, 16.65mmol) and N,N-dimethylformamide (10ml), heat to 50℃ for 3 hours, then add isopropanol (5ml), continue heating at 50℃ for 15 hours. After the reaction, concentrate the reaction solution, and purify the residue by flash column chromatography (PE / EA=100:0-0:100 gradient elution) to obtain 2.37g of colorless oil.

[0322] 1 H NMR (400MHz, CD3OD) δ7.43(d,J=8.4Hz,1H),7.20(s,1H),6.89(s,1H),5.37–5.13(m,1H),1.36(d,J=8.0,6.4Hz,6H).

[0323] Intermediate 4: N-ethyl-5-fluoro-2-hydroxy-N-isopropylbenzenethioamide

[0324]

[0325] In the reaction flask, add N-ethyl-5-fluoro-2-hydroxy-N-isopropylbenzamide (500mg, 2.22mmol), Lawesson's reagent (538mg, 1.33mmol) and toluene (20ml), heat to reflux, and react for 10 hours. After the reaction, concentrate the reaction solution, and purify the residue by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 450mg of white solid. MS (m / z): 242.1 [M+H] +

[0326] Intermediate 5-1: 4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenol

[0327]

[0328] In the reaction flask, (1-isopropyl-1H-pyrazol-5-yl)boric acid (330mg, 2.14mmol), 2-bromo-4-fluorophenol (341mg, 1.79mmol), Pd(dppf)Cl2·CH2Cl2 (147mg, 0.18mmol), potassium carbonate (50mg, 0.36mmol), dioxane (25ml) and water (5ml) were added in sequence, and heated to 100°C under nitrogen protection for 15 hours. After the reaction, the reaction solution was concentrated and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 140mg of yellow solid. MS (m / z): 221.4 [M+H] +

[0329] The following intermediates were prepared by referring to the preparation process of intermediate 5-1, using corresponding raw materials and reagents under appropriate conditions recognized by those skilled in the art.

[0330]

[0331]

[0332] Intermediate 6-1: 7-Fluoro-1-isopropyl-1H-indazole-4-phenol

[0333]

[0334] (A) 4-Bromo-7-fluoro-1-isopropyl-1H-indazole

[0335] In the reaction bottle, add 4-bromo-7-fluoro-1H-indazole (1.5g, 6.98mmol) and dry tetrahydrofuran (20ml), cool to 0°C, add 60% sodium hydride (560mg, 13.96mmol) in batches, continue stirring at 0°C for 30 minutes, add iodoisopropyl (1.423g, 8.37mmol), and then stir at room temperature for 15 hours. After the reaction is completed, quench with water, extract with ethyl acetate, concentrate the organic phase, and purify the residue by flash column chromatography (petroleum ether / ethyl acetate = 100:0-0:100 gradient elution) to obtain 1.2g of 4-bromo-7-fluoro-1-isopropyl-1H-indazole. MS (m / z): 257.2, 259.2 [M+H] + and 4-bromo-7-fluoro-2-isopropyl-2H-indazole 600 mg. MS (m / z): 257.2, 259.2 [M+H] +

[0336] (B) 7-Fluoro-1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

[0337] In the reaction flask, add 4-bromo-7-fluoro-1-isopropyl-1H-indazole (1.2g, 4.67mmol), bis(pinacolato)diboron (1.78g, 7.01mmol), Pd(dppf)Cl2·CH2Cl2 (377mg, 0.46mmol), potassium acetate (1.37g, 13.96mmol) and dioxane (30ml) in sequence, heat to 100℃ under nitrogen protection, and react for 15 hours. After the reaction, concentrate the reaction solution, and purify the residue by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 1.13g of yellow solid. MS (m / z): 305.4 [M+H] +

[0338] (C) 7-Fluoro-1-isopropyl-1H-indazole-4-ol

[0339] In the reaction flask, add 7-fluoro-1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (1.13g, 3.72mmol), 1 mol / L sodium hydroxide aqueous solution (3.72ml, 3.72mmol) and methanol (15ml), add hydrogen peroxide (0.5ml) dropwise at room temperature, stir for 1 hour, after the reaction is completed, add ethyl acetate, wash with saturated sodium sulfite solution and saturated brine, concentrate the organic phase, and purify the residue by flash column chromatography (petroleum ether / ethyl acetate = 100:0-0:100 gradient elution) to obtain 600mg of white solid. MS (m / z): 195.1 [M+H] +

[0340] The following intermediates were prepared by referring to the preparation process of intermediate 6-1, using corresponding raw materials and reagents under appropriate conditions recognized by those skilled in the art.

[0341]

[0342] Intermediate 7-1: 2-((5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazine-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0343]

[0344] (A) tert-Butyl 2-(3-chloro-6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

[0345] In the reaction bottle, tert-butyl 2-(3,6-dichloro-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (7.07g, 18.9mmol), N-ethyl-5-fluoro-2-hydroxy-N-isopropylbenzamide (4.26g, 18.9mmol), DBU (9.50g, 62.4mmol) and tetrahydrofuran (50ml) were added in sequence, and the temperature was raised to 40°C and stirred for reaction overnight. Water was added to dilute the reaction solution and extracted with ethyl acetate three times. The ethyl acetate phase was washed with water and saturated sodium chloride in sequence and dried with sodium sulfate. After drying, the solvent was concentrated to remove the solvent and purified by flash column chromatography (petroleum ether / ethyl acetate = 100:0-0:100 gradient elution) to obtain 7.55g of yellow solid. MS (m / z): 563.4 [M+H] +

[0346] (B) tert-Butyl 2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

[0347] In the reaction flask, 2-(3-chloro-6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (7.55g, 13.4mmol), palladium carbon (1g) and methanol (100ml) were added in sequence. After replacing the air, a hydrogen balloon was added and the reaction was stirred at room temperature for 15 hours. The palladium carbon was removed by filtration, and after concentration, it was purified by flash column chromatography (petroleum ether / ethyl acetate = 100:0-0:100 gradient elution) to obtain 4.8g of yellow solid. MS (m / z): 529.4 [M+H] +

[0348] (C) 2-((5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0349] In the reaction bottle, tert-butyl 2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (4.8 g, 9.1 mmol), concentrated hydrochloric acid (10 ml) and methanol (100 ml) were added in sequence, and the reaction was stirred at room temperature for 1 hour. After concentration to remove the solvent, the residue was dissolved in dichloromethane, and the solution was washed with saturated sodium carbonate and saturated sodium chloride in sequence, dried with sodium sulfate, and concentrated to obtain 3.74 g of white solid. MS (m / z): 429.2 [M+H] +

[0350] The following intermediates were prepared by referring to the preparation process of intermediate 7-1, using corresponding raw materials and reagents under appropriate conditions recognized by those skilled in the art.

[0351]

[0352]

[0353]

[0354]

[0355]

[0356] Intermediate 8: N-ethyl-5-fluoro-N-isopropyl-2-((3-(methylamino)-5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide

[0357]

[0358] (A) tert-Butyl 2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-3-(methylamino)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

[0359] In a sealed tube, add tert-butyl 2-(3-chloro-6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (150 mg, 0.266 mmol) and 30% methylamine ethanol solution (2 ml), heat to 90°C in a sealed state and stir to react for 1 hour. After the reaction is completed, concentrate, and the residue is purified by flash column chromatography (petroleum ether / ethyl acetate = 100:0-0:100 gradient elution) to obtain 80 mg of a yellow solid. MS (m / z): 558.3 ​​[M+H] +

[0360] (B) N-ethyl-5-fluoro-N-isopropyl-2-((3-(methylamino)-5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide

[0361] In the reaction flask, add 2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-3-(methylamino)-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (80 mg, 0.143 mmol) and 6 mol / L hydrochloric acid methanol solution (5 ml), and then stir at room temperature for 2 hours. After the reaction is completed, concentrate, dissolve the residue in dichloromethane, wash with saturated sodium bicarbonate solution and brine, dry the organic phase with anhydrous sodium sulfate, and concentrate to obtain 60 mg of white solid. MS (m / z): 458.3 [M+H] +

[0362] Intermediate 9: N-ethyl-5-fluoro-N-isopropyl-2-((3-methyl-5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide

[0363]

[0364] (A) tert-Butyl 2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-3-methyl-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

[0365] In the reaction bottle, 2-(3-chloro-6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (200 mg, 0.355 mmol), trimethylcyclotriboroxane (178 mg, 1.421 mmol), tetrakis(triphenylphosphine)palladium (41 mg, 0.0355 mmol), potassium carbonate (98 mg, 0.71 mmol) and dioxane (20 ml) were added, and the mixture was heated to 110° C. and stirred for 15 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated and the residue was purified by flash column chromatography (water / methanol=100:0-0:100 gradient elution) to obtain 150 mg of a white solid. MS (m / z): 543.6 [M+H] +

[0366] (B) N-ethyl-5-fluoro-N-isopropyl-2-((3-methyl-5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide

[0367] In the reaction flask, add tert-butyl 2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-3-methyl-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (150 mg, 0.276 mmol) and 6.0 mol / L methanol solution of hydrochloric acid (5 ml), and then stir at room temperature for 2 hours. After the reaction is completed, concentrate, dissolve the residue in dichloromethane, wash with saturated sodium bicarbonate solution and brine, dry the organic phase with anhydrous sodium sulfate, and concentrate to obtain 120 mg of white solid. MS (m / z): 443.3 [M+H] +

[0368] Intermediate 10-1: N-ethyl-5-fluoro-N-isopropyl-2-((5-(7-(piperidin-4-ylmethyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazine-6-yl)oxy)benzamide

[0369]

[0370] (A) tert-Butyl 4-((2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carboxylate

[0371] In the reaction flask, 2-((5-(2,7-diazaspiro[3.5]nonane-2-yl)-1,2,4-triazine-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (400 mg, 0.93 mmol), tert-butyl 4-formylpiperidine-1-carboxylate (298 mg, 1.4 mmol), methanol (10 ml) and acetic acid (1 ml) were added in sequence, and then sodium cyanoborohydride (120 mg, 1.91 mmol) was added. The reaction was carried out at room temperature for 5 hours, and after concentrating to remove the solvent, it was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 450 mg of solid. MS (m / z): 626.4 [M+H] +

[0372] (B) N-ethyl-5-fluoro-N-isopropyl-2-((5-(7-(piperidin-4-ylmethyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide

[0373] In a reaction flask, tert-butyl 4-((2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)piperidine-1-carboxylate (450 mg, 0.72 mmol) was dissolved in dichloromethane (10 ml), trifluoroacetic acid (4 ml) was added, and the mixture was reacted at room temperature for 5 hours. After concentration to remove the solvent, the residue was dissolved in dichloromethane, the solution was neutralized with saturated sodium carbonate, washed with saturated sodium chloride, dried with sodium sulfate, concentrated, and purified using flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 350 mg of solid. MS (m / z): 526.3 [M+H] +

[0374] The following intermediates were prepared by referring to the preparation process of intermediate 10-1, using corresponding raw materials and reagents under appropriate conditions recognized by those skilled in the art.

[0375]

[0376]

[0377] Intermediate 11: 1-(Pyridin-2-yl)piperidine-4-carboxylic acid

[0378]

[0379] (A) 1-(6-bromopyridin-2-yl)piperidine-4-carboxylic acid ethyl ester

[0380] In the reaction flask, piperidine-4-carboxylic acid ethyl ester (314 mg, 2.0 mmol), 2,6-dibromopyridine (474 ​​mg, 2.0 mmol), cesium carbonate (975 mg, 3.0 mmol) and dimethyl sulfoxide (5 ml) were added in sequence, and heated to 100°C for 15 hours. The reaction solution was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 495 mg of white solid. MS (m / z): 313.2 [M+H] +

[0381] (B) 1-(pyridin-2-yl)piperidine-4-carboxylic acid ethyl ester

[0382] In the reaction flask, add 1-(6-bromopyridin-2-yl)piperidine-4-carboxylic acid ethyl ester (495 mg, 1.58 mmol), palladium carbon (50 mg) and methanol (10 ml) in sequence, and react under hydrogen for 2 hours. After the reaction is completed, filter and concentrate the filtrate to obtain 400 mg of light yellow solid, which is directly used in the next reaction. MS (m / z): 235.2 [M+H] +

[0383] (C) 1-(Pyridin-2-yl)piperidine-4-carboxylic acid

[0384] In a reaction flask, add 1-(pyridin-2-yl)piperidin-4-carboxylic acid ethyl ester (401 mg, 1.71 mmol), lithium hydroxide monohydrate (199 mg, 4.74 mmol), methanol (8 ml) and water (2 ml), and react at room temperature for 2 hours. Use 1 mol / L dilute hydrochloric acid to adjust the pH of the reaction solution to 5-6, extract with ethyl acetate three times, dry over anhydrous sodium sulfate, filter and concentrate to obtain 183 mg of white solid, which is directly used in the next step. MS (m / z): 207.2 [M+H] +

[0385] Intermediate 12-1: 1-(pyridin-2-yl)piperidine-4-carboxaldehyde

[0386]

[0387] (A) Piperidine-4-carboxaldehyde trifluoroacetate

[0388] In a reaction flask, tert-butyl 4-formylpiperidin-1-carboxylate (2.13 g, 10.0 mmol) and trifluoroacetic acid (5 ml) were dissolved in dichloromethane (15 ml). The reaction solution was stirred at room temperature for 15 hours. After the reaction was completed, the reaction solution was concentrated to dryness to obtain 2.27 g of crude product, which was used directly in the next step without further purification. MS (m / z): 146.4 [M+H] +

[0389] (B) 1-(Pyridin-2-yl)piperidine-4-carboxaldehyde

[0390] In a reaction flask, piperidine-4-carboxaldehyde trifluoroacetate (454mg, 2.0mmol), 2-fluoropyridine (388mg, 4.0mmol) and potassium carbonate (553mg, 4.0mmol) were dissolved in N,N-dimethylformamide (5ml), and the reaction solution was heated to reflux for 4 hours. After the reaction was completed, it was diluted with water, extracted with ethyl acetate and concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 90mg of the product. MS (m / z): 223.4 [M+OCH3] +

[0391] The following intermediates were prepared by referring to the preparation process of intermediate 12-1, using corresponding raw materials and reagents under appropriate conditions recognized by those skilled in the art.

[0392]

[0393] Intermediate 13-1: 5-Formyl-4-methyl-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-indole-2-yl

[0394]

[0395] In the reaction bottle, 5-formyl-4-methyl-1H-indole-2-carbonitrile (0.50g, 2.71mmol), 2-(2-bromoethoxy)tetrahydro-2H-pyran (0.68g, 3.25mmol), cesium carbonate (1.32g, 4.05mmol) and N,N-dimethylformamide (10ml) were added in sequence, heated to 50°C, and reacted for 5 hours. After the reaction, water (30ml) was added to quench the reaction, extracted with ethyl acetate three times, and dried over anhydrous sodium sulfate. Concentration gave a crude product, which was purified by flash column chromatography (petroleum ether / ethyl acetate = 100:0-0:100 gradient elution) to give 0.62g of a yellow solid. MS (m / z): 313.2 [M+H] +

[0396] The following intermediates were prepared by referring to the preparation process of intermediate 13-1, using corresponding raw materials and reagents under appropriate conditions recognized by those skilled in the art.

[0397]

[0398] Intermediates 14 and 15:

[0399] 5-Formyl-4-methyl-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-indole-2-carboxylic acid,

[0400] 5-Formyl-4-methyl-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-indole-2-carboxamide

[0401]

[0402] In a reaction flask, 5-formyl-4-methyl-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-indole-2-carbonitrile (Intermediate 13-1, 200 mg, 0.64 mmol), potassium hydroxide (143 mg, 2.55 mmol), methanol (8 ml) and water (6 ml) were added in sequence, heated to 100°C, and reacted for 16 hours. After the reaction was completed, the reaction solution was concentrated and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution).

[0403] Peak 1 is compound A, intermediate 14, carboxylic acid compound 50 mg, MS (m / z): 332.1 [M+H] + .

[0404] Peak 2 is compound B, intermediate 15, amide compound 150 mg, MS (m / z): 331.1 [M+H] + Intermediate 16: tert-Butyl 2-cyano-3-(3,6-dihydro-2H-pyran-4-yl)-5-formyl-4-methyl-1H-indole-1-carboxylate

[0405]

[0406] (A) 5-Formyl-3-iodo-4-methyl-1H-indole-2-carbonitrile

[0407] In the reaction bottle, add 5-formyl-4-methyl-1H-indole-2-carbonitrile (500mg, 2.71mmol) and N,N-dimethylformamide (10ml), then add N-iodosuccinimide (732mg, 3.26mmol), and stir at room temperature for 4 hours. After the reaction is completed, pour the reaction solution into water, filter, and dry the filter cake to obtain 720mg of yellow solid. MS (m / z): 311.0 [M+H] +

[0408] (B) tert-Butyl 2-cyano-5-formyl-3-iodo-4-methyl-1H-indole-1-carboxylate

[0409] In a reaction flask, add 5-formyl-3-iodo-4-methyl-1H-indole-2-carbonitrile (720 mg, 2.32 mmol), di-tert-butyl dicarbonate (1.01 g, 4.63 mmol), 4-dimethylaminopyridine (28 mg, 0.23 mmol) and tetrahydrofuran (50 ml), stir at room temperature for 15 hours, concentrate the reaction solution, and purify the residue by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 700 mg of a white solid. MS (m / z): 433.0 [M+Na] +

[0410] (C) tert-Butyl 2-cyano-3-(3,6-dihydro-2H-pyran-4-yl)-5-formyl-4-methyl-1H-indole-1-carboxylate

[0411] In the reaction flask, 2-cyano-5-formyl-3-iodo-4-methyl-1H-indole-1-carboxylic acid tert-butyl ester (350mg, 0.85mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (358mg, 1.70mmol), Pd(dppf)Cl2·CH2Cl2 (70mg, 0.086mmol), potassium carbonate (295mg, 2.13mmol), dioxane (20ml) and water (5ml) were added in sequence, and heated to 100°C under nitrogen protection for 3 hours. After the reaction, the reaction solution was concentrated and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 200mg of white solid. MS (m / z): 367.6 [M+H] +

[0412] Intermediate 17: 3-(2-cyano-5-formyl-4-methyl-1H-indol-1-yl)-2-hydroxypropionic acid ethyl ester

[0413]

[0414] In the reaction flask, 5-formyl-4-methyl-1H-indole-2-carbonitrile (500mg, 2.71mmol), ethylene oxide-2-carboxylic acid ethyl ester (630mg, 5.43mmol), cesium carbonate (1.7g, 5.22mmol) and N,N-dimethylformamide (10ml) were added in sequence, heated to 80°C, and reacted for 16 hours. After the reaction, the reaction solution was concentrated and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 100mg of solid. MS (m / z): 301.1 [M+H] +

[0415] Intermediate 18-1: 5-(4-formylpiperidin-1-yl)-2-cyanopyridine

[0416]

[0417] In the reaction flask, piperidine-4-carboxaldehyde (250mg, 1.1mmol), 5-bromo-2-cyanopyridine (200mg, 1.1mmol), Pd2(dba)3 (100mg, 0.11mmol), Xantphos (145mg, 0.25mmol), cesium carbonate (1g, 3.1mmol) and dioxane (10ml) were added in sequence, and heated to 100°C under nitrogen protection for 16 hours. After the reaction, the reaction solution was concentrated and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 50mg of oily liquid. MS (m / z): 216.2 [M+H] +

[0418] The following intermediates were prepared by referring to the preparation process of intermediate 18-1, using corresponding raw materials and reagents under appropriate conditions recognized by those skilled in the art.

[0419]

[0420] Intermediate 19-1: 1-(2-methoxypyridin-4-yl)piperidine-4-carboxaldehyde

[0421]

[0422] (A) (1-(2-methoxypyridin-4-yl)piperidin-4-yl)methanol

[0423] In the reaction flask, piperidin-4-ylmethanol (615mg, 5.3mmol), 4-bromo-2-methoxypyridine (1000mg, 5.3mmol), potassium carbonate (2.2g, 15.9mmol) and N,N-dimethylformamide (10ml) were added in sequence, heated to 110°C, and reacted for 16 hours. After the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 500mg of oily liquid. MS (m / z): 223.2 [M+H] +

[0424] (B) 1-(2-methoxypyridin-4-yl)piperidine-4-carbaldehyde

[0425] In the reaction flask, (1-(2-methoxypyridin-4-yl)piperidin-4-yl)methanol (100 mg, 0.45 mmol) and dichloromethane (5 ml) were added in sequence, and Dess-Martin periodinane (382 mg, 0.9 mmol) was added, and the reaction was carried out at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 50 mg of an oily liquid. MS (m / z): 221.1 [M+H] +

[0426] The following intermediates were prepared by referring to the preparation process of intermediate 19-1, using corresponding raw materials and reagents under appropriate conditions recognized by those skilled in the art.

[0427]

[0428] Intermediate 20: 2-((4-Formyl-3-methylphenyl)amino)acetonitrile

[0429]

[0430] (A) (4-amino-2-methylphenyl)methanol

[0431] In a reaction flask, add (2-methyl-4-nitrophenyl)methanol (500 mg, 3.0 mmol), palladium carbon (100 mg) and ethanol (20 ml), and stir at room temperature under hydrogen for 15 hours. After the reaction is completed, filter and concentrate the filtrate to obtain 413 mg of yellow solid. MS (m / z): 138.2 [M+H] +

[0432] (B) 2-((4-(Hydroxymethyl)-3-methylphenyl)amino)acetonitrile

[0433] In a sealed tube, (4-amino-2-methylphenyl)methanol (413 mg, 3.0 mmol), 2-chloroacetonitrile (227 mg, 3.0 mmol), potassium carbonate (1.24 g, 9.0 mmol), sodium iodide (450 mg, 3.0 mmol) and acetonitrile (50 ml) were added, and then heated to reflux and stirred for 15 hours. After the reaction was completed, the residue was concentrated and purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 200 mg of a yellow solid. MS (m / z): 177.2 [M+H] +

[0434] (C) 2-((4-Formyl-3-methylphenyl)amino)acetonitrile

[0435] In a reaction flask, add 2-((4-(hydroxymethyl)-3-methylphenyl)amino)acetonitrile (150 mg, 0.851 mmol), manganese dioxide (592 mg, 6.81 mmol) and dichloromethane (20 ml), stir at room temperature for 15 hours, filter after the reaction, concentrate the filtrate and purify it by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 12 mg of yellow solid. MS (m / z): 175.2 [M+18] +

[0436] Intermediate 21: 1-(6-methoxypyridazin-4-yl)piperidine-4-carboxaldehyde

[0437]

[0438] (A)(1-(6-chloropyridazin-4-yl)piperidin-4-yl)methanol

[0439] In the reaction flask, piperidin-4-ylmethanol (576mg, 5mmol), 5-bromo-3-chloropyridazine (967mg, 5mmol), triethylamine (3ml) and dioxane (20ml) were added in sequence, heated to 100°C, and reacted for 16 hours. After the reaction, the reaction solution was concentrated and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 620mg of oily liquid. MS (m / z): 228.1 [M+H] +

[0440] (B) (1-(6-methoxypyridazin-4-yl)piperidin-4-yl)methanol

[0441] In the reaction flask, (1-(6-chloropyridazine-4-yl)piperidin-4-yl)methanol (620mg, 2.72mmol), sodium methoxide (734mg, 13.6mmol) and dioxane (20ml) were added in sequence, heated to 100°C, and reacted for 16 hours. After the reaction, the reaction solution was concentrated and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 450mg of oily liquid. MS (m / z): 224.2 [M+H] +

[0442] (C) 1-(6-methoxypyridazin-4-yl)piperidine-4-carbaldehyde

[0443] In a reaction flask, (1-(6-methoxypyridazine-4-yl)piperidin-4-yl)methanol (420 mg, 1.88 mmol) and dichloromethane (25 ml) were added in sequence, and Dess-Martin periodinane (1595 mg, 3.76 mmol) was added, and the reaction was carried out at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 170 mg of an oily liquid. MS (m / z): 222.2 [M+H] +

[0444] Intermediate 22: tert-butyl (6-(4-formylpiperidin-1-yl)pyridazin-3-yl)carbamate

[0445]

[0446] (A) (1-(6-aminopyridazin-3-yl)piperidin-4-yl)methanol

[0447] In the reaction bottle, 6-chloropyridazine-3-amine (1.0 g, 7.72 mmol), piperidin-4-ylmethanol (0.98 g, 8.50 mmol), triethylamine (1.54 g, 15.2 mmol) and tert-butanol (30 ml) were added in sequence, and microwave heating was performed at 200°C for 2 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 0.51 g of a light yellow solid. MS (m / z): 209.4 [M+H] +

[0448] (B) tert-Butyl (6-(4-(hydroxymethyl)piperidin-1-yl)pyridazin-3-yl)carbamate

[0449] In the reaction flask, (1-(6-aminopyridazine-3-yl)piperidin-4-yl)methanol (0.51 g, 2.45 mmol), di-tert-butyl dicarbonate (0.52 g, 2.38 mmol), 4-dimethylaminopyridine (30 mg, 0.245 mmol) and 1,4-dioxane (20 ml) were added in sequence, and heated to 80°C for 2 hours. After the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 0.18 g of a light yellow solid. MS (m / z): 309.2 [M+H] +

[0450] (C) tert-Butyl (6-(4-formylpiperidin-1-yl)pyridazin-3-yl)carbamate

[0451] In a reaction flask, add tert-butyl (6-(4-(hydroxymethyl)piperidin-1-yl)pyridazin-3-yl)carbamate (180 mg, 0.58 mmol), dichloromethane (10 ml) and Dess-Martin periodinane (492 mg, 1.16 mmol). Stir at room temperature for 2 hours. After the reaction is completed, wash with saturated sodium bicarbonate solution and sodium bisulfite solution. The organic phase is concentrated and the residue is purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 230 mg of the product. MS (m / z): 307.2 [M+H] +

[0452] Intermediate 23: 4-(4-Formylpiperidin-1-yl)nicotinate methyl ester

[0453]

[0454] (A) 6-chloro-4-(4-(hydroxymethyl)piperidin-1-yl)nicotinate

[0455] In the reaction flask, 4-bromo-6-chloronicotinic acid methyl ester (1.25g, 5.0mmol), piperidin-4-ylmethanol (0.57g, 5.0mmol), cesium carbonate (3.25g, 10.0mmol) and dimethyl sulfoxide (20ml) were added in sequence, and heated to 60°C for 5 hours. The reaction solution was quenched with water (20ml), extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 0.46g of a light yellow solid. MS (m / z): 285.2 [M+H] +

[0456] (B) 4-(4-(Hydroxymethyl)piperidin-1-yl)nicotinate

[0457] In the reaction bottle, add 6-chloro-4-(4-(hydroxymethyl)piperidin-1-yl)nicotinate (0.46g, 1.62mmol), palladium carbon (46mg) and methanol (20ml) in sequence, and react under hydrogen for 2 hours. After the reaction is completed, filter and concentrate the filtrate to obtain 0.39g of white solid, which is directly used in the next reaction. MS (m / z): 251.2 [M+H] +

[0458] (C) 4-(4-Formylpiperidin-1-yl)nicotinate methyl ester

[0459] In a reaction flask, add 4-(4-(hydroxymethyl)piperidin-1-yl)nicotinate methyl ester (390 mg, 1.56 mmol) and dichloromethane (20 ml), and add Dess-Martin periodinane (992 mg, 2.34 mmol) in batches under an ice bath. Stir at room temperature for 4 hours, wash with saturated sodium bicarbonate solution and sodium bisulfite solution after the reaction, concentrate the organic phase, and purify the residue by flash column chromatography (water / acetonitrile = 100:0-0:100 gradient elution) to obtain 160 mg of the product. MS (m / z): 249.2 [M+H] +

[0460] Intermediate 24-1: 1-(6-methoxypyridazin-3-yl)piperidine-4-carboxaldehyde

[0461]

[0462] (A) 3-Chloro-6-methoxypyridazine

[0463] In the reaction flask, add 3,6-dichloropyridazine (1.5 g, 10 mmol), sodium methoxide (2.72 g, 50 mmol) and methanol (30 ml) in sequence and stir at room temperature for 15 hours. After the reaction is completed, the reaction solution is concentrated, the residue is dissolved in dichloromethane, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain 1.0 g of a white solid. MS (m / z): 145.2, 147.2 [M+H] +

[0464] (B) (1-(6-methoxypyridazin-3-yl)piperidin-4-yl)methanol

[0465] In the reaction flask, 3-chloro-6-methoxypyridazine (1.0 g, 6.92 mmol), piperidin-4-ylmethanol (797 mg, 6.92 mmol), Pd2(dba)3 (317 mg, 0.35 mmol), BINAP (430 mg, 0.65 mmol), sodium tert-butoxide (1.33 g, 13.84 mmol) and toluene (18 ml) were added in sequence, and heated to 100°C under nitrogen protection for 15 hours. After the reaction, the reaction solution was concentrated and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 300 mg of yellow oil. MS (m / z): 224.2 [M+H] +

[0466] (C) 1-(6-methoxypyridazin-3-yl)piperidine-4-carbaldehyde

[0467] In a reaction flask, add (1-(6-methoxypyridazine-3-yl)piperidin-4-yl)methanol (300 mg, 1.34 mmol), dichloromethane (20 ml) and Dess-Martin periodinane (855 mg, 2.02 mmol). Stir at room temperature for 3 hours. After the reaction is completed, wash with saturated sodium bicarbonate solution and sodium bisulfite solution. The organic phase is concentrated and the residue is purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 120 mg of the product. MS (m / z): 222.2 [M+H] +

[0468] The following intermediates were prepared by referring to the preparation process of intermediate 24-1, using corresponding raw materials and reagents under appropriate conditions recognized by those skilled in the art.

[0469]

[0470]

[0471] *MS data show the molecular weight of acetal

[0472] Intermediate 25: 6-(4-Formylpiperidin-1-yl)pyridine-2-carboxamide

[0473]

[0474] (A) Methyl 6-(4-(Hydroxymethyl)piperidin-1-yl)pyridine-2-carboxylate

[0475] In the reaction flask, add methyl 6-chloropyridine-2-carboxylate (1.71g, 10mmol), piperidin-4-ylmethanol (1.15g, 10mmol), palladium acetate (224mg, 1.0mmol), Xphos (478mg, 1.0mmol), cesium carbonate (6.50g, 20.0mmol) and 1,4-dioxane (30ml) in sequence, heat to 80°C under nitrogen protection, and react for 15 hours. After the reaction is completed, filter, concentrate the filtrate, and purify the residue by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 1.17g of yellow oil. MS (m / z): 251.2 [M+H] +

[0476] (B) 6-(4-(Hydroxymethyl)piperidin-1-yl)pyridine-2-carboxamide

[0477] In a sealed tube, methyl 6-(4-(hydroxymethyl)piperidin-1-yl)pyridine-2-carboxylate (1.17 g, 4.67 mmol) and ammonia methanol solution (20 ml, 7 mol / L) were added in sequence, and heated to 80°C for 2 hours. After the reaction, the reaction solution was concentrated to obtain 0.80 g of a light yellow solid, which was directly used in the next reaction. MS (m / z): 236.2 [M+H] +

[0478] (C) 6-(4-Formylpiperidin-1-yl)pyridine-2-carboxamide

[0479] In a reaction flask, add 6-(4-(hydroxymethyl)piperidin-1-yl)pyridine-2-carboxamide (235 mg, 1.0 mmol) and dichloromethane (10 ml), and add Dess-Martin periodinane (848 mg, 2.0 mmol) in batches under an ice bath. Stir at room temperature for 15 hours, wash with saturated sodium bicarbonate solution and sodium bisulfite solution after the reaction, concentrate the organic phase, and purify the residue by flash column chromatography (petroleum ether / ethyl acetate = 100:0-0:100 gradient elution) to obtain 57 mg of the product. MS (m / z): 234.1 [M+H] +

[0480] Intermediate 26: 1-(4-methoxypyridin-2-yl)piperidine-4-carboxaldehyde

[0481]

[0482] (A) 1-(4-methoxypyridin-2-yl)piperidine-4-carboxylic acid ethyl ester

[0483] In the reaction flask, 2-bromo-4-methoxypyridine (500mg, 2.67mmol), ethyl piperidine-4-carboxylate (628mg, 4mmol), Pd2(dba)3 (244mg, 0.267mmol), Xantphos (308mg, 0.534mmol), cesium carbonate (1.7g, 5.22mmol) and dioxane (20ml) were added in sequence, and heated to 100°C under nitrogen protection for 16 hours. After the reaction, the reaction solution was concentrated and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 100mg of oily liquid. MS (m / z): 265.2 [M+H] +

[0484] (B) (1-(4-methoxypyridin-2-yl)piperidin-4-yl)methanol

[0485] In the reaction flask, add 1-(4-methoxypyridin-2-yl)piperidine-4-carboxylic acid ethyl ester (100 mg, 0.38 mmol) and tetrahydrofuran (5 ml) in sequence, cool to 0°C, add lithium aluminum hydride (29 mg, 0.76 mmol), and react at room temperature for 5 hours. After the reaction is completed, the reaction solution is concentrated, and the residue is purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 60 mg of oily liquid. MS (m / z): 223.2 [M+H] +

[0486] (C) 1-(4-methoxypyridin-2-yl)piperidine-4-carbaldehyde

[0487] In the reaction flask, (1-(4-methoxypyridin-2-yl)piperidin-4-yl)methanol (60 mg, 0.27 mmol) and dichloromethane (5 ml) were added in sequence, and Dess-Martin periodinane (230 mg, 0.54 mmol) was added, and the reaction was carried out at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 40 mg of oily liquid. MS (m / z): 221.2 [M+H] +

[0488] Intermediate 27-1: 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)piperidine-4-carboxaldehyde

[0489]

[0490] (A) Ethyl 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)piperidine-4-carboxylate

[0491] In the reaction flask, 2-bromo-6-(((tert-butyldimethylsilyl)oxy)methyl)pyridine (500mg, 1.66mmol), ethyl piperidine-4-carboxylate (521mg, 3.32mmol) and toluene (5ml) were added in sequence, heated to 120°C, and reacted for 16 hours. After the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 150mg of oily liquid. MS (m / z): 379.2 [M+H] +

[0492] (B) (1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)piperidin-4-yl)methanol

[0493] In the reaction flask, 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)piperidine-4-carboxylic acid ethyl ester (150 mg, 0.40 mmol) and tetrahydrofuran (5 ml) were added in sequence, cooled to 0°C, lithium aluminum hydride (30 mg, 0.79 mmol) was added, and the reaction was carried out at room temperature for 5 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 100 mg of an oily liquid. MS (m / z): 337.2 [M+H] +

[0494] (C) 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)piperidine-4-carbaldehyde

[0495] In the reaction flask, (1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)piperidin-4-yl)methanol (100 mg, 0.3 mmol) and dichloromethane (5 ml) were added in sequence, and Dess-Martin periodinane (252 mg, 0.59 mmol) was added, and the reaction was carried out at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 50 mg of an oily liquid. MS (m / z): 335.3 [M+H] +

[0496] The following intermediates were prepared by referring to the preparation process of intermediate 27-1, using corresponding raw materials and reagents under appropriate conditions recognized by those skilled in the art.

[0497]

[0498] Intermediate 28: 4-(Pyridin-2-yl)benzaldehyde

[0499]

[0500] (A) Methyl 4-(pyridin-2-yl)benzoate

[0501] In the reaction flask, (4-(methoxycarbonyl)phenyl)boric acid (800mg, 4.4mmol), 2-bromopyridine (500mg, 3.2mmol), tetrakis(triphenylphosphine)palladium (367mg, 0.32mmol), potassium carbonate (1g, 7.2mmol), dioxane (8ml) and water (2ml) were added in sequence, and heated to 100°C under nitrogen protection for 5 hours. After the reaction, the reaction solution was concentrated and the residue was purified by flash column chromatography (PE / EA=100:0-0:100 gradient elution) to obtain 500mg of oily liquid. MS (m / z): 214.1[M+H] +

[0502] (B) (4-(Pyridin-2-yl)phenyl)methanol

[0503] In the reaction flask, methyl 4-(pyridin-2-yl)benzoate (200 mg, 0.94 mmol) and tetrahydrofuran (10 ml) were added in sequence, cooled to 0°C, lithium aluminum hydride (71 mg, 1.88 mmol) was added, and the reaction was carried out at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 150 mg of an oily liquid. MS (m / z): 186.1 [M+H] +

[0504] (C) 4-(Pyridin-2-yl)benzaldehyde

[0505] In a reaction flask, (4-(pyridin-2-yl)phenyl)methanol (150 mg, 0.81 mmol) and dichloromethane (5 ml) were added in sequence, and Dess-Martin periodinane (688 mg, 1.62 mmol) was added, and the reaction was carried out at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 100 mg of an oily liquid. MS (m / z): 184.1 [M+H] +

[0506] Intermediate 29: 4-(Pyridin-2-yl)cyclohex-3-ene-1-carbaldehyde

[0507]

[0508] (A) Methyl 4-(pyridin-2-yl)cyclohex-3-ene-1-carboxylate

[0509] In a reaction flask, (4-(methoxycarbonyl)cyclohex-1-en-1-yl)boric acid (873 mg, 4.75 mmol), 2-bromopyridine (500 mg, 3.16 mmol), Pd(dppf)Cl2·CH2Cl2 (130 mg, 0.18 mmol), potassium carbonate (1.1 g, 8.0 mmol), dioxane (30 ml) and water (6 ml) were added in sequence, and heated to 100°C under nitrogen protection for 5 hours. After the reaction, the reaction solution was concentrated and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 500 mg of a yellow solid. MS (m / z): 218.2 [M+H] +

[0510] (B) (4-(pyridin-2-yl)cyclohex-3-en-1-yl)methanol

[0511] In a reaction flask, add 4-(pyridin-2-yl)cyclohex-3-ene-1-carboxylic acid methyl ester (500 mg, 2.30 mmol) and dry tetrahydrofuran (15 ml), cool to 0°C, add diisobutylaluminum hydride (2.76 ml, 2.76 mmol) dropwise under nitrogen protection, then return to room temperature and stir for 15 hours, quench with saturated ammonium chloride solution, concentrate the reaction solution, and purify the residue by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 400 mg of yellow oil. MS (m / z): 190.2 [M+H] +

[0512] (C) 4-(Pyridin-2-yl)cyclohex-3-ene-1-carbaldehyde

[0513] In a reaction flask, (4-(pyridin-2-yl)cyclohex-3-ene-1-yl)methanol (400 mg, 2.11 mmol), dichloromethane (20 ml) and Dess-Martin periodinane (1.8 g, 4.24 mmol) were added. Stir at room temperature for 3 hours. After the reaction was completed, the product was washed with saturated sodium bicarbonate solution and sodium bisulfite solution. The organic phase was concentrated and the residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 100:0-0:100 gradient elution) to obtain 380 mg of a white solid. MS (m / z): 188.7 [M+H] +

[0514] Intermediate 30: 2-Methoxyquinazoline-6-carboxaldehyde

[0515]

[0516] (A) (2-amino-5-bromophenyl)methanol

[0517] In the reaction flask, add lithium aluminum hydride (2.77g, 73.01mmol) and dry tetrahydrofuran (40ml), then dropwise add methyl 2-amino-5-bromobenzoate (5.6g, 24.34mmol) dissolved in tetrahydrofuran (40ml), and stir at room temperature for 15 hours. After the reaction is completed, quench with saturated magnesium sulfate solution (5ml), then add solid magnesium sulfate (5g), filter and concentrate the filtrate, and purify the residue by flash column chromatography (dichloromethane / methanol = 100:0-0:100 gradient elution) to obtain 3.2g of white solid. MS (m / z): 202.0, 204.0 [M+H] +

[0518] (B) 2-Amino-5-bromobenzaldehyde

[0519] In a reaction flask, add (2-amino-5-bromophenyl)methanol (3.2 g, 15.84 mmol), manganese dioxide (9.65 g, 111.0 mmol) and dichloromethane (60 ml), stir at room temperature for 15 hours, filter and concentrate the filtrate, and purify the residue by flash column chromatography (petroleum ether / ethyl acetate = 100:0-0:100 gradient elution) to obtain 2.5 g of yellow solid. MS (m / z): 200.0, 202.0 [M+H] +

[0520] (C) 6-Bromoquinazoline-2-ol

[0521] In the reaction flask, add 2-amino-5-bromobenzaldehyde (800 mg, 4.0 mmol) and urea (1.92 g, 32.0 mmol), heat to 170°C and stir for 1 hour. Cool to room temperature, add water (30 ml), continue stirring for 20 minutes, filter, and dry the filter cake to obtain 850 mg of white solid. MS (m / z): 225.0, 227.0 [M+H] +

[0522] (D) 6-Bromo-2-chloroquinazoline

[0523] In the reaction flask, add 6-bromoquinazoline-2-ol (850 mg, 3.78 mmol) and phosphorus oxychloride (10 ml), heat and reflux overnight. Cool to room temperature, concentrate the reaction solution, stir the residue in saturated sodium bicarbonate solution for 30 minutes, filter, and dry the filter cake to obtain 450 mg of yellow solid. MS (m / z): 243.0, 245.0 [M+H] +

[0524] (E)6-Bromo-2-methoxyquinazoline

[0525] In the reaction flask, add 6-bromo-2-chloroquinazoline (450 mg, 1.85 mmol), sodium methoxide (300 mg, 5.54 mmol) and methanol (50 ml), heat under reflux and stir for 15 hours, concentrate the reaction solution, and purify the residue by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 400 mg of white solid. MS (m / z): 239.0, 241.0 [M+H] +

[0526] (F)2-Methoxyquinazoline-6-carbonitrile

[0527] In a reaction flask, add 6-bromo-2-methoxyquinazoline (400 mg, 1.67 mmol), zinc cyanide (235 mg, 2.00 mmol), tetrakis(triphenylphosphine)palladium (193 mg, 0.167 mmol) and N,N-dimethylformamide (8.0 ml), heat to 100°C and stir for 4 hours under nitrogen protection, cool to room temperature, and purify by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 200 mg of a yellow solid. MS (m / z): 186.1 [M+H] +

[0528] (G) 2-Methoxyquinazoline-6-carbaldehyde

[0529] In a reaction flask, add 2-methoxyquinazoline-6-carbonitrile (180 mg, 0.97 mmol), acetic acid (5.0 ml) and pyridine (5.0 ml), then add Raney nickel (90 mg) and sodium dihydrogen phosphate monohydrate (401 mg, 2.91 mmol) in sequence, heat to 75 ° C and stir for 15 hours, cool to room temperature, concentrate, and purify the residue by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 70 mg of yellow solid. MS (m / z): 189.2 [M+H] +

[0530] Intermediate 31:2-Methylquinazoline-6-carboxaldehyde

[0531]

[0532] (A) N-(4-bromo-2-formylphenyl)acetamide

[0533] In the reaction flask, add 2-amino-5-bromobenzaldehyde (500mg, 2.5mmol), pyridine (395mg, 5.0mmol) and dichloromethane (20ml), then add acetyl chloride (235mg, 3.0mmol) dropwise, and stir at room temperature for 15 hours. After the reaction is completed, concentrate, and the residue is purified by flash column chromatography (petroleum ether / ethyl acetate = 100:0-0:100 gradient elution) to obtain 420mg of yellow solid. MS (m / z): 242.0, 244.0 [M+H] +

[0534] (B) 6-Bromo-2-methylquinazoline

[0535] In a sealed tube, add N-(4-bromo-2-formylphenyl)acetamide (420 mg, 1.74 mmol) and ammonia methanol solution (15 ml, 7 mol / L), then heat at 80°C in a sealed tube and stir to react for 15 hours. After the reaction is completed, concentrate and purify the residue by flash column chromatography (petroleum ether / ethyl acetate = 100:0-0:100 gradient elution) to obtain 250 mg of a yellow solid. MS (m / z): 223.0, 225.0 [M+H] +

[0536] (C) 2-Methylquinazoline-6-carbonitrile

[0537] In a reaction flask, add 6-bromo-2-methylquinazoline (200 mg, 0.897 mmol), zinc cyanide (105 mg, 0.897 mmol), tetrakis(triphenylphosphine)palladium (104 mg, 0.09 mmol) and N,N-dimethylformamide (5.0 ml), heat to 100°C and stir for 1 hour under nitrogen protection, cool to room temperature, and purify by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 100 mg of yellow solid. MS (m / z): 188.2 [M+18] +

[0538] (D) 2-Methylquinazoline-6-carboxaldehyde

[0539] In a reaction flask, add 2-methylquinazoline-6-carbonitrile (100 mg, 0.59 mmol), acetic acid (1.5 ml) and pyridine (1.5 ml), then add Raney nickel (50 mg) and sodium dihydrogen phosphate monohydrate (245 mg, 1.78 mmol) in sequence, heat to 75 ° C and stir for 15 hours, cool to room temperature, concentrate, and purify the residue by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 15 mg of yellow solid. MS (m / z): 191.2 [M+18] +

[0540] Intermediate 32: 1-(1-methyl-1H-pyrazol-3-yl)piperidine-4-carboxaldehyde

[0541] (A) 1-(1-methyl-1H-pyrazol-3-yl)piperidine-4-carboxylic acid ethyl ester

[0542] In the reaction bottle, add 4-bromo-2-(2-bromoethyl)butyric acid ethyl ester (1.86g, 6.16mmol), 1-methyl-1H-pyrazole-3-amine (600mg, 6.18mmol), diisopropylethylamine (2.4g, 18.57mmol) and N,N-dimethylacetamide (10ml), microwave heating at 120℃ for 2 hours, cool to room temperature, and purify by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 1.2g of white solid. MS (m / z): 238.4 [M+H] +

[0543] (B) (1-(1-methyl-1H-pyrazol-3-yl)piperidin-4-yl)methanol

[0544] In a reaction flask, add 1-(1-methyl-1H-pyrazol-3-yl)piperidine-4-carboxylic acid ethyl ester (1.2g, 5.06mmol) and dry tetrahydrofuran (15ml), cool to 0°C, add diisobutylaluminum hydride (6.07ml, 6.07mmol, 1.0 mol / L toluene solution) dropwise under nitrogen protection, then return to room temperature and stir for 15 hours, quench with saturated ammonium chloride solution, concentrate the reaction solution, and purify the residue by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 600mg of an oily substance. MS (m / z): 196.2 [M+H] +

[0545] (C) 1-(1-methyl-1H-pyrazol-3-yl)piperidine-4-carbaldehyde

[0546] In a reaction flask, add (1-(1-methyl-1H-pyrazol-3-yl)piperidin-4-yl)methanol (600 mg, 3.07 mmol), dichloromethane (20 ml) and Dess-Martin periodinane (1.95 g, 4.60 mmol). Stir at room temperature for 2 hours. After the reaction is completed, wash with saturated sodium bicarbonate solution and sodium bisulfite solution. The organic phase is concentrated and the residue is purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 120 mg of a yellow solid. MS (m / z): 194.2 [M+H] +

[0547] Intermediate 33: (S)-3-(6-methoxypyridin-3-yl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-carbaldehyde

[0548]

[0549] (A) (S)-3-(6-methoxypyridin-3-yl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-carbonitrile

[0550] In the reaction flask, (S)-7-bromo-3-(6-methoxypyridin-3-yl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (500mg, 1.55mmol), zinc cyanide (145mg, 1.24mmol), tetrakis(triphenylphosphine)palladium (179mg, 0.155mmol) and N,N-dimethylformamide (8ml) were added in sequence, and heated to 120°C under nitrogen protection for 16 hours. After the reaction, the reaction solution was concentrated and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 200mg of yellow solid. MS (m / z): 270.1 [M+H] +

[0551] (B) (S)-3-(6-methoxypyridin-3-yl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-carboxylic acid

[0552] In the reaction flask, add (S)-3-(6-methoxypyridin-3-yl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-carbonitrile (200mg, 0.74mmol), potassium hydroxide (166mg, 2.96mmol), methanol (5ml) and water (5ml) in sequence, heat to 100℃, and react for 16 hours. After the reaction, concentrate the reaction solution, and purify the residue by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 150mg of white solid. MS (m / z): 289.1 [M+H] +

[0553] (C) (S)-3-(6-methoxypyridin-3-yl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-carboxylic acid methyl ester

[0554] In a reaction flask, (S)-3-(6-methoxypyridin-3-yl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-carboxylic acid (150 mg, 0.52 mmol) was dissolved in dichloromethane (5 ml), oxalyl chloride (200 mg, 1.58 mmol) and 1 drop of N,N-dimethylformamide were added, and the mixture was reacted at room temperature for 2 hours. Methanol (10 ml) was added and the mixture was reacted at room temperature for 1 hour. After the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 100:0-0:100 gradient elution) to obtain 150 mg of an oily liquid. MS (m / z): 303.1 [M+H] +

[0555] (D) (S)-(3-(6-methoxypyridin-3-yl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)methanol

[0556] In the reaction flask, add (S)-3-(6-methoxypyridin-3-yl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-carboxylic acid methyl ester (150mg, 0.5mmol) and tetrahydrofuran (5ml) in sequence, cool to 0°C, add lithium aluminum hydride (75mg, 1.98mmol), and react at room temperature for 3 hours. After the reaction is completed, the reaction solution is concentrated, and the residue is purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 100mg of oily liquid. MS (m / z): 275.1 [M+H] +

[0557] (E)(S)-3-(6-methoxypyridin-3-yl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-carbaldehyde

[0558] In the reaction flask, (S)-(3-(6-methoxypyridin-3-yl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)methanol (100 mg, 0.36 mmol) and dichloromethane (5 ml) were added in sequence, and Dess-Martin periodinane (309 mg, 0.73 mmol) was added, and the reaction was carried out at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 60 mg of oily liquid. MS (m / z): 273.1 [M+H] +

[0559] Intermediate 34: 5-Chloro-6-methoxy-4-methylpyridine-3-carbaldehyde

[0560]

[0561] In the reaction flask, add 5-bromo-3-chloro-2-methoxy-4-methylpyridine (200 mg, 0.85 mmol) and dry tetrahydrofuran (8 ml), cool to -78 ° C, add n-butyl lithium (0.34 ml, 0.85 mmol) dropwise, add ethyl formate (63 mg, 0.85 mmol) after 15 minutes, and then stir at room temperature for 2 hours. After the reaction is completed, the reaction solution is concentrated, and the residue is purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 50 mg of oily liquid. MS (m / z): 186.1 [M+H] +

[0562] Intermediate 35: 4-Hydroxy-4-(pyridin-2-yl)cyclohexane-1-carbaldehyde

[0563]

[0564] (A) 4-Hydroxy-4-(pyridin-2-yl)cyclohexane-1-carboxylic acid ethyl ester

[0565] In the reaction flask, add 2-bromopyridine (0.87g, 5.5mmol) and anhydrous tetrahydrofuran (10ml) in sequence, cool to -78℃, add 1.6 mol / L n-butyl lithium solution (3.4ml, 5.44mmol) dropwise, add 4-oxocyclohexane-1-carboxylic acid ethyl ester (0.85g, 5mmol) dropwise after 30 minutes, and the mixture continues to react at -78℃ for 1 hour. The reaction solution is quenched with saturated aqueous ammonium chloride solution (10ml), extracted with ethyl acetate three times, the organic phase is dried and concentrated, and the residue is purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 0.43g of yellow oil. MS (m / z): 250.2 [M+H] +

[0566] (B) 4-(Hydroxymethyl)-1-(pyridin-2-yl)cyclohexan-1-ol

[0567] In the reaction bottle, 4-hydroxy-4-(pyridin-2-yl)cyclohexane-1-carboxylic acid ethyl ester (0.43g, 1.72mmol) and tetrahydrofuran (10ml) were added in sequence, cooled in an ice bath, 1 mol / L diisobutylaluminum hydride solution (3.44ml, 3.44mmol) was added dropwise, and then the temperature was raised to room temperature for 2 hours. The reaction solution was quenched with saturated aqueous ammonium chloride solution (10ml), extracted three times with ethyl acetate, the organic phase was dried and concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 0.24g of yellow oil. MS (m / z): 208.1 [M+H] +

[0568] (C) 4-Hydroxy-4-(pyridin-2-yl)cyclohexane-1-carbaldehyde

[0569] In a reaction flask, add 4-(hydroxymethyl)-1-(pyridin-2-yl)cyclohexan-1-ol (0.24 g, 1.16 mmol) and dichloromethane (15 ml), and add Dess-Martin periodinane (0.98 g, 2.31 mmol) in batches under an ice bath. Stir at room temperature for 2 hours, wash with saturated sodium bicarbonate solution and sodium bisulfite solution after the reaction, concentrate the organic phase, and purify the residue by flash column chromatography (petroleum ether / ethyl acetate = 100:0-0:100 gradient elution) to obtain 56 mg of the product. MS (m / z): 206.1 [M+H] +

[0570] Intermediate 36: 3-Formyl-1-methyl-1H-pyrazole-5-carboxamide

[0571]

[0572] (A) 3-(Hydroxymethyl)-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester

[0573] In the reaction flask, add 1-methyl-1H-pyrazole-3,5-dicarboxylic acid methyl ester (991mg, 5.0mmol) and tetrahydrofuran (20ml) in sequence, cool to 0°C, add 1 mol / L diisobutylaluminum hydride (10ml, 10.0mmol), and react at room temperature for 2 hours. After the reaction is completed, the reaction solution is concentrated, and the residue is purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 500mg of oily liquid. MS (m / z): 171.1 [M+H] +

[0574] (B) 3-(Hydroxymethyl)-1-methyl-1H-pyrazole-5-carboxamide

[0575] In the reaction flask, 3-(hydroxymethyl)-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester (500 mg, 2.94 mmol) and ammonia water (10 ml) were added in sequence and reacted at room temperature for 15 hours. After the reaction, the reaction solution was concentrated and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 456 mg of oily liquid. MS (m / z): 156.2 [M+H] +

[0576] (C) 3-Formyl-1-methyl-1H-pyrazole-5-carboxamide

[0577] In the reaction flask, 3-(hydroxymethyl)-1-methyl-1H-pyrazole-5-carboxamide (450 mg, 2.9 mmol) and dichloromethane (25 ml) were added in sequence, and Dess-Martin periodinane (1230 mg, 2.9 mmol) was added, and the reaction was carried out at room temperature for 15 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 260 mg of oily liquid. MS (m / z): 154.0 [M+H] +

[0578] Intermediate 37: 4-(2-oxopyridin-1(2H)-yl)cyclohexane-1-carbaldehyde

[0579]

[0580] (A) Methyl 4-(2-oxopyridin-1(2H)-yl)cyclohexane-1-carboxylate

[0581] In the reaction flask, 4-hydroxycyclohexane-1-carboxylic acid methyl ester (1.58g, 10mmol), pyridine-2(1H)-one (951mg, 10mmol), diisopropyl azodicarboxylate (2.02g, 10mmol), triphenylphosphine (2.6g, 10mmol) and tetrahydrofuran (40ml) were added in sequence and reacted at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 310mg of oily liquid. MS (m / z): 236.4 [M+H] +

[0582] (B) 1-(4-(Hydroxymethyl)cyclohexyl)pyridin-2(1H)-one

[0583] In the reaction flask, 4-(2-oxopyridin-1(2H)-yl)cyclohexane-1-carboxylic acid methyl ester (310 mg, 1.32 mmol) and tetrahydrofuran (10 ml) were added in sequence, cooled to -78°C, 1 mol / L diisobutylaluminum hydride (1.32 ml, 1.32 mmol) was added, and the reaction was carried out at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 170 mg of oily liquid. MS (m / z): 208.0 [M+H] +

[0584] (C) 4-(2-oxopyridin-1(2H)-yl)cyclohexane-1-carbaldehyde

[0585] In a reaction flask, 1-(4-(hydroxymethyl)cyclohexyl)pyridin-2(1H)-one (170 mg, 0.82 mmol) and dichloromethane (15 ml) were added in sequence, and Dess-Martin periodinane (383 mg, 0.90 mmol) was added, and the reaction was carried out at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 70 mg of an oily liquid. MS (m / z): 206.1 [M+H] +

[0586] Intermediate 38: 1-(5-methoxypyridin-2-yl)piperidine-4-carboxaldehyde

[0587]

[0588] (A) 1-(5-bromopyridin-2-yl)piperidine-4-carboxylic acid ethyl ester

[0589] In the reaction flask, add 2,5-dibromopyridine (2.37g, 10mmol), ethyl piperidine-4-carboxylate (1.57g, 10mmol), cesium carbonate (3.26g, 10mmol) and N,N-dimethylformamide (30ml) in sequence, heat to 110°C, and react for 16 hours. After the reaction, add water, then extract with ethyl acetate, concentrate the organic phase, and purify the residue by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 2.6g of oily liquid. MS (m / z): 313.2 [M+H] +

[0590] (B) 1-(5-Hydroxypyridin-2-yl)piperidine-4-carboxylic acid ethyl ester

[0591] In a reaction flask, add 1-(5-bromopyridin-2-yl)piperidine-4-carboxylic acid ethyl ester (2.6g, 8.3mmol), bis(pinacolato)diboron (4.2g, 16.5mmol), Pd(dppf)Cl2·CH2Cl2 (607mg, 0.83mmol), potassium acetate (1.63g, 16.6mmol) and dioxane (40ml) in sequence, heat to 100℃ under nitrogen protection, and react for 16 hours. Concentrate the reaction solution, dissolve in methanol (100ml) and water (20ml), add sodium hydroxide (664mg, 16.6mmol) and hydrogen peroxide (2ml) at 0℃, and react at room temperature for 2 hours. After the reaction is completed, add sodium thiosulfate to quench the reaction, extract with ethyl acetate, concentrate the organic phase, and purify the residue by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 1.1g of solid. MS (m / z): 251.2 [M+H] +

[0592] (C) 1-(5-methoxypyridin-2-yl)piperidine-4-carboxylic acid ethyl ester

[0593] In the reaction flask, add 1-(5-hydroxypyridin-2-yl)piperidine-4-carboxylic acid ethyl ester (1.1g, 4.39mmol), sodium hydrogen (210mg, 8.75mmol) and N,N-dimethylformamide (20ml) in sequence. Add iodomethane (748mg, 5.27mmol) and react at room temperature for 2 hours. After the reaction, add water, extract with ethyl acetate, concentrate the organic phase, and purify the residue by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 620mg of oily liquid. MS (m / z): 265.4 [M+H] +

[0594] (D)(1-(5-methoxypyridin-2-yl)piperidin-4-yl)methanol

[0595] In the reaction flask, add 1-(5-methoxypyridin-2-yl)piperidine-4-carboxylic acid ethyl ester (620 mg, 2.35 mmol) and tetrahydrofuran (10 ml) in sequence, cool to 0°C, add lithium aluminum hydride (177 mg, 4.67 mmol), and react at room temperature for 5 hours. After the reaction is completed, the reaction solution is concentrated, and the residue is purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 370 mg of oily liquid. MS (m / z): 223.4 [M+H] +

[0596] (E) 1-(5-methoxypyridin-2-yl)piperidine-4-carbaldehyde

[0597] In the reaction flask, (1-(5-methoxypyridin-2-yl)piperidin-4-yl)methanol (370 mg, 1.66 mmol) and dichloromethane (15 ml) were added in sequence, and Dess-Martin periodinane (848 mg, 2.00 mmol) was added, and the reaction was carried out at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 65 mg of oily liquid. MS (m / z): 221.4 [M+H] +

[0598] Intermediate 39: 5-Formyl-N-methylbenzofuran-2-carboxamide

[0599]

[0600] (A) Methyl 5-bromobenzofuran-2-carboxylate

[0601] In the reaction flask, 5-bromo-2-hydroxybenzaldehyde (2.01g, 10mmol), 2-bromoacetic acid methyl ester (2.30g, 15mmol), potassium carbonate (2.76g, 20mmol) and N, N-dimethylformamide (20ml) were added in sequence, heated to 110°C, and reacted for 5 hours. After the reaction, water was added, extracted with ethyl acetate, the organic phase was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 1.6g of solid. MS (m / z): 255.0 [M+H] +

[0602] (B) 5-Bromo-N-methylbenzofuran-2-carboxamide

[0603] In the reaction flask, 5-bromobenzofuran-2-carboxylic acid methyl ester (765 mg, 3 mmol) and methylamine methanol solution (20 ml) were added in sequence, heated to 80°C, and reacted for 16 hours. After the reaction was completed, the reaction solution was concentrated and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 762 mg of oily liquid. MS (m / z): 254.2 [M+H] +

[0604] (C) 5-Formyl-N-methylbenzofuran-2-carboxamide

[0605] In the reaction flask, add 5-bromo-N-methylbenzofuran-2-carboxamide (508mg, 2mmol) and dry tetrahydrofuran (20ml), cool to -78°C, add 1.6 mol / L n-butyl lithium solution (1.37ml, 2.2mmol) dropwise, add N,N-dimethylformamide (0.5ml) after 1 hour, and then stir at room temperature for 1 hour. After the reaction, concentrate the reaction solution, and purify the residue by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 180mg of oily liquid. MS (m / z): 204.2 [M+H] +

[0606] Intermediate 40: 5-Formyl-N,3-dimethylbenzofuran-2-carboxamide

[0607]

[0608] (A) Methyl 2-(2-acetyl-4-bromophenoxy)acetate

[0609] In the reaction bottle, 1-(5-bromo-2-hydroxyphenyl)ethan-1-one (1.07g, 5.0mmol), methyl 2-bromoacetate (765mg, 5.0mmol), potassium carbonate (830mg, 6.0mmol) and N,N-dimethylformamide (20ml) were added in sequence, heated to 110°C, and reacted for 5 hours. After the reaction, water was added, extracted with ethyl acetate, the organic phase was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 980mg of solid. MS (m / z): 287.2 [M+H] +

[0610] (B) Methyl 5-bromo-3-methylbenzofuran-2-carboxylate

[0611] In the reaction flask, methyl 2-(2-acetyl-4-bromophenoxy)acetate (980 mg, 3.41 mmol), DBU (1036 mg, 6.81 mmol) and tetrahydrofuran (20 ml) were added in sequence, heated to 100°C, and reacted for 2 hours. After the reaction, water was added, extracted with ethyl acetate, the organic phase was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 630 mg of solid. MS (m / z): 269.2 [M+H] +

[0612] (C) 5-Bromo-N,3-dimethylbenzofuran-2-carboxamide

[0613] In the reaction flask, 5-bromo-3-methylbenzofuran-2-carboxylic acid methyl ester (630 mg, 2.34 mmol) and methylamine methanol solution (20 ml) were added in sequence, heated to 80°C, and reacted for 16 hours. After the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 550 mg of oily liquid. MS (m / z): 270.4 [M+H] +

[0614] (D) 5-Formyl-N,3-dimethylbenzofuran-2-carboxamide

[0615] In the reaction flask, add 5-bromo-N,3-dimethylbenzofuran-2-carboxamide (534mg, 2mmol) and dry tetrahydrofuran (20ml), cool to -78°C, add 1.6 mol / L n-butyl lithium solution (1.37ml, 2.2mmol) dropwise, add N,N-dimethylformamide (0.5ml) after 1 hour, and then stir at room temperature for 1 hour. After the reaction is completed, concentrate the reaction solution, and purify the residue by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 260mg of oily liquid. MS (m / z): 218.2 [M+H] +

[0616] Example 2

[0617] Preparation of Compound 1-184 Compound 1: 2-((5-(7-((1-(cyclopropanecarbonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)-1,2,4-triazine-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0618]

[0619] In the reaction flask, add intermediate 10-1 (40 mg, 0.076 mmol), cyclopropanecarboxylic acid (10 mg, 0.116 mmol), HATU (43 mg, 0.113 mmol), N, N-diisopropylethylamine (29 mg, 0.224 mmol) and dichloromethane (5 ml) in sequence. React at room temperature for 16 hours, concentrate to remove the solvent, and purify the residue by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 22 mg of white solid. MS (m / z): 594.4 [M+H] + .

[0620] 1 H NMR(400MHz,DMSO-d6)δ8.43(d,J=0.4Hz,1H),7.42(dd,J=6.1,3.5Hz,1H), 7.35–7.31(m,2H),4.29(s,1H),4.19(s,3H),3.78(s,2H),3.64–3.55(m,1H) ,3.08–2.97(m,2H),2.31(s,4H),2.06(d,J=6.9Hz,2H),2.00–1.87(m,2H), 1.76–1.62(m,8H),1.10–1.00(m,6H),0.95–0.90(m,3H),0.68–0.62(m,6H).

[0621] The following compounds were prepared by referring to the preparation process of compound 1, using corresponding intermediates and reagents under appropriate conditions recognized by those skilled in the art.

[0622]

[0623]

[0624]

[0625]

[0626]

[0627]

[0628] Compound 18: 2-((5-(7-((1-(1-acryloylazetidine-3-carbonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazine-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0629]

[0630] (A) Benzyl 3-(4-((2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carbonyl)azetidine-1-carboxylate

[0631] In the reaction flask, add intermediate 10-1 (150 mg, 0.29 mmol), 1-((benzyloxy)carbonyl)azetidine-3-carboxylic acid (106 mg, 0.45 mmol), HATU (132 mg, 0.35 mmol), triethylamine (90 mg, 0.90 mmol) and N,N-dimethylformamide (3 ml) in sequence, and react at room temperature for 2 hours. The reaction solution is purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 220 mg of light yellow solid. MS (m / z): 743.4 [M+H] +

[0632] (B) 2-((5-(7-((1-(azetidine-3-carbonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0633] In the reaction bottle, 3-(4-((2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)piperidine-1-carbonyl)azetidine-1-carboxylic acid benzyl ester (220 mg, 0.30 mmol), methanol (5 ml) and palladium carbon (22 mg) were added in sequence, and the mixture was reacted at room temperature under hydrogen for 15 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain 140 mg of crude product, which was directly used in the next step. MS (m / z): 609.2 [M+H] +

[0634] (C) 2-((5-(7-((1-(1-acryloylazetidine-3-carbonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0635] In the reaction bottle, 2-((5-(7-((1-(azetidine-3-carbonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)-1,2,4-triazine-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (70 mg, 0.12 mmol), acrylic acid (17 mg, 0.24 mmol), HATU (54 mg, 0.14 mmol), triethylamine (33 mg, 0.33 mmol) and N,N-dimethylformamide (3 ml) were added in sequence and reacted at room temperature for 2 hours. The reaction solution was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 13.7 mg of light yellow solid. MS (m / z): 663.4 [M+H] +

[0636] 1 H NMR(400MHz,CD3OD)δ8.38(s,1H),7.42-7.40(m,1H),7.31–7.15(m,2H),6.32-6.29(m,1H),6.25-6.22(m,1H ),5.76-5.73(m,1H),4.48-4.45(m,3H),4.38-4.35(m,2H),4.27-4.24(m,1H),4.17-4.14(m,1H),3.97–3.88 (m,2H),3.82-3.78(m,2H),3.68-3.65(m,1H),3.49-3.46(m,1H),3.25-3.23(m,1H),3.09-3.05(m,1H),2.72 -2.68(m,1H),2.55-2.49(m,4H),2.28-2.25(m,2H),1.89-1.83(m,7H),1.21–1.02(m,9H),0.82-0.78(m,2H).

[0637] Compound 19: 2-((5-(7-((1-(1-(dimethylcarbamoyl)cyclopropane-1-carbonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0638]

[0639] (A) 1-(4-((2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carbonyl)cyclopropane-1-carboxylic acid methyl ester

[0640] In the reaction flask, add intermediate 10-1 (80 mg, 0.15 mmol), 1-(methoxycarbonyl)cyclopropane-1-carboxylic acid (36 mg, 0.25 mmol), HATU (68 mg, 0.18 mmol), triethylamine (45 mg, 0.45 mmol) and N,N-dimethylformamide (3 ml) in sequence, and react at room temperature for 2 hours. The reaction solution is purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 69 mg of light yellow solid. MS (m / z): 652.4 [M+H] +

[0641] (B) 1-(4-((2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carbonyl)cyclopropane-1-carboxylic acid

[0642] In the reaction flask, 1-(4-((2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)piperidine-1-carbonyl)cyclopropane-1-carboxylic acid methyl ester (69 mg, 0.11 mmol), lithium hydroxide monohydrate (14 mg, 0.33 mmol), tetrahydrofuran (4 ml) and water (1 ml) were added in sequence and reacted at room temperature for 15 hours. The pH of the reaction solution was adjusted to 5-6 with 1 mol / L dilute hydrochloric acid, and the crude product was concentrated to obtain a crude product, which was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 47 mg of a white solid. MS (m / z): 638.4 [M+H] +

[0643] (C) 2-((5-(7-((1-(1-(dimethylcarbamoyl)cyclopropane-1-carbonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0644] In the reaction flask, 1-(4-((2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)piperidine-1-carbonyl)cyclopropane-1-carboxylic acid (47 mg, 0.074 mmol), dimethylamine hydrochloride (12 mg, 0.15 mmol), HATU (32 mg, 0.084 mmol), triethylamine (21 mg, 0.21 mmol) and N,N-dimethylformamide (3 ml) were added in sequence and reacted at room temperature for 2 hours. The reaction solution was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 11.3 mg of a light yellow solid. MS (m / z): 665.6 [M+H] +

[0645] 1 H NMR(400MHz,CD3OD)δ8.43(s,1H),8.41(s,1H),7.43-7.40(m,1H),7.27-7.23(m,2H) ,4.45-4.42(m,3H),4.27-4.23(m,1H),4.01-3.98(m,2H),3.84-3.79(m,1H),3.49-3. 46(m,1H),3.22-3.18(m,1H),3.09(s,3H),2.99-2.96(m,4H),2.93(s,3H),2.72-2.68 (m,3H),2.07-2.02(m,5H),1.82-1.78(m,2H),1.31–1.04(m,14H),0.82-0.78(m,2H).

[0646] Compound 20: 2-((5-(7-((1-acryloylpiperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0647]

[0648] In the reaction flask, add intermediate 10-1 (53 mg, 0.1 mmol), triethylamine (0.5 ml) and dichloromethane (5 ml) in sequence, add acryloyl chloride (19 mg, 0.2 mmol) at 0°C, and react at room temperature for 2 hours. After the reaction, concentrate the reaction solution, and purify the residue by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 5 mg of white solid. MS (m / z): 580.3 [M+H] +

[0649] 1H NMR (400MHz, CD3OD) δ8.36(s,1H),7.37(dd,J=9.2,4.5Hz,1H),7.23(t,J=8.5Hz,1H),7.14(d,J=8.1Hz,1H) ,6.70(dd,J=16.9,10.7Hz,1H),6.12(dd,J=16.9,1.9Hz,1H),5.67(dd,J=10.7,1.9Hz,1H),4.43-4.14(m,2 H),4.11-3.90(m,2H),3.89-3.75(m,1H),3.48-3.36(m,1H),3.18-3.04(m,1H),2.84-2.67(m,1H),2.62-2. 42(m,4H),2.31(d,J=6.7Hz,2H),1.92–1.80(m,7H),1.40-1.24m,3H),1.24–0.99(m,9H),0.97-0.76(m,2H).

[0650] The following compounds were prepared by referring to the preparation process of compound 20, using corresponding intermediates and reagents under appropriate conditions recognized by those skilled in the art.

[0651]

[0652]

[0653]

[0654]

[0655]

[0656] Compound 26: N-cyclopropyl-4-((2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carboxamide

[0657]

[0658] (A) N-cyclopropyl-1H-imidazole-1-carboxamide

[0659] Cyclopropylamine (693 mg, 7.41 mmol), N,N'-carbonyldiimidazole (1.15 g, 8.16 mmol) and dichloromethane (30 ml) were added to the reaction flask and stirred overnight at room temperature. The reaction solution was concentrated and purified by flash column chromatography (dichloromethane / methanol = 100:0-0:100 gradient elution) to obtain 907 mg of a white solid product. MS (m / z): 152.1 [M+H] +

[0660] (B) N-cyclopropyl-4-((2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carboxamide

[0661] In a reaction flask, add N-cyclopropyl-1H-imidazole-1-carboxamide (40 mg, 0.27 mmol), intermediate 10-1 (70 mg, 0.133 mmol), triethylamine (27 mg, 0.27 mmol) and dichloromethane (10 ml), stir at room temperature overnight, then concentrate the reaction solution, and purify the residue by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 50 mg of a white solid product. MS (m / z): 609.4 [M+H] +

[0662] 1 H NMR(400MHz,CD3OD)δ8.38(s,1H),8.34(s,1H),7.38-7.35(m,1H),7.28-7.20(m,1H),7.18-7.1 2(m,1H),4.45–4.16(m,2H),3.95(d,J=13.2Hz,4H),3.87–3.75(m,1H),3.52–3.33(m,1H),3.18 -3.08(m,1H),2.90–2.69(m,6H),2.60–2.47(m,3H),2.03-1.97(m,4H),1.92-1.82(m,1H),1.75 (d,J=13.1Hz,2H),1.25–1.01(m,9H),0.95-0.75(m,2H),0.67–0.59(m,2H),0.46–0.39(m,2H).

[0663] The following compounds were prepared by referring to the preparation process of compound 26, using corresponding intermediates and reagents under appropriate conditions recognized by those skilled in the art.

[0664]

[0665]

[0666]

[0667]

[0668] Compound 36: 4-((2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)-N-(2-fluorophenyl)piperidine-1-carboxamide

[0669]

[0670] (A) 1-Fluoro-2-isocyanatobenzene

[0671] In the reaction flask, add 2-fluoroaniline (200mg, 1.78mmol), pyridine (570mg, 7.21mmol) and dichloromethane (20ml), add triphosgene (540mg, 1.82mmol) dropwise under nitrogen protection, and stir at room temperature for 15 hours. After the reaction, the reaction solution is washed with 1 mol / L dilute hydrochloric acid and saturated sodium chloride aqueous solution, and the crude product obtained by concentrating the organic phase is directly used for the next reaction. MS (m / z): 241.1 [2M+H] +

[0672] (B) 4-((2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)-N-(2-fluorophenyl)piperidine-1-carboxamide

[0673] In a sealed tube, add the crude product 1-fluoro-2-isocyanate benzene (150 mg) obtained in the previous step, intermediate 10-1 (50 mg, 0.095 mmol), triethylamine (19 mg, 0.19 mmol) and dichloromethane (20 ml), then heat to 80 ° C and stir to react for 15 hours. After the reaction is completed, concentrate and purify the residue by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 30 mg of white solid. MS (m / z): 663.4 [M+H] +

[0674] 1H NMR(400MHz,CD3OD)δ8.35(s,1H),8.18(d,J=4.8Hz,1H),7.76-7.73(m,1H),7.69-7.65(m,1H),7.41–7.34(m,1H) ,7.26-7.22(m,1H),7.17-7.10(m,1H),7.02–6.92(m,1H),4.40–4.20(m,2H),4.13(d,J=13.2Hz,2H),4.05–3.74( m,3H),3.55–3.33(m,1H),3.19–3.06(m,1H),2.93(t,J=12.2Hz,2H),2.47-2.33(br,4H),2.21(d,J=6.4Hz,2H),1 .89-1.86(m,5H),1.85-1.77(m,2H),1.24-1.17(m,3H),1.16-1.12(m,4H),1.07-1.01(m,2H),0.91–0.72(m,2H).

[0675] The following compounds were prepared by referring to the preparation process of compound 36, using corresponding intermediates and reagents under appropriate conditions recognized by those skilled in the art.

[0676]

[0677] Compound 38: N-ethyl-5-fluoro-N-isopropyl-2-((5-(7-((1-(6-(trifluoromethyl)pyridazin-3-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide

[0678]

[0679] In the reaction flask, add intermediate 10-1 (70 mg, 0.13 mmol), 3-chloro-6-(trifluoromethyl)pyridazine (29 mg, 0.16 mmol), potassium carbonate (46 mg, 0.33 mmol) and N, N-dimethylformamide (5 ml) in sequence, heat to 120 ° C, and react for 3 hours. After the reaction is completed, cool to room temperature and purify by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 35 mg of white solid. MS (m / z): 672.4 [M+H] +

[0680] 1H NMR (400MHz, CD3OD) δ8.45(s,1H),8.40(s,1H),7.64(d,J=9.7Hz,1H),7.42-7.38(m,1H),7.33(d,J=9.8Hz,1H),7. 30–7.19(m,2H),4.55(d,J=13.5Hz,2H),4.44-4.38(m,2H),4.02-3.96(m,2H),3.86–3.74(m,1H),3.54–3.41(m,1H) ,3.27–3.17(m,1H),3.08(t,J=12.1Hz,2H),3.03–2.70(m,4H),2.63(d,J=6.6Hz,2H),2.14-2.07(m,1H),2.06-1.98 (m,4H),1.91(d,J=12.8Hz,2H),1.35–1.25(m,2H),1.20-1.12(m,6H),1.06(t,J=7.1Hz,1H),0.79(d,J=6.2Hz,2H).

[0681] The following compounds were prepared by referring to the preparation process of compound 38, using corresponding intermediates and reagents under appropriate conditions recognized by those skilled in the art.

[0682]

[0683]

[0684]

[0685]

[0686]

[0687]

[0688] Compound 55: 2-((5-(7-((1-([1,2,4]triazolo[1,5-a]pyridin-7-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0689]

[0690] In the reaction flask, add intermediate 10-1 (100 mg, 0.19 mmol), 7-bromo-[1,2,4]triazolo[1,5-a]pyridine (56 mg, 0.28 mmol), Pd2(dba)3 (17 mg, 0.019 mmol), Xantphos (22 mg, 0.038 mmol), cesium carbonate (155 mg, 0.48 mmol) and dioxane (25 ml) in sequence, heat to 100 ° C under nitrogen protection, and react for 15 hours. After the reaction is completed, the reaction solution is concentrated and the residue is purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 25 mg of white solid. MS (m / z): 643.4 [M+H] +

[0691] 1 H NMR(400MHz,CD3OD)δ8.45-8.42(m,2H),8.32(s,1H),8.15(s,1H),7.43-7.38(m,1H),7.33–7.2 0(m,2H),7.03-7.01(m,1H),6.83(d,J=2.3Hz,1H),4.47(s,2H),4.08-3.96(m,4H),3.86-3.79( m,1H),3.56-3.42(m,1H),3.28-3.08(br,4H),3.02-2.95(m,4H),2.20-2.11(m,5H),1.94(d,J= 12.5Hz,2H),1.48-1.36(m,2H),1.20-1.12(m,6H),1.07(t,J=7.1Hz,1H),0.80(d,J=6.0Hz,2H).

[0692] The following compounds were prepared by referring to the preparation process of compound 55, using corresponding intermediates and reagents under appropriate conditions recognized by those skilled in the art.

[0693]

[0694] Compound 57: N-ethyl-5-fluoro-N-isopropyl-2-((5-(7-((1-(pyridin-2-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide

[0695]

[0696] In a reaction flask, intermediate 7-1 (43 mg, 0.1 mmol) and intermediate 12-1 (38 mg, 0.2 mmol) were dissolved in 20 ml of methanol, and then sodium cyanoborohydride (63 mg, 1.0 mmol) was added to the solution, and the reaction solution was stirred at room temperature for 15 hours. After the reaction was completed, the reaction solution was concentrated and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 19 mg of product. MS (m / z): 603.4 [M+H] +

[0697] 1 H NMR(400MHz,CD3OD)δ8.38(s,1H),8.34(s,1H),7.38-7.35(m,1H),7.28-7.20(m,1H),7.18-7.1 2(m,1H),4.45–4.16(m,2H),3.95(d,J=13.2Hz,4H),3.87–3.75(m,1H),3.52–3.33(m,1H),3.18- 3.08(m,1H),2.90–2.69(m,6H),2.60–2.47(m,3H),1.98(t,J=5.5Hz,4H),1.92-1.82(m,1H),1.7 5(d,J=13.1Hz,2H),1.25–1.01(m,9H),0.95–0.75(m,2H),0.67–0.59(m,2H),0.46–0.39(m,2H).

[0698] The following compounds were prepared by referring to the preparation process of compound 57, using corresponding intermediates and reagents under appropriate conditions recognized by those skilled in the art.

[0699]

[0700]

[0701]

[0702]

[0703]

[0704]

[0705]

[0706]

[0707]

[0708]

[0709]

[0710]

[0711]

[0712]

[0713]

[0714]

[0715]

[0716]

[0717]

[0718]

[0719]

[0720]

[0721]

[0722]

[0723] Compound 131: 2-((5-(7-((2-cyano-3-(3,6-dihydro-2H-pyran-4-yl)-4-methyl-1H-indol-5-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0724]

[0725] (A) tert-Butyl 2-cyano-3-(3,6-dihydro-2H-pyran-4-yl)-5-((2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)-4-methyl-1H-indole-1-carboxylate

[0726] In a reaction flask, add intermediate 16 (86 mg, 0.24 mmol), intermediate 7-1 (50 mg, 0.12 mmol), triethylamine (0.065 ml, 0.47 mmol) and dichloromethane (15 ml), stir at room temperature for 1 hour, then add sodium acetate borohydride (99 mg, 0.47 mmol), and continue stirring for 15 hours. After the reaction is completed, the reaction solution is concentrated, and the residue is purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 38 mg of yellow solid. MS (m / z): 779.4 [M+H] +

[0727] (B) 2-((5-(7-((2-cyano-3-(3,6-dihydro-2H-pyran-4-yl)-4-methyl-1H-indol-5-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0728] In the reaction flask, add 2-cyano-3-(3,6-dihydro-2H-pyran-4-yl)-5-((2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)-4-methyl-1H-indole-1-carboxylic acid tert-butyl ester (60 mg, 0.077 mmol) and methanol solution of hydrochloric acid (5 ml, 6 mol / L) and react at room temperature for 1 hour. After the reaction is completed, concentrate and purify the residue by flash column chromatography (dichloromethane / methanol = 100:0-0:100 gradient elution) to obtain 40 mg of white solid. MS (m / z): 679.3 [M+H] +

[0729] 1 H NMR(400MHz,CD3OD)δ12.20(s,1H),8.43(s,1H),8.14(s,1H),7.45-7.38(m,1H),7.3 7-7.29(m,2H),7.19(q,J=8.6Hz,2H),5.86(s,1H),4.26-4.15(m,4H),3.87-3.76(m, 4H),3.61–3.56(m,1H),3.45(s,2H),3.36–3.32(m,1H),3.10-2.93(m,1H),2.48(s,3 H),2.42-2.17(m,6H),1.75-1.63(br,4H),1.11–0.88(m,7H),0.68(d,J=6.1Hz,2H).

[0730] Compound 132: N-ethyl-5-fluoro-2-((5-(7-((1-(6-(hydroxymethyl)pyridin-2-yl)piperidin-4-yl)methyl)-

[0731] 2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-isopropylbenzamide

[0732]

[0733] (A) 2-((5-(7-((1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0734] In the reaction flask, add intermediate 7-1 (40 mg, 0.093 mmol), intermediate 27-1 (62 mg, 0.185 mmol), sodium cyanoborohydride (12 mg, 0.191 mmol), methanol (5 ml) and acetic acid (0.5 ml) in sequence, and react at room temperature for 5 hours. After the reaction is completed, the reaction solution is concentrated, and the residue is purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 40 mg of white solid. MS (m / z): 747.5 [M+H] +

[0735] (B) N-ethyl-5-fluoro-2-((5-(7-((1-(6-(hydroxymethyl)pyridin-2-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-isopropylbenzamide

[0736] In the reaction bottle, 2-((5-(7-((1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)-1,2,4-triazine-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (40 mg, 0.05 mmol), tetrabutylammonium fluoride (30 mg, 0.12 mmol) and tetrahydrofuran (5 ml) were added in sequence and reacted at room temperature for 5 hours. After the reaction was completed, the reaction solution was concentrated and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 7 mg of white solid. MS (m / z): 633.3 [M+H] +

[0737] 1H NMR(400MHz, DMSO-d6)δ8.43(s,1H),7.44(dd,J=14.1,6.5Hz,2H),7.35–7.31(m,2H),6.63(dd ,J=15.5,7.7Hz,2H),5.13(t,J=5.9Hz,1H),4.34(d,J=5.9Hz,2H),4.25–4.18(m,4H),3.78(s,2 H),3.63–3.55(m,1H),3.03(d,J=41.9Hz,1H),2.67(d,J=11.5Hz,2H),2.31(s,4H),2.07(d,J=6 .7Hz,2H),1.71(d,J=10.3Hz,8H),1.10–1.02(m,6H),1.00–0.91(m,3H),0.70(d,J=6.5Hz,2H).

[0738] Compound 133: N-ethyl-5-fluoro-N-isopropyl-2-((5-(7-((1-(6-vinylpyridazin-3-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide

[0739]

[0740] (A) 2-((5-(7-((1-(6-chloropyridazin-3-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0741] In the reaction flask, add intermediate 10-1 (350 mg, 0.67 mmol), 3,6-dichloropyridazine (99 mg, 0.67 mmol), potassium carbonate (184 mg, 1.33 mmol) and N,N-dimethylformamide (10 ml), heat to 120 ° C and stir to react for 2 hours. After the reaction is completed, purify by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 260 mg of yellow solid. MS (m / z): 638.3, 640.3 [M+H] +

[0742] (B) N-ethyl-5-fluoro-N-isopropyl-2-((5-(7-((1-(6-vinylpyridazin-3-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide

[0743] In a reaction flask, 2-((5-(7-((1-(6-chloropyridazin-3-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (100 mg, 0.16 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (37 mg, 0.24 mmol), potassium carbonate (54 mg, 0.39 mmol), Pd(dppf)Cl2·CH2Cl2 (13 mg, 0.018 mmol), dioxane (20 ml) and water (3 ml) were added, and then heated to 100°C and stirred for 15 hours. After the reaction was completed, the residue was concentrated and purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 15 mg of a white solid. MS (m / z): 630.6 [M+H] +

[0744] 1 H NMR (400MHz, CD3OD) δ8.38 (s, 1H), 7.65 (d, J = 9.7Hz, 1H), 7.43-7.40 (m, 1H), 7.28-7.19 (m, 3H), 6.89-6.82 (m,1H),5.95(d,J=17.9Hz,1H),5.45(d,J=11.2Hz,1H),4.43-4.32(m,4H),3.97-3.86(m,2H),3.84-3.78( m,1H),3.58-3.45(m,1H),3.28-3.17(m,1H),2.97(t,J=12.0Hz,2H),2.60-2.30(m,4H),2.22(d,J=6.4Hz, 2H),1.92-1.85(m,7H),1.25-1.19(m,3H),1.18-1.10(m,5H),1.06(t,J=7.1Hz,1H),0.81(d,J=5.9Hz,2H).

[0745] The following compounds were prepared by referring to the preparation process of compound 133, using corresponding intermediates and reagents under appropriate conditions recognized by those skilled in the art.

[0746]

[0747] Compound 135: N-ethyl-5-fluoro-N-isopropyl-2-((5-(7-((4-(pyridin-2-yl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide

[0748]

[0749] Compound 123 (100 mg, 0.167 mmol), palladium carbon (15 mg) and methanol (15 ml) were added to the reaction flask and reacted at room temperature for 15 hours under a hydrogen balloon. After the reaction was completed, the filtrate was concentrated and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 80 mg of a white solid. MS (m / z): 602.4 [M+H] +

[0750] 1 H NMR(400MHz,CD3OD)δ8.48–8.43(m,1H),8.43(s,1H),8.35(s,1H),7.82–7.72(m,1H),7.44–7.20(m,5H) ,4.47(s,2H),4.20-4.05(m,2H),3.88-3.75(m,1H),3.55-3.42(m,1H),3.30-3.17(m,4H),2.98(d,J=5. 4Hz,1H),2.85-2.68(m,1H),2.32-2.24(m,1H),2.21-2.15(m,4H),2.04-1.95(m,2H),1.88–1.73(m,5H) ,1.72-1.61(m,1H),1.32-1.26(m,1H),1.25-1.11(m,7H),1.08(t,J=7.1Hz,1H),0.80(d,J=5.7Hz,2H).

[0751] Compound 136: 6-(4-((2-(6-((5,6'-difluoro-5'-hydroxy-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)nicotinonitrile

[0752]

[0753] (A) 6-(4-((2-(6-((5,6'-difluoro-5'-oxo-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)nicotinonitrile

[0754] In the reaction flask, add intermediate 7-15 (80 mg, 0.19 mmol), intermediate 12-6 (65 mg, 0.30 mmol), methanol (5 ml) and sodium cyanoborohydride (25 mg, 0.40 mmol) in sequence, and react at room temperature for 2 hours. The reaction solution is quenched with saturated aqueous ammonium chloride solution (2 ml), extracted with dichloromethane three times, dried over anhydrous sodium sulfate, and concentrated to obtain a residue, which is purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 49 mg of a yellow solid. MS (m / z): 627.8 [M+H] +

[0755] (B) 6-(4-((2-(6-((5,6'-difluoro-5'-hydroxy-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)nicotinonitrile

[0756] In a reaction flask, 6-(4-((2-(6-((5,6'-difluoro-5'-oxo-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)piperidin-1-yl)nicotinonitrile (49 mg, 0.08 mmol), methanol (5 ml), cerium trichloride (19 mg, 0.08 mmol) and sodium borohydride (3 mg, 0.08 mmol) were added in sequence and reacted in an ice bath for 1 hour. The reaction solution was quenched with saturated aqueous ammonium chloride solution (2 ml), extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to obtain a residue which was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 15.6 mg of a yellow solid. MS (m / z): 629.8 [M+H] +

[0757] 1H NMR (400MHz, CD3OD) δ8.35 (d, J = 2.3Hz, 1H), 8.33 (s, 1H), 7.68-7.64 (m, 1H), 7.26-7.23 (m,1H),7.16–7.01(m,2H),6.82(d,J=9.2Hz,1H),4.51–4.41(m,3H),4.38-4.35(m,1H), 4.19–4.12(m,1H),3.94-3.90(m,2H),2.95(t,J=11.8Hz,2H),2.45-2.40(m,4H),2.20-2 .15(m,4H),1.96–1.82(m,8H),1.73–1.66(m,2H),1.53-1.48(m,1H),1.20–1.08(m,2H).

[0758] Compound 137: N-ethyl-5-fluoro-N-isopropyl-2-((5-(7-((1-(oxetane-3-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide

[0759]

[0760] In the reaction flask, add intermediate 10-1 (45 mg, 0.086 mmol), oxetane-3-one (12 mg, 0.17 mmol), sodium cyanoborohydride (11 mg, 0.18 mmol), methanol (5 ml) and acetic acid (0.5 ml) in sequence, and react at room temperature for 5 hours. After the reaction is completed, the reaction solution is concentrated, and the residue is purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 12.4 mg of oily liquid. MS (m / z): 582.4 [M+H] +

[0761] 1H NMR(400MHz,DMSO-d6)δ8.43(d,J=0.9Hz,1H),7.43–7.39(m,1H),7.35–7.31(m,2H),4 .48(t,J=6.2Hz,2H),4.36(d,J=6.0Hz,2H),4.18(s,2H),3.77(s,2H),3.59(dt,J=13.1 ,6.6Hz,1H),3.06–3.01(m,2H),2.61(d,J=11.3Hz,2H),2.27(s,4H),2.04(d,J=7.1Hz ,2H),1.67–1.62(m,10H),1.10–1.03(m,6H),1.00–0.93(m,3H),0.69(d,J=6.1Hz,2H).

[0762] The following compounds were prepared by referring to the preparation process of compound 137, using corresponding intermediates and reagents under appropriate conditions recognized by those skilled in the art.

[0763]

[0764] Compound 139: 2-((5-(3-(1-(((2-cyano-4-methyl-1H-indol-5-yl)methyl)(methyl)amino)cyclopropyl)azetidin-1-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0765]

[0766] (A) 2-((5-(3-(1-(((2-cyano-4-methyl-1H-indol-5-yl)methyl)amino)cyclopropyl)azetidin-1-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0767] In the reaction flask, add intermediate 7-18 (55 mg, 0.13 mmol), 5-formyl-4-methyl-1H-indole-2-carbonitrile (25 mg, 0.14 mmol), triethylamine (54 mg, 0.53 mmol), sodium acetate borohydride (112 mg, 0.53 mmol) and dichloromethane (8 ml) in sequence, and react at room temperature for 16 hours. After the reaction is completed, the reaction solution is concentrated, and the residue is purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 28 mg of white solid. MS (m / z): 583.3 [M+H] +

[0768] (B) 2-((5-(3-(1-(((2-cyano-4-methyl-1H-indol-5-yl)methyl)(methyl)amino)cyclopropyl)azetidin-1-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0769] In the reaction flask, 2-((5-(3-(1-(((2-cyano-4-methyl-1H-indol-5-yl)methyl)amino)cyclopropyl)azetidin-1-yl)-1,2,4-triazine-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (10 mg, 0.017 mmol), aqueous formaldehyde solution (0.2 ml), sodium cyanoborohydride (2 mg, 0.032 mmol), methanol (5 ml) and acetic acid (0.5 ml) were added in sequence and reacted at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 7.4 mg of a white solid. MS (m / z): 597.3 [M+H] +

[0770] 1 H NMR (400MHz, DMSO-d6) δ12.23(s,1H),8.43(s,1H),7.44–7.39(m,2H),7.34–7.28(m,2H),7.15(t,J=5.6Hz,2H),4.60(s,1H),4.20(s,2 H),3.73–3.53(m,6H),3.13(s,1H),2.42(s,3H),2.01(s,3H),1.09–1.04(m,6H),0.92–0.79(m,3H),0.69(d,J=5.5Hz,2H),0.65(s,2H).

[0771] The following compounds were prepared by referring to the preparation process of compound 139, using corresponding intermediates and reagents under appropriate conditions recognized by those skilled in the art.

[0772]

[0773]

[0774] Compound 144: N-ethyl-5-fluoro-N-isopropyl-2-((5-(7-((1-(2-methoxy-N-methylacetylamino)cyclopropyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide

[0775]

[0776] (A) N-ethyl-5-fluoro-N-isopropyl-2-((5-(7-((1-(2-methoxyacetylamino)cyclopropyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide

[0777] In the reaction flask, add intermediate 10-3 (50 mg, 0.1 mmol), 2-methoxyacetic acid (9 mg, 0.1 mmol), triethylamine (20 mg, 0.2 mmol), HATU (57 mg, 0.15 mmol) and N, N-dimethylformamide (5 ml), and stir at room temperature for 15 hours. After the reaction, purify by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 40 mg of yellow solid. MS (m / z): 570.4 [M+H] +

[0778] (B) N-ethyl-5-fluoro-N-isopropyl-2-((5-(7-((1-(2-methoxy-N-methylacetylamino)cyclopropyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide

[0779] In the reaction bottle, N-ethyl-5-fluoro-N-isopropyl-2-((5-(7-((1-(2-methoxyacetylamino)cyclopropyl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)-1,2,4-triazine-6-yl)oxy)benzamide (40 mg, 0.07 mmol) and N,N-dimethylformamide (5 ml) were added, sodium hydride (4.2 mg, 0.105 mmol) was added at room temperature, and the reaction was stirred at room temperature for half an hour, and then iodomethane (10 mg, 0.07 mmol) was added and continued to stir for 15 hours. After the reaction was completed, it was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 25 mg of a white solid. MS (m / z): 584.4 [M+H] +

[0780] 1H NMR(400MHz,DMSO-d6)δ8.46(s,1H),8.40-8.37(m,1H),7.44-7.36(m,1H),7.32-7.17(m,2H),4.5 1–4.16(m,3H),4.08(s,1H),4.01-3.76(m,3H),3.52-3.45(m,1H),3.42-3.38(m,3H),3.25-3.03(m ,4H),3.01-2.96(m,3H),2.95–2.91(m,1H),2.60-2.40(m,2H),2.15-1.97(m,3H),1.88-1.81(m,1 H),1.23-1.18(m,2H),1.17-1.11(m,4H),1.10-1.01(m,2H),0.99-0.86(m,2H),0.85-0.70(m,3H).

[0781] Compound 145: 3-(((1-(1-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)azetidin-3-yl)cyclopropyl)(methyl)amino)methyl)-1-methyl-1H-pyrazole-5-carboxamide

[0782] (A) 3-(((1-(1-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)azetidin-3-yl)cyclopropyl)amino)methyl)-1-methyl-1H-pyrazole-5-carboxamide

[0783] In the reaction flask, add intermediate 7-18 (150 mg, 0.36 mmol), intermediate 36 (110 mg, 0.72 mmol), triethylamine (1 ml), sodium cyanoborohydride (113 mg, 1.8 mmol) and methanol (10 ml) in sequence, and react at room temperature for 2 hours. After the reaction is completed, the reaction solution is concentrated, and the residue is purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 90 mg of solid. MS (m / z): 552.2 [M+H] +

[0784] (B) 3-(((1-(1-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)azetidin-3-yl)cyclopropyl)(methyl)amino)methyl)-1-methyl-1H-pyrazole-5-carboxamide

[0785] In the reaction flask, 3-(((1-(1-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazine-5-yl)azetidin-3-yl)cyclopropyl)amino)methyl)-1-methyl-1H-pyrazole-5-carboxamide (80 mg, 0.15 mmol), aqueous formaldehyde solution (1 ml), sodium cyanoborohydride (45 mg, 0.72 mmol) and methanol (5 ml) were added in sequence and reacted at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 63 mg of a white solid. MS (m / z): 566.8 [M+H] +

[0786] 1 H NMR(400MHz,CD3OD)δ8.37(s,1H),7.45–7.35(m,1H),7.31-7.17(m,2H),6.69(s,1H),4.72(s,1H),4.33-4.19(m,2H),4.05(s,3H),3.86-3.7 4(m,2H),3.72-3.56(m,4H),3.54-3.42(m,1H),2.26(s,3H),1.32-2.2 6(m,2H),1.23-1.11(m,7H),1.05(t,J=7.1Hz,1H),0.81–0.76(m,5H).

[0787] Compound 146: 2-((5-(3-(1-(((5-cyano-1-methyl-1H-pyrazol-3-yl)methyl)(methyl)amino)cyclopropyl)azetidin-1-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0788]

[0789] Compound 145 (50 mg, 0.088 mmol) and pyridine (2 ml) were added to the reaction flask in sequence, and 2 drops of phosphorus oxychloride were added at 0°C. The mixture was reacted at room temperature for 1 hour. After the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 19 mg of a white solid. MS (m / z): 548.6 [M+H] +

[0790] 1H NMR(400MHz,CD3OD)δ8.39(s,1H),7.43-7.36(m,1H),7.31-7.17(m,2H),6.82 (s,1H),4.80-4.65(m,1H),4.35-4.22(m,2H),3.98(s,3H),3.86–3.76(m,4H) ,3.72-2.64(m,1H),3.52-3.43(m,1H),2.31(s,3H),1.33-1.27(m,2H),1.20( d,J=6.9Hz,2H),1.17-1.12ms,4H),1.06(t,J=7.1Hz,1H),0.83-0.77(m,5H).

[0791] Compound 147: 2-((5-(7-((1-(3-amino-2-hydroxy-3-oxopropyl)piperidin-4-yl)methyl)-2,7-diazepine

[0792] Spiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0793]

[0794] (A) 3-(4-((2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-2-hydroxypropionic acid ethyl ester

[0795] In the reaction flask, add intermediate 10-1 (100 mg, 0.19 mmol), ethyl 2-oxirane carboxylate (44 mg, 0.38 mmol), triethylamine (38 mg, 0.38 mmol) and methanol (5 ml) in sequence, heat to 80 ° C, and react for 16 hours. After the reaction is completed, the reaction solution is concentrated and the residue is purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 40 mg of oily liquid. MS (m / z): 642.4 [M+H] +

[0796] (B) 2-((5-(7-((1-(3-amino-2-hydroxy-3-oxopropyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0797] In the reaction flask, 3-(4-((2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)piperidin-1-yl)-2-hydroxypropionic acid ethyl ester (40 mg, 0.062 mmol) and ammonia methanol solution (10 ml) were added in sequence, heated to 100°C, and reacted for 16 hours. After the reaction was completed, the reaction solution was concentrated and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 6 mg of white solid. MS (m / z): 613.4 [M+H] +

[0798] 1 H NMR(400MHz,CD3OD)δ8.36(s,1H),7.39(dt,J=9.4,4.8Hz,1H),7.30–7.23(m,1H),7.19(dd,J=8.0,3.0Hz,1H),4.35 (d,J=13.6Hz,2H),4.14(dd,J=8.5,3.5Hz,1H),3.91(d,J=8.1Hz,2H),3.80(dt,J=13.2,6.6Hz,1H),2.99–2.96(m,2H ),2.68(dd,J=13.1,3.5Hz,1H),2.55(dd,J=12.0,7.5Hz,1H),2.33–2.28(m,4H),2.18(d,J=6.5Hz,2H),2.13–2.07(m ,1H),1.86(d,J=8.3Hz,4H),1.74(s,2H),1.56(s,2H),1.21(t,J=11.1Hz,4H),1.12-1.08(m,6H),0.88–0.80(m,3H).

[0799] The following compounds were prepared by referring to the preparation process of compound 147, using corresponding intermediates and reagents under appropriate conditions recognized by those skilled in the art.

[0800]

[0801] Compound 149: 6-(4-((2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)nicotinamide formate

[0802]

[0803] (A) 2-((5-(7-((1-(5-cyanopyridin-2-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0804] In the reaction flask, add intermediate 10-1 (80 mg, 0.15 mmol), 6-chloronicotinonitrile (41 mg, 0.30 mmol), potassium carbonate (52 mg, 0.38 mmol) and DMSO (3 ml) in sequence, and heat to 60 ° C for 3 hours. The reaction solution is purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 72 mg of white solid. MS (m / z): 628.3 [M+H] +

[0805] (B) 6-(4-((2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)nicotinamide formate

[0806] In the reaction flask, 2-((5-(7-((1-(5-cyanopyridin-2-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)-1,2,4-triazine-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (72 mg, 0.12 mmol), potassium carbonate (30 mg, 0.22 mmol) and DMSO (3 ml) were added in sequence, and hydrogen peroxide (0.1 ml) was added dropwise. The reaction was allowed to react at room temperature for 3 hours. The reaction solution was quenched with saturated aqueous ammonium chloride solution (5 ml), extracted three times with ethyl acetate, washed with saturated aqueous sodium bisulfate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a residue which was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 32.5 mg of a light yellow solid. MS (m / z): 646.4 [M+H] +

[0807] 1H NMR(400MHz,CD3OD)δ8.62-8.59(m,1H),8.41(s,1H),8.38(s,1H),7.96-7.93(m,1H),7.42-7 .39(m,1H),7.32–7.19(m,2H),6.84-6.81(m,1H),4.49-4.45(m,4H),4.03-4.00(m,2H),3.88 –3.75(m,1H),3.49-3.45(m,1H),3.25-3.15(m,5H),2.99-2.95(m,2H),2.91-2.87(m,2H),2. 15-2.09(m,5H),1.89-1.85(m,2H),1.29-1.25(m,2H),1.20–1.06(m,7H),0.81-0.76(m,2H).

[0808] Compound 150: 4-(4-((2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)nicotinamide

[0809]

[0810] (A) 4-(4-((2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)nicotinate

[0811] In the reaction flask, add intermediate 7-1 (68 mg, 0.16 mmol), intermediate 23 (60 mg, 0.24 mmol), methanol (5 ml) and sodium cyanoborohydride (20 mg, 0.32 mmol) in sequence, and react at room temperature for 2 hours. The reaction solution is quenched with saturated aqueous ammonium chloride solution (2 ml), extracted with dichloromethane three times, dried over anhydrous sodium sulfate, and concentrated to obtain a residue, which is purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 72 mg of a yellow solid. MS (m / z): 661.4 [M+H] +

[0812] (B) 4-(4-((2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)nicotinamide

[0813] In a sealed tube, 4-(4-((2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)piperidin-1-yl)nicotinate (72 mg, 0.11 mmol) and 7 mol / L ammonia methanol solution (8 ml, 0.56 mmol) were added in sequence, and heated to 80°C for 40 hours. After the reaction, the reaction solution was concentrated to obtain a crude product, which was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 32.5 mg of a light yellow solid. MS (m / z): 646.4 [M+H] +

[0814] 1 H NMR(400MHz,CD3OD)δ8.41(s,1H),8.36(s,1H),8.26-8.23(m,1H),7.39-7.36(m,1H),7.26-7 .23(m,1H),7.18–7.11(m,1H),6.98-6.94(m,1H),4.35-4.30(m,2H),3.97–3.79(m,2H),3.59 -3.55(m,2H),3.13-3.09(m,1H),2.92-2.88(m,2H),2.43-2.38(m,4H),2.24-2.21(m,2H),1. 90–1.82(m,6H),1.78-1.75(m,1H),1.38-1.32(m,4H),1.21–0.97(m,7H),0.89-0.85(m,2H).

[0815] The following compounds were prepared by referring to the preparation process of compound 150, using corresponding intermediates and reagents under appropriate conditions recognized by those skilled in the art.

[0816]

[0817] Compound 152: 5-((2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)-1-(2-hydroxyethyl)-N,4-dimethyl-1H-indole-2-carboxamide

[0818]

[0819] (A) 5-((2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)-N,4-dimethyl-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-indole-2-carboxamide

[0820] In a reaction flask, 5-((2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)-4-methyl-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-indole-2-carboxylic acid (30 mg, 0.04 mmol; prepared from intermediate 7-1 and intermediate 14 according to the preparation process of compound 57), methylamine hydrochloride (8 mg, 0.12 mmol), HATU (23 mg, 0.06 mmol), N,N-diisopropylethylamine (21 mg, 0.16 mmol) and dichloromethane (5 ml) were added in sequence and reacted at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 20 mg of solid. MS (m / z): 757.4 [M+H] +

[0821] (B) 5-((2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)-1-(2-hydroxyethyl)-N,4-dimethyl-1H-indole-2-carboxamide

[0822] In a reaction flask, 5-((2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)-N,4-dimethyl-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-indole-2-carboxamide (20 mg, 0.026 mmol) was dissolved in methanol (5 ml), 2 drops of concentrated hydrochloric acid were added, and the reaction was carried out at room temperature for 0.5 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 11 mg of a white solid. MS (m / z): 673.4 [M+H] +1H NMR(400MHz, DMSO-d6)δ8.43(s,1H),7.42(dd,J=6.4,3.6Hz,1H),7.36–7.31(m,2H),7.28 (d,J=8.5Hz,1H),7.11–7.07(m,2H),4.52(t,J=5.8Hz,2H),4.20(s,2H),3.79(s,2H),3.6 3(t,J=5.5Hz,2H),3.58(d,J=6.7Hz,1H),3.47(s,3H),3.06–3.00(m,3H),2.75(d,J=4.4H z,3H),2.45(s,3H),2.41–2.24(m,3H),1.70(s,4H),1.07–0.97(m,6H),0.91–0.67(m,3H).

[0823] The following compounds were prepared by referring to the preparation process of compound 152, using corresponding intermediates and reagents under appropriate conditions recognized by those skilled in the art.

[0824]

[0825]

[0826]

[0827] Compound 164: 2-((5-(7-((1-(6-aminopyridin-2-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0828]

[0829] (A) tert-butyl(tert-butyloxycarbonyl)(6-(4-((2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)pyridin-2-yl)carbamate

[0830] In the reaction flask, add intermediate 10-1 (50 mg, 0.10 mmol), (6-bromopyridin-2-yl) (tert-butoxycarbonyl) carbamic acid tert-butyl ester (74 mg, 0.20 mmol), Pd2(dba)3 (9 mg, 0.01 mmol), Xantphos (12 mg, 0.02 mmol), cesium carbonate (65 mg, 0.20 mmol) and 1,4-dioxane (5 ml) in sequence, heat to 100 ° C under nitrogen protection, and react for 15 hours. After the reaction is completed, the reaction solution is concentrated, and the residue is purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 14 mg of yellow solid. MS (m / z): 818.5 [M+H] +

[0831] (B) 2-((5-(7-((1-(6-aminopyridin-2-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0832] In the reaction flask, tert-butyl (tert-butyloxycarbonyl)(6-(4-((2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)piperidin-1-yl)pyridin-2-yl)carbamate (14 mg, 0.017 mmol), concentrated hydrochloric acid (0.25 ml) and methanol (2 ml) were added in sequence, and the reaction was carried out at room temperature for 30 minutes. The reaction solution was concentrated and the residue was purified by flash column chromatography (water / methanol=100:0-0:100 gradient elution) to obtain 4.5 mg of a yellow solid. MS (m / z): 618.4 [M+H] +

[0833] 1H NMR (400MHz, a mixture of CDCl3 and CD3OD)δ8.36(s,1H),7.38-7.35(m,1H),7.26–7.19(m,2H),7.13-7.10(m,1H),6. 00-5.97(m,1H),5.89-5.86(m,1H),4.38-4.35(m,2H),4.15-4.12(m,2H),3.93-3. 90(m,2H),3.86–3.76(m,1H),2.72-2.68(m,2H),2.47-2.41(m,3H),2.22-2.17(m, 2H),1.90-1.85(m,5H),1.81-1.77(m,3H),1.25–1.02(m,11H),0.82-0.78(m,2H).

[0834] Compound 165: N-ethyl-5-fluoro-N-isopropyl-2-((5-(7-((1-(pyrimidin-4-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide

[0835]

[0836] (A) 2-((5-(7-((1-(6-chloropyrimidin-4-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0837] In the reaction flask, add intermediate 10-1 (50 mg, 0.095 mmol), 4,6-dichloropyrimidine (14 mg, 0.094 mmol), triethylamine (19 mg, 0.1902 mmol) and dichloromethane (10 ml), and stir at room temperature for 15 hours. After the reaction is completed, concentrate and purify the residue by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 30 mg of yellow solid. MS (m / z): 638.3 [M+H] +

[0838] (B) N-ethyl-5-fluoro-N-isopropyl-2-((5-(7-((1-(pyrimidin-4-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide

[0839] In the reaction bottle, 2-((5-(7-((1-(6-chloropyrimidin-4-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)-1,2,4-triazine-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (30 mg, 0.047 mmol), palladium carbon (6 mg) and methanol (10 ml) were added, and the mixture was reacted at room temperature for 15 hours under hydrogen. After the reaction was completed, the mixture was filtered, the filtrate was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 20 mg of a white solid. MS (m / z): 604.4 [M+H] +

[0840] 1 H NMR (400MHz, DMSO-d6) δ8.43 (s, 2H), 8.14 (s, 1H), 8.10 (d, J = 5.7Hz, 1H), 7.46-7.36 (m, 1H), 7. 36-7.27(m,2H),6.77(d,J=5.9Hz,1H),4.42-4.30(m,2H),4.19(s,2H),3.82-3.73(m,2H),3.63 –3.55(m,1H),3.42-3.30(m,1H),3.10-2.92(m,1H),2.84(t,J=11.9Hz,2H),2.44-2.15(br,4H ),2.10(d,J=6.4Hz,2H),1.85-1.65(m,7H),1.21(s,1H),1.11–0.91(m,8H),0.74-0.63(m,2H).

[0841] The following compounds were prepared by referring to the preparation process of compound 165, using corresponding intermediates and reagents under appropriate conditions recognized by those skilled in the art.

[0842]

[0843] Compound 169: N-ethyl-5-fluoro-N-isopropyl-2-((5-(7-((1-(pyrazolo[1,5-a]pyrimidine-3-carbonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide

[0844]

[0845] (A) 2-((5-(7-((1-(6-bromopyrazolo[1,5-a]pyrimidine-3-carbonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0846] In the reaction flask, add intermediate 10-1 (50 mg, 0.10 mmol), 6-bromopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (48 mg, 0.20 mmol), HATU (49 mg, 0.13 mmol), triethylamine (30 mg, 0.30 mmol) and N,N-dimethylformamide (3 ml) in sequence, and react at room temperature for 1 hour. The reaction solution is purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 61 mg of light yellow solid. MS (m / z): 749.2 [M+H] +

[0847] (B) N-ethyl-5-fluoro-N-isopropyl-2-((5-(7-((1-(pyrazolo[1,5-a]pyrimidine-3-carbonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide

[0848] In the reaction bottle, 2-((5-(7-((1-(6-bromopyrazolo[1,5-a]pyrimidine-3-carbonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)-1,2,4-triazine-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (61 mg, 0.081 mmol), palladium carbon (6 mg) and methanol (6 ml) were added in sequence, and the mixture was reacted under hydrogen for 2 hours. After the reaction was completed, the mixture was filtered, the filtrate was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 16.5 mg of the product. MS (m / z): 671.4 [M+H] +

[0849] 1H NMR (400MHz, CD3OD) δ9.02-8.99(m,1H),8.67(s,1H),8.41-8.38(m,2H),7.40-7.37(m,1H ),7.35–7.19(m,2H),7.15-7.13(m,1H),4.70-4.68(m,1H),4.46-4.43(m,2H),4.12-4.08 (m,3H),3.82-3.79(m,1H),3.48-3.45(m,1H),3.16-3.11(m,6H),2.92-2.86(m,3H),2.13 -2.08(m,5H),1.86-1.82(m,2H),1.33-1.30(m,2H),1.26–0.99(m,7H),0.82-0.77(m,2H).

[0850] Compound 170: 4-((2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazine-5-

[0851] 2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carboxylic acid methyl ester

[0852]

[0853] (A) 4-((2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carboxylic acid 4-nitrophenyl ester

[0854] In the reaction flask, add intermediate 10-1 (45 mg, 0.086 mmol), bis(4-nitrobenzene) carbonate (33 mg, 0.11 mmol), N,N-diisopropylethylamine (22 mg, 0.17 mmol) and N,N-dimethylformamide (5 ml) in sequence, and react at room temperature for 2 hours. After the reaction, concentrate the reaction solution, and purify the residue by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 50 mg of solid. MS (m / z): 691.4 [M+H] +

[0855] (B) 4-((2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carboxylic acid methyl ester

[0856] In the reaction flask, 4-nitrophenyl 4-((2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)piperidine-1-carboxylate (30 mg, 0.043 mmol), sodium methoxide (5 mg, 0.093 mmol) and methanol (5 ml) were added in sequence, heated to 80°C, and reacted for 5 hours. After the reaction was completed, the reaction solution was concentrated and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 6 mg of white solid. MS (m / z): 584.4 [M+H] +

[0857] 1 H NMR(400MHz, DMSO-d6)δ8.42(s,1H),7.43–7.38(m,1H),7.32(dd,J=9.9,5.8 Hz,2H),4.17(s,2H),3.90(s,2H),3.76(s,2H),3.59(d,J=6.7Hz,1H),3.53(s ,3H),3.03–2.97(m,1H),2.71(s,2H),2.30(s,4H),2.03(d,J=6.8Hz,2H),1. 72–1.61(m,8H),1.09–0.99(m,6H),0.96–0.92(m,3H),0.68(d,J=5.8Hz,2H).

[0858] Compound 171: 2-((5-(7-(1-(1-(5,6-dimethoxypyridazin-3-yl)piperidin-4-yl)ethyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0859]

[0860] (A) 1-(1-(5,6-dimethoxypyridazin-3-yl)piperidin-4-yl)ethan-1-one

[0861] In the reaction flask, add 6-chloro-3,4-dimethoxypyridazine (523mg, 3mmol), 1-(piperidin-4-yl)ethan-1-one (572mg, 4.5mmol), Pd2(dba)3 (137mg, 0.15mmol), BINAP (187mg, 0.3mmol), sodium methoxide (324mg, 6mmol) and toluene (30ml) in sequence, heat to 110°C under nitrogen protection, and react for 16 hours. After the reaction, concentrate the reaction solution, and purify the residue by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 110mg of solid. MS (m / z): 266.2 [M+H] +

[0862] (B) 1-(1-(5,6-dimethoxypyridazin-3-yl)piperidin-4-yl)ethan-1-ol

[0863] In the reaction flask, add 1-(1-(5,6-dimethoxypyridazin-3-yl)piperidin-4-yl)ethan-1-one (110 mg, 0.42 mmol) and methanol (10 ml) in sequence, cool to 0°C, add sodium borohydride (46 mg, 1.22 mmol), and react at room temperature for 1 hour. After the reaction, concentrate the reaction solution, and purify the residue by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 80 mg of solid. MS (m / z): 268.4 [M+H] +

[0864] (C) 1-(1-(5,6-dimethoxypyridazin-3-yl)piperidin-4-yl)ethyl methanesulfonate

[0865] In the reaction flask, add 1-(1-(5,6-dimethoxypyridazin-3-yl)piperidin-4-yl)ethan-1-ol (80 mg, 0.3 mmol), triethylamine (1 ml) and dichloromethane (10 ml) in sequence, cool to 0°C, add methanesulfonyl chloride (52 mg, 0.45 mmol), and react at room temperature for 2 hours. After the reaction is completed, the reaction solution is concentrated and the residue is purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 50 mg of solid. MS (m / z): 346.1 [M+H] +

[0866] (D) 2-((5-(7-(1-(1-(5,6-dimethoxypyridazin-3-yl)piperidin-4-yl)ethyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0867] In the reaction flask, add intermediate 7-1 (50 mg, 0.12 mmol), 1-(1-(5,6-dimethoxypyridazin-3-yl)piperidin-4-yl)ethyl methanesulfonate (50 mg, 0.15 mmol), potassium carbonate (33 mg, 0.24 mmol) and dioxane (10 ml) in sequence, heat to 100 ° C, and react for 15 hours. After the reaction is completed, the reaction solution is concentrated and the residue is purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 10 mg of white solid. MS (m / z): 678.4 [M+H] +

[0868] 1 H NMR(400MHz,CD3OD)δ8.41(s,1H),8.36(s,2H),7.44-7.36(m,1H),7.32–7.20(m,2H),6. 56(s,1H),4.44(s,2H),4.08-3.98(m,5H),3.95(s,3H),3.87-3.73(m,1H),3.67-3.55(m ,2H),3.53-3.41(m,1H),3.26-3.03(m,6H),2.42-2.29(m,1H),2.17-2.03(m,5H),1.92- 1.82(m,2H),1.79-1.66(m,1H),1.34-1.24(m,4H),1.20–1.03(m,7H),0.92-0.74(m,3H).

[0869] Compound 172: N-ethyl-5-fluoro-N-isopropyl-2-((5-(7-(1-(pyridin-2-yl)piperidine-4-carbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide

[0870]

[0871] In the reaction flask, add intermediate 7-1 (50 mg, 0.12 mmol), intermediate 11 (24 mg, 0.12 mmol), HATU (46 mg, 0.12 mmol), triethylamine (36 mg, 0.36 mmol) and N, N-dimethylformamide (3 ml) in sequence, and react at room temperature for 1 hour. The reaction solution is purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 24.6 mg of light yellow solid. MS (m / z): 617.4 [M+H] +

[0872] 1H NMR(400MHz,CD3OD)δ8.38(s,1H),7.43-7.40(m,1H),7.33–7.23(m,1H),7.21-7.18( m,1H),6.68(s,1H),4.39-4.36(m,2H),4.17–4.06(m,2H),3.95(s,3H),3.94–3.89(m, 2H),3.88(s,3H),3.83-3.80(m,1H),3.26–3.14(m,1H),2.88-2.85(m,2H),2.46-2.41 (m,3H),2.24-2.20(m,2H),1.88-1.83(m,7H),1.37–1.00(m,11H),0.83-0.79(m,2H).

[0873] Compound 173: N-ethyl-5-fluoro-N-isopropyl-2-((5-(7-((4-(pyridin-2-yl)piperazin-1-yl)methyl)-2-azaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide

[0874]

[0875] (A) tert-Butyl 7-(4-(pyridin-2-yl)piperazine-1-carbonyl)-2-azaspiro[3.5]nonane-2-carboxylate

[0876] In the reaction flask, 1-(pyridin-2-yl)piperazine (480 mg, 2.9 mmol), 2-(tert-butyloxycarbonyl)-2-azaspiro[3.5]nonane-7-carboxylic acid (792 mg, 2.9 mmol), HATU (1678 mg, 4.4 mmol), N,N-diisopropylethylamine (1140 mg, 8.8 mmol) and dichloromethane (10 ml) were added in sequence and reacted at room temperature for 16 hours. After the reaction, the reaction solution was concentrated and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 500 mg of solid. MS (m / z): 415.1 [M+H] +

[0877] (B) (4-(pyridin-2-yl)piperazin-1-yl)(2-azaspiro[3.5]nonan-7-yl)methanone

[0878] In the reaction flask, tert-butyl 7-(4-(pyridin-2-yl)piperazine-1-carbonyl)-2-azaspiro[3.5]nonane-2-carboxylate (500 mg, 1.2 mmol), dichloromethane (5 ml) and trifluoroacetic acid (2 ml) were added in sequence and reacted at room temperature for 16 hours. After the reaction was completed, it was neutralized with sodium bicarbonate aqueous solution and concentrated. The residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 300 mg of solid. MS (m / z): 315.2 [M+H] +

[0879] (C) 7-((4-(pyridin-2-yl)piperazin-1-yl)methyl)-2-azaspiro[3.5]nonane

[0880] In the reaction flask, (4-(pyridin-2-yl)piperazine-1-yl)(2-azaspiro[3.5]nonane-7-yl)methanone (300 mg, 0.95 mmol), tetrahydrofuran (10 ml) and lithium aluminum hydride (72 mg, 1.90 mmol) were added in sequence and heated to 70°C for 3 days. After the reaction, the reaction solution was concentrated and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 150 mg of solid. MS (m / z): 301.2 [M+H] +

[0881] (D) 2-(3,6-dichloro-1,2,4-triazine-5-yl)-7-((4-(pyridin-2-yl)piperazin-1-yl)methyl)-2-azaspiro[3.5]nonane

[0882] In the reaction flask, 7-((4-(pyridin-2-yl)piperazine-1-yl)methyl)-2-azaspiro[3.5]nonane (130 mg, 0.43 mmol), 3,5,6-trichloro-1,2,4-triazine (116 mg, 0.63 mmol), triethylamine (131 mg, 1.30 mmol) and dichloromethane (5 ml) were added in sequence and reacted at room temperature for 3 hours. After the reaction, the reaction solution was concentrated and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 120 mg of solid. MS (m / z): 448.2 [M+H] +

[0883] (E) 2-((3-chloro-5-(7-((4-(pyridin-2-yl)piperazin-1-yl)methyl)-2-azaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0884] In the reaction flask, 2-(3,6-dichloro-1,2,4-triazine-5-yl)-7-((4-(pyridin-2-yl)piperazine-1-yl)methyl)-2-azaspiro[3.5]nonane (120 mg, 0.27 mmol), N-ethyl-5-fluoro-2-hydroxy-N-isopropylbenzamide (61 mg, 0.27 mmol), DBU (101 mg, 0.67 mmol) and tetrahydrofuran (5 ml) were added in sequence and reacted at 40°C for 16 hours. After the reaction was completed, the reaction solution was concentrated and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 30 mg of solid. MS (m / z): 637.4 [M+H] +

[0885] (F) N-ethyl-5-fluoro-N-isopropyl-2-((5-(7-((4-(pyridin-2-yl)piperazin-1-yl)methyl)-2-azaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide

[0886] In the reaction flask, 2-((3-chloro-5-(7-((4-(pyridin-2-yl)piperazine-1-yl)methyl)-2-azaspiro[3.5]nonane-2-yl)-1,2,4-triazine-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (20 mg, 0.03 mmol), palladium carbon (10 mg) and methanol (5 ml) were added in sequence, and the mixture was reacted at room temperature for 5 hours under hydrogen. After the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 6 mg of solid. MS (m / z): 603.4 [M+H] +

[0887] 1 H NMR (400MHz, DMSO-d6) δ8.41(s,1H),8.06(d,J=4.3Hz,1H),7.48(t,J=7.8Hz,1H),7.41(d,J=4 .6Hz,1H),7.32(s,2H),6.76(d,J=8.6Hz,1H),6.61–6.57(m,1H),4.17–4.13(m,2H),3.79–3.71 (m,2H),3.62–3.54(m,1H),3.41(s,4H),3.07(s,1H),2.36(s,4H),2.08(s,2H),1.85(s,2H),1. 70(s,2H),1.46(s,4H),1.01(dd,J=14.0,7.0Hz,6H),0.88–0.84(m,3H),0.67(d,J=5.0Hz,2H).

[0888] Compound 175: 2-((5-(7-((2-cyano-4-methyl-1H-indol-5-yl)methyl-d)-2,7-diazaspiro[3.5]

[0889] Nonane-2-yl)-1,2,4-triazine-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0890]

[0891] In the reaction bottle, add intermediate 7-1 (100 mg, 0.23 mmol), 5-formyl-4-methyl-1H-indole-2-carbonitrile (86 mg, 0.46 mmol), NaBD3CN (30 mg, 0.46 mmol), THF (5 ml) and MeOH (5 ml) in sequence, react at room temperature for 3 days, quench the reaction solution with 0.2 ml saturated ammonium chloride solution, concentrate to obtain a crude product, and purify it by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 24.3 mg of a white solid. MS (m / z): 598.3 [M+H] +

[0892] 1 H NMR(400MHz,CD3OD)δ8.36(s,1H),7.42-7.38(m,1H),7.30–7.23(m,3H),7.22–7.16(m,2H),4.36-4.32(m,2H),3.92-3.88(m,2H),3.84–3.72( m,1H),3.54(s,1H),3.50–3.37(m,1H),3.27–3.14(m,1H),2.54-2.26( m,4H),2.53(s,3H),1.82(s,4H),1.21–0.99(m,7H),0.80-0.75(m,2H).

[0893] The following compounds were prepared by referring to the preparation process of compound 175, using corresponding intermediates and reagents under appropriate conditions recognized by those skilled in the art.

[0894]

[0895] Compound 177: 2-((5-(7-((1-(5,6-dimethoxypyridazin-3-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N-isopropylbenzamide

[0896]

[0897] (A) 2-((5-(7-((1-(5,6-dimethoxypyridazin-3-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluorobenzoic acid

[0898] Compound 106 (300 mg, 0.47 mmol), sodium hydroxide (57 mg, 1.41 mmol), THF (8 ml) and water (2 ml) were added to the reaction flask in sequence and reacted at 50°C for 15 hours. The reaction solution was adjusted to pH 5-6 with 1N dilute hydrochloric acid, concentrated and purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 30 mg of a white solid. MS (m / z): 595.2 [M+H] +

[0899] (B) 2-((5-(7-((1-(5,6-dimethoxypyridazin-3-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N-isopropylbenzamide

[0900] In the reaction bottle, 2-((5-(7-((1-(5,6-dimethoxypyridazin-3-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)-1,2,4-triazine-6-yl)oxy)-5-fluorobenzoic acid (30 mg, 0.05 mmol), isopropylamine (6 mg, 0.10 mmol), HATU (23 mg, 0.06 mmol), triethylamine (15 mg, 0.15 mmol) and DMF (2 ml) were added in sequence and reacted at room temperature for 2 hours. The reaction solution was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 7 mg of light yellow solid. MS (m / z): 636.6 [M+H] +

[0901] 1 H NMR (400MHz, CD3OD) δ8.33(d,J=0.7Hz,1H),7.35–7.25(m,3H),6.67(s,1H),4.58(s,1H),4.43(s,2H),4.12(d,J=13.0Hz,2H),3.94(s,3H),3 .87(s,3H),2.85(t,J=11.7Hz,2H),2.43(s,3H),2.22(d,J=6.6Hz,2H),1.93–1.82(m,7H),1.25(d,J=16.5Hz,5H),1.08(s,3H),1.06(s,3H).

[0902] Compound 178: 2-((5-(7-((1-(5,6-dimethoxypyridazin-3-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluorobenzamide and Compound 179: (Z)-2-((5-(7-((1-(5,6-dimethoxypyridazin-3-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluorobenzamide

[0903]

[0904] In the reaction bottle, intermediate 7-26 (72 mg, 0.19 mmol), intermediate 24-3 (81 mg, 0.32 mmol), NaBH (OAc) 3 (81 mg, 0.38 mmol) and THF (5 ml) were added in sequence and reacted at room temperature for 5 hours. The reaction solution was quenched with 0.5 ml of saturated ammonium chloride, concentrated and purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain two light yellow solid products, namely compound 178 (26.6 mg) and compound 179 (14.2 mg).

[0905] Compound 178: MS (m / z): 622.4 [M+H] +

[0906] 1 H NMR(400MHz,CD3OD)δ8.86(s,1H),7.50–7.37(m,3H),7.05(s,1H),4.73-4.70(m,1H),4. 45-4.42(m,1H),4.35-4.32(m,1H),4.21-4.17(m,2H),4.08-4.05(m,4H),3.99–3.94(m, 4H),3.69-3.65(m,2H),3.35-3.32(m,1H),3.29-3.25(m,1H),3.16–3.06(m,4H),2.39-2 .32(m,5H),2.11-2.06(m,2H),1.51-1.46(m,2H),1.29-1.26(m,1H),1.16-1.11(m,3H).

[0907] Compound 179: MS (m / z): 622.4 [M+H] +

[0908] 1H NMR(400MHz,CD3OD)δ8.51(s,1H),8.28(s,1H),7.05-7.02(m,1H),6.95-6.92(m ,1H),6.83(s,1H),6.63-6.60(m,1H),4.42–4.32(m,1H),4.19-4.14(m,3H),4.04 -4.00(m,3H),3.95(s,6H),3.28–3.15(m,4H),3.09-3.05(m,2H),2.99-2.96(m, 2H),2.22-2.17(m,5H),1.98-1.94(m,2H),1.43-1.38(m,2H),1.26-1.20(m,3H).

[0909] Compound 184: 2-((5-(7-((1-(5,6-dimethoxypyridazin-3-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluorobenzoic acid

[0910]

[0911] In the reaction flask, methyl 2-((5-(7-((1-(5,6-dimethoxypyridazin-3-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)-1,2,4-triazine-6-yl)oxy)-5-fluorobenzoate (250 mg, 0.41 mmol; prepared from intermediate 7-24 and intermediate 24-3 according to the preparation process of compound 57), NaOH (33 mg, 0.82 mmol), THF (4 ml) and water (1 ml) were added in sequence and stirred at room temperature for 16 hours. After the reaction was completed, it was adjusted to neutral with dilute hydrochloric acid, concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0-0:100 gradient elution) to obtain 4 mg of white solid. MS (m / z): 595.3 [M+H] +

[0912] 1H NMR (400MHz, CD3OD) δ8.41 (s, 1H), 8.22 (s, 1H), 7.39 (d, J = 8.7Hz, 1H), 7.14 (dd,J=8.7,4.7Hz,1H),7.06(t,J=6.7Hz,1H),6.63(s,1H),4.49(s,2H),4.0 7(d,J=12.7Hz,2H),3.93(s,2H),3.86(d,J=0.6Hz,3H),3.80(s,3H),3.03( s,3H),2.83(t,J=11.2Hz,2H),2.77(s,2H),2.12–1.92(m,8H),1.50(s,2H).

[0913] Example 3: Molecular level determination of the activity of the compounds of the present invention on the binding of Menin and MLL proteins (fluorescence polarization method)

[0914] 1. Reagents, materials and instruments:

[0915] Recombinant human Menin protein (2-610): ChemPartner, CP2021020801;

[0916] MLL peptide (6-FAM-Ahx-SG-40): GL Biochem, 865700;

[0917] Hydrochloride solution buffer (Tris): Sigma, T2194-1L;

[0918] NaCl: Invitrogen, AM9760G;

[0919] TCEP: Sigma, 646547;

[0920] DMSO: Sigma, D4540;

[0921] 384-well plate: Corning, 4514;

[0922] Envision:PerkinElmer.

[0923] 2. Prepare the reaction solution

[0924] 1) Buffer: Add 20 mL Tris and 4 mL NaCl to 376 mL ddH2O, adjust the pH to 7.5, and add TCEP before testing, with a dilution ratio of 1:500.

[0925] 2) 5X test compound: the test compound was gradiently diluted with the buffer to 5 times the reaction concentration, so that the final concentrations of the compound were 1.000, 0.333, 0.111, 0.037, 0.012, 0.004, 0.001, and 0.0005 μM, respectively.

[0926] 3) 2.5X Menin protein reaction solution: dilute the Menin protein to 5 nM with buffer.

[0927] 4) 2.5X MLL peptide reaction solution: dilute the MLL peptide to 5 nM with buffer.

[0928] 3. Methods

[0929] 1) Binding reaction (20 μL system)

[0930] Add 4 μL of 5X test compound to each reaction well of the 384-well plate, and add the corresponding volume of 10% DMSO to the control well. Add 8 μL of Menin protein reaction solution to each well except the control well. After standing at room temperature for 30 minutes, add 8 μL of MLL peptide reaction solution to each well. The final DMSO concentration of the test compound well and the control well is 2%. Seal the 384-well plate to avoid light and incubate at room temperature for 30 minutes.

[0931] Set up three groups of controls:

[0932] The blank control group was buffer only;

[0933] The negative control group contained only the MLL peptide reaction solution;

[0934] The positive control group contained Menin protein reaction solution and MLL polypeptide reaction solution.

[0935] 2) Detection

[0936] The vertical polarization S value and the horizontal polarization P value were measured using Envison (the excitation light wavelength was 480 nm and the emission light wavelength was 535 nm).

[0937] 4. Data Analysis

[0938] Calculation of G factor: G = ((1000-mP) × corrected S) / ((1000+mP) × corrected P)

[0939] Corrected S is the negative control group S value minus the blank control group S value

[0940] Corrected P is the negative control group P value minus the blank control group P value

[0941] Fluorescence polarization value mP: mP = [(SP×G) / (S+P×G)]×1000

[0942] Inhibition rate % (IR) = [(mP 阳性对照 -mP 待测样品 ) / (mP 阳性对照 -mP 阴性对照 )]×100%

[0943] 5.IC 50 Calculation: XL-Fit software for Microsoft Excel from ID Business Solutions (Guildford, UK) TM (Version 5.3) Calculation.

[0944] 6. Test Results

[0945]

[0946]

[0947]

[0948] Example 4 Cell proliferation assay

[0949] 1. Cell lines

[0950] MV-4-11 (ATCC, CRL-9591), a human acute myeloid leukemia cell line carrying the MLL-AF4 mutation, was cultured in IMDM medium containing 10% heat-inactivated fetal bovine serum (HIFBS) and 50 μM β-mercaptoethanol.

[0951] 2. Reagents, Materials, and Instruments

[0952] IMDM culture medium: GIBCO, 12440-053;

[0953] HIFBS:GIBCO,10100-147;

[0954] β-Mercaptoethanol: Sigma, M3148;

[0955] 2.0 Detection kit (CTG): Promega, G9243;

[0956] DMSO: Sigma, D4540;

[0957] 96-well cell culture plate: Corning, 3903;

[0958] Envision:PerkinElmer.

[0959] 3. Methods

[0960] MV-4-11 cells were resuspended in culture medium and added to a 96-well plate at a density of 3000 cells / well, with a volume of 100 μL / well, and cultured in a cell culture incubator at 5% CO2 and 37°C for 4 hours. The compounds to be tested were added to the cell culture plate after gradient dilution with culture medium, and the final concentrations of the compounds were 1.100, 0.367, 0.122, 0.041, 0.014, 0.005, 0.002, and 0.001 μM, respectively. The blank control wells were added with the corresponding volume of DMSO dilution, and the final concentration of DMSO in the experimental group and the control group was 0.1%. The cell plate was placed in a cell culture incubator at 5% CO2 and 37°C for 3 days.

[0961] 4. Detection

[0962] On the 0th and 3rd day of drug action, CTG reagent was added to the cell plate at 50 μL / well, and after shaking in the dark at room temperature for 10 min, the chemiluminescence value of each well was detected using Envision.

[0963] 5. Data Analysis

[0964] Inhibition rate % = 100-(luminescence value of the sample to be tested-luminescence value on day 0) / (luminescence value of the cell well-luminescence value on day 0) × 100

[0965] in:

[0966] Luminescence value of the test sample: represents the chemiluminescence value of the cell wells after being acted on by the test compound for 3 days.

[0967] Luminescence value day 0: represents the chemiluminescence value of the cell wells on day 0.

[0968] Luminescence value cell well: represents the chemiluminescence value of the cell well without compound treatment after 3 days.

[0969] 6.GI 50 calculate:

[0970] XL-Fit, a software add-on for Microsoft Excel from ID Business Solutions (Guildford, UK) TM (Version 5.3) Calculation.

[0971] 7. Test Results

[0972]

[0973]

Claims

1. Compound of formula (I): or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof, wherein: R1 is selected from hydrogen, halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -O-(C 1-6 Alkyl) and -O-(C 1-6 haloalkyl); R2 is selected from hydrogen, halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, -O-(C 1-6 Alkyl), -O-(C 1-6 Haloalkyl), -O-(C 3-8 Cycloalkyl), -O-(4-8 membered heterocyclic group), C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, phenyl, 5-12 membered heteroaryl, -S-(C 1-6 Alkyl), -S-(C 3-8 Cycloalkyl), -S-(4-8 membered heterocyclic group), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NHCONH2, -NHCO(C 1-6 Alkyl), -CONR a R b ,-CSNR a R b 、-COR c and-COOR e ; wherein said C 3-8 The cycloalkyl, 4-8 membered heterocyclyl, phenyl and 5-12 membered heteroaryl are each optionally substituted by one or more groups independently selected from the following: halogen, -OH, oxo, -CN, -NH2, -CONH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, -O-(C 1-6 Alkyl), -O-(C 1-6 Haloalkyl), -S-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -CONH(C 1-6 alkyl) and -CON(C 1-6 Alkyl)2; R3 is selected from hydrogen, halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -O-(C 1-6 Alkyl) and -O-(C 1-6 haloalkyl); Or R2 and R3 together with the carbon atom to which they are attached form a 5-6 membered heteroaryl or a 4-6 membered heterocyclic group; wherein the 5-6 membered heteroaryl and the 4-6 membered heterocyclic group are each optionally substituted by one or more groups independently selected from the following: halogen, -OH, oxo, -CN, -NH2, -CONH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, -O-(C 1-6 Alkyl) and -O-(C 1-6 haloalkyl); R5 is selected from hydrogen, halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, -O-(C 1-6 Alkyl), -O-(C 1-6 Haloalkyl), C 3-8 Cyclic hydrocarbon group, 4-8 membered heterocyclic group, -S-(C 1-6 alkyl), -NHCONH2, -NHCO(C 1-6 Alkyl) and -NR a R b ; Cy1 is a 4-12 membered heterocyclic group, which is optionally substituted by one or more groups independently selected from the following: halogen, -OH, oxo, -CN, -NH2, -CONH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, -O-(C 1-6 Alkyl) and -O-(C 1-6 haloalkyl); Cy2 is selected from C 3-8 Cycloalkyl, 4-9 membered heterocyclyl, aryl and 5-14 membered heteroaryl; R4 is independently selected from halogen, -CN, -OH, oxo, -SH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-(C 1-6 Alkyl), -O-(C 1-6 Haloalkyl), -O-(C 3-8 Cycloalkyl), -O-(4-8 membered heterocyclic group), -(C 1-6 alkyl) m -(C 3-8 Cycloalkyl), -(C 1-6 alkyl) m -(4-8 membered heterocyclic group), -(C 1-6 alkyl) m -phenyl, -(C 1-6 alkyl) m -(5-12 membered heteroaryl), -S-(C 1-6 Alkyl), -S-(C 3-8 Cyclic hydrocarbon group), -S-(4-8 membered heterocyclic group), -NHCONH2, -CONR a R b 、-COR c 、-COOR e 、-NR a R b 、-NR d COR c 、-NR d S(O) n R f 、-S(O) n R f and -S(O) n NR a R b ; wherein said C 1-6 Alkyl, C 3-8 The cycloalkyl, 4-8 membered heterocyclyl, phenyl and 5-12 membered heteroaryl are each optionally substituted by one or more groups independently selected from the group consisting of halogen, -OH, oxo, -SH, -CN, -NH2, -CONH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, -O-(C 1-6 Alkyl), -O-(C 1-6 Haloalkyl), -O-(C 3-8 Cyclic hydrocarbon group), -O-(4-8 membered heterocyclic group), -S-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -CO(C 1-6 alkyl), -CO(C 2-6 -alkenyl), -CO(C 2-6 Alkynyl), -CONH(C 1-6 Alkyl), -CON(C 1-6 Alkyl)2, C 3-8 Cycloalkyl and 4-8 membered heterocyclic groups; L does not exist, or L is CH2; R a , R b , R c , R d and R e are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(C 1-6 alkyl) m -(C 3-8 Cycloalkyl), -(C 1-6 alkyl) m -(4-8 membered heterocyclic group), -(C 1-6 alkyl) m -phenyl and -(C 1-6 alkyl) m -(5-12 membered heteroaryl); wherein the C 1-6 Alkyl, C 3-8 The cycloalkyl, 4-8 membered heterocyclyl, phenyl and 5-12 membered heteroaryl are each optionally substituted by one or more groups independently selected from the group consisting of halogen, -OH, oxo, -SH, -CN, -NH2, -CONH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, -O-(C 1-6 Alkyl), -O-(C 1-6 Haloalkyl), -O-(C 3-8 Cyclic hydrocarbon group), -O-(4-8 membered heterocyclic group), -S-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NH(C 3-8 Cyclic hydrocarbon group), -NH (4-8 membered heterocyclic group), -CO (C 1-6 alkyl), -CO(C 2-6 -alkenyl), -CO(C 2-6 Alkynyl), -CO(C 3-8 Cyclic hydrocarbon group), -CO (4-8 membered heterocyclic group), -CONH (C 1-6 alkyl), -CONH(C 3-8 Cyclic hydrocarbon), -CONH (4-8 membered heterocyclic) and -CON (C 1-6 Alkyl)2; R f is -CH3; p is 0, 1, 2, 3, 4 or 5; m is 0 or 1; n is 1 or 2; Provided that R4 is not -NH(6-membered nitrogen-containing heteroaryl) or -NH(F-substituted phenyl).

2. The compound according to claim 1 or its pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer, or a deuterated compound thereof, wherein: R1 is halogen, CN or C 1-6 Haloalkyl; R2 is selected from hydrogen, -O-(C 1-6 Alkyl), C 3-8 Cycloalkyl, 4-8 membered heterocyclic, 5-12 membered heteroaryl, -CONR a R b ,-CSNR a R b 、-COR c and-COOR e ; wherein said C 3-8 The cycloalkyl, 4-8 membered heterocyclyl and 5-12 membered heteroaryl are each optionally substituted by one or more groups independently selected from the following: halogen, -OH, oxo, -CN, -NH2, -CONH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, -O-(C 1-6 Alkyl) and -O-(C 1-6 haloalkyl); R3 is hydrogen; Or R2 and R3 together with the carbon atom to which they are attached form a 5-6 membered heteroaryl group; wherein the 5-6 membered heteroaryl group is optionally substituted by one or more groups independently selected from the following: 1-6 alkyl; R5 is selected from hydrogen, C 1-6 Alkyl and -NR a R b ; Cy1 is a 4-12 membered heterocyclic group; Cy2 is selected from C 3-8 Cycloalkyl, 4-9 membered heterocyclyl, aryl and 5-14 membered heteroaryl; R4 is independently selected from halogen, -CN, -OH, oxo, C 1-6 Alkyl, -O-(C 1-6 Alkyl), -(C 1-6 alkyl) m -(C 3-8 Cycloalkyl), -(C 1-6 alkyl) m -(4-8 membered heterocyclic group), -(C 1-6 alkyl) m -phenyl, -(C 1-6 alkyl) m -(5-12 membered heteroaryl), -CONR a R b 、-COR c 、-COOR e 、-NR a R b 、-NR d COR c 、-NR d S(O) n R f 、-S(O) n R f and -S(O) n NR a R b ; wherein said C 1-6 Alkyl, C 3-8 The cycloalkyl, 4-8 membered heterocyclyl, phenyl and 5-12 membered heteroaryl are each optionally substituted by one or more groups independently selected from the following: halogen, -OH, oxo, -CN, -NH2, -CONH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, -O-(C 1-6 Alkyl), -O-(C 1-6 Haloalkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -CONH(C 1-6 Alkyl), -CON(C 1-6 Alkyl)2, C 3-8 Cycloalkyl and 4-8 membered heterocyclic groups; L does not exist, or L is CH2; R a , R b , R c , R d and R e are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, -(C 1-6 alkyl) m -(C 3-8 Cycloalkyl), -(C 1-6 alkyl) m -(4-8 membered heterocyclic group), -(C 1-6 alkyl) m -phenyl and -(C 1-6 alkyl) m -(5-12 membered heteroaryl); wherein the C 1-6 Alkyl, C 3-8 The cycloalkyl, 4-8 membered heterocyclyl, phenyl and 5-12 membered heteroaryl are each optionally substituted by one or more groups independently selected from the following: halogen, -OH, -CN, -CONH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 Alkyl)-OH, -O-(C 1-6 Alkyl), -NH(C 3-8 Cyclic hydrocarbon), -CO(C 2-6 alkenyl) and -CON(C 1-6 Alkyl)2; R f is -CH3; p is 0, 1, 2 or 3; m is 0 or 1; n is 1 or 2; Provided that R4 is not -NH(6-membered nitrogen-containing heteroaryl) or -NH(F-substituted phenyl).

3. A compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof, wherein: The compound is a compound of formula (I-1): in: Z is N or CH; preferably, Z is N; n1, n2, n3 and n4 are independently selected from 1 and 2, respectively.

4. A compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof, wherein: The compound is a compound of formula (I-2): Wherein: n5 and n6 are independently selected from 1 and 2 respectively.

5. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof, wherein: R1 is halogen; preferably, R1 is F or Cl; more preferably, R1 is F.

6. A compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof, wherein: R2 is selected from hydrogen, -O-(C 1-6 Alkyl), C 3-8 Cycloalkyl, 4-8 membered heterocyclic, 5-12 membered heteroaryl, -CONR a R b ,-CSNR a R b 、-COR c and-COOR e , where R a , R b , R c and R e are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, C 3-8 Cycloalkyl and 4-8 membered heterocyclic group; wherein said C 3-8 The cycloalkyl, 4-8 membered heterocyclyl and 5-12 membered heteroaryl are each optionally substituted by one or more groups independently selected from the following: halogen, -OH, oxo, -CN, -NH2, -CONH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, -O-(C 1-6 Alkyl) and -O-(C 1-6 haloalkyl); Preferably, R2 is selected from hydrogen, -O-(C 1-6 Alkyl), C 3-6 Cycloalkyl, 4-6 membered heterocyclic, 5-6 membered heteroaryl, -CONR a R b ,-CSNR a R b 、-COR c and-COOR e , where R a , R b , R c and R e are independently selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and 4-6 membered heterocyclic group; wherein said C 3-6 The cycloalkyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl are each optionally substituted by one or more groups independently selected from the group consisting of halogen, -OH and C 1-6 alkyl; More preferably, R2 is selected from -COO(C 1-6 alkyl) and -CON(C 1-6 Alkyl)2; Most preferably, R2 is -CON(C 1-6 Alkyl)2.

7. The compound according to claim 1 or its pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer, or a deuterated compound thereof, wherein: R3 is hydrogen.

8. A compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof, wherein: R2 and R3 together with the carbon atom to which they are attached form a 5-6 membered heteroaryl group; wherein the 5-6 membered heteroaryl group is optionally substituted by one or more groups independently selected from the following: 1-6 Preferably, R2 and R3 together with the carbon atom to which they are attached form a pyrazolyl group; wherein the pyrazolyl group is optionally substituted by one or more groups independently selected from the following: 1-6 alkyl.

9. A compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof, wherein: R5 is selected from hydrogen, C 1-6 Alkyl, -NH2, -NH(C 1-6 Alkyl) and -N(C 1-6 Preferably, R5 is selected from hydrogen, C 1-6 Alkyl and -NH(C 1-6 More preferably, R5 is hydrogen.

10. The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof, wherein: L is CH2.

11. A compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof, wherein: Cy2 is selected from C 3-8 Cycloalkyl, 4-8 membered heterocyclyl, phenyl and 5-12 membered heteroaryl; preferably, Cy2 is selected from C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl and 8-10 membered heteroaryl.

12. The compound according to claim 11 or its pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer, or a deuterated compound thereof, wherein: Cy2 is selected from cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl, pyrrolidinyl, piperidinyl, piperazinyl, phenyl, pyridinyl, pyridonyl, pyrimidinyl, indolyl, indazolyl, benzofuranyl, benzoxazolyl, imidazopyridinyl, quinolinyl, quinolinonyl, quinazolinyl and dihydro-[1,4]dioxinopyridinyl.

13. The compound according to claim 12 or its pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer, or a deuterated compound thereof, wherein: Cy2 is selected from Preferably, Cy2 is selected from More preferably, Cy2 is Or Cy2 is Or Cy2 is 14. A compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof, wherein: R4 is independently selected from halogen, -CN, -OH, oxo, C 1-6 Alkyl, -O-(C 1-6 Alkyl), -(C 1-6 alkyl) m -(C 3-8 Cycloalkyl), -(C 1-6 alkyl) m -(4-8 membered heterocyclic group), -(C 1-6 alkyl) m -phenyl, -(C 1-6 alkyl) m -(5-12 membered heteroaryl), -CONR a R b 、-COR c 、-COOR e 、-NR a R b 、-NR d COR c 、-NR d S(O) n R f and -S(O) n R f ; wherein said C 1-6 Alkyl, C 3-8 The cycloalkyl, 4-8 membered heterocyclyl, phenyl and 5-12 membered heteroaryl are each optionally substituted by one or more groups independently selected from the following: halogen, -OH, oxo, -CN, -NH2, -CONH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, -O-(C 1-6 Alkyl), -O-(C 1-6 Haloalkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -CONH(C 1-6 Alkyl), -CON(C 1-6 Alkyl)2, C 3-8 Cycloalkyl and 4-8 membered heterocyclic groups; Preferably, R4 is independently selected from halogen, -CN, -OH, oxo, C 1-6 Alkyl, -O-(C 1-6 Alkyl), -(C 1-6 alkyl) m -(4-8 membered heterocyclic group), -(C 1-6 alkyl) m -phenyl, -(C 1-6 alkyl) m -(5-12 membered heteroaryl), -CONR a R b 、-COR c 、-COOR e 、-NR a R b 、-NR d COR c 、-NR d S(O) n R f and -S(O) n R f ; wherein said C 1-6 Alkyl, 4-8 membered heterocyclyl, phenyl and 5-12 membered heteroaryl are each optionally substituted by one or more groups independently selected from the following: halogen, -OH, oxo, -CN, -NH2, -CONH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -(C 1-6 Alkyl)-OH, -O-(C 1-6 Alkyl) and C 3-8 Cycloalkyl; Provided that R4 is not -NH(6-membered nitrogen-containing heteroaryl) or -NH(F-substituted phenyl).

15. The compound according to claim 14 or its pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer, or deuterated compound thereof, wherein: R4 is independently selected from: 1) Halogen; 2)-CN; 3) -OH; 4) Oxo; 5) C 1-6 Alkyl, which is optionally substituted by one or more groups independently selected from the following: -OH, - CN and -CONH2; 6)-O-(C 1-6 alkyl); 7)-(C 1-6 alkyl) m -(4-6 membered heterocyclic group); preferably, the 4-6 membered heterocyclic group is selected from oxetanyl and dihydropyranyl; 8)-(C 1-6 alkyl) m -phenyl; wherein the phenyl is optionally substituted by one or more groups independently selected from the following: -CN; 9)-(C 1-6 alkyl) m -(5-12 membered heteroaryl); preferably, the 5-12 membered heteroaryl is selected from 5-6 membered heteroaryl and 8-10 membered heteroaryl; more preferably, the 5-12 membered heteroaryl is selected from pyrazolyl, oxazolyl, pyridyl, pyridone, pyrimidinyl, pyridazinyl, pyridazinone, pyrazinyl, 1,2,4-triazinyl, indolyl, imidazopyridazinyl, [1,2,4]triazolopyridinyl, pyrazolopyrimidinyl, dihydro- pyrimidopyridazinyl and dihydro-[1,4]dioxinopyridazinyl; most preferably, the 5-12 membered heteroaryl is selected from pyridyl and pyridazinyl; Wherein, the 5-12 membered heteroaryl is optionally substituted by one or more groups independently selected from the following: halogen, -OH, oxo, -CN, -NH2, -CONH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -(C 1-6 Alkyl)-OH, -O-(C 1-6 Alkyl) and C 3-8 Preferably, the 5-12 membered heteroaryl is optionally substituted by one or more groups independently selected from the following: halogen, -OH, -CN, -CONH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -(C 1-6 Alkyl)-OH, -O-(C 1-6 Alkyl) and C 3-8 Cycloalkyl; 10)-CONR a R b ; Among them, R a and R b are independently selected from hydrogen, C 1-6 Alkyl, -(C 1-6 alkyl) m -(C 3-6 Cycloalkyl), -(C 1-6 alkyl) m -(4-6 membered heterocyclic group), -(C 1-6 alkyl) m -phenyl and -(C 1-6 alkyl) m -(5-6 membered heteroaryl); wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl are each optionally substituted by one or more groups independently selected from the group consisting of halogen and -O-(C 1-6 alkyl); 11) -COR c ; Among them, R c Selected from C 1-6 Alkyl, C 2-6 Alkenyl, -(C 1-6 alkyl) m -(C 3-8 Cycloalkyl), - (C 1-6 alkyl) m -(4-6 membered heterocyclic group), -(C 1-6 alkyl) m -phenyl and -(C 1-6 alkyl) m -(5-10 membered heteroaryl); wherein the C 1-6 Alkyl, C 3-8 The cycloalkyl, 4-6 membered heterocyclyl, phenyl and 5-10 membered heteroaryl are each optionally substituted by one or more groups independently selected from the following: halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -O-(C 1-6 Alkyl), -NH(C 3-6 Cyclic hydrocarbon), -CO(C 2-6 alkenyl) and -CON(C 1-6 Alkyl)2; 12)-COOR e ; Among them, R e Selected from hydrogen and C 1-6 alkyl; 13)-NR a R b ; Among them, R a and R b are independently selected from hydrogen, C 1-6 Alkyl and -(C 1-6 alkyl) m -(5-10 wherein the C 1-6 The alkyl and 5-10 membered heteroaryl groups are each optionally substituted by one or more groups independently selected from the group consisting of halogen, -OH, -CN, -CONH2, C 1-6 Alkyl, -(C 1-6 Alkyl)-OH and -O-(C 1-6 alkyl), provided that R4 is not -NH (6-membered nitrogen-containing heteroaryl); 14)-NR d COR c ; Among them, R d Selected from hydrogen and C 1-6 Alkyl; R c C 1-6 Alkyl, which is optionally substituted by one or more groups independently selected from the group consisting of: -CN and -O-(C 1-6 alkyl); 15)-NR d S(O) n R f ; Among them, R d is hydrogen; R f is -CH3; 16)-S(O) n R f ; Among them, R f It is -CH3.

16. The compound according to claim 1 or its pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer, or a deuterated compound thereof, wherein the compound is a compound of formula (I-3): in: n1, n2, n3 and n4 are independently selected from 1 and 2; preferably, n1 and n2 are both 1, and n3 and n4 are both 2; R1 is halogen; preferably, R1 is F or Cl; more preferably, R1 is F; R2 is selected from hydrogen, -O-(C 1-6 Alkyl), C 3-8 Cycloalkyl, 4-8 membered heterocyclic, 5-12 membered heteroaryl, -CONR a R b ,-CSNR a R b 、-COR c and-COOR e ,in, R a , R b , R c and R e are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, C 3-8 Cycloalkyl and 4-8 membered heterocyclic group; wherein said C 3-8 The cycloalkyl, 4-8 membered heterocyclyl and 5-12 membered heteroaryl are each optionally substituted by one or more groups independently selected from the following: halogen, -OH, oxo, -CN, -NH2, -CONH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-CN, -O-(C 1-6 Alkyl) and -O-(C 1-6 Preferably, R2 is selected from hydrogen, -O-(C 1-6 Alkyl), C 3-6 Cycloalkyl, 4-6 membered heterocyclic, 5-6 membered heteroaryl, -CONR a R b ,-CSNR a R b 、-COR c and-COOR e , where R a , R b , R c and R e are independently selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and 4-6 membered heterocyclic group; wherein said C 3-6 The cycloalkyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl are each optionally substituted by one or more groups independently selected from the group consisting of halogen, -OH and C 1-6 More preferably, R2 is selected from -COO(C 1-6 alkyl) and -CON(C 1-6 Most preferably, R2 is -CON(C 1-6 Alkyl)2; R3 is hydrogen; Or R2 and R3 together with the carbon atom to which they are attached form a 5-6 membered heteroaryl group; wherein the 5-6 membered heteroaryl group is optionally substituted by one or more groups independently selected from the following: 1-6 Preferably, R2 and R3 together with the carbon atom to which they are attached form a pyrazolyl group; wherein the pyrazolyl group is optionally substituted by one or more groups independently selected from the following: 1-6 alkyl; R5 is selected from hydrogen, C 1-6 Alkyl, -NH2, -NH(C 1-6 Alkyl) and -N(C 1-6 Preferably, R5 is selected from hydrogen, C 1-6 Alkyl and -NH(C 1-6 More preferably, R5 is hydrogen; Cy2 is selected from C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl and 8-10 membered heteroaryl; preferably, Cy2 is selected from cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl, pyrrolidinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyridonyl, pyrimidinyl, indolyl, indazolyl, benzofuranyl, benzoxazolyl, imidazopyridinyl, quinolyl, quinolinonyl, quinazolinyl and dihydro-[1,4]dioxinopyridinyl; more preferably, Cy2 is selected from Most preferably, Cy2 is R4 is independently selected from halogen, -CN, -OH, oxo, C 1-6 Alkyl, -O-(C 1-6 Alkyl), -(C 1-6 alkyl) m -(4-8 membered heterocyclic group), -(C 1-6 alkyl) m -phenyl, -(C 1-6 alkyl) m -(5-12 membered heteroaryl), -CONR a R b 、-COR c 、-COOR e 、-NR a R b 、-NR d COR c 、-NR d S(O) n R f and -S(O) n R f ; wherein said C 1-6 Alkyl, 4-8 membered heterocyclyl, phenyl and 5-12 membered heteroaryl are each optionally substituted by one or more groups independently selected from the following: halogen, -OH, oxo, -CN, -NH2, -CONH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -(C 1-6 Alkyl)-OH, -O-(C 1-6 Alkyl) and C 3-8 Preferably, R4 is independently selected from: 1) Halogen; 2)-CN; 3) -OH; 4) Oxo; 5) C 1-6 Alkyl, optionally substituted with one or more groups independently selected from: -OH, -CN and -CONH2; 6)-O-(C 1-6 alkyl); 7)-(C 1-6 alkyl) m -(4-6 membered heterocyclic group); preferably, the 4-6 membered heterocyclic group is selected from oxetanyl and dihydropyranyl; 8)-(C 1-6 alkyl) m -phenyl; wherein the phenyl is optionally substituted by one or more groups independently selected from the following: -CN; 9)-(C 1-6 alkyl) m -(5-12 membered heteroaryl); preferably, the 5-12 membered heteroaryl is selected from 5-6 membered heteroaryl and 8-10 membered heteroaryl; more preferably, the 5-12 membered heteroaryl is selected from pyrazolyl, oxazolyl, pyridyl, pyridonyl, pyrimidinyl, pyridazinyl, pyridazinonyl, pyrazinyl, 1,2,4-triazine, indolyl, imidazopyridazine, [1,2,4]triazolopyridinyl, pyrazolopyrimidine Preferably, the 5-12 membered heteroaryl group is selected from pyridinyl and pyridazinyl; Wherein, the 5-12 membered heteroaryl is optionally substituted by one or more groups independently selected from the following: halogen, -OH, oxo, -CN, -NH2, -CONH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -(C 1-6 Alkyl)-OH, -O-(C 1-6 Alkyl) and C 3-8 Cycloalkyl; Preferably, the 5-12 membered heteroaryl is optionally substituted by one or more groups independently selected from the following: halogen, -OH, -CN, -CONH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkyne Base, C 1-6 Haloalkyl, -(C 1-6 Alkyl)-OH, -O-(C 1-6 Alkyl) and C 3-8 Cycloalkyl; 10)-CONR a R b ; Among them, R a and R b are independently selected from hydrogen, C 1-6 Alkyl, -(C 1-6 alkyl) m -(C 3-6 Cycloalkyl), -(C 1-6 alkyl) m -(4-6 membered heterocyclic group), -(C 1-6 alkyl) m -phenyl and -(C 1-6 alkyl) m -(5-6 membered heteroaryl); wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic ring The phenyl and 5-6 membered heteroaryl groups are each optionally substituted by one or more groups independently selected from the following: halogen and -O-(C 1-6 alkyl); 11) -COR c ; Among them, R c Selected from C 1-6 Alkyl, C 2-6 Alkenyl, -(C 1-6 alkyl) m -(C 3-8 Cycloalkyl), -(C 1-6 alkyl) m -(4-6 membered heterocyclic group), -(C 1-6 alkyl) m -phenyl and -(C 1-6 alkyl) m -(5-10 membered heteroaryl); wherein the C 1-6 Alkyl, C 3-8 The cycloalkyl, 4-6 membered heterocyclyl, phenyl and 5-10 membered heteroaryl groups are each optionally substituted by one or more groups independently selected from the following: halogen Element, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -O-(C 1-6 Alkyl), -NH(C 3-6 Cyclic hydrocarbon), -CO(C 2-6 alkenyl) and -CON(C 1-6 Alkyl)2; 12)-COOR e ; Among them, R e Selected from hydrogen and C 1-6 alkyl; 13)-NR a R b ; Among them, R a and R b are independently selected from hydrogen and C 1-6 Alkyl; wherein the C 1-6 The alkyl group is optionally substituted with one or more groups independently selected from: -CN and -O- (C 1-6 alkyl); 14)-NR d COR c ; Among them, R d Selected from hydrogen and C 1-6 Alkyl; R c C 1-6 Alkyl, which is optionally One or more groups independently selected from the following: -CN and -O-(C 1-6 alkyl); 15)-NR d S(O) n R f ; Among them, R d is hydrogen; R f is -CH3; 16)-S(O) n R f ; Among them, R f is -CH3; L is CH2; p is 0, 1, 2 or 3; m is 0 or 1; n is 1 or 2; preferably, n is 2.

17. The compound according to claim 1 or its pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer, or a deuterated compound thereof, wherein the compound is a compound of formula (I-4): in: n5 and n6 are independently selected from 1 and 2 respectively; preferably, n5 and n6 are both 1; R1 is halogen; preferably, R1 is F; R2 is -CON(C 1-6 Alkyl)2; R3 is hydrogen; R5 is hydrogen; Cy2 is selected from C 3-8 Cycloalkyl and 4-8 membered heterocyclic groups; preferably, Cy2 is selected from cyclopropyl and pyrrolidinyl; more preferably, Cy2 is selected from Most preferably, Cy2 is R4 is independently selected from -(C 1-6 alkyl) m -(5-12 membered heteroaryl) and -NR a R b ;in, The 5-12 membered heteroaryl groups are each optionally substituted by one or more groups independently selected from the following: -CN and C 1-6 Alkyl; preferably, R4 is independently selected from: 1)-(C 1-6 wherein the indolyl group is optionally substituted by one or more groups independently selected from the following: -CN and C 1-6 alkyl; 2)-NR a R b ; Among them, R a and R b are independently selected from hydrogen, C 1-6 Alkyl and -(C 1-6 alkyl) m - (5-10 membered heteroaryl); wherein said C 1-6 The alkyl group and the 5-10 membered heteroaryl group are each optionally is substituted by one or more groups independently selected from: -OH, -CN, C 1-6 Alkyl and -(C 1-6 alkyl)-OH, provided that R4 is not -NH(6-membered nitrogen-containing heteroaryl); p is 0, 1 or 2; preferably, p is 1; m is 0 or 1.

18. A compound or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof, selected from:

19. A pharmaceutical composition comprising the compound according to any one of claims 1 to 18 and / or a pharmaceutically acceptable salt thereof, and optionally comprising a pharmaceutically acceptable excipient.

20. A method for inhibiting menin-MLL interaction in vivo or in vitro, comprising contacting an effective amount of the compound according to any one of claims 1 to 18 and / or a pharmaceutically acceptable salt thereof with menin.

21. Use of a compound according to any one of claims 1 to 18 and / or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing a disease mediated by or at least partially mediated by menin-MLL interaction, wherein the disease mediated by or at least partially mediated by menin-MLL interaction is preferably cancer; the cancer is preferably a hematological malignancy or a solid tumor, including leukemia, lymphoma and myeloma; the cancer is more preferably selected from acute leukemia, chronic leukemia, myeloid leukemia, myeloid leukemia, lymphocytic leukemia, lymphoblastic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), B-cell acute lymphocytic leukemia (B-ALL), T-cell prolymphocytic leukemia (T-PLL), or the like. LL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia, large granular lymphocytic leukemia, hairy cell leukemia (HCL), mixed lineage leukemia (MLL), MLL-related leukemia, MLL-rearranged leukemia (MLL-r), MLL-PTD leukemia, MLL-positive leukemia, NPM1 mutant leukemia, leukemias displaying the HOX / MEIS1 gene expression signature, myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), multiple myeloma (MM), Hodgkin lymphoma, non-Hodgkin lymphoma, diffuse large B-cell lymphoma (DLBCL), B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, follicular lymphoma (FL), Waldenstrom macroglobulinemia, prostate cancer, breast cancer, lung cancer, liver cancer, colon cancer, colorectal cancer, pancreatic cancer, melanoma, glioblastoma (GBM).

22. A method for treating or preventing a disease in an individual, comprising administering to an individual in need thereof an effective amount of a compound and / or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein the disease is mediated by or at least partially mediated by menin-MLL interaction; the disease is preferably cancer; the cancer is preferably a hematological malignancy or a solid tumor, including leukemia, lymphoma and myeloma; the cancer is more preferably selected from acute leukemia, chronic leukemia, myeloid leukemia, myeloid leukemia, lymphocytic leukemia, lymphoblastic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), B-cell acute lymphocytic leukemia (B-ALL), T-cell prolymphocytic leukemia (T-PLL), chronic lymphocytic ... Leukemia (CLL), chronic myeloid leukemia, large granular lymphocytic leukemia, hairy cell leukemia (HCL), mixed lineage leukemia (MLL), MLL-related leukemia, MLL-rearranged leukemia (MLL-r), MLL-PTD leukemia, MLL-positive leukemia, NPM1 mutant leukemia, leukemias displaying the HOX / MEIS1 gene expression signature, myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), multiple myeloma (MM), Hodgkin lymphoma, non-Hodgkin lymphoma, diffuse large B-cell lymphoma (DLBCL), B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, follicular lymphoma (FL), Waldenstrom macroglobulinemia, prostate cancer, breast cancer, lung cancer, liver cancer, colon cancer, colorectal cancer, pancreatic cancer, melanoma, glioblastoma (GBM).

23. A compound according to any one of claims 1 to 18 and / or a pharmaceutically acceptable salt thereof for use as a medicament.

24. The compound and / or pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, for use in treating or preventing a disease mediated by or at least partially mediated by menin-MLL interaction, wherein the disease is preferably cancer; the cancer is preferably a hematological malignancy or a solid tumor, including leukemia, lymphoma and myeloma; the cancer is more preferably selected from acute leukemia, chronic leukemia, myeloid leukemia, myeloid leukemia, lymphocytic leukemia, lymphoblastic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), B-cell acute lymphocytic leukemia (B-ALL), T-cell prolymphocytic leukemia (T-PLL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), Leukemia, large granular lymphocytic leukemia, hairy cell leukemia (HCL), mixed lineage leukemia (MLL), MLL-related leukemia, MLL-rearranged leukemia (MLL-r), MLL-PTD leukemia, MLL-positive leukemia, NPM1 mutant leukemia, leukemias displaying the HOX / MEIS1 gene expression signature, myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), multiple myeloma (MM), Hodgkin lymphoma, non-Hodgkin lymphoma, diffuse large B-cell lymphoma (DLBCL), B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, follicular lymphoma (FL), Waldenstrom macroglobulinemia, prostate cancer, breast cancer, lung cancer, liver cancer, colon cancer, colorectal cancer, pancreatic cancer, melanoma, glioblastoma (GBM).

25. A drug combination comprising a compound according to any one of claims 1 to 18 and / or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent, wherein the additional therapeutic agent is preferably selected from: an anti-tumor agent, an anti-inflammatory agent or an immunomodulator, wherein the anti-tumor agent includes a chemotherapeutic agent, an immune checkpoint inhibitor or agonist, and a targeted therapeutic agent.

26. Compounds of formula (III): or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof, wherein: R1, R2, R3 and R5 are as defined in any one of claims 1 to 17; R7 is hydrogen or an amino protecting group; preferably, R7 is hydrogen or an amino protecting group selected from the group consisting of Boc (tert-butyloxycarbonyl), benzyl, Pmb (p-methoxybenzyl) and Cbz (benzyloxycarbonyl); more preferably, R7 is hydrogen or Boc (tert-butyloxycarbonyl); Provided that, when R5 is H or chlorine, R2 is not -C(O)N(CH(CH3)2)2, -C(O)N(CH(CH3)2)(CH3), -C(O)N(CH(CH3)2)(CH2CH3), -C(O)N(CH(CH3)2)(CH2CHF2), -C(O)N(CH(CH3)2)(CH2CF3), -C(O)N(CH(CH3)2)(CH2CH2OH), -C(O)N(cyclopropyl)2, -C(O)N(CH(CH3)2)(cyclopropyl), -C(O)N(CH2CH3)(cyclopropyl), -C(O)N(CH(CH3)2)(cyclobutyl), pyrimidinyl substituted by isopropyl, and pyrazolyl substituted by isopropyl and / or chlorine.

27. A compound selected from: or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated compound thereof.

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