Triazine compounds and their uses

Abstract

Provided are triazine compounds of formula (I), pharmaceutical compositions containing same, methods for their preparation and uses. JPEG2025530791000200.jpg41128

Description

[Technical Field]

[0001] The present invention relates to triazine compounds, pharmaceutical compositions containing same, processes for their preparation and uses. [Background technology]

[0002] The development of acute leukemia is associated with genetic heterogeneity and epigenetic abnormalities (Rodriguez-Paredes M, et al. Nat Med. 2011;17(3):330-339), which poses significant challenges for the treatment of acute leukemia. The MLL (mixed lineage leukemia) protein, also known as MLL1 or KMT2A, is a protein expressed in hematopoietic cells and is required for their normal development. It consists of two subunits, an N-terminal and a C-terminal, formed by cleavage of the MLL protein precursor. The MLL protein contains two major functional domains: a C-terminal SET (Su(var)3-9, Enhancer-of-zeste, and Trithorax) domain with histone H3 lysine 4 (H3K4) methyltransferase activity and an N-terminal DNA-binding domain (AT-hook sequence). MLL proteins normally form complexes with chaperonins and regulate gene expression through epigenetic mechanisms (Krivtsov AV, et al. Nat Rev Cancer. 2007;7:823-33).

[0003] Studies have shown that MLL gene translocations occur in approximately 5% to 10% of patients with acute leukemia (including AML and ALL) and are particularly prevalent in childhood leukemia, accounting for approximately 80% of acute lymphoblastic leukemia (ALL) cases in infants and young children, which are highly resistant to chemotherapy (Teachey DT, et al. Br J Haematol. 2013;162(5):606-620). MLL translocations can result in the fusion of the MLL N-terminal fragment to more than 80 chaperonins (Slany RK, et al. Haematologica. 2009;94(7):984-993). Genome-wide gene expression analysis of samples from MLL-fusion leukemia and MLL wild-type leukemia revealed significant differences in their gene expression profiles. The most frequently overexpressed genes in MLL-fusion leukemia are the HOX (homeobox) cluster genes (especially HOXA7-HOXA10) and MEIS1, a cofactor of HOX genes. HOX family genes encode transcription factors, thereby controlling developmental processes, particularly 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 both stem cells and early lineage progenitor cells, and their expression levels decrease with differentiation. Persistent expression of MEIS1 and HOX genes has been observed in various leukemias, including MLL-fusion leukemia (Kawagoe H, et al. Leukemia (1999) 13:687-98). Thus, dysregulated expression of HOX developmental regulators and their cofactor MEIS1 by MLL fusion proteins plays a key role in the stem cell-like characteristics of MLL fusion leukemias, conferring or maintaining self-renewal properties, growth, and survival advantages to these cells, thereby promoting the tumorigenic potential of MLL fusion proteins (Winters AC, et al. Front Pediatr. 2017;5:4). In addition to gene fusions caused by translocations, MLL partial tandem duplications (PTDs) can also be found in 5%-10% of children and adults with ALL and AML.Epidemiological studies have shown that MLL-PTDs are associated with poorer recurrence-free survival in patients with acute leukemia (Dohner K, et al. J Clin Oncol. 2002;20:3254-61). Therefore, there is a great medical need for treatment of leukemia caused by MLL abnormalities, and new therapeutic approaches for leukemia must be developed.

[0004] Studies have shown that the oncogenic function of MLL fusion proteins primarily depends on their direct interaction with menin protein (Yokoyama A, et al. Cell. 2005; 123(2):207-218). Menin is a 67-kDa protein encoded by the MEN1 (multiple endocrine neoplasia I) gene located on chromosome 11q13. Menin is widely expressed and primarily localized in the nucleus. Although menin lacks defined biological functional domains, the menin protein can bind to various functional proteins, participate in the regulation of 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 N-terminal menin-binding motif (MBM) of MLL fusion proteins and recruit MLL or MLL fusion proteins to target genes, including HOXA9 or MEIS1 (Grembecca J, et al. J. Biol. Chem. 2010;285(52):40690-40698).

[0005] Studies have shown that when MLL fusion proteins lose their binding to menin protein, they lose their oncogenic properties in vitro and in vivo (Caslini C, et al. Cancer. Res. 2007;67(15):7275-7283).

[0006] In addition, when the N-terminus of the MLL-ENL fusion protein is mutated, the fusion protein does not bind to menin, thereby inhibiting HOX gene expression and its potential to induce leukemia in mice (Yokoyama A, et al. Cell. 2005). The MLL fusion protein / menin interaction can be inhibited by using small molecule inhibitors that can significantly inhibit the proliferation of MLL fusion-associated leukemia cells and promote cell differentiation (Grembeka J, et al. Nat. Chem. Biol. 2012;8(3):277-284).

[0007] NPM1 is a widely expressed nucleophosmin that shuttles between the nucleus and cytoplasm as a chaperone molecule, participates in ribosome biogenesis, and maintains genome stability (Heath EM, et al. Leukemia. 2017;31(4):798-807). Studies have shown that NPM1 mutations are found in 20% to 30% of patients with AML (Papaemanuil E, et al. N Engl J Med. 2016;374:2209-21). Furthermore, studies have shown that menin / MLL1 wild-type interactions also play an important role in acute myeloid leukemia harboring mutations in the NPM1 gene. After treatment with first-generation menin-MLL1 inhibitors, AML cells harboring NPM1 mutations undergo growth arrest and differentiation (Uckelmann HJ, et al. Science. 2020;367:586-90). These results further support that more potent menin-MLL1 inhibitors may be developed for leukemia patients with NPM1 mutations.

[0008] Currently, several small molecule menin inhibitors for acute leukemia are being investigated in preclinical or clinical trials. However, small molecule menin inhibitors currently in clinical trials still have major drawbacks, such as menin inhibitory activity that needs improvement, insufficient compound stability, and poor pharmacokinetic properties, making it difficult for compound exposure to reach clinically effective doses. Therefore, it is of great clinical importance to develop a new generation of more potent small molecule menin inhibitors with good pharmacokinetic properties and reduced toxicity and side effects. Summary of the Invention

[0009] The present invention addresses the aforementioned needs in the art. The present invention provides inhibitor compounds with novel structures that have menin inhibitory activity. Compared with existing inhibitors in the prior art, the compounds of the present invention have equivalent or enhanced menin inhibitory activity and better pharmacokinetic properties due to their improved structural patterns, so that they can be administered in a convenient manner, are more easily absorbed in vivo, and have less toxicity and side effects.

[0010] Thus, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated form thereof, wherein: R1 is 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 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 1~6alkyl)-CN, -O-(C 1~6 alkyl), -O-(C 1~6 haloalkyl), -O-(C 3~8 cycloalkyl), -O-(4- to 8-membered heterocyclyl), C 3~8 Cycloalkyl, 4-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, -S-(C 1~6 alkyl), -S-(C 3~8 cycloalkyl), -S-(4- to 8-membered heterocyclyl), -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 Selected from C 3~8 Cycloalkyl, 4- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl are each optionally selected from the group consisting of halogen, —OH, oxo, —CN, —NH, —CONH, 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 substituted with one or more groups independently selected from alkyl; R3 is hydrogen, halogen, -CN, -OH, -NH2, C 1~6 Alkyl, C 1~6 Haloalkyl, -O-(C 1~6 alkyl) and -O-(C 1~6haloalkyl); or R2 and R3 together with the carbon atoms to which they are attached form a 5- to 6-membered heteroaryl or a 4- to 6-membered heterocyclyl, wherein the 5- to 6-membered heteroaryl and the 4- to 6-membered heterocyclyl are each optionally selected from the group consisting of 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 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 Cycloalkyl, 4-8 membered heterocyclyl, -S-(C 1~6 alkyl), -NHCONH2, -NHCO(C 1~6 alkyl) and -NR a R b is selected from Cy1 is a 4- to 12-membered heterocyclyl, optionally containing 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-(C1~6 alkyl) and -O-(C 1~6 haloalkyl); Cy2 is C 3~8 selected from cycloalkyl, 4- to 9-membered heterocyclyl, aryl, and 5- to 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- to 8-membered heterocyclyl), -(C 1~6 alkyl) m -(C 3~8 cycloalkyl), -(C 1~6 alkyl) m -(4- to 8-membered heterocyclyl), -(C 1~6 alkyl) m -phenyl, -(C 1~6 alkyl) m -(5-12 membered heteroaryl), -S-(C 1~6 alkyl), -S-(C 3~8 Cycloalkyl), -S-(4- to 8-membered heterocyclyl), -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 Selected from C 1~6 Alkyl, C 3~8 Cycloalkyl, 4- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl are each optionally selected from the group consisting of halogen, —OH, oxo, —SH, —CN, —NH, —CONH, C1~6 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 cycloalkyl), -O-(4- to 8-membered heterocyclyl), -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 substituted with one or more groups independently selected from cycloalkyl and 4- to 8-membered heterocyclyl; L is absent or L is CH; R a , R b , R c , R d and R e are each independently 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- to 8-membered heterocyclyl), -(C 1~6 alkyl) m -phenyl and -(C 1~6 alkyl) m -(5- to 12-membered heteroaryl), 1~6 Alkyl, C 3~8Cycloalkyl, 4- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl are each optionally selected from the group consisting of halogen, —OH, oxo, —SH, —CN, —NH, —CONH, 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 cycloalkyl), -O-(4- to 8-membered heterocyclyl), -S-(C 1~6 alkyl), -NH(C 1~6 alkyl), -N(C 1~6 alkyl)2, -NH(C 3~8 cycloalkyl), -NH(4- to 8-membered heterocyclyl), -CO(C 1~6 alkyl), -CO(C 2~6 alkenyl), -CO(C 2~6 alkynyl), -CO(C 3~8 cycloalkyl), -CO(4- to 8-membered heterocyclyl), -CONH(C 1~6 alkyl), -CONH(C 3~8 cycloalkyl), -CONH(4- to 8-membered heterocyclyl) and -CON(C 1~6 substituted with one or more groups independently selected from alkyl; 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 (phenyl substituted with F), or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated form thereof.

[0011] The above-mentioned compounds and active compounds (including compounds of the general formula and specific compounds) disclosed in the context of the present invention, and pharmaceutically acceptable salts thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers thereof, or deuterated forms thereof, are collectively referred to herein as "compounds of the present invention."

[0012] The present invention also provides pharmaceutical compositions comprising a compound of the present invention and, optionally, a pharmaceutically acceptable excipient.

[0013] The present invention also provides methods for inhibiting menin-MLL interaction in vivo or in vitro, comprising contacting menin with an effective amount of a compound of the present invention.

[0014] The present invention also provides a method for treating or preventing a disease mediated, or at least in part, by menin-MLL interaction, comprising administering to a subject in need thereof an effective amount of a compound of the present invention.

[0015] The present invention also provides a method for treating or preventing cancer, comprising administering to a subject in need thereof an effective amount of a compound of the present invention.

[0016] The present invention also provides the use of the compounds of the present invention in the treatment or prevention of diseases mediated, or at least in part, by menin-MLL interaction.

[0017] The present invention also provides the use of a compound of the present invention for the treatment or prevention of cancer.

[0018] The present invention also provides the use of a compound of the invention in the manufacture of a medicament for treating or preventing a disease mediated, or at least in part, by menin-MLL interaction.

[0019] The invention also provides the use of a compound of the invention in the manufacture of a medicament for the treatment or prevention of cancer.

[0020] The present invention also provides a compound of the present invention for inhibiting menin-MLL interaction in vivo or in vitro.

[0021] The present invention also provides a compound of the present invention for use as a pharmaceutical.

[0022] The present invention also provides the compounds of the present invention for use as pharmaceuticals for treating or preventing diseases mediated by, or at least in part by, menin-MLL interaction, in particular for treating or preventing cancer.

[0023] The present invention also provides a pharmaceutical 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 active agent, an anti-inflammatory agent or an immunomodulatory agent, wherein the anti-tumor active agent includes a chemotherapeutic agent, an immune checkpoint inhibitor or agonist, and a targeted therapeutic agent.

[0024] The present invention further provides a kit for treating or preventing a disease mediated, or at least in part mediated, by menin-MLL interaction. The kit may comprise a pharmaceutical composition of the invention and instructions for use, wherein the pharmaceutical composition comprises a compound of the invention.

[0025] In some embodiments of the present invention, "diseases mediated by, or at least in part by, menin-MLL interaction" refer to cancers, such as hematological malignancies or solid tumors, including acute leukemia, chronic leukemia, myeloid leukemia, myelogenous leukemia, and the like. 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 myelocytic 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 mutation These include leukemias, lymphomas, and myelomas such as dysplastic leukemias, leukemias that exhibit the HOX / MEIS1 gene expression signature, myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), multiple myeloma (MM), Hodgkin's lymphoma, non-Hodgkin's 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, and glioblastoma (GBM). DETAILED DESCRIPTION OF THE INVENTION

[0026] definition As used herein, the following words, phrases and symbols are generally intended to have the meanings indicated below, unless otherwise indicated by the context in which they are used.

[0027] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -O(C 1~6 alkyl) is attached to the rest of the molecule via an oxygen atom 1~6 Refers to alkyl bonds.

[0028] As used herein, the term "alkyl" refers to an alkyl group having 1 to 18 carbon atoms (C 1~18 ), preferably 1 to 10 carbon atoms (C 1~10 ), more preferably 1 to 6 carbon atoms (C 1~6 ), and even more preferably 1 to 4 carbon atoms (C 1~4 ) or 1 to 3 carbon atoms (C 1~3 ) refers to a straight or branched chain saturated hydrocarbon radical containing 1~6 "Alkyl" refers to an alkyl containing 1 to 6 carbon atoms. 1~3 "Alkyl" refers to an alkyl containing 1 to 3 carbon atoms. 1~6 Examples of alkyl include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl, i-propyl), butyl (e.g., n-butyl, i-butyl, s-butyl, and t-butyl), pentyl (e.g., n-pentyl, i-pentyl, neopentyl), hexyl, etc. As a linker (e.g., in the definition of L) or between two dashes ("-") (e.g., -(C 1~6 alkyl)-OH) When used, alkyl refers to alkylene.

[0029] As used herein, the term "alkenyl" refers to an alkyl group containing one or more, e.g., one, two, or three, carbon-carbon double bonds (C=C) and having 2 to 18 carbon atoms (C 2~18 ), preferably 2 to 10 carbon atoms (C 2~10 ), more preferably 2 to 6 carbon atoms (C 2~6 ), and even more preferably 2 to 4 carbon atoms (C 2~4 ) refers to a straight or branched chain unsaturated hydrocarbon radical containing 2~6 "Alkenyl" refers to an alkenyl containing 2 to 6 carbon atoms. 2~4 "Alkenyl" refers to an alkenyl containing 2 to 4 carbon atoms. 2~6Examples of alkenyl include, but are not limited to, vinyl, propenyl (e.g., 2-propenyl), and butenyl (e.g., 2-butenyl). The point of attachment of an alkenyl may or may not be on the double-bonded carbon.

[0030] As used herein, the term "alkynyl" refers to an alkyl group having one or more, e.g., one, two, or three, carbon-carbon triple bonds. [ka] and contains 2 to 18 carbon atoms (C 2~18 ), preferably 2 to 10 carbon atoms (C 2~10 ), more preferably 2 to 6 carbon atoms (C 2~6 ), and even more preferably 2 to 4 carbon atoms (C 2~4 ) refers to a straight or branched chain unsaturated hydrocarbon radical containing 2~6 "Alkynyl" refers to an alkynyl containing 2 to 6 carbon atoms. 2~4 "Alkynyl" refers to an alkynyl containing 2 to 4 carbon atoms. 2~6 Examples of alkynyl include, but are not limited to, ethynyl, propynyl (e.g., 2-propynyl), and butynyl (e.g., 2-butynyl), etc. The point of attachment of an alkynyl may or may not be on the triple bonded carbon.

[0031] As used herein, the term "halogen" or "halo" means fluoro, chloro, bromo, and iodo, preferably fluoro, chloro, and bromo, more preferably fluoro and chloro.

[0032] As used herein, the term "haloalkyl" refers to an alkyl group, as defined herein, in which one or more, e.g., 1, 2, 3, 4, 5, or all, hydrogen atoms are replaced with halogen atoms, and when one or more hydrogen atoms are replaced with halogen atoms, the halogen atoms may be the same or different from one another. For example, "C 1~6"Haloalkyl" refers to a haloalkyl as defined herein containing 1 to 6 carbon atoms. 1~4 "Haloalkyl" refers to a haloalkyl as defined herein containing 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.

[0033] As used herein, the term "cycloalkyl" refers to a group having 3 to 12 ring carbon atoms (C 3~12 ), e.g., 3 to 8 ring carbon atoms (C 3~8 ), 5 to 7 ring carbon atoms (C 5~7 ), 4 to 7 ring carbon atoms (C 4~7 ) or 3 to 6 ring carbon atoms (C 3~6 ) and may have one or more rings, for example, 1, 2 or 3 rings, preferably 1 or 2 rings, and may be saturated or partially unsaturated cyclic hydrocarbon groups. For example, "C 3~8 "Cycloalkyl" or "3- to 8-membered cycloalkyl" refers to a cycloalkyl containing 3 to 8 ring carbon atoms; 3~6 "Cycloalkyl" or "3- to 6-membered cycloalkyl" refers to a cycloalkyl containing 3 to 6 ring carbon atoms. Cycloalkyls can include fused or bridged rings, or spirocyclic rings. The rings of a cycloalkyl can be saturated or have one or more, e.g., one or two, double bonds (i.e., partially unsaturated), but are not fully conjugated and are not aryls as defined herein. Examples of cycloalkyls 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.

[0034] As used herein, the terms "heterocyclyl" and "heterocycle" can be used interchangeably and refer to a saturated or partially unsaturated cyclic radical having 3 to 12 ring atoms, e.g., 4 to 12 ring atoms (4-12-membered heterocyclyl), 3 to 8 ring atoms (3-8-membered heterocyclyl), 4 to 9 ring atoms (4-9-membered heterocyclyl), 4 to 8 ring atoms (4-8-membered heterocyclyl), 4 to 6 ring atoms (4-6-membered heterocyclyl), or 4 to 5 ring atoms (4-5-membered heterocyclyl), containing one or more, e.g., 1, 2, or 3, preferably 1 or 2, heteroatoms independently selected from N, O, and S in the ring, with the remaining ring atoms being carbon, which may have one or more rings, e.g., 1, 2, or 3, preferably 1 or 2 rings. Heterocyclyl also includes N or S heteroatoms optionally oxidized to various oxidation states. The point of attachment of the heterocyclyl can be on the N heteroatom or on the carbon. For example, a "4- to 9-membered heterocyclyl or a 4- to 9-membered heterocycle" refers to a heterocyclyl having 4 to 9 (4, 5, 6, 7, 8, or 9) ring atoms including at least one, for example, 1, 2, or 3, preferably 1 or 2 heteroatoms independently selected from N, O, and S; a "4- to 8-membered heterocyclyl or a 4- to 8-membered heterocycle" refers to a heterocyclyl having 4 to 8 (4, 5, 6, 7, or 8) ring atoms including at least one, for example, 1, 2, or 3, preferably 1 or 2 heteroatoms independently selected from N, O, and S; and a "4- to 6-membered heterocyclyl or a 4- to 6-membered heterocycle" refers to a heterocyclyl having 4 to 6 (4, 5, or 6) ring atoms including 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 also includes monocyclic, fused or bridged rings, or spiro rings. The rings of a heterocyclyl may be saturated or may have one or more, e.g., one or two, double bonds (i.e., partially unsaturated), but are not fully conjugated and are not heteroaryls as defined herein.Examples of heterocyclyl include 4- to 12-membered heterocyclyl, 4- to 9-membered heterocyclyl, 4- to 8-membered heterocyclyl, and 4- to 6-membered heterocyclyl, such as 4- to 12-membered monocyclic or fused or bridged heterocyclyl, such as oxetanyl, azetidinyl, pyrrolidyl, tetrahydrofuranyl, dioxolanyl, dioxanyl, tetrahydropyranyl, dihydropyranyl (e.g., 3,6-dihydro-2H-pyranyl and 3,4-dihydro-2H-pyranyl), morpholinyl, thiomorpholinyl, and the like. These include, but are not limited to, linyl, piperidyl, piperazinyl, tetrahydropyridyl, dihydropyridyl, dihydropyrimidyl, dihydropyridazinyl, pyrazolidinyl, diazaspiro[3.5]nonyl (e.g., 2,7-diazaspiro[3.5]nonyl), azaspiro[3.5]nonyl (e.g., 2-azaspiro[3.5]nonyl), diazaspiro[3.4]octyl (e.g., 2,6-diazaspiro[3.4]octyl), and oxaspiro[3.3]heptyl.

[0035] As used herein, the terms "aryl" or "aromatic ring" can be used interchangeably and each refer to a carbocyclic hydrocarbon radical of 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms, consisting of one ring or multiple, e.g., two fused rings, at least one of which is aromatic. Examples of aryl include, but are not limited to, phenyl, naphthalenyl, 1,2,3,4-tetrahydronaphthalenyl, phenanthryl, indenyl, indanyl, azulenyl, preferably phenyl or naphthalenyl, more preferably phenyl.

[0036] As used herein, the terms "heteroaryl" and "heteroaromatic ring" can be used interchangeably and refer to a monocyclic, bicyclic, or tricyclic ring system having 5 to 15 ring atoms, preferably 5 to 14 ring atoms, more preferably 5 to 12 ring atoms, even more preferably 5 to 10 ring atoms, and most preferably 5 to 6 or 8 to 10 ring atoms, respectively, in which at least one ring is a 5- or 6-membered aromatic ring containing one or more, e.g., 1 to 4, heteroatoms independently selected from N, O, and S, and the S and N may optionally be oxidized to various oxidation states. When the total number of S and O atoms in a heteroaryl group exceeds 1, the S and O heteroatoms are not adjacent to one another. Preferably, the heteroaryl is a 5- to 12-membered heteroaryl. For example, a heteroaryl can be: 5-6 membered monocyclic heteroaryl, i.e., monocyclic ring aromatic hydrocarbyl 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, 5- or 6-membered heteroaryl, for example, 5- or 6-membered nitrogen- or oxygen- or sulfur-containing heteroaryl, 5- or 6-membered nitrogen- and oxygen- and / or sulfur-containing heteroaryl, for example, pyridyl, N-oxidopyridyl, pyridinonyl (i.e., oxopyridyl), , for example, 2-oxopyridyl), pyrazinyl, pyrimidyl, triazinyl (for example, 1,2,4-triazinyl), pyridazinyl, pyridazinonyl (i.e., oxopyridazinyl, for example, 3-oxopyridazinyl), pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, triazolyl (for example, 1,2,4-triazolyl), thienyl, furanyl, pyranyl, pyrrolyl, and 8-10 membered bicyclic heteroaryl, i.e., bicyclic aromatic hydrocarbyl having 8, 9 or 10 ring atoms, preferably 9-10 membered bicyclic heteroaryl, in which the ring atoms contain 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), the remaining ring atoms being carbon atoms, and in which 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, a benzyl- or benzoyl-containing bicyclic heteroaryl. benzodioxolyl, benzoxazolyl, benzisoxazolyl, benzothienyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, indolyl, indazolyl, purinyl, quinolinyl, quinolinonyl (i.e., oxoquinolinyl, e.g., 2-oxoquinolinyl), isoquinolinyl, dihydroquinolinyl, quinazolinyl, quinoxalinyl, imidazopyrimidyl (e.g., imidazo[1,2-c]pyrimidyl), imidazopyrazinyl (e.g., imidazo[1,2-a]pyrazinyl), imidazopyridyl (e.g., imidazo[1,2 -a]pyridyl), imidazopyridazinyl (e.g., imidazo[1,2-b]pyridazinyl), pyrrolopyrazinyl (e.g., pyrrolo[1,2-a]pyrazinyl), pyrrolopyridyl (e.g., 1H-pyrrolo[2,3-b]pyridyl), pyrrolopyrimidyl (e.g., pyrrolo[3,4-d]pyrimidyl), pyrazolopyrazinyl (e.g., pyrazolo[1,5-a]pyrazinyl), pyrazolopyridyl (e.g., 1H-pyrazolo[3,4-b]pyridyl), pyrazolopyrimidyl (e.g., pyrazolo[1,5-a]pyrimidyl), triazolopyrimidyl (e.g., [1,2,4]triazolo[4,3-c]pyrimidyl and [1,2,4]triazolo[1,5-c]pyrimidyl), triazolopyrazinyl (e.g., [1,2,4]triazolo[1,5-a]pyrazinyl), triazolopyridyl (e.g., [1,2,4]triazolo[4,3-a]pyridyl and

[0124] triazolo[1,5-a]pyridyl), tetrazolopyridyl (e.g., tetrazolo[1,5-a]pyridyl), dihydropyrimidopyridazinyl (e.g., 3,4-dihydro-2H-pyrimido[1,2-b]pyridazinyl), dihydro-[1,4]dioxinopyridyl (e.g., 2,3-dihydro-[1,4]dioxino[2,3-b]pyridyl), dihydro-[1,4]dioxinopyridazinyl (e.g., 6,7-dihydro-[1,4]dioxino[2,3-c]pyridazinyl), and 8- to 10-membered bicyclic heteroaryls.

[0037] As used herein, the term "-OH" refers to a hydroxy radical.

[0038] As used herein, the term "-CN" refers to a cyano radical.

[0039] As used herein, the term "oxo" refers to =O.

[0040] As used herein, the term "amino-protecting group," also referred to as a nitrogen-protecting group, refers to a group that reversibly blocks or protects amino and / or amide functional groups so that reactions can proceed on other functional groups in a compound. Examples of amino-protecting groups include, but are not limited to, Boc (tert-butoxycarbonyl), benzyl, Pmb (p-methoxybenzyl), alkanoyl, triphenylmethyl, benzoyl, succinyl, phthaloyl, Fmoc (9-fluorenylmethoxycarbonyl), Cbz (benzyloxycarbonyl), and the like, preferably Boc (tert-butoxycarbonyl), benzyl, Pmb (p-methoxybenzyl), and Cbz (benzyloxycarbonyl), more preferably Boc (tert-butoxycarbonyl).

[0041] As used herein, the terms "any" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted with one or more" includes unsubstituted and substituted with one, two, three, or more of the described substituents. Those of skill in the art will understand that with respect to any group containing one or more substituents, such group is not intended to introduce any substitution or substitution pattern that is sterically impractical, chemically incorrect, synthetically impractical, and / or inherently unstable.

[0042] As used herein, the term "substituted" or "substituted with" means that one or more (e.g., 1, 2, 3, or 4) hydrogens on the specified atom or group are replaced with one or more (e.g., 1, 2, 3, or 4) substituents, preferably substituents selected from the group of designated substituents or radicals, provided that the replacement does not exceed the normal valence of the designated atom. The substituents may be the same as or different from each other. As used herein, the term "substituted with one or more groups independently selected from" or "substituted with one or more" means that one or more hydrogens on the specified atom or group are independently replaced with one or more radicals from the group of designated substituents or radicals, which may be the same as or different from each other. Preferably, "substituted with one or more groups independently selected from" or "substituted with one or more" means that the specified atom or group is substituted with one, two, three, or four radicals independently selected from the group of designated substituents or radicals, which may be the same as or different from each other. In some embodiments, when a substituent is oxo (i.e., =0), two hydrogens on a single atom are replaced with oxo. Any substituent can be any radical, provided that the combination of substituents and / or variables results in a chemically precise and stable compound. A chemically precise and stable compound means a compound that is sufficiently robust to withstand sufficient isolation from a reaction mixture to allow identification of the compound's chemical structure. Preferably, the substituents are those exemplified in the compounds of the examples of this application.

[0043] Unless otherwise specified, substituents are named on the core structure. For example, when (cycloalkyl)alkyl is listed as a possible substituent, it is understood that the point of attachment of this substituent to the core structure is on the alkyl portion.

[0044] Those skilled in the art ("POSITA") will understand that some of the compounds of formula (I) may contain one or more chiral centers and, therefore, may exist in two or more stereoisomeric forms. Racemates of these isomers, mixtures enriched in individual isomers and one enantiomer, and, when two chiral centers are present, diastereomers and mixtures somewhat enriched in a particular diastereomer, are within the scope of the present invention. POSITA will further understand that the present invention includes all individual stereoisomers (e.g., enantiomers, diastereomers), racemic or partially resolved mixtures of the compounds of formula (I), and, where appropriate, their individual tautomeric forms.

[0045] Racemates can be used as is or resolved into individual isomers. This resolution can yield stereochemically pure compounds or mixtures enriched in one or more isomers. Methods for separating isomers are well known (see Allinger NL and Eliel ELin, "Topics in Stereochemistry," Vol. 6, Wiley Interscience, 1971) and include physical methods such as chromatography using chiral adsorbents. Individual isomers can be prepared in chiral form from chiral precursors. Alternatively, individual isomers can be chemically separated from a mixture by forming diastereomeric salts 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 crystallizing the salts, and then liberating one or both of the resolved bases to yield one or both substantially free of the other (optionally repeating the process), i.e., in a form with greater than 95% optical purity. Alternatively, the racemate can be covalently bound to a chiral compound (auxiliary) to produce diastereomers, which can be separated by chromatography or fractional crystallization, and then the chiral auxiliary is chemically removed to give the pure enantiomers.

[0046] As used herein, the term "tautomer" refers to a structural isomer of a compound produced by the rapid migration of atoms at two positions in a molecule. Tautomers are readily interconverted into each other; for example, enol and ketone forms are typical tautomers.

[0047] "Pharmaceutically acceptable salt" is intended to mean a salt of a free acid or free base of a compound of formula (I) that is non-toxic, biologically acceptable, or biologically suitable for administration to a subject to be treated or prevented. For example, acid addition salts include salts derived from inorganic acids and organic acids. See, for example, S. M. 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.

[0048] In addition, if a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product is a free base, an acid addition salt, particularly a pharmaceutically acceptable acid addition salt, can be produced by dissolving the free base in a suitable solvent and treating the solution with an acid, following conventional procedures for preparing acid addition salts from basic compounds. POSITA will recognize various synthetic methodologies that can be used without undue experimentation to prepare non-toxic, pharmaceutically acceptable acid or base addition salts.

[0049] The term "solvate" refers to a solvent addition form containing either a stoichiometric or non-stoichiometric amount of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the solid state, thereby forming a solvate. When the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more water molecules or less than one water molecule with one molecule of a substance in which the water retains its molecular state as HO; such a combination can form one or more hydrates, for example, a hemihydrate, a monohydrate, and a dihydrate.

[0050] The term "deuteride" refers to a compound formed by replacing one or more, e.g., 1, 2, 3, 4, 5, or 6, hydrogen atoms in a compound with its deuterium isotope, where the abundance of the deuterium isotope (degree of deuteration) of the element deuterium at the replacement positions is at least greater than the natural abundance. In some embodiments, the deuteride in a compound of Formula (I) or a compound of its subformulas (I-1), (I-2), (I-3), or (I-4) has a degree of deuteration 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 therebetween). In some embodiments, the compounds of formula (I) or its sub-formulae (I-1), (I-2), (I-3), (I-4) have a degree of deuteration of more than 99.9%, up to 100%.

[0051] As used herein, "group(s)" and "radical(s)" are synonymous and are intended to refer to a functional group or fragment of a molecule capable of being attached to another fragment of the molecule.

[0052] The term "active ingredient" is used to refer to a chemical substance that has biological activity. In some embodiments, an "active ingredient" is a chemical substance that has pharmaceutical utility.

[0053] As used herein, the term "pharmaceutical combination" refers to a product obtained by mixing or combining two or more active ingredients, including fixed and non-fixed combinations of active ingredients, such as kits, and 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. A "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 in separate entities, wherein the administration provides therapeutically effective levels of the compounds to the patient.

[0054] The terms "treating" or "treatment" or "prevention" of a disease or disorder, in the context of achieving a therapeutic benefit, refer to the administration of one or more pharmaceutical agents, particularly a compound of the invention, to a subject having a disease or disorder, a symptom of a disease or disorder, or a predisposition to a disease or disorder, with the intent to cure, cure, alleviate, relieve, alter, correct, ameliorate, improve, or affect the disease or disorder, the symptom of a disease or disorder, or the predisposition to a disease or disorder. In some embodiments, the disease or disorder is a cancer, such as a hematological malignancy, including leukemia, lymphoma, and myeloma, or a solid tumor.

[0055] In the context of chemical reactions, the terms "treating," "contacting," and "reacting" refer to the addition or mixing of two or more reagents under appropriate conditions to produce a indicated and / or desired product. It is understood that the reaction that produces the indicated and / or desired product does not necessarily result directly from the combination of the two reagents initially added; i.e., there may be one or more intermediates that are produced in the mixture that ultimately result in the formation of the indicated and / or desired product.

[0056] As used herein, the term "effective amount" refers to an amount or dose of a menin inhibitor sufficient to generally provide a therapeutic benefit in a patient in need of treatment or prevention of a disease or disorder mediated, or at least in part, by menin-MLL interaction. Effective amounts or doses of active ingredients of the present disclosure may be ascertained by methods such as modeling, dose escalation studies, or clinical trials, and by considering factors such as the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease or disorder, the subject's previous or ongoing treatments, the subject's health status and response to the drugs, and the judgment of the attending physician.

[0057] Exemplary doses range from about 0.0001 to about 200 mg of active agent per kg of subject body weight per day, e.g., about 0.001 to 100 mg / kg / day, or about 0.01 to 35 mg / kg / day, or about 0.1 to 10 mg / kg / day, in single or divided dose units (e.g., BID, TID, QID). For a 70 kg human, exemplary ranges for suitable dosages are about 0.05 to about 7 g / day, or about 0.2 to about 5 g / day. Once improvement of the patient's disease or disorder occurs, the dose can be adjusted for maintenance treatment. For example, the dosage or frequency of administration, or both, can be reduced, depending on the symptoms, to a level at which the desired therapeutic effect is maintained. Of course, treatment may be discontinued once symptoms have been alleviated to an appropriate level. However, patients may require intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0058] The terms "inhibition" or "inhibiting" refer to a decrease in the baseline activity of a biological activity or process. The term "inhibition of menin-MLL interaction," for purposes of this disclosure, is a practical pharmaceutical activity and refers to a decrease in menin-MLL interaction as a direct or indirect response to the presence of a compound of the present invention, compared to menin-MLL interaction in the absence of the compound. The decrease in interaction may be due to the direct interaction of the compound of the present invention with menin, or may be due to the interaction of the compound of the present invention with one or more other factors that affect the menin-MLL interaction. For example, the presence of a compound of the present invention may decrease menin-MLL interaction by directly binding to menin, by another factor (directly or indirectly) decreasing menin-MLL interaction, or by decreasing (directly or indirectly) the amount of menin present in a cell or organism.

[0059] As used herein, the term "subject" or "patient" refers to mammals and non-mammals. Mammals refer to any member of the mammalian genus, including, but not limited to, humans; non-human primates, such as chimpanzees and other ape and monkey species; farm animals, such as cows, horses, sheep, goats, and pigs; domestic animals, such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, and the like. The term "subject" or "patient" does not denote a particular age or sex. In some embodiments, the subject or patient is human.

[0060] In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of 20%.

[0061] Technical and scientific terms used herein but not specifically defined have the meanings commonly understood by POSITA to which this disclosure pertains.

[0062] All numerical ranges herein shall be construed as disclosing each and every numerical value and subset of numerical values ​​within the range, regardless of whether they are specifically disclosed otherwise. For example, when referring to any range of values, it should be considered to refer to all values ​​within the range of values, e.g., all integers within the range of values. For example, C as used herein 1~6 represents the inclusion of 1, 2, 3, 4, 5 or 6 C. The invention relates to all values ​​contained within ranges, to all smaller ranges, and to the upper or lower limits of numerical ranges. MODE FOR CARRYING OUT THE INVENTION

[0063] Embodiment 1. A compound of formula (I): [ka] or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated form thereof, wherein: R1 is 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 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- to 8-membered heterocyclyl), C 3~8 Cycloalkyl, 4-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, -S-(C 1~6 alkyl), -S-(C 3~8 cycloalkyl), -S-(4- to 8-membered heterocyclyl), -NH(C1~6 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 Selected from C 3~8 Cycloalkyl, 4- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl are each optionally selected from the group consisting of halogen, —OH, oxo, —CN, —NH, —CONH, 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 substituted with one or more groups independently selected from alkyl; R3 is 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 atoms to which they are attached form a 5- to 6-membered heteroaryl or a 4- to 6-membered heterocyclyl, wherein the 5- to 6-membered heteroaryl and the 4- to 6-membered heterocyclyl are each optionally selected from the group consisting of halogen, -OH, oxo, -CN, -NH2, -CONH2, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6Haloalkyl, -(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 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 Cycloalkyl, 4-8 membered heterocyclyl, -S-(C 1~6 alkyl), -NHCONH2, -NHCO(C 1~6 alkyl) and -NR a R b is selected from Cy1 is a 4- to 12-membered heterocyclyl, optionally containing 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 C 3~8 selected from cycloalkyl, 4- to 12-membered heterocyclyl, aryl, and 5- to 14-membered heteroaryl; R4 is independently selected from halogen, -CN, -OH, oxo, -SH, C 1~6 Alkyl, C 2~6Alkenyl, C 2~6 Alkynyl, -O-(C 1~6 alkyl), -O-(C 1~6 haloalkyl), -O-(C 3~8 cycloalkyl), -O-(4- to 8-membered heterocyclyl), -(C 1~6 alkyl) m -(C 3~8 cycloalkyl), -(C 1~6 alkyl) m -(4- to 8-membered heterocyclyl), -(C 1~6 alkyl) m -phenyl, -(C 1~6 alkyl) m -(5-12 membered heteroaryl), -S-(C 1~6 alkyl), -S-(C 3~8 Cycloalkyl), -S-(4- to 8-membered heterocyclyl), -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 Selected from C 1~6 Alkyl, C 3~8 Cycloalkyl, 4- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl are each optionally selected from the group consisting of halogen, —OH, oxo, —SH, —CN, —NH, —CONH, 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 1~6haloalkyl), -O-(C 3~8 cycloalkyl), -O-(4- to 8-membered heterocyclyl), -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 substituted with one or more groups independently selected from cycloalkyl and 4- to 8-membered heterocyclyl; L is absent or L is C 1~6 alkyl or CO, R a , R b , R c , R d , R e and R f are each independently 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- to 8-membered heterocyclyl), -(C 1~6 alkyl) m -phenyl and -(C 1~6 alkyl) m -(5- to 12-membered heteroaryl), 1~6 Alkyl, C 3~8 Cycloalkyl, 4- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl are each optionally selected from the group consisting of halogen, —OH, oxo, —SH, —CN, —NH, —CONH, 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 1~6alkyl)-OH, -(C 1~6 alkyl)-CN, -O-(C 1~6 alkyl), -O-(C 1~6 haloalkyl), -O-(C 3~8 cycloalkyl), -O-(4- to 8-membered heterocyclyl), -S-(C 1~6 alkyl), -NH(C 1~6 alkyl), -N(C 1~6 alkyl)2, -NH(C 3~8 cycloalkyl), -NH(4- to 8-membered heterocyclyl), -CO(C 1~6 alkyl), -CO(C 2~6 alkenyl), -CO(C 2~6 alkynyl), -CO(C 3~8 cycloalkyl), -CO(4- to 8-membered heterocyclyl), -CONH(C 1~6 alkyl), -CONH(C 3~8 cycloalkyl), -CONH(4- to 8-membered heterocyclyl) and -CON(C 1~6 substituted with one or more groups independently selected from alkyl; p is 0, 1, 2, 3, 4 or 5; m is 0 or 1, A compound, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated form thereof, wherein n is 1 or 2.

[0064] Embodiment 1.1. Cy2 is C 3~8 cycloalkyl, 4- to 12-membered monocyclic or fused or bridged heterocyclyl, aryl and 5- to 14-membered heteroaryl, preferably Cy2 is C 3~8 The compound of embodiment 1, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, or a deuterated form thereof, wherein the compound is selected from cycloalkyl, 4- to 9-membered heterocyclyl, aryl, and 5- to 14-membered heteroaryl.

[0065] Embodiment 1.2. A compound according to embodiment 1 or 1.1, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated form thereof, wherein L is absent or L is CH2.

[0066] Embodiment 1.3.R f is —CH3, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, or a deuterated form thereof.

[0067] Embodiment 1.4. A compound according to any one of embodiments 1 to 1.3, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated form thereof, provided that R4 is not -NH (6-membered nitrogen-containing heteroaryl) or -NH (phenyl substituted with F), and further provided that R4 is not -NH (6-membered heteroaryl) or -NH (phenyl substituted with F).

[0068] Embodiment 2. R1 is halogen, CN or C 1~6 is haloalkyl, R2 is hydrogen, -O-(C 1~6 alkyl), C 3~8 Cycloalkyl, 4-8 membered heterocyclyl, 5-12 membered heteroaryl, -CONR a R b , -CSNR a R b , -COR c and -COOR e Selected from C 3~8 Cycloalkyl, 4- to 8-membered heterocyclyl, and 5- to 12-membered heteroaryl are each optionally selected from the group consisting of halogen, —OH, oxo, —CN, —NH, —CONH, C 1~6 Alkyl, C 1~6 Haloalkyl, -(C 1~6 alkyl)-O-(C 1~6 alkyl), -(C 1~6alkyl)-OH, -(C 1~6 alkyl)-CN, -O-(C 1~6 alkyl) and -O-(C 1~6 haloalkyl); R3 is hydrogen, or or R2 and R3 together with the carbon atom to which they are attached form a 5- to 6-membered heteroaryl, which 5- to 6-membered heteroaryl is optionally selected from the group consisting of C 1~6 substituted with one or more groups independently selected from alkyl; R5 is hydrogen, C 1~6 Alkyl and -NR a R b is selected from Cy1 is a 4- to 12-membered heterocyclyl; Cy2 is C 3~8 selected from cycloalkyl, 4- to 9-membered heterocyclyl, aryl, and 5- to 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- to 8-membered heterocyclyl), -(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 Selected from C1~6 Alkyl, C 3~8 Cycloalkyl, 4- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl are each optionally selected from the group consisting of halogen, —OH, oxo, —CN, —NH, —CONH, 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 substituted with one or more groups independently selected from cycloalkyl and 4- to 8-membered heterocyclyl; L is absent or L is CH; R a , R b , R c , R d and R e are each independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, -(C 1~6 alkyl) m -(C 3~8 cycloalkyl), -(C 1~6 alkyl) m -(4- to 8-membered heterocyclyl), -(C 1~6 alkyl) m -phenyl and -(C 1~6 alkyl) m -(5- to 12-membered heteroaryl), 1~6 Alkyl, C 3~8 Cycloalkyl, 4- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl are each optionally selected from the group consisting of halogen, —OH, —CN, —CONH, C 1~6 Alkyl, C 1~6Haloalkyl, -(C 1~6 alkyl)-OH, -O-(C 1~6 alkyl), -NH(C 3~8 cycloalkyl), -CO(C 2~6 alkenyl) and -CON(C 1~6 substituted with one or more groups independently selected from alkyl; R f is -CH3, p is 0, 1, 2, or 3; m is 0 or 1, n is 1 or 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 deuterated form thereof, with the proviso that R4 is not -NH (6-membered nitrogen-containing heteroaryl) or -NH (phenyl substituted with F), and further R4 is not -NH (6-membered heteroaryl) or -NH (phenyl substituted with F).

[0069] Embodiment 3. The compound is a compound of formula (I-1): [ka] During the ceremony, Z is N or CH, preferably Z is N; The compound of any one of embodiments 1-2, wherein n1, n2, n3, and n4 are each independently selected from 1 and 2, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, or a deuterated version thereof.

[0070] Embodiment 4. The compound is a compound of formula (I-2): [ka] wherein n5 and n6 are each independently selected from 1 and 2, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, or a deuterated version thereof.

[0071] Embodiment 5. A compound according to any one of embodiments 1 to 4, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated form thereof, wherein R1 is halogen, preferably R1 is F or Cl, more preferably R1 is F.

[0072] Embodiment 6. R2 is hydrogen, —O—(C 1~6 alkyl), C 3~8 Cycloalkyl, 4-8 membered heterocyclyl, 5-12 membered heteroaryl, -CONR a R b , -CSNR a R b , -COR c and -COOR e Selected from R a , R b , R c and R e are each independently 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- to 8-membered heterocyclyl; 3~8 Cycloalkyl, 4- to 8-membered heterocyclyl, and 5- to 12-membered heteroaryl are each optionally selected from the group consisting of halogen, —OH, oxo, —CN, —NH, —CONH, C 1~6 Alkyl, C 1~6 Haloalkyl, -(C 1~6 alkyl)-O-(C 1~6 alkyl), -(C 1~6 alkyl)-OH, -(C 1~6alkyl)-CN, -O-(C 1~6 alkyl) and -O-(C 1~6 haloalkyl); Preferably, R2 is hydrogen, —O—(C 1~6 alkyl), C 3~6 Cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, -CONR a R b , -CSNR a R b , -COR c and -COOR e Selected from R a , R b , R c and R e However, each independently, C 1~6 Alkyl, C 3~6 cycloalkyl and 4- to 6-membered heterocyclyl; 3~6 Cycloalkyl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl are each optionally selected from halogen, —OH, and C 1~6 substituted with one or more groups independently selected from alkyl; More preferably, R2 is -COO(C 1~6 alkyl) and -CON(C 1~6 alkyl)2; Most preferably, R2 is -CON(C 1~6 or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, or a deuterated form thereof, wherein R is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 39, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 6

[0073] Embodiment 7. A compound according to embodiment 1, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, or a deuterated form thereof, wherein R3 is hydrogen.

[0074] Embodiment 8. R2 and R3 together with the carbon atom to which they are attached form a 5-6 membered heteroaryl, which 5-6 membered heteroaryl is optionally selected from the group consisting of C1~6 alkyl, preferably R and R taken together with the carbon atom to which they are attached form a pyrazolyl, which pyrazolyl is optionally substituted with one or more groups independently selected from C 1~6 The compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, or a deuterated form thereof, wherein the compound is substituted with one or more groups independently selected from alkyl.

[0075] Embodiment 9. R5 is hydrogen, C 1~6 Alkyl, -NH2, -NH(C 1~6 alkyl) and -N(C 1~6 alkyl)2, preferably R5 is selected from hydrogen, C 1~6 Alkyl, and -NH(C 1~6 or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, or a deuterated form thereof, wherein R5 is selected from the group consisting of: alkyl;

[0076] Embodiment 10. A compound according to any one of embodiments 1 to 9, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, or a deuterated form thereof, wherein L is CH2.

[0077] Embodiment 11. Cy2 is C 3~8 cycloalkyl, 4- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl, preferably Cy2 is C 3~6 The compound of any one of embodiments 1 to 10, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, or a deuterated form thereof, wherein the compound is selected from cycloalkyl, 4- to 6-membered heterocyclyl, phenyl, 5- to 6-membered heteroaryl, and 8- to 10-membered heteroaryl.

[0078] Embodiment 12. The compound of embodiment 11, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, or deuterated form thereof, wherein Cy2 is selected from cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl, pyrrolidyl, piperidyl, piperazinyl, phenyl, pyridyl, pyridinonyl, pyrimidyl, indolyl, indazolyl, benzofuranyl, benzoxazolyl, imidazopyridyl, quinolinyl, quinolinonyl, quinazolinyl, and dihydro-[1,4]dioxinopyridyl.

[0079] Embodiment 13. Cy2 is [ka] is selected from Preferably, Cy2 is [ka] is selected from More preferably, Cy2 is [ka] or Cy2 is [ka] or Cy2 is [ka] or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, or a deuterated form thereof.

[0080] Embodiment 14. R4 is independently halogen, -CN, -OH, oxo, C 1~6 Alkyl, -O-(C 1~6 alkyl), -(C 1~6 alkyl) m -(C 3~8 cycloalkyl), -(C1~6 alkyl) m -(4- to 8-membered heterocyclyl), -(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 Selected from C 1~6 Alkyl, C 3~8 Cycloalkyl, 4- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl are each optionally selected from the group consisting of halogen, —OH, oxo, —CN, —NH, —CONH, 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 substituted with one or more groups independently selected from cycloalkyl and 4- to 8-membered heterocyclyl; 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- to 8-membered heterocyclyl), -(C 1~6alkyl) 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 Selected from C 1~6 Alkyl, 4- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl are each optionally selected from the group consisting of halogen, —OH, oxo, —CN, —NH, —CONH, 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 substituted with one or more groups independently selected from cycloalkyl; A compound according to any one of embodiments 1 to 13, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated form thereof, provided that R4 is not -NH (6-membered nitrogen-containing heteroaryl) or -NH (phenyl substituted with F), and further provided that R4 is not -NH (6-membered heteroaryl) or -NH (phenyl substituted with F).

[0081] Embodiment 15. R4 independently represents: 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; 1~6 Alkyl, 6)-O-(C 1~6 alkyl), 7)-(C 1~6 alkyl) m -(4- to 6-membered heterocyclyl), preferably, the 4- to 6-membered heterocyclyl is selected from oxetanyl and dihydropyranyl; 1~6 alkyl) m -(4- to 6-membered heterocyclyl), 8)-(C 1~6 alkyl) m -phenyl, wherein the phenyl is optionally substituted with one or more groups independently selected from -CN, -(C 1~6 alkyl) m -phenyl, 9)-(C 1~6 alkyl) m -(5-12 membered heteroaryl), preferably, the 5-12 membered heteroaryl is selected from 5- to 6-membered heteroaryl and 8- to 10-membered heteroaryl, more preferably, the 5- to 12 membered heteroaryl is selected from pyrazolyl, oxazolyl, pyridyl, pyridinonyl, pyrimidyl, pyridazinyl, pyridazinonyl, pyrazinyl, 1,2,4-triazinyl, indolyl, imidazopyridazinyl, [1,2,4]triazolopyridyl, pyrazolopyrimidyl, dihydropyrimidopyridazinyl, and dihydro-[1,4]dioxinopyridazinyl, most preferably, the 5- to 12 membered heteroaryl is selected from pyridyl and pyridazinyl; The 5- to 12-membered heteroaryl is optionally selected from the group consisting of halogen, —OH, oxo, —CN, —NH, —CONH, 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, and preferably 5-12 membered heteroaryl, optionally substituted with one or more groups independently selected from halogen, —OH, —CN, —CONH, C 1~6 Alkyl, C 2~6 Alkenyl, C2~6 Alkynyl, C 1~6 Haloalkyl, -(C 1~6 alkyl)-OH, -O-(C 1~6 alkyl) and C 3~8 substituted with one or more groups independently selected from cycloalkyl, -(C 1~6 alkyl) m -(5- to 12-membered heteroaryl), 10)-CONR a R b and R a and R b are each independently hydrogen, C 1~6 Alkyl, -(C 1~6 alkyl) m -(C 3~6 cycloalkyl), -(C 1~6 alkyl) m -(4- to 6-membered heterocyclyl), -(C 1~6 alkyl) m -phenyl and -(C 1~6 alkyl) m -(5- to 6-membered heteroaryl), 1~6 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl are each optionally substituted with halogen and —O—(C 1~6 alkyl), -CONR a R b , 11)-COR c and R c But C 1~6 Alkyl, C 2~6 Alkenyl, -(C 1~6 alkyl) m -(C 3~8 cycloalkyl), -(C 1~6 alkyl) m -(4- to 6-membered heterocyclyl), -(C 1~6 alkyl) m -phenyl and -(C 1~6 alkyl) m -(5- to 10-membered heteroaryl), 1~6 Alkyl, C 3~8Cycloalkyl, 4- to 6-membered heterocyclyl, phenyl, and 5- to 10-membered heteroaryl are each optionally substituted with halogen, —OH, —CN, C 1~6 Alkyl, C 1~6 Haloalkyl, -O-(C 1~6 alkyl), -NH(C 3~6 cycloalkyl), -CO(C 2~6 alkenyl) and -CON(C 1~6 -COR c , 12)-COOR e and R e But hydrogen and C 1~6 alkyl, -COOR e , 13)-NR a R b and R a and R b are each independently hydrogen, C 1~6 Alkyl and -(C 1~6 alkyl) m -(5- to 10-membered heteroaryl), 1~6 The alkyl and 5- to 10-membered heteroaryl are each optionally selected from halogen, —OH, —CN, —CONH, C 1~6 Alkyl, -(C 1~6 alkyl)-OH and -O-(C 1~6 substituted with one or more groups independently selected from -N, -N- ... a R b , 14)-NR d COR c and R d But hydrogen and C 1~6 alkyl, and R c optionally, -CN and -O-(C 1~6 alkyl), C 1~6 alkyl, -NR d COR c , 15)-NR d S(O) n R f and R d is hydrogen and R f is -CH3, -NR d S(O) n R f , 16)-S(O) n R f and R f is -CH3, -S(O) n R f or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, or a deuterated form thereof.

[0082] Embodiment 16. The compound is a compound of formula (I-3): [ka] During the ceremony, n1, n2, n3 and n4 are each independently selected from 1 and 2, preferably both n1 and n2 are 1 and both n3 and n4 are 2; R1 is halogen, preferably R1 is F or Cl, more preferably R1 is F; R2 is hydrogen, -O-(C 1~6 alkyl), C 3~8 Cycloalkyl, 4-8 membered heterocyclyl, 5-12 membered heteroaryl, -CONR a R b , -CSNR a R b , -COR c and -COOR e Selected from R a , R b , R c and R e are each independently hydrogen, 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, C 3~8 cycloalkyl and 4- to 8-membered heterocyclyl; 3~8 Cycloalkyl, 4- to 8-membered heterocyclyl, and 5- to 12-membered heteroaryl are each optionally selected from the group consisting of halogen, —OH, oxo, —CN, —NH, —CONH, 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), and preferably R2 is hydrogen, —O—(C 1~6 alkyl), C 3~6 Cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, -CONR a R b , -CSNR a R b , -COR c and -COOR e Selected from R a , R b , R c and R e However, each independently, C 1~6 Alkyl, C 3~6 cycloalkyl and 4- to 6-membered heterocyclyl; 3~6 Cycloalkyl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl are each optionally selected from halogen, —OH, and C 1~6 alkyl, and more preferably R2 is substituted with one or more groups independently selected from -COO(C 1~6 alkyl) and -CON(C 1~6 alkyl)2, most preferably R2 is selected from -CON(C 1~6 alkyl)2, R3 is hydrogen, or or R2 and R3 together with the carbon atom to which they are attached form a 5- to 6-membered heteroaryl, which 5- to 6-membered heteroaryl is optionally selected from the group consisting of C 1~6 alkyl, preferably R and R taken together with the carbon atom to which they are attached form a pyrazolyl, which pyrazolyl is optionally substituted with one or more groups independently selected from C 1~6 substituted with one or more groups independently selected from alkyl; R5 is hydrogen, C 1~6 Alkyl, -NH2, -NH(C 1~6 alkyl) and -N(C 1~6 alkyl)2, preferably R5 is selected from hydrogen, C 1~6 Alkyl, and -NH(C 1~6 alkyl), more preferably R5 is hydrogen; Cy2 is C 3~6 Cy2 is selected from cycloalkyl, 4- to 6-membered heterocyclyl, phenyl, 5- to 6-membered heteroaryl and 8- to 10-membered heteroaryl, preferably Cy2 is selected from cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl, pyrrolidyl, piperidyl, piperazinyl, phenyl, pyridyl, pyridinonyl, pyrimidyl, indolyl, indazolyl, benzofuranyl, benzoxazolyl, imidazopyridyl, quinolinyl, quinolinonyl, quinazolinyl and dihydro-[1,4]dioxinopyridyl, more preferably Cy2 is selected from [ka] and most preferably Cy2 is selected from: [ka] and R4 is independently selected from halogen, -CN, -OH, oxo, C 1~6 Alkyl, -O-(C 1~6 alkyl), -(C 1~6 alkyl) m -(4- to 8-membered heterocyclyl), -(C 1~6 alkyl) m -phenyl, -(C1~6 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 Selected from C 1~6 Alkyl, 4- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl are each optionally selected from the group consisting of halogen, —OH, oxo, —CN, —NH, —CONH, 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 R4 is independently substituted with one or more groups 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; 1~6 Alkyl, 6)-O-(C 1~6 alkyl), 7)-(C 1~6 alkyl) m -(4- to 6-membered heterocyclyl), preferably, the 4- to 6-membered heterocyclyl is selected from oxetanyl and dihydropyranyl; 1~6 alkyl) m -(4- to 6-membered heterocyclyl), 8)-(C 1~6 alkyl) m-phenyl, wherein the phenyl is optionally substituted with one or more groups independently selected from -CN, -(C 1~6 alkyl) m -phenyl, 9)-(C 1~6 alkyl) m -(5-12 membered heteroaryl), preferably, the 5-12 membered heteroaryl is selected from 5- to 6-membered heteroaryl and 8- to 10-membered heteroaryl, more preferably, the 5- to 12 membered heteroaryl is selected from pyrazolyl, oxazolyl, pyridyl, pyridinonyl, pyrimidyl, pyridazinyl, pyridazinonyl, pyrazinyl, 1,2,4-triazinyl, indolyl, imidazopyridazinyl, [1,2,4]triazolopyridyl, pyrazolopyrimidyl, dihydropyrimidopyridazinyl, and dihydro-[1,4]dioxinopyridazinyl, most preferably, the 5- to 12 membered heteroaryl is selected from pyridyl and pyridazinyl; The 5- to 12-membered heteroaryl is optionally selected from the group consisting of halogen, —OH, oxo, —CN, —NH, —CONH, 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, and preferably 5-12 membered heteroaryl, optionally substituted with one or more groups independently selected from halogen, —OH, —CN, —CONH, 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 -(Ci_6 alkyl)m-(5- to 12-membered heteroaryl) substituted with one or more groups independently selected from cycloalkyl; 10)-CONR a R b and R a and R bare each independently hydrogen, C 1~6 Alkyl, -(C 1~6 alkyl) m -(C 3~6 cycloalkyl), -(C 1~6 alkyl) m -(4- to 6-membered heterocyclyl), -(C 1~6 alkyl) m -phenyl and -(C 1~6 alkyl) m -(5- to 6-membered heteroaryl), 1~6 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl are each optionally substituted with halogen and —O—(C 1~6 alkyl), -CONR a R b , 11)-COR c and R c But C 1~6 Alkyl, C 2~6 Alkenyl, -(C 1~6 alkyl) m -(C 3~8 cycloalkyl), -(C 1~6 alkyl) m -(4- to 6-membered heterocyclyl), -(C 1~6 alkyl) m -phenyl and -(C 1~6 alkyl) m -(5- to 10-membered heteroaryl), 1~6 Alkyl, C 3~8 Cycloalkyl, 4- to 6-membered heterocyclyl, phenyl, and 5- to 10-membered heteroaryl are each optionally substituted with halogen, —OH, —CN, C 1~6 Alkyl, C 1~6 Haloalkyl, -O-(C 1~6 alkyl), -NH(C 3~6 cycloalkyl), -CO(C 2~6 alkenyl) and -CON(C 1~6 -COR c , 12)-COOR e and R e But hydrogen and C 1~6 alkyl, -COOR e , 13)-NR a R b and R a and R b are each independently hydrogen and C 1~6 alkyl, C 1~6 Alkyl is optionally selected from -CN and -O-(C 1~6 alkyl), -NR a R b , 14)-NR d COR c and R d But hydrogen and C 1~6 alkyl, and R c optionally, -CN and -O-(C 1~6 C substituted with one or more groups independently selected from 1~6 alkyl, -NR d COR c , 15)-NR d S(O) n R f and R d is hydrogen and R f is -CH3, -NR d S(O) n R f , 16)-S(O) n R f and R f is -CH3, -S(O) n R f , selected from L is CH2, p is 0, 1, 2, or 3; m is 0 or 1, The compound of embodiment 1, wherein n is 1 or 2, preferably n is 2, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, or a deuterated form thereof.

[0083] Embodiment 17. The compound is a compound of formula (I-4): [ka] During the ceremony, n5 and n6 are each independently selected from 1 and 2, preferably both n5 and n6 are 1; R1 is halogen, preferably R1 is F; R2 is -CON(C 1~6 alkyl)2, R3 is hydrogen, R5 is hydrogen; Cy2 is C 3~8 cycloalkyl and 4- to 8-membered heterocyclyl, preferably Cy2 is selected from cyclopropyl and pyrrolidyl, more preferably Cy2 is [ka] and most preferably Cy2 is selected from: [ka] and R4 is independently -(C 1~6 alkyl) m -(5- to 12-membered heteroaryl) and -NR a R b wherein the 5- to 12-membered heteroaryl is optionally selected from -CN and C 1~6 alkyl, preferably R4 is independently selected from 1)-(C 1~6 alkyl)-indolyl, wherein indolyl is optionally selected from -CN and C 1~6 substituted with one or more groups independently selected from alkyl, -(C1~6 alkyl)-indolyl, 2)-NR a R b and R a and R b are each independently hydrogen, C 1~6 Alkyl and -(C 1~6 alkyl) m -(5- to 10-membered heteroaryl), 1~6 The alkyl and 5- to 10-membered heteroaryl are each optionally selected from —OH, —CN, C 1~6 Alkyl, and -(C 1~6 -NH (6-membered nitrogen-containing heteroaryl), and substituted with one or more groups independently selected from -NR a R b , selected from p is 1 or 2, preferably p is 1; The compound of embodiment 1, wherein m is 0 or 1, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, or a deuterated form thereof.

[0084] Embodiment 18. A compound selected from the following: or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, or a deuterated form thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10]

[0085] Embodiment 19. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 18 and / or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

[0086] Embodiment 20. A method of inhibiting menin-MLL interaction in vivo or in vitro, comprising contacting menin with an effective amount of a compound of any one of embodiments 1 to 18 and / or a pharmaceutically acceptable salt thereof.

[0087] Embodiment 21. Use of a compound according to any one of embodiments 1 to 18 and / or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease mediated by, or at least in part through, menin-MLL interaction, wherein the disease mediated by, or at least in part through menin-MLL interaction is preferably cancer, wherein the cancer is preferably a hematological malignancy or a solid tumor, including leukemia, lymphoma, and myeloma, and more preferably acute leukemia, chronic leukemia, myeloid leukemia, myelogenous 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 prolymphocyte leukemia (T-ALL), or T-cell lymphoma. Myeloid 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-mutated leukemia, leukemia with HOX / MEIS1 gene expression signature, myelodysplastic syndrome (MDS), bone marrow leukemia The use is selected from myeloproliferative neoplasms (MPN), multiple myeloma (MM), Hodgkin's lymphoma, non-Hodgkin's 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, and glioblastoma (GBM).

[0088] Embodiment 22. A method for treating or preventing a disease in a subject, comprising administering to a subject in need thereof an effective amount of a compound according to any one of embodiments 1 to 18 and / or a pharmaceutically acceptable salt thereof, wherein the disease is a disease mediated, or at least in part mediated, by menin-MLL interaction, and the disease is preferably cancer, and the cancer is preferably a hematological malignancy or solid tumor, including leukemia, lymphoma, and myeloma, and more preferably 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-PL), L), chronic lymphocytic leukemia (CLL), chronic myelocytic 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-mutated leukemia, leukemia with HOX / MEIS1 gene expression signature, myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), multiple myeloma (MM), Hodgkin's lymphoma, non-Hodgkin's 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, and glioblastoma (GBM).

[0089] Embodiment 23. A compound according to any one of embodiments 1 to 18 and / or a pharmaceutically acceptable salt thereof for use as a pharmaceutical.

[0090] Embodiment 24. A compound according to any one of embodiments 1 to 18 and / or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease mediated by, or at least in part through, menin-MLL interaction, wherein the disease is preferably cancer, and the cancer is preferably a hematological malignancy or a solid tumor, including leukemia, lymphoma, and myeloma, and more preferably acute leukemia, chronic leukemia, myeloid leukemia, myelogenous 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 lymphocyte leukemia, and / or large granular lymphocyte leukemia. Myeloid leukemia, hairy cell leukemia (HCL), mixed lineage leukemia (MLL), MLL-related leukemia, MLL-rearranged leukemia (MLL-r), MLL-PTD leukemia, MLL-positive leukemia, NPM1-mutated leukemia, leukemia showing HOX / MEIS1 gene expression signature, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), multiple myeloma (MM), Hodgkin's lymphoma, non-Hodgkin's lymphoma, 19. The compound of any one of embodiments 1-18 and / or a pharmaceutically acceptable salt thereof, selected from 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, and glioblastoma (GBM).

[0091] Embodiment 25. A pharmaceutical combination comprising a compound according to any one of embodiments 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 active agent, an anti-inflammatory agent, or an immunomodulatory agent, and the anti-tumor active agent includes a chemotherapeutic agent, an immune checkpoint inhibitor or agonist, and a targeted therapeutic agent.

[0092] Embodiment 26. A compound of formula (II): [ka] or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated form thereof, wherein: R6 is an amino protecting group, preferably R6 is an amino protecting group selected from Boc (tert-butoxycarbonyl), benzyl, Pmb (p-methoxybenzyl) and Cbz (benzyloxycarbonyl), more preferably R6 is Boc (tert-butoxycarbonyl); X1 is halogen, preferably X1 is chlorine; A compound, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated form thereof, wherein X2 is hydrogen or halogen, preferably X2 is hydrogen or chlorine, more preferably X2 is chlorine.

[0093] Embodiment 27. The compound of embodiment 26, wherein: [ka] or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated form thereof.

[0094] Embodiment 28. A compound of formula (III): [ka] or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated form thereof, wherein: R1, R2, R3 and R5 are as defined in any one of embodiments 1 to 17; A compound, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated form thereof, wherein R7 is hydrogen or an amino protecting group, preferably R7 is hydrogen or an amino protecting group selected from Boc (tert-butoxycarbonyl), benzyl, Pmb (p-methoxybenzyl) and Cbz (benzyloxycarbonyl), more preferably R7 is hydrogen or Boc (tert-butoxycarbonyl).

[0095] Embodiment 28.1. A compound according to embodiment 28, wherein R5 is H or Cl and R2 is not C(O)N(CH(CH3)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), -C(O)N(CH(CH3)2)(cyclopropyl), -C(O)N(CH2CH3)(cyclopropyl), -C(O)N(CH(CH3)2)(cyclobutyl), pyrimidyl substituted with isopropyl, and pyrazolyl substituted with isopropyl and / or Cl.

[0096] Embodiment 29. The compound of embodiment 28, selected from: [Table 2] or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated form thereof.

[0097] The various embodiments of the present invention (including the examples below) and the features of the various embodiments are to be construed as being in any combination with one another, and the various solutions resulting from these mutual combinations are all included within the scope of the present invention, as are the solutions resulting from the mutual combinations that are specifically and individually described herein, unless the context clearly dictates otherwise.

[0098] Beneficial effects of the present invention: As mentioned above, the binding and interaction between MLL fusion proteins and menin proteins is known to be crucial for MLL proteins to exert their oncogenic functions. Inhibition or interference with MLL-menin interaction can significantly inhibit cell proliferation in MLL fusion protein-associated cancer diseases. The present inventors have surprisingly found that compounds of the present invention having the above-described structural features can significantly inhibit the binding activity of menin and MLL proteins and potently inhibit cell proliferation in cell lines harboring mutations, thereby having potential value as antiproliferative, proapoptotic, and / or anti-invasive pharmaceuticals for preventing, suppressing, and / or treating diseases mediated, or at least in part, by menin-MLL interaction, such as cancers or tumors as defined herein.

[0099] Specifically, studies have 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, particularly the compounds of the examples herein, exhibit inhibitory activity against protein binding at the molecular level in MLL and menin protein binding assays (fluorescence polarization method), with IC50 values ​​generally ranging from 0.1 nM to 10 μM, for example, from 0.1 nM to 5 μM, preferably from 0.1 nM to 1 μM, more preferably from 0.1 nM to 100 nM, and most preferably from 0.1 nM to 50 nM, as verified in Example 3; Potent cell proliferation inhibitory activity: The compounds of the present invention, particularly the compounds of the Examples herein, exhibit potent proliferation inhibitory 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, for example, 0.1 nM to 5 μM, preferably 0.1 nM to 1 μM, more preferably 1 nM to 100 nM, and most preferably 1 nM to 50 nM, as verified in Example 4; expected favorable pharmacokinetic properties; and Expected satisfactory safety and fewer toxicities and side effects.

[0100] General synthesis method The compounds of formula (I) and / or pharmaceutically acceptable salts thereof described herein can be synthesized by methods known in the art or disclosed in this patent application using commercially available starting materials. The synthetic routes shown in Schemes 1-3 illustrate general methods for synthesizing the compounds of the present invention.

[0101] Method 1: [ka] As shown in Scheme 1, a compound of formula (1-1) is subjected to a substitution reaction with a compound of formula (1-2) under alkaline conditions (e.g., but not limited to, triethylamine) to give a compound of formula (1-3). A compound of formula (1-3) is subjected to a substitution reaction with a compound of formula (1-4) under alkaline conditions (e.g., but not limited to, DBU) to give a compound of formula (1-5). The compound of formula (1-5) is reduced and dechlorinated under the action of a catalyst (e.g., but not limited to, Pd / C) to give a compound of formula (1-6), which is converted to a compound of formula (1-7) by a Boc-removal reaction under acidic conditions (e.g., but not limited to, HCl). The compound of formula (1-7) is then subjected to a reductive amination reaction with a compound of formula (1-8) under the action of a reducing agent (e.g., but not limited to, sodium triacetoxyborohydride, sodium cyanoborohydride, etc.) to obtain a compound of formula (I-3) (wherein R5 = H and L = CH2). Alternatively, the compound of formula (1-7) is subjected to a condensation reaction with a compound of formula (1-9) under the action of a condensing agent (e.g., but not limited to, HATU) to obtain a compound of formula (I-3) (wherein R5 = H and L = CO). R1, R2, R3, R4, Cy2, n1, n2, n3, n4, and p are as defined herein.

[0102] Method 2: [ka] As shown in Scheme 2, a compound of formula (1-5) can be subjected to a substitution reaction with a compound of formula (2-1) under alkaline conditions (e.g., but not limited to, triethylamine) to give a compound of formula (2-3) (wherein R5 = -NR a R b Alternatively, the compound of formula (1-5) can be coupled with a compound of formula (2-2) under the catalysis of a palladium reagent (such as, but not limited to, Pd(PPh3)4) to produce a compound of formula (2-3) (wherein R5 = C 1~6 The compound of formula (2-3) (wherein R5=-NR a R b or R5=C 1~6 The compound of formula (2-4) is then subjected to a reductive amination reaction with a compound of formula (2-5) under the action of a reducing agent (e.g., but not limited to, sodium triacetoxyborohydride, sodium cyanoborohydride, etc.) to give a compound of formula (I-3) (wherein L = CH2 and R5 = -NR a R b or R5=C 1~6 R1, R2, R3, R4, R a , R b , Cy2, n1, n2, n3, n4 and p are as defined herein, and M is a boronic anhydride, borate or boronic acid.

[0103] Method 3: [ka] As shown in Scheme 3, a compound of formula (1-1) is subjected to a substitution reaction with a compound of formula (3-1) under alkaline conditions (e.g., but not limited to, triethylamine) to give a compound of formula (3-2). A compound of formula (3-2) is subjected to a substitution reaction with a compound of formula (3-3) under alkaline conditions (e.g., but not limited to, DBU) to give a compound of formula (3-4). The compound of formula (3-4) is reduced and dechlorinated under the action of a catalyst (e.g., but not limited to, Pd / C) to give a compound of formula (3-5). The compound of formula (3-5) is subjected to a Boc removal reaction under acidic conditions (e.g., but not limited to, HCl) to give a compound of formula (3-6). The compound of formula (3-6) is then subjected to reductive amination with a compound of formula (3-7) under the action of a reducing agent (such as, but not limited to, sodium triacetoxyborohydride, sodium cyanoborohydride, etc.) to give a compound of formula (I-4) (wherein R5 = H), where R1, R2, R3, R4, Cy2, n5, n6, and p are as defined herein.

[0104] The substituents of the compounds thus obtained can be further modified to give other desired compounds. Synthetic chemical transformations are described, for example, in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions.

[0105] Prior to use, the compound(s) of the invention may be purified by column chromatography, high performance liquid chromatography, crystallization, or other suitable method.

[0106] Pharmaceutical Compositions and Uses A compound of the invention (e.g., any of the compounds of the Examples described herein) is used alone or in combination with one or more additional therapeutic agents to formulate a pharmaceutical composition comprising (a) an effective amount of a compound of the invention, (b) a pharmaceutically acceptable excipient (e.g., one or more pharmaceutically acceptable carriers), and, optionally, (c) at least one additional therapeutic agent.

[0107] Pharmaceutically acceptable excipients refer to excipients that are compatible with the active ingredients of the composition (and in some embodiments, can stabilize the active ingredients) and are not harmful to the subject being treated. For example, solubilizing agents such as cyclodextrins (which form specific, more soluble complexes with the compounds of the present invention) can be used as pharmaceutical excipients for delivering the active ingredients. Other examples of excipients include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments such as D&C Yellow #10. Suitable pharmaceutical excipients are disclosed in Remington's Pharmaceutical Sciences, a standard reference text in the field.

[0108] Pharmaceutical compositions containing compounds of the present invention can be administered in a variety of known ways, such as orally, topically, rectally, parenterally, by inhalation spray, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0109] The pharmaceutical compositions described herein can be prepared in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories. In some embodiments, pharmaceutical compositions containing the compounds of the present invention are formulated for intravenous infusion, topical administration, or oral administration.

[0110] Oral compositions can be any orally acceptable dosage form, including but not limited to tablets, capsules, emulsions, and aqueous suspensions, dispersions and solutions.The carriers commonly used for tablets include lactose and cornstarch.Lubricants such as magnesium stearate are also usually added to tablets.For oral administration in capsule form, useful diluents include lactose and dry cornstarch.When aqueous suspensions or emulsions are orally administered, active ingredients can be suspended or dissolved in an oil phase combined with emulsifiers or suspending agents.If desired, certain sweeteners, flavorings or colorings can be added.

[0111] In some embodiments, the compounds of the present invention can be present in tablets in amounts of 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 compounds of the present invention can be present in capsules in amounts of 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, 100, 125, 150, 200, 250, 300, 400, and 500 mg.

[0112] Sterile injectable compositions (e.g., aqueous or oleaginous suspensions) can be formulated according to techniques known in the art using suitable dispersing or wetting agents (e.g., Tween 80) and suspending agents. Sterile injectable compositions can also be provided as sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among the pharmaceutically acceptable vehicles and solvents that can be used are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as solvents or suspending media (e.g., synthetic mono- or diglycerides). Fatty acids (e.g., oleic acid and its glyceride derivatives) and natural pharmaceutically acceptable oils (e.g., olive oil or castor oil, especially their polyoxyethylated versions) can be used as sterile injectable media. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, or carboxymethylcellulose or similar dispersing agents.

[0113] Inhalation compositions may be prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0114] Topical compositions can be formulated in the form of oils, creams, lotions, ointments, etc. Suitable carriers for the compositions include vegetable or mineral oils, white petrolatum (white soft paraffin), branched-chain fats or oils, animal fats, and high molecular weight alcohols (greater than C12). In some embodiments, the pharmaceutically acceptable carrier is one in which the active ingredient is soluble. Emulsifiers, stabilizers, humectants, and antioxidants may also be included, as well as agents imparting color or fragrance, if desired. Additionally, transdermal penetration enhancers may be used in these topical formulations. Examples of such enhancers can be found in U.S. Pat. Nos. 3,989,816 and 4,444,762.

[0115] Cream can be formulated from a mixture of mineral oil, self-emulsifying beeswax and water, into which the active ingredient dissolved in a small amount of oil (e.g., almond oil) is mixed.An example of such a cream is one that contains, by weight, about 40 parts water, about 20 parts beeswax, about 40 parts mineral oil and about 1 part almond oil.Ointment can be formulated 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 such an ointment is one that contains about 30% by weight of almond oil and about 70% by weight of white soft paraffin.

[0116] The effectiveness of the compounds of the present invention in inhibiting menin-MLL interaction can be evaluated using suitable in vitro assays. Compounds of the present invention can also be tested for their effectiveness in preventing or treating cancer by in vivo assays. For example, compounds of the present invention can be administered to animals (e.g., mouse models) with cancer, and their therapeutic effects can be evaluated. If preclinical results are successful, dosage ranges and routes of administration for animals, such as humans, can be predicted.

[0117] Compounds of the invention may be shown to have sufficient preclinical utility to merit clinical trials, for example, where they are expected to demonstrate beneficial therapeutic or prophylactic effects in subjects with cancer.

[0118] As used herein, the term "cancer" refers to a cellular disorder characterized by uncontrolled or unregulated cell proliferation, reduced cell differentiation, inappropriate ability to invade surrounding tissues, and / or the ability to grow de novo at ectopic sites. The term "cancer" includes, but is not limited to, solid tumors and hematological malignancies, such as leukemia, lymphoma, or myeloma. The term "cancer" encompasses diseases of the skin, tissues, organs, bone, cartilage, blood, and blood vessels. The term "cancer" further encompasses primary cancers, metastatic cancers, recurrent cancers, and refractory cancers.

[0119] 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 carcinoma, bronchioloalveolar carcinoma (BAC), and adenocarcinoma of the lung; ovarian cancer, including, for example, advanced epithelial carcinoma or primary peritoneal carcinoma; cervical cancer; These include endometrial cancer; gastric cancer; esophageal cancer; cholangiocarcinoma; 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 carcinoma; mesothelioma; mesothelial carcinoma; choriocarcinoma; muscle carcinoma; connective tissue cancer; and thyroid cancer.

[0120] Non-limiting examples of hematological malignancies include acute leukemia; chronic leukemia; myeloid leukemia; myeloid leukemia; lymphocytic leukemia; chronic lymphocytic leukemia; lymphoblastic leukemia; acute lymphoblastic leukemia; acute myeloid leukemia (AML); juvenile acute myeloid leukemia; chronic myeloid leukemia (CML), including accelerated-phase CML and blastic phase CML (CML-BP); acute lymphocytic leukemia (ALL); T-cell acute lymphocytic leukemia; B-cell Acute lymphocytic leukemia (B-ALL); T-cell prolymphocytic leukemia (T-PLL); chronic lymphocytic leukemia (CLL), including high-risk CLL; chronic myeloid leukemia; large granular lymphocytic leukemia; human acute monocytic leukemia (M(5)); hairy cell leukemia (HCL); mixed lineage leukemia (MLL); MLL-related leukemia; MLL-rearranged leukemia (MLL-r); MLL-PTD leukemia; MLL-positive leukemia; NPM1 mutation Leukemias showing 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 lymphoma; These include non-Burkitt's high-grade B-cell malignant lymphoma; extranodal marginal zone B-cell lymphoma; multiple myeloma (MM); Waldenstrom's macroglobulinemia; myeloproliferative neoplasms (MPN); myelodysplastic syndromes, including refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), and refractory anemia with excess blasts in transition (RAEB-T); and myeloproliferative syndromes.

[0121] In some embodiments, the solid tumor is prostate cancer, breast cancer, lung cancer, liver cancer, colon cancer, colorectal cancer, pancreatic cancer, melanoma, glioblastoma (GBM).

[0122] In some embodiments, the hematological malignancy is 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, and the like. These include: associated leukemia, MLL-rearranged leukemia (MLL-r), MLL-PTD leukemia, MLL-positive leukemia, NPM1-mutated leukemia, leukemia with HOX / MEIS1 gene expression signature, myelodysplastic syndromes (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), and Waldenstrom's macroglobulinemia.

[0123] The compounds of the invention can be used, for example, to achieve a beneficial therapeutic or prophylactic effect in subjects with cancer.

[0124] In addition, a compound of the present invention (e.g., a compound of any of the Examples described herein) can be administered in combination with an additional therapeutic agent for the treatment of a disease or disorder described herein, such as cancer. The additional therapeutic agent may be administered separately from the compound of the present invention or may be included with the components of a pharmaceutical composition according to the present disclosure, e.g., a fixed-dose combination pharmaceutical. In some embodiments, the additional therapeutic agent is one known or discovered to be effective in treating a disease mediated, at least in part, by menin-MLL interaction, such as another menin inhibitor or a compound active against another target relevant to the particular disease. The combination may serve to increase efficacy (e.g., by including in the combination a compound that enhances the efficacy or effectiveness of the compound of the present invention), reduce one or more side effects, or reduce the required dose of the compound of the present invention.

[0125] In some embodiments, a compound of the present invention (e.g., any of the compounds of the Examples described herein) can be administered in combination with an additional therapeutic agent, such as an anti-tumor active agent, an anti-inflammatory agent, or an immunomodulatory agent, including chemotherapeutic agents, immune checkpoint inhibitors or agonists, and targeted therapeutic agents. As used herein, the term "anti-tumor active agent" refers to any agent (including, but not limited to, chemotherapeutic agents, immune checkpoint inhibitors or agonists, and targeted therapeutic agents) administered to a subject suffering from cancer for the purpose of treating the cancer.

[0126] 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, idarubicin, and daunorubicin); alkylating agents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, carmustine, lomustine, semustine, streptozocin, dacarbazine, methotrexate, mitomycin C, and cyclophosphamide). DNA intercalators (e.g., cisplatin, oxaliplatin, and carboplatin); free radical generators such as bleomycin; nucleoside mimetics (e.g., 5-fluorouracil, capecitabine, gemcitabine, fludarabine, cytarabine, azacitidine, mercaptopurine, thioguanine, pentostatin, and hydroxyurea); paclitaxel, docetaxel, and related analogs; vincristine, vinblastine, and related analogs; thalidomide and related analogs (e.g., CC-5013 and CC-4047).

[0127] Non-limiting examples of immune checkpoint inhibitors or agonists include PD-1 inhibitors, e.g., anti-PD-1 antibodies such as pembrolizumab, nivolumab, and PDR001 (spartalizumab); PD-L1 inhibitors, e.g., anti-PD-L1 antibodies such as atezolizumab, durvalumab, and avelumab; CTLA-4 inhibitors, e.g., anti-CTLA-4 antibodies, e.g., ipilimumab; and BTLA inhibitors, LAG-3 inhibitors, TIM3 inhibitors, TIGIT inhibitors, VISTA inhibitors, OX-40 agonists, and the like.

[0128] 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 downregulate cell proliferation, such as anti-CD20 antibodies (e.g., anti-HER2 monoclonal antibodies (e.g., rituximab, ibritumomab tiuxetan, and tositumomab), anti-Her2 monoclonal antibodies (e.g., trastuzumab), anti-EGFR antibodies (e.g., cetuximab), and anti-VEGF antibodies (e.g., bevacizumab); angiogenesis inhibitors, e.g., lenalidomide; and other protein or enzyme inhibitors (these proteins or enzymes are known to be upregulated, overexpressed, or activated in cancer, and their inhibition can downregulate cell replication). [Example]

[0129] The following examples are intended to be purely illustrative and should not be construed as limiting in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but one of ordinary skill in the art will understand that some experimental error and deviation should be accounted for. Unless otherwise indicated, parts are parts by weight, temperatures are in degrees Celsius, and pressures are at or near atmospheric. All MS data were determined using an Agilent 6120 or Agilent 1100. All NMR data were generated using a Varian 400 NMR instrument. All reagents used in this invention, except for certain synthetic intermediates, are commercially available. All compound names, except for reagents, are generated using Chemdraw 19.0. Flash column chromatography is performed using a conventional silica gel column unless otherwise specified or contradicted by context.

[0130] Where an atom with open valence(s) is present in any one of the structures disclosed herein, the open balance(s) are hydrogen atom(s) omitted for convenience.

[0131] In this application, if the name and structure of a compound disagree, when the two are both given for that compound, the structure of the compound will prevail unless the context indicates that the structure of the compound is incorrect and the name is correct. [Table 3-1] [Table 3-2] Example 1 Preparation of intermediates Intermediate 1-1: tert-butyl 2-(3,6-dichloro-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate [ka]

[0132] 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) in a reaction flask. Then, 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 under ice bath conditions. The mixture was warmed to room temperature and stirred for 1 hour. After completion of the reaction, the reaction solution was washed with water and saturated brine, followed by separation. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (eluting with a gradient of petroleum ether / ethyl acetate = 100:0 to 0:100) to give 7.07 g of a yellow solid. MS (m / z): 374.2, 376.2 [M+H] + .

[0133] The following intermediates were prepared according to the procedure for preparing Intermediate 1-1 using the corresponding starting materials and reagents under appropriate conditions recognized by one skilled in the art. [Table 4] Intermediate 2-1: N-ethyl-5-fluoro-2-hydroxy-N-isopropylbenzamide [ka]

[0134] (A) N-ethyl-5-fluoro-N-isopropyl-2-methoxybenzamide To a reaction flask, thionyl chloride (20 ml) was added, followed by 5-fluoro-2-methoxybenzoic acid (5.1 g, 30.0 mmol). The mixture was heated to 80°C with stirring and allowed to react for 2 hours. The reaction solution was concentrated to remove the solvent, and the residue was dissolved in dichloromethane (100 ml). The solution was cooled to 0°C, and triethylamine (4.55 g, 45.0 mmol) and N-ethylpropan-2-amine (3.14 g, 36.0 mmol) were added. The mixture was warmed to room temperature, stirred, and allowed to react for 2 hours. After the reaction was complete, the reaction solution was concentrated to remove the solvent. The residue was purified by flash column chromatography (eluting with a gradient of petroleum ether / ethyl acetate = 100:0 to 0:100) to give 6.6 g of a yellow solid. MS (m / z): 240.0 [M+H] + .

[0135] (B) N-ethyl-5-fluoro-2-hydroxy-N-isopropylbenzamide In a reaction flask, N-ethyl-5-fluoro-N-isopropyl-2-methoxybenzamide (6.6 g, 27.58 mmol) was dissolved in dichloromethane (150 ml). The mixture was cooled to 0°C, and then boron tribromide (33 ml, 36.0 mmol) was added. The resulting mixture was warmed to room temperature, then stirred and reacted for 48 hours. The reaction solution was concentrated to remove the solvent, yielding 5.4 g of a yellow solid. MS (m / z): 226.0 [M+H] + .

[0136] The following intermediates were prepared according to the procedure for preparing intermediate 2-1 using the corresponding starting materials and reagents under appropriate conditions recognized by one skilled in the art. [Table 5] Intermediate 3: Isopropyl 5-fluoro-2-hydroxybenzoate [ka]

[0137] (A) 5-Fluoro-2-hydroxybenzoic acid 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) were added to a reaction flask, and the mixture was heated to 60° C. and reacted for 15 hours. The reaction solution was cooled to room temperature, adjusted to pH 2.0 with 1 mol / L dilute hydrochloric acid, filtered, and the filter cake was dried to obtain 2.6 g of a white solid. MS (m / z): 157.1 [M+H] + .

[0138] (B) Isopropyl 5-fluoro-2-hydroxybenzoate 5-Fluoro-2-hydroxybenzoic acid (2.6 g, 16.65 mmol), N,N'-carbonyldiimidazole (2.7 g, 16.65 mmol), and N,N-dimethylformamide (10 ml) were added to a reaction flask, and the mixture was heated to 50 °C and reacted for 3 hours. Isopropanol (5 ml) was then added, and the resulting mixture was heated to 50 °C and reacted for 15 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of PE / EA = 100:0 to 0:100) to obtain 2.37 g of a colorless oil.

[0139] 1 H NMR(400MHz,CD3OD)δ 7.43(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,H). Intermediate 4: N-ethyl-5-fluoro-2-hydroxy-N-isopropylbenzothioamide [ka]

[0140] N-ethyl-5-fluoro-2-hydroxy-N-isopropylbenzamide (500 mg, 2.22 mmol), Lawesson's reagent (538 mg, 1.33 mmol), and toluene (20 mL) were added to a reaction flask, and the mixture was heated to reflux and reacted for 10 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 450 mg of a white solid. MS (m / z): 242.1 [M+H] + . Intermediate 5-1: 4-Fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenol [ka]

[0141] To a reaction flask, (1-isopropyl-1H-pyrazol-5-yl)boronic acid (330 mg, 2.14 mmol), 2-bromo-4-fluorophenol (341 mg, 1.79 mmol), Pd(dppf)Cl₂·CHCl₂ (147 mg, 0.18 mmol), potassium carbonate (50 mg, 0.36 mmol), dioxane (25 mL), and water (5 mL) were sequentially added. The mixture was heated to 100 °C and reacted under nitrogen protection for 15 h. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 140 mg of a yellow solid. MS (m / z): 221.4 [M+H] + .

[0142] The following intermediates were prepared according to the procedure for preparing intermediate 5-1 using the corresponding starting materials and reagents under appropriate conditions recognized by one skilled in the art. [Table 6] Intermediate 6-1: 7-Fluoro-1-isopropyl-1H-indazol-4-ol [ka]

[0143] (A) 4-Bromo-7-fluoro-1-isopropyl-1H-indazole 4-Bromo-7-fluoro-1H-indazole (1.5 g, 6.98 mmol) and anhydrous tetrahydrofuran (20 ml) were added to a reaction flask, and the mixture was cooled to 0 °C. Sodium hydride (60%, 560 mg, 13.96 mmol) was added in batches, and the mixture was stirred at 0 °C for an additional 30 minutes. Iodoisopropane (1.423 g, 8.37 mmol) was added, and the resulting mixture was stirred at room temperature for 15 hours. After the reaction was complete, the reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of petroleum ether / ethyl acetate = 100:0 to 0:100) to give 1.2 g of 4-bromo-7-fluoro-1-isopropyl-1H-indazole (MS (m / z): 257.2, 259.2 [M+H]). + ) and 600 mg of 4-bromo-7-fluoro-2-isopropyl-2H-indazole (MS (m / z): 257.2, 259.2 [M+H] + ) was obtained.

[0144] (B) 7-Fluoro-1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 4-Bromo-7-fluoro-1-isopropyl-1H-indazole (1.2 g, 4.67 mmol), bis(pinacolato)diboron (1.78 g, 7.01 mmol), Pd(dppf)Cl₂·C₂Cl₂ (377 mg, 0.46 mmol), potassium acetate (1.37 g, 13.96 mmol), and dioxane (30 mL) were added sequentially. The mixture was heated to 100 °C and reacted under nitrogen protection for 15 h. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 1.13 g of a yellow solid. MS (m / z): 305.4 [M+H] + .

[0145] (C) 7-Fluoro-1-isopropyl-1H-indazol-4-ol A reaction flask was charged with 7-fluoro-1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (1.13 g, 3.72 mmol), 1 mol / L aqueous sodium hydroxide solution (3.72 mL, 3.72 mmol), and methanol (15 mL). Hydrogen peroxide (0.5 mL) was added dropwise at room temperature, and the mixture was stirred for 1 hour. After the reaction was complete, ethyl acetate was added, and the mixture was washed with saturated sodium sulfite solution and saturated brine. The organic phase was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of petroleum ether / ethyl acetate = 100:0 to 0:100) to give 600 mg of a white solid. MS (m / z): 195.1 [M+H] + .

[0146] The following intermediates were prepared according to the procedure for preparing intermediate 6-1 using the corresponding starting materials and reagents under appropriate conditions recognized by one skilled in the art. [Table 7] Intermediate 7-1: 2-((5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide [ka]

[0147] (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 To a reaction flask, tert-butyl 2-(3,6-dichloro-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (7.07 g, 18.9 mmol), N-ethyl-5-fluoro-2-hydroxy-N-isopropylbenzamide (4.26 g, 18.9 mmol), DBU (9.50 g, 62.4 mmol), and tetrahydrofuran (50 mL) were added sequentially. The mixture was warmed to 40 °C and then stirred overnight. The reaction solution was diluted with water and extracted three times with ethyl acetate. The ethyl acetate phase was washed sequentially with water and saturated sodium chloride and then dried over sodium sulfate. After drying, the solution was concentrated to remove the solvent, and the residue was purified by flash column chromatography (eluting with a gradient of petroleum ether / ethyl acetate = 100:0 to 0:100) to give 7.55 g of a yellow solid. MS(m / z):563.4[M+H] + .

[0148] (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 To a reaction flask, 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 (7.55 g, 13.4 mmol), palladium on carbon (1 g), and methanol (100 ml) were added sequentially. The air was purged with a hydrogen balloon, and the mixture was stirred and reacted at room temperature for 15 hours. The reaction solution was filtered to remove the palladium on carbon and concentrated. The residue was purified by flash column chromatography (eluting with a gradient of petroleum ether / ethyl acetate = 100:0 to 0:100) to give 4.8 g of a yellow solid. MS (m / z): 529.4 [M+H] + .

[0149] (C) 2-((5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide To a reaction flask, tert-butyl 2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-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 sequentially, and the mixture was stirred and reacted at room temperature for 1 hour. The reaction solution was concentrated to remove the solvent, and the residue was dissolved in dichloromethane. The resulting solution was washed sequentially with saturated sodium carbonate and saturated sodium chloride, dried over sodium sulfate, and concentrated to give 3.74 g of a white solid. MS (m / z): 429.2 [M+H] + .

[0150] The following intermediates were prepared according to the procedure for preparing intermediate 7-1 using the corresponding starting materials and reagents under appropriate conditions recognized by one skilled in the art. [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] 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 [ka]

[0151] (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 To a sealed tube, 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 (150 mg, 0.266 mmol) and 30% methylamine in ethanol (2 mL) were added, and the mixture was heated to 90 °C, stirred, and reacted under sealed conditions for 1 h. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of petroleum ether / ethyl acetate = 100:0 to 0:100) to give 80 mg of a yellow solid. MS (m / z): 558.3 ​​[M+H] + .

[0152] (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 To a reaction flask, 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 (80 mg, 0.143 mmol) and a 6 mol / L solution of hydrochloric acid in methanol (5 ml) were added, and the mixture was stirred and reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate solution and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to give 60 mg of a white solid. MS (m / z): 458.3 [M+H] + . 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 [ka]

[0153] (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 To a reaction flask, 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 (200 mg, 0.355 mmol), trimethylboroxine (178 mg, 1.421 mmol), tetra(triphenylphosphine)palladium (41 mg, 0.0355 mmol), potassium carbonate (98 mg, 0.71 mmol), and dioxane (20 mL) were added. The mixture was heated to 110 °C, stirred, and reacted under nitrogen protection for 15 h. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 150 mg of a white solid. MS (m / z): 543.6 [M+H] + .

[0154] (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 To a reaction flask, 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 (150 mg, 0.276 mmol) and a 6.0 mol / L solution of hydrochloric acid in methanol (5 ml) were added, and the mixture was stirred and reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate solution and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to give 120 mg of a white solid. MS (m / z): 443.3 [M+H] + . 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-triazin-6-yl)oxy)benzamide [ka]

[0155] (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 To a reaction flask, 2-((5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-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, followed by sodium cyanoborohydride (120 mg, 1.91 mmol). The mixture was reacted at room temperature for 5 hours, and the reaction solution was concentrated to remove the solvent. The residue was then purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 450 mg of a solid. MS (m / z): 626.4 [M+H] + .

[0156] (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 In a reaction flask, 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 (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. The reaction solution was concentrated to remove the solvent, and the residue was dissolved in dichloromethane. The resulting solution was neutralized with saturated sodium carbonate, washed with saturated sodium chloride, dried over sodium sulfate, and concentrated. The residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 350 mg of a solid. MS (m / z): 526.3 [M+H] + .

[0157] The following intermediates were prepared according to the procedure for preparing intermediate 10-1 using the corresponding starting materials and reagents under appropriate conditions recognized by one skilled in the art. [Table 9-1] [Table 9-2] Intermediate 11: 1-(pyridin-2-yl)piperidine-4-carboxylic acid [ka]

[0158] (A) Ethyl 1-(6-bromopyridin-2-yl)piperidine-4-carboxylate Ethyl piperidine-4-carboxylate (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 sequentially to the reaction flask, and the mixture was heated to 100 °C and reacted for 15 hours. The reaction solution was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 495 mg of a white solid. MS (m / z): 313.2 [M+H] + .

[0159] (B) Ethyl 1-(pyridin-2-yl)piperidine-4-carboxylate Ethyl 1-(6-bromopyridin-2-yl)piperidine-4-carboxylate (495 mg, 1.58 mmol), palladium on carbon (50 mg), and methanol (10 ml) were added to the reaction flask, and the mixture was reacted under hydrogen for 2 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to give 400 mg of a pale yellow solid, which was used directly in the next reaction. MS (m / z): 235.2 [M+H] + .

[0160] (C) 1-(pyridin-2-yl)piperidine-4-carboxylic acid Ethyl 1-(pyridin-2-yl)piperidine-4-carboxylate (401 mg, 1.71 mmol), lithium hydroxide monohydrate (199 mg, 4.74 mmol), methanol (8 mL), and water (2 mL) were added to a reaction flask, and the mixture was reacted at room temperature for 2 hours. The reaction solution was adjusted to pH 5-6 with 1 mol / L dilute hydrochloric acid, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give 183 mg of a white solid, which was used directly in the next reaction. MS (m / z): 207.2 [M+H] + . Intermediate 12-1: 1-(pyridin-2-yl)piperidine-4-carbaldehyde [ka]

[0161] (A) Piperidine-4-carbaldehyde trifluoroacetate In a reaction flask, tert-butyl 4-formylpiperidine-1-carboxylate (2.13 g, 10.0 mmol) and trifluoroacetic acid (5 mL) were dissolved in dichloromethane (15 mL), and 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 reaction without further purification. MS (m / z): 146.4 [M+H] + .

[0162] (B) 1-(pyridin-2-yl)piperidine-4-carbaldehyde In a reaction flask, piperidine-4-carbaldehyde trifluoroacetate (454 mg, 2.0 mmol), 2-fluoropyridine (388 mg, 4.0 mmol), and potassium carbonate (553 mg, 4.0 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction solution was heated to reflux for 4 hours. After the reaction was complete, the reaction solution was diluted with water, extracted with ethyl acetate, and concentrated. The residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 90 mg of product. MS (m / z): 223.4 [M+OCH3] + .

[0163] The following intermediates were prepared according to the procedure for preparing intermediate 12-1 using the corresponding starting materials and reagents under appropriate conditions recognized by one skilled in the art. [Table 10] Intermediate 13-1: 5-formyl-4-methyl-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-indole-2-carbonitrile [ka]

[0164] 5-Formyl-4-methyl-1H-indole-2-carbonitrile (0.50 g, 2.71 mmol), 2-(2-bromoethoxy)tetrahydro-2H-pyran (0.68 g, 3.25 mmol), cesium carbonate (1.32 g, 4.05 mmol), and N,N-dimethylformamide (10 mL) were added sequentially to a reaction flask. The mixture was heated to 50 °C and reacted for 5 h. After completion of the reaction, the reaction solution was quenched with water (30 mL), extracted three times with ethyl acetate, and dried over anhydrous sodium sulfate. The solution was concentrated to give the crude product, which was purified by flash column chromatography (eluting with a gradient of petroleum ether / ethyl acetate = 100:0 to 0:100) to give 0.62 g of a yellow solid. MS (m / z): 313.2 [M+H] + .

[0165] The following intermediates were prepared according to the procedure for preparing intermediate 13-1 using the corresponding starting materials and reagents under appropriate conditions recognized by one skilled in the art. [Table 11] Intermediates 14 and 15: 5-formyl-4-methyl-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-indole-2-carboxylic acid, 5-Formyl-4-methyl-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-indole-2-carboxamide [ka]

[0166] 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 to a reaction flask, and the mixture was heated to 100°C and reacted for 16 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluted with a gradient of water / methanol = 100:0 to 0:100).

[0167] Peak 1 is compound A, intermediate 14, 50 mg of carboxylic acid compound, MS (m / z): 332.1 [M+H] + is.

[0168] Peak 2 is compound B, intermediate 15, 150 mg of amide compound, MS (m / z): 331.1 [M+H] + is. Intermediate 16: tert-butyl 2-cyano-3-(3,6-dihydro-2H-pyran-4-yl)-5-formyl-4-methyl-1H-indole-1-carboxylate [ka]

[0169] (A) 5-Formyl-3-iodo-4-methyl-1H-indole-2-carbonitrile 5-Formyl-4-methyl-1H-indole-2-carbonitrile (500 mg, 2.71 mmol) and N,N-dimethylformamide (10 ml) were added to the reaction flask, followed by N-iodosuccinimide (732 mg, 3.26 mmol), and the mixture was stirred and reacted at room temperature for 4 hours. After the reaction was complete, the reaction solution was poured into water, filtered, and the filter cake was dried to give 720 mg of a yellow solid. MS (m / z): 311.0 [M+H] + .

[0170] (B) tert-Butyl 2-cyano-5-formyl-3-iodo-4-methyl-1H-indole-1-carboxylate To a reaction flask were added 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), and the mixture was stirred at room temperature for 15 h. The reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 700 mg of a white solid. MS (m / z): 433.0 [M+Na] + .

[0171] (C) tert-Butyl 2-cyano-3-(3,6-dihydro-2H-pyran-4-yl)-5-formyl-4-methyl-1H-indole-1-carboxylate To a reaction flask, tert-butyl 2-cyano-5-formyl-3-iodo-4-methyl-1H-indole-1-carboxylate (350 mg, 0.85 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (358 mg, 1.70 mmol), Pd(dppf)Cl₂·CHCl₂ (70 mg, 0.086 mmol), potassium carbonate (295 mg, 2.13 mmol), dioxane (20 mL), and water (5 mL) were sequentially added. The mixture was heated to 100 °C and reacted under nitrogen protection for 3 h. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 200 mg of a white solid. MS (m / z): 367.6 [M+H]. + . Intermediate 17: Ethyl 3-(2-cyano-5-formyl-4-methyl-1H-indol-1-yl)-2-hydroxypropanoate [ka]

[0172] 5-Formyl-4-methyl-1H-indole-2-carbonitrile (500 mg, 2.71 mmol), ethyl oxirane-2-carboxylate (630 mg, 5.43 mmol), cesium carbonate (1.7 g, 5.22 mmol), and N,N-dimethylformamide (10 mL) were added sequentially to the reaction flask, and the mixture was heated to 80 °C and reacted for 16 h. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 100 mg of a solid. MS (m / z): 301.1 [M+H] + . Intermediate 18-1: 5-(4-formylpiperidin-1-yl)picolinonitrile [ka]

[0173] Piperidine-4-carbaldehyde (250 mg, 1.1 mmol), 5-bromopicolinonitrile (200 mg, 1.1 mmol), Pd2(dba)3 (100 mg, 0.11 mmol), Xantphos (145 mg, 0.25 mmol), cesium carbonate (1 g, 3.1 mmol), and dioxane (10 mL) were added sequentially to a reaction flask. The mixture was heated to 100 °C and reacted for 16 h under nitrogen protection. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 50 mg of an oily liquid. MS (m / z): 216.2 [M+H] + .

[0174] The following intermediates were prepared according to the procedure for preparing intermediate 18-1 using the corresponding starting materials and reagents under appropriate conditions recognized by one skilled in the art. [Table 12] Intermediate 19-1: 1-(2-methoxypyridin-4-yl)piperidine-4-carbaldehyde [ka]

[0175] (A) (1-(2-methoxypyridin-4-yl)piperidin-4-yl)methanol Piperidin-4-ylmethanol (615 mg, 5.3 mmol), 4-bromo-2-methoxypyridine (1000 mg, 5.3 mmol), potassium carbonate (2.2 g, 15.9 mmol), and N,N-dimethylformamide (10 mL) were added sequentially to the reaction flask, and the mixture was heated to 110 °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 (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 500 mg of an oily liquid. MS (m / z): 223.2 [M+H] + .

[0176] (B) 1-(2-Methoxypyridin-4-yl)piperidine-4-carbaldehyde To the reaction flask, (1-(2-methoxypyridin-4-yl)piperidin-4-yl)methanol (100 mg, 0.45 mmol) and dichloromethane (5 mL) were added, followed by Dess-Martin periodinane (382 mg, 0.9 mmol), and the mixture was allowed to react at room temperature for 3 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 50 mg of an oily liquid. MS (m / z): 221.1 [M+H] + .

[0177] The following intermediates were prepared according to the procedure for preparing intermediate 19-1 using the corresponding starting materials and reagents under appropriate conditions recognized by one skilled in the art. [Table 13] Intermediate 20: 2-((4-formyl-3-methylphenyl)amino)acetonitrile [ka]

[0178] (A) (4-amino-2-methylphenyl)methanol To a reaction flask were added (2-methyl-4-nitrophenyl)methanol (500 mg, 3.0 mmol), palladium on carbon (100 mg), and ethanol (20 ml). The mixture was stirred and reacted under hydrogen at room temperature for 15 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to give 413 mg of a yellow solid. MS (m / z): 138.2 [M+H] + .

[0179] (B) 2-((4-(hydroxymethyl)-3-methylphenyl)amino)acetonitrile To 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. The mixture was heated to reflux, stirred, and reacted for 15 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 200 mg of a yellow solid. MS (m / z): 177.2 [M+H] + .

[0180] (C) 2-((4-formyl-3-methylphenyl)amino)acetonitrile 2-((4-(hydroxymethyl)-3-methylphenyl)amino)acetonitrile (150 mg, 0.851 mmol), manganese dioxide (592 mg, 6.81 mmol), and dichloromethane (20 mL) were added to the reaction flask, and the mixture was stirred at room temperature for 15 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 12 mg of a yellow solid. MS (m / z): 175.2 [M+18] + . Intermediate 21: 1-(6-methoxypyridazin-4-yl)piperidine-4-carbaldehyde [ka]

[0181] (A) (1-(6-chloropyridazin-4-yl)piperidin-4-yl)methanol Piperidin-4-ylmethanol (576 mg, 5 mmol), 5-bromo-3-chloropyridazine (967 mg, 5 mmol), triethylamine (3 mL), and dioxane (20 mL) were added sequentially to the reaction flask, and the mixture was 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 (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 620 mg of an oily liquid. MS (m / z): 228.1 [M+H] + .

[0182] (B) (1-(6-methoxypyridazin-4-yl)piperidin-4-yl)methanol To the reaction flask, (1-(6-chloropyridazin-4-yl)piperidin-4-yl)methanol (620 mg, 2.72 mmol), sodium methoxide (734 mg, 13.6 mmol), and dioxane (20 mL) were added sequentially, and the mixture was 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 (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 450 mg of an oily liquid. MS (m / z): 224.2 [M+H] + .

[0183] (C) 1-(6-Methoxypyridazin-4-yl)piperidine-4-carbaldehyde To the reaction flask, (1-(6-methoxypyridazin-4-yl)piperidin-4-yl)methanol (420 mg, 1.88 mmol) and dichloromethane (25 mL) were added, followed by Dess-Martin periodinane (1595 mg, 3.76 mmol), and the mixture was allowed to react at room temperature for 3 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 170 mg of an oily liquid. MS (m / z): 222.2 [M+H] + . Intermediate 22: tert-butyl (6-(4-formylpiperidin-1-yl)pyridazin-3-yl)carbamate [ka]

[0184] (A) (1-(6-aminopyridazin-3-yl)piperidin-4-yl)methanol 6-Chloropyridazin-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 sequentially to the reaction flask, and the mixture was heated to 200 °C in a microwave oven for 2 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 0.51 g of a pale yellow solid. MS (m / z): 209.4 [M+H] + .

[0185] (B) tert-butyl (6-(4-(hydroxymethyl)piperidin-1-yl)pyridazin-3-yl)carbamate To the reaction flask, (1-(6-aminopyridazin-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 sequentially. The mixture was heated to 80 °C and reacted for 2 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 0.18 g of a pale yellow solid. MS (m / z): 309.2 [M+H] + .

[0186] (C) tert-Butyl (6-(4-formylpiperidin-1-yl)pyridazin-3-yl)carbamate To a reaction flask were added 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). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution 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 (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 230 mg of product. MS (m / z): 307.2 [M+H] + . Intermediate 23: Methyl 4-(4-formylpiperidin-1-yl)nicotinate [ka]

[0187] (A) Methyl 6-chloro-4-(4-(hydroxymethyl)piperidin-1-yl)nicotinate Methyl 4-bromo-6-chloronicotinate (1.25 g, 5.0 mmol), piperidin-4-ylmethanol (0.57 g, 5.0 mmol), cesium carbonate (3.25 g, 10.0 mmol), and dimethyl sulfoxide (20 mL) were added sequentially to a reaction flask, and the mixture was heated to 60 °C and reacted for 5 hours. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product, which was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 0.46 g of a pale yellow solid. MS (m / z): 285.2 [M+H] + .

[0188] (B) Methyl 4-(4-(hydroxymethyl)piperidin-1-yl)nicotinate Methyl 6-chloro-4-(4-(hydroxymethyl)piperidin-1-yl)nicotinate (0.46 g, 1.62 mmol), palladium on carbon (46 mg), and methanol (20 ml) were added to the reaction flask in this order, and the mixture was reacted under hydrogen for 2 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to give 0.39 g of a white solid, which was used directly in the next reaction. MS (m / z): 251.2 [M+H] + .

[0189] (C) Methyl 4-(4-formylpiperidin-1-yl)nicotinate Methyl 4-(4-(hydroxymethyl)piperidin-1-yl)nicotinate (390 mg, 1.56 mmol) and dichloromethane (20 mL) were added to a reaction flask, and Dess-Martin periodinane (992 mg, 2.34 mmol) was added in batches under ice bath conditions. The mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was washed with saturated sodium bicarbonate and sodium bisulfite solutions, the organic phase was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / acetonitrile = 100:0 to 0:100) to give 160 mg of product. MS (m / z): 249.2 [M+H] + . Intermediate 24-1: 1-(6-methoxypyridazin-3-yl)piperidine-4-carbaldehyde [ka]

[0190] (A) 3-chloro-6-methoxypyridazine 3,6-Dichloropyridazine (1.5 g, 10 mmol), sodium methoxide (2.72 g, 50 mmol), and methanol (30 ml) were added sequentially to the reaction flask, and the mixture was stirred at room temperature for 15 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was dissolved in dichloromethane, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to give 1.0 g of a white solid. MS (m / z): 145.2, 147.2 [M+H] + .

[0191] (B) (1-(6-methoxypyridazin-3-yl)piperidin-4-yl)methanol 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 sequentially to a reaction flask. The mixture was heated to 100 °C and reacted under nitrogen protection for 15 h. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 300 mg of a yellow oil. MS (m / z): 224.2 [M+H] + .

[0192] (C) 1-(6-Methoxypyridazin-3-yl)piperidine-4-carbaldehyde To a reaction flask were added (1-(6-methoxypyridazin-3-yl)piperidin-4-yl)methanol (300 mg, 1.34 mmol), dichloromethane (20 mL), and Dess-Martin periodinane (855 mg, 2.02 mmol). The mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution 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 (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 120 mg of product. MS (m / z): 222.2 [M+H] + .

[0193] The following intermediates were prepared according to the procedure for preparing intermediate 24-1 using the corresponding starting materials and reagents under appropriate conditions recognized by one skilled in the art. [Table 14] *MS indicates data as the molecular weight of acetal. Intermediate 25: 6-(4-formylpiperidin-1-yl)picolinamide [ka]

[0194] (A) Methyl 6-(4-(hydroxymethyl)piperidin-1-yl)picolinate Methyl 6-chloropicolinate (1.71 g, 10 mmol), piperidin-4-ylmethanol (1.15 g, 10 mmol), palladium acetate (224 mg, 1.0 mmol), Xphos (478 mg, 1.0 mmol), cesium carbonate (6.50 g, 20.0 mmol), and 1,4-dioxane (30 mL) were added sequentially to a reaction flask. The mixture was heated to 80 °C and reacted for 15 h under nitrogen protection. After completion of the reaction, the reaction solution was filtered, the filtrate was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 1.17 g of a yellow oil. MS (m / z): 251.2 [M+H] + .

[0195] (B) 6-(4-(hydroxymethyl)piperidin-1-yl)picolinamide Methyl 6-(4-(hydroxymethyl)piperidin-1-yl)picolinate (1.17 g, 4.67 mmol) and ammonia in methanol (20 ml, 7 mol / L) were added sequentially to the sealed tube, and the mixture was heated to 80° C. and reacted for 2 hours. After the reaction was completed, the reaction solution was concentrated to give 0.80 g of a pale yellow solid, which was used directly in the next reaction. MS (m / z): 236.2 [M+H] + .

[0196] (C) 6-(4-formylpiperidin-1-yl)picolinamide A reaction flask was charged with 6-(4-(hydroxymethyl)piperidin-1-yl)picolinamide (235 mg, 1.0 mmol) and dichloromethane (10 mL), and Dess-Martin periodinane (848 mg, 2.0 mmol) was added in batches under ice bath conditions. The mixture was stirred at room temperature for 15 hours. After completion of the reaction, the reaction solution was washed with saturated aqueous sodium bicarbonate and sodium bisulfite solutions, the organic phase was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of petroleum ether / ethyl acetate = 100:0 to 0:100) to give 57 mg of product. MS (m / z): 234.1 [M+H] + . Intermediate 26: 1-(4-Methoxypyridin-2-yl)piperidine-4-carbaldehyde [ka]

[0197] (A) Ethyl 1-(4-methoxypyridin-2-yl)piperidine-4-carboxylate 2-Bromo-4-methoxypyridine (500 mg, 2.67 mmol), ethyl piperidine-4-carboxylate (628 mg, 4 mmol), Pd2(dba)3 (244 mg, 0.267 mmol), Xantphos (308 mg, 0.534 mmol), cesium carbonate (1.7 g, 5.22 mmol), and dioxane (20 mL) were added sequentially to the reaction flask. The mixture was heated to 100 °C and reacted under nitrogen protection for 16 h. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 100 mg of an oily liquid. MS (m / z): 265.2 [M+H] + .

[0198] (B) (1-(4-methoxypyridin-2-yl)piperidin-4-yl)methanol Ethyl 1-(4-methoxypyridin-2-yl)piperidine-4-carboxylate (100 mg, 0.38 mmol) and tetrahydrofuran (5 mL) were added sequentially to the reaction flask, and the mixture was cooled to 0°C. Lithium aluminum hydride (29 mg, 0.76 mmol) was added, and the mixture was 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 (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 60 mg of an oily liquid. MS (m / z): 223.2 [M+H] + .

[0199] (C) 1-(4-Methoxypyridin-2-yl)piperidine-4-carbaldehyde To the reaction flask, (1-(4-methoxypyridin-2-yl)piperidin-4-yl)methanol (60 mg, 0.27 mmol) and dichloromethane (5 mL) were added, followed by Dess-Martin periodinane (230 mg, 0.54 mmol), and the mixture was allowed to react at room temperature for 3 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 40 mg of an oily liquid. MS (m / z): 221.2 [M+H] + . Intermediate 27-1: 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)piperidine-4-carbaldehyde [ka]

[0200] (A) Ethyl 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)piperidine-4-carboxylate 2-Bromo-6-(((tert-butyldimethylsilyl)oxy)methyl)pyridine (500 mg, 1.66 mmol), ethyl piperidine-4-carboxylate (521 mg, 3.32 mmol), and toluene (5 mL) were added to the reaction flask in this order, and the mixture was heated to 120°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 (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 150 mg of an oily liquid. MS (m / z): 379.2 [M+H] + .

[0201] (B) (1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)piperidin-4-yl)methanol Ethyl 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)piperidine-4-carboxylate (150 mg, 0.40 mmol) and tetrahydrofuran (5 ml) were added sequentially to a reaction flask, and the mixture was cooled to 0°C. Lithium aluminum hydride (30 mg, 0.79 mmol) was added, and the mixture was 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 (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 100 mg of an oily liquid. MS (m / z): 337.2 [M+H] + .

[0202] (C) 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)piperidine-4-carbaldehyde To 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, followed by Dess-Martin periodinane (252 mg, 0.59 mmol), and the mixture was allowed to react at room temperature for 3 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 50 mg of an oily liquid. MS (m / z): 335.3 [M+H] + .

[0203] The following intermediates were prepared according to the procedure for preparing intermediate 27-1 using the corresponding starting materials and reagents under appropriate conditions recognized by one skilled in the art. [Table 15] Intermediate 28: 4-(pyridin-2-yl)benzaldehyde [ka]

[0204] (A) Methyl 4-(pyridin-2-yl)benzoate To a reaction flask, (4-(methoxycarbonyl)phenyl)boronic acid (800 mg, 4.4 mmol), 2-bromopyridine (500 mg, 3.2 mmol), tetra(triphenylphosphine)palladium (367 mg, 0.32 mmol), potassium carbonate (1 g, 7.2 mmol), dioxane (8 mL), and water (2 mL) were sequentially added. The mixture was heated to 100 °C and reacted for 5 h under nitrogen protection. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of PE / EA = 100:0 to 0:100) to obtain 500 mg of an oily liquid. MS (m / z): 214.1 [M+H] + .

[0205] (B) (4-(pyridin-2-yl)phenyl)methanol Methyl 4-(pyridin-2-yl)benzoate (200 mg, 0.94 mmol) and tetrahydrofuran (10 ml) were added sequentially to the reaction flask, and the mixture was cooled to 0°C. Lithium aluminum hydride (71 mg, 1.88 mmol) was added, and the mixture was 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 (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 150 mg of an oily liquid. MS (m / z): 186.1 [M+H] + .

[0206] (C) 4-(pyridin-2-yl)benzaldehyde To the reaction flask, (4-(pyridin-2-yl)phenyl)methanol (150 mg, 0.81 mmol) and dichloromethane (5 mL) were added, followed by Dess-Martin periodinane (688 mg, 1.62 mmol), and the mixture was allowed to react at room temperature for 3 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 100 mg of an oily liquid. MS (m / z): 184.1 [M+H] + . Intermediate 29: 4-(pyridin-2-yl)cyclohex-3-ene-1-carbaldehyde [ka]

[0207] (A) Methyl 4-(pyridin-2-yl)cyclohex-3-ene-1-carboxylate To a reaction flask, (4-(methyloxycarbonyl)cyclohex-1-en-1-yl)boronic acid (873 mg, 4.75 mmol), 2-bromopyridine (500 mg, 3.16 mmol), Pd(dppf)Cl₂·CHCl₂ (130 mg, 0.18 mmol), potassium carbonate (1.1 g, 8.0 mmol), dioxane (30 mL), and water (6 mL) were sequentially added. The mixture was heated to 100 °C and reacted under nitrogen protection for 5 h. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 500 mg of a yellow solid. MS (m / z): 218.2 [M+H] + .

[0208] (B) (4-(pyridin-2-yl)cyclohex-3-en-1-yl)methanol Methyl 4-(pyridin-2-yl)cyclohex-3-ene-1-carboxylate (500 mg, 2.30 mmol) and anhydrous tetrahydrofuran (15 ml) were added to a reaction flask, and the mixture was cooled to 0°C. Diisobutylaluminum hydride (2.76 ml, 2.76 mmol) was added dropwise under nitrogen protection, and the mixture was warmed to room temperature and stirred for 15 hours. The reaction solution was quenched with saturated aqueous ammonium chloride solution, concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 400 mg of a yellow oil. MS (m / z): 190.2 [M+H] + .

[0209] (C) 4-(pyridin-2-yl)cyclohex-3-ene-1-carbaldehyde To a reaction flask were added (4-(pyridin-2-yl)cyclohex-3-en-1-yl)methanol (400 mg, 2.11 mmol), dichloromethane (20 mL), and Dess-Martin periodinane (1.8 g, 4.24 mmol). The mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was washed with saturated aqueous sodium bicarbonate and sodium bisulfite solutions, the organic phase was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of petroleum ether / ethyl acetate = 100:0 to 0:100) to give 380 mg of a white solid. MS (m / z): 188.7 [M+H] + . Intermediate 30: 2-Methoxyquinazoline-6-carbaldehyde [ka]

[0210] (A) (2-amino-5-bromophenyl)methanol Lithium aluminum hydride (2.77 g, 73.01 mmol) and anhydrous tetrahydrofuran (40 mL) were added to the reaction flask, followed by the dropwise addition of methyl 2-amino-5-bromobenzoate (5.6 g, 24.34 mmol) dissolved in tetrahydrofuran (40 mL). The mixture was stirred and allowed to react at room temperature for 15 hours. After the reaction was complete, the reaction solution was quenched with saturated magnesium sulfate solution (5 mL) and solid magnesium sulfate (5 g) was added. The mixture was filtered, the filtrate was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of dichloromethane / methanol = 100:0 to 0:100) to give 3.2 g of a white solid. MS (m / z): 202.0, 204.0 [M+H] + .

[0211] (B) 2-amino-5-bromobenzaldehyde To a reaction flask were added (2-amino-5-bromophenyl)methanol (3.2 g, 15.84 mmol), manganese dioxide (9.65 g, 111.0 mmol), and dichloromethane (60 mL). The mixture was stirred at room temperature for 15 hours and then filtered. The filtrate was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of petroleum ether / ethyl acetate = 100:0 to 0:100) to give 2.5 g of a yellow solid. MS (m / z): 200.0, 202.0 [M+H] + .

[0212] (C) 6-Bromoquinazolin-2-ol 2-Amino-5-bromobenzaldehyde (800 mg, 4.0 mmol) and urea (1.92 g, 32.0 mmol) were added to a reaction flask, and the mixture was heated to 170° C., stirred, and reacted for 1 hour. The reaction solution was cooled to room temperature, and water (30 ml) was added. The mixture was stirred for an additional 20 minutes, filtered, and the filter cake was dried to give 850 mg of a white solid. MS (m / z): 225.0, 227.0 [M+H] + .

[0213] (D) 6-Bromo-2-chloroquinazoline To the reaction flask were added 6-bromoquinazolin-2-ol (850 mg, 3.78 mmol) and phosphorus oxychloride (10 ml), and the mixture was heated to reflux overnight. The reaction solution was cooled to room temperature and concentrated. The residue was stirred in saturated sodium bicarbonate solution for 30 minutes, filtered, and the filter cake was dried to give 450 mg of a yellow solid. MS (m / z): 243.0, 245.0 [M+H] + .

[0214] (E) 6-Bromo-2-methoxyquinazoline To a reaction flask were added 6-bromo-2-chloroquinazoline (450 mg, 1.85 mmol), sodium methoxide (300 mg, 5.54 mmol), and methanol (50 mL). The mixture was heated to reflux and stirred for 15 hours. The reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 400 mg of a white solid. MS (m / z): 239.0, 241.0 [M+H] + .

[0215] (F) 2-Methoxyquinazoline-6-carbonitrile To a reaction flask were added 6-bromo-2-methoxyquinazoline (400 mg, 1.67 mmol), zinc cyanide (235 mg, 2.00 mmol), tetra(triphenylphosphine)palladium (193 mg, 0.167 mmol), and N,N-dimethylformamide (8.0 mL). The mixture was heated to 100 °C and stirred under nitrogen for 4 h. The mixture was cooled to room temperature and purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 200 mg of a yellow solid. MS (m / z): 186.1 [M+H] + .

[0216] (G) 2-Methoxyquinazoline-6-carbaldehyde To a reaction flask were added 2-methoxyquinazoline-6-carbonitrile (180 mg, 0.97 mmol), acetic acid (5.0 mL), and pyridine (5.0 mL), followed by Raney nickel (90 mg) and sodium dihydrogen phosphate monohydrate (401 mg, 2.91 mmol). The mixture was heated to 75 °C and stirred for 15 h. The mixture was cooled to room temperature and concentrated. The residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 70 mg of a yellow solid. MS (m / z): 189.2 [M+H] + . Intermediate 31: 2-Methylquinazoline-6-carbaldehyde [ka]

[0217] (A) N-(4-bromo-2-formylphenyl)acetamide To a reaction flask were added 2-amino-5-bromobenzaldehyde (500 mg, 2.5 mmol), pyridine (395 mg, 5.0 mmol), and dichloromethane (20 mL), followed by dropwise addition of acetyl chloride (235 mg, 3.0 mmol). The mixture was stirred and allowed to react at room temperature for 15 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of petroleum ether / ethyl acetate = 100:0 to 0:100) to give 420 mg of a yellow solid. MS (m / z): 242.0, 244.0 [M+H] + .

[0218] (B) 6-Bromo-2-methylquinazoline N-(4-bromo-2-formylphenyl)acetamide (420 mg, 1.74 mmol) and ammonia in methanol (15 mL, 7 mol / L) were added to a sealed tube, and the mixture was heated to 80 °C, stirred, and reacted for 15 hours under sealed conditions. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of petroleum ether / ethyl acetate = 100:0 to 0:100) to give 250 mg of a yellow solid. MS (m / z): 223.0, 225.0 [M+H] + .

[0219] (C) 2-Methylquinazoline-6-carbonitrile To a reaction flask were added 6-bromo-2-methylquinazoline (200 mg, 0.897 mmol), zinc cyanide (105 mg, 0.897 mmol), tetra(triphenylphosphine)palladium (104 mg, 0.09 mmol), and N,N-dimethylformamide (5.0 mL). The mixture was heated to 100 °C and stirred under nitrogen for 1 h. The mixture was cooled to room temperature and purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 100 mg of a yellow solid. MS (m / z): 188.2 [M+18] + .

[0220] (D) 2-Methylquinazoline-6-carbaldehyde To a reaction flask were added 2-methylquinazoline-6-carbonitrile (100 mg, 0.59 mmol), acetic acid (1.5 mL), and pyridine (1.5 mL), followed by Raney nickel (50 mg) and sodium dihydrogen phosphate monohydrate (245 mg, 1.78 mmol). The mixture was heated to 75 °C and stirred for 15 h. The mixture was cooled to room temperature and concentrated. The residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 15 mg of a yellow solid. MS (m / z): 191.2 [M+18] + . Intermediate 32: 1-(1-methyl-1H-pyrazol-3-yl)piperidine-4-carbaldehyde [ka]

[0221] (A) Ethyl 1-(1-methyl-1H-pyrazol-3-yl)piperidine-4-carboxylate Ethyl 4-bromo-2-(2-bromoethyl)butyrate (1.86 g, 6.16 mmol), 1-methyl-1H-pyrazol-3-amine (600 mg, 6.18 mmol), diisopropylethylamine (2.4 g, 18.57 mmol), and N,N-dimethylacetamide (10 ml) were added to a reaction flask. The mixture was heated to 120 °C in a microwave oven for 2 h, cooled to room temperature, and purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 1.2 g of a white solid. MS (m / z): 238.4 [M+H] + .

[0222] (B) (1-(1-methyl-1H-pyrazol-3-yl)piperidin-4-yl)methanol Ethyl 1-(1-methyl-1H-pyrazol-3-yl)piperidine-4-carboxylate (1.2 g, 5.06 mmol) and anhydrous tetrahydrofuran (15 ml) were added to a reaction flask, and the mixture was cooled to 0°C. Diisobutylaluminum hydride (6.07 ml, 6.07 mmol, 1.0 mol / L in toluene) was added dropwise under nitrogen protection, and the mixture was warmed to room temperature and stirred for 15 hours. The reaction solution was quenched with saturated aqueous ammonium chloride solution, concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 600 mg of an oil. MS (m / z): 196.2 [M+H] + .

[0223] (C) 1-(1-methyl-1H-pyrazol-3-yl)piperidine-4-carbaldehyde To a reaction flask were added (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). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution 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 (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 120 mg of a yellow solid. MS (m / z): 194.2 [M+H] + . Intermediate 33: (S)-3-(6-Methoxypyridin-3-yl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-carbaldehyde [ka]

[0224] (A) (S)-3-(6-methoxypyridin-3-yl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-carbonitrile To a reaction flask, (S)-7-bromo-3-(6-methoxypyridin-3-yl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (500 mg, 1.55 mmol), zinc cyanide (145 mg, 1.24 mmol), tetra(triphenylphosphine)palladium (179 mg, 0.155 mmol), and N,N-dimethylformamide (8 mL) were sequentially added. The mixture was heated to 120 °C and reacted under nitrogen protection for 16 h. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 200 mg of a yellow solid. MS (m / z): 270.1 [M+H] + .

[0225] (B) (S)-3-(6-methoxypyridin-3-yl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-carboxylic acid To a reaction flask, (S)-3-(6-methoxypyridin-3-yl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-carbonitrile (200 mg, 0.74 mmol), potassium hydroxide (166 mg, 2.96 mmol), methanol (5 mL), and water (5 mL) were added sequentially. The mixture was heated to 100 °C and reacted for 16 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 150 mg of a white solid. MS (m / z): 289.1 [M+H] + .

[0226] (C) Methyl (S)-3-(6-methoxypyridin-3-yl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-carboxylate 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 one drop of N,N-dimethylformamide were added, and the mixture was allowed to react at room temperature for 2 hours. Methanol (10 mL) was added, and the mixture was allowed to react at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of petroleum ether / ethyl acetate = 100:0 to 0:100) to obtain 150 mg of an oily liquid. MS (m / z): 303.1 [M+H] + .

[0227] (D) (S)-(3-(6-methoxypyridin-3-yl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)methanol Methyl (S)-3-(6-methoxypyridin-3-yl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-carboxylate (150 mg, 0.5 mmol) and tetrahydrofuran (5 mL) were added sequentially to a reaction flask, and the mixture was cooled to 0°C. Lithium aluminum hydride (75 mg, 1.98 mmol) was added, and the mixture was reacted at room temperature for 3 hours. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 100 mg of an oily liquid. MS (m / z): 275.1 [M+H] + .

[0228] (E)(S)-3-(6-Methoxypyridin-3-yl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-carbaldehyde To 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, followed by Dess-Martin periodinane (309 mg, 0.73 mmol). The mixture was allowed to react at room temperature for 3 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 60 mg of an oily liquid. MS (m / z): 273.1 [M+H] + . Intermediate 34: 5-chloro-6-methoxy-4-methylnicotinaldehyde [ka]

[0229] 5-Bromo-3-chloro-2-methoxy-4-methylpyridine (200 mg, 0.85 mmol) and anhydrous tetrahydrofuran (8 mL) were added to a reaction flask, and the mixture was cooled to -78 °C. n-Butyllithium (0.34 mL, 0.85 mmol) was added dropwise, and after 15 minutes, ethyl formate (63 mg, 0.85 mmol) was added. The mixture was then stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 50 mg of an oily liquid. MS (m / z): 186.1 [M+H] + . Intermediate 35: 4-Hydroxy-4-(pyridin-2-yl)cyclohexane-1-carbaldehyde [ka]

[0230] (A) Ethyl 4-hydroxy-4-(pyridin-2-yl)cyclohexane-1-carboxylate 2-Bromopyridine (0.87 g, 5.5 mmol) and anhydrous tetrahydrofuran (10 mL) were added sequentially to the reaction flask, and the mixture was cooled to -78 °C. A 1.6 mol / L n-butyllithium solution (3.4 mL, 5.44 mmol) was added dropwise, followed by ethyl 4-oxocyclohexane-1-carboxylate (0.85 g, 5 mmol) 30 minutes later. The mixture was allowed to react at -78 °C for an additional hour. The reaction solution was quenched with saturated aqueous ammonium chloride (10 mL) and extracted three times with ethyl acetate. The organic phase was dried and concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 0.43 g of a yellow oil. MS (m / z): 250.2 [M+H] + .

[0231] (B) 4-(hydroxymethyl)-1-(pyridin-2-yl)cyclohexan-1-ol Ethyl 4-hydroxy-4-(pyridin-2-yl)cyclohexane-1-carboxylate (0.43 g, 1.72 mmol) and tetrahydrofuran (10 mL) were added sequentially to the reaction flask, and the mixture was cooled in an ice bath. After adding 1 mol / L diisobutylaluminum hydride solution (3.44 mL, 3.44 mmol), the mixture was warmed to room temperature and reacted for 2 hours. The reaction solution was quenched with saturated aqueous ammonium chloride (10 mL) and extracted three times with ethyl acetate. The organic phase was dried and concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 0.24 g of a yellow oil. MS (m / z): 208.1 [M+H] + .

[0232] (C) 4-Hydroxy-4-(pyridin-2-yl)cyclohexane-1-carbaldehyde A reaction flask was charged with 4-(hydroxymethyl)-1-(pyridin-2-yl)cyclohexan-1-ol (0.24 g, 1.16 mmol) and dichloromethane (15 mL), and Dess-Martin periodinane (0.98 g, 2.31 mmol) was added in batches under ice bath conditions. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was washed with saturated aqueous sodium bicarbonate and sodium bisulfite solutions, the organic phase was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of petroleum ether / ethyl acetate = 100:0 to 0:100) to give 56 mg of product. MS (m / z): 206.1 [M+H] + . Intermediate 36: 3-Formyl-1-methyl-1H-pyrazole-5-carboxamide [ka]

[0233] (A) Methyl 3-(hydroxymethyl)-1-methyl-1H-pyrazole-5-carboxylate Methyl 1-methyl-1H-pyrazole-3,5-dicarboxylate (991 mg, 5.0 mmol) and tetrahydrofuran (20 mL) were added sequentially to the reaction flask, and the mixture was cooled to 0°C. 1 mol / L diisobutylaluminum hydride (10 mL, 10.0 mmol) was added, and the mixture was reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 500 mg of an oily liquid. MS (m / z): 171.1 [M+H] + .

[0234] (B) 3-(hydroxymethyl)-1-methyl-1H-pyrazole-5-carboxamide Methyl 3-(hydroxymethyl)-1-methyl-1H-pyrazole-5-carboxylate (500 mg, 2.94 mmol) and aqueous ammonia (10 mL) were added sequentially to the reaction flask, and the mixture was allowed to react at room temperature for 15 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 456 mg of an oily liquid. MS (m / z): 156.2 [M+H] + .

[0235] (C) 3-Formyl-1-methyl-1H-pyrazole-5-carboxamide 3-(Hydroxymethyl)-1-methyl-1H-pyrazole-5-carboxamide (450 mg, 2.9 mmol) and dichloromethane (25 mL) were added to the reaction flask, followed by Dess-Martin periodinane (1230 mg, 2.9 mmol), and the mixture was allowed to react at room temperature for 15 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 260 mg of an oily liquid. MS (m / z): 154.0 [M+H] + . Intermediate 37: 4-(2-oxopyridin-1(2H)-yl)cyclohexane-1-carbaldehyde [ka]

[0236] (A) Methyl 4-(2-oxopyridin-1(2H)-yl)cyclohexane-1-carboxylate Methyl 4-hydroxycyclohexane-1-carboxylate (1.58 g, 10 mmol), pyridin-2(1H)-one (951 mg, 10 mmol), diisopropyl azodicarboxylate (2.02 g, 10 mmol), triphenylphosphine (2.6 g, 10 mmol), and tetrahydrofuran (40 mL) were added sequentially to a reaction flask, and the mixture was reacted at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 310 mg of an oily liquid. MS (m / z): 236.4 [M+H] + .

[0237] (B) 1-(4-(hydroxymethyl)cyclohexyl)pyridin-2(1H)-one Methyl 4-(2-oxopyridin-1(2H-yl)cyclohexane-1-carboxylate) (310 mg, 1.32 mmol) and tetrahydrofuran (10 ml) were added to the reaction flask, and the mixture was cooled to −78° C. 1 mol / L diisobutylaluminum hydride (1.32 ml, 1.32 mmol) was added, and the mixture was 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 (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 170 mg of an oily liquid. MS (m / z): 208.0 [M+H] + .

[0238] (C) 4-(2-oxopyridine-1(2H)cyclohexane-1-carbaldehyde 1-(4-(hydroxymethyl)cyclohexyl)pyridin-2(1H)-one (170 mg, 0.82 mmol) and dichloromethane (15 mL) were added to the reaction flask, followed by Dess-Martin periodinane (383 mg, 0.90 mmol), and the mixture was allowed to react at room temperature for 3 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 70 mg of an oily liquid. MS (m / z): 206.1 [M+H]+ . Intermediate 38: 1-(5-methoxypyridin-2-yl)piperidine-4-carbaldehyde [ka]

[0239] (A) Ethyl 1-(5-bromopyridin-2-yl)piperidine-4-carboxylate 2,5-Dibromopyridine (2.37 g, 10 mmol), ethyl piperidine-4-carboxylate (1.57 g, 10 mmol), cesium carbonate (3.26 g, 10 mmol), and N,N-dimethylformamide (30 ml) were added sequentially to a reaction flask, and the mixture was heated to 110 °C and reacted for 16 hours. After the reaction was complete, water was added, and the mixture was then extracted with ethyl acetate. The organic phase was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 2.6 g of an oily liquid. MS (m / z): 313.2 [M+H] + .

[0240] (B) Ethyl 1-(5-hydroxypyridin-2-yl)piperidine-4-carboxylate Ethyl 1-(5-bromopyridin-2-yl)piperidine-4-carboxylate (2.6 g, 8.3 mmol), bis(pinacolato)diboron (4.2 g, 16.5 mmol), Pd(dppf)Cl2·CHCl2 (607 mg, 0.83 mmol), potassium acetate (1.63 g, 16.6 mmol), and dioxane (40 mL) were added sequentially to a reaction flask. The mixture was heated to 100 °C and reacted for 16 h under nitrogen protection. The reaction solution was concentrated and dissolved in methanol (100 mL) and water (20 mL). Sodium hydroxide (664 mg, 16.6 mmol) and hydrogen peroxide (2 mL) were added at 0 °C, and the mixture was reacted at room temperature for 2 h. After completion of the reaction, the reaction solution was quenched with sodium thiosulfate and extracted with ethyl acetate. The organic phase was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 1.1 g of a solid. MS (m / z): 251.2 [M+H] + .

[0241] (C) Ethyl 1-(5-methoxypyridin-2-yl)piperidine-4-carboxylate Ethyl 1-(5-hydroxypyridin-2-yl)piperidine-4-carboxylate (1.1 g, 4.39 mmol), sodium hydride (210 mg, 8.75 mmol), and N,N-dimethylformamide (20 mL) were added to a reaction flask, successively. Iodomethane (748 mg, 5.27 mmol) was added, and the mixture was allowed to react at room temperature for 2 hours. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate. The organic phase was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 620 mg of an oily liquid. MS (m / z): 265.4 [M+H] + .

[0242] (D) (1-(5-methoxypyridin-2-yl)piperidin-4-yl)methanol Ethyl 1-(5-methoxypyridin-2-yl)piperidine-4-carboxylate (620 mg, 2.35 mmol) and tetrahydrofuran (10 mL) were added sequentially to the reaction flask, and the mixture was cooled to 0°C. Lithium aluminum hydride (177 mg, 4.67 mmol) was added, and the mixture was 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 (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 370 mg of an oily liquid. MS (m / z): 223.4 [M+H] + .

[0243] (E) 1-(5-Methoxypyridin-2-yl)piperidine-4-carbaldehyde To the reaction flask, (1-(5-methoxypyridin-2-yl)piperidin-4-yl)methanol (370 mg, 1.66 mmol) and dichloromethane (15 mL) were added, followed by Dess-Martin periodinane (848 mg, 2.00 mmol), and the mixture was allowed to react at room temperature for 3 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 65 mg of an oily liquid. MS (m / z): 221.4 [M+H] + . Intermediate 39: 5-Formyl-N-methylbenzofuran-2-carboxamide [ka]

[0244] (A) Methyl 5-bromobenzofuran-2-carboxylate 5-Bromo-2-hydroxybenzaldehyde (2.01 g, 10 mmol), methyl 2-bromoacetate (2.30 g, 15 mmol), potassium carbonate (2.76 g, 20 mmol), and N,N-dimethylformamide (20 ml) were added sequentially to a reaction flask, and the mixture was heated to 110 °C and reacted for 5 hours. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate. The organic phase was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 1.6 g of a solid. MS (m / z): 255.0 [M+H] + .

[0245] (B) 5-Bromo-N-methylbenzofuran-2-carboxamide Methyl 5-bromobenzofuran-2-carboxylate (765 mg, 3 mmol) and methanamine in methanol (20 mL) were added sequentially to the reaction flask, and the mixture was 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 (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 762 mg of an oily liquid. MS (m / z): 254.2 [M+H] + .

[0246] (C) 5-Formyl-N-methylbenzofuran-2-carboxamide 5-Bromo-N-methylbenzofuran-2-carboxamide (508 mg, 2 mmol) and anhydrous tetrahydrofuran (20 mL) were added to a reaction flask, and the mixture was cooled to -78 °C. A 1.6 mol / L n-butyllithium solution (1.37 mL, 2.2 mmol) was added dropwise, followed by the addition of N,N-dimethylformamide (0.5 mL) after 1 hour. The mixture was then stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 180 mg of an oily liquid. MS (m / z): 204.2 [M+H] + . Intermediate 40: 5-Formyl-N,3-dimethylbenzofuran-2-carboxamide [ka]

[0247] (A) Methyl 2-(2-acetyl-4-bromophenoxy)acetate 1-(5-Bromo-2-hydroxyphenyl)ethan-1-one (1.07 g, 5.0 mmol), methyl 2-bromoacetate (765 mg, 5.0 mmol), potassium carbonate (830 mg, 6.0 mmol), and N,N-dimethylformamide (20 mL) were added sequentially to a reaction flask, and the mixture was heated to 110 °C and reacted for 5 hours. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate. The organic phase was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 980 mg of a solid. MS (m / z): 287.2 [M+H] + .

[0248] (B) Methyl 5-bromo-3-methylbenzofuran-2-carboxylate Methyl 2-(2-acetyl-4-bromophenoxy)acetate (980 mg, 3.41 mmol), DBU (1036 mg, 6.81 mmol), and tetrahydrofuran (20 ml) were added to the reaction flask in this order, and the mixture was heated to 100°C and reacted for 2 hours. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate. The organic phase was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 630 mg of a solid. MS (m / z): 269.2 [M+H] + .

[0249] (C) 5-Bromo-N,3-dimethylbenzofuran-2-carboxamide Methyl 5-bromo-3-methylbenzofuran-2-carboxylate (630 mg, 2.34 mmol) and methanamine in methanol (20 mL) were added sequentially to the reaction flask, and the mixture was 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 (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 550 mg of an oily liquid. MS (m / z): 270.4 [M+H] + .

[0250] (D) 5-Formyl-N,3-dimethylbenzofuran-2-carboxamide 5-Bromo-N,3-dimethylbenzofuran-2-carboxamide (534 mg, 2 mmol) and anhydrous tetrahydrofuran (20 mL) were added to a reaction flask, and the mixture was cooled to -78 °C. A 1.6 mol / L n-butyllithium solution (1.37 mL, 2.2 mmol) was added dropwise, followed by the addition of N,N-dimethylformamide (0.5 mL) after 1 hour. The mixture was then stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 260 mg of an oily liquid. MS (m / z): 218.2 [M+H] + . Example 2 Preparation of Compound 1-184 Compound 1: 2-((5-(7-((1-(cyclopropanecarbonyl)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 [ka]

[0251] To a reaction flask, 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) were sequentially added. The mixture was reacted at room temperature for 16 hours, and the reaction solution was concentrated to remove the solvent. The residue was then purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 22 mg of a white solid. MS (m / z): 594.4 [M+H] + .

[0252] 1 H NMR(400MHz,DMSO-d6)δ 8.43(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).

[0253] The following compounds were prepared according to the procedure for preparing Compound 1 using the corresponding intermediates and reagents under appropriate conditions recognized by one skilled in the art. [Table 16-1] [Table 16-2] [Table 16-3] [Table 16-4] 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-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide [ka]

[0254] (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 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) were added sequentially to a reaction flask, and the mixture was allowed to react at room temperature for 2 hours. The reaction solution was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 220 mg of a pale yellow solid. MS (m / z): 743.4 [M+H] + .

[0255] (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 To a reaction flask, 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 (220 mg, 0.30 mmol), methanol (5 mL), and palladium on carbon (22 mg) were added sequentially, and the mixture was reacted under hydrogen at room temperature for 15 hours. The reaction solution was filtered, and the filtrate was concentrated to give 140 mg of crude product, which was used directly in the next reaction. MS (m / z): 609.2 [M+H] + .

[0256] (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 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 (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 sequentially to a reaction flask, and the mixture was reacted at room temperature for 2 hours. The reaction solution was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 13.7 mg of a pale yellow solid. MS (m / z): 663.4 [M+H] + .

[0257] 1H NMR(400MHz,CD3OD)δ 8.38(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). 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 [ka]

[0258] (A) Methyl 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-carboxylate Intermediate 10-1 (80 mg, 0.15 mmol), 1-(methyloxycarbonyl)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) were added sequentially to a reaction flask, and the mixture was allowed to react at room temperature for 2 hours. The reaction solution was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 69 mg of a pale yellow solid. MS (m / z): 652.4 [M+H] + .

[0259] (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 Methyl 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-carboxylate (69 mg, 0.11 mmol), lithium hydroxide monohydrate (14 mg, 0.33 mmol), tetrahydrofuran (4 mL), and water (1 mL) were added sequentially to a reaction flask, and the mixture was reacted at room temperature for 15 hours. The reaction solution was adjusted to pH 5-6 with 1 mol / L dilute hydrochloric acid and concentrated to give the crude product. This was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 47 mg of a white solid. MS (m / z): 638.4 [M+H] + .

[0260] (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 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 (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 sequentially to a reaction flask, and the mixture was allowed to react at room temperature for 2 hours. The reaction solution was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 11.3 mg of a pale yellow solid. MS (m / z): 665.6 [M+H] + .

[0261] 1 H NMR(400MHz,CD3OD)δ 8.43(s,1H),8.41(s,1H),7.43-7.40(m,1H),7.27-7.23(m,2H),4.45-4.42(m,3 H),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,3 H),2.07-2.02(m,5H),1.82-1.78(m,2H),1.31-1.04(m,14H),0.82-0.78(m,2H). 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 [ka]

[0262] Intermediate 10-1 (53 mg, 0.1 mmol), triethylamine (0.5 mL), and dichloromethane (5 mL) were added to a reaction flask, followed by acryloyl chloride (19 mg, 0.2 mmol) at 0°C. The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 5 mg of a white solid. MS (m / z): 580.3 [M+H] + .

[0263] 1 H NMR(400MHz,CD3OD)δ 8.36(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,2H),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).

[0264] The following compounds were prepared according to the procedure for preparing compound 20 using the corresponding intermediates and reagents under appropriate conditions recognized by one skilled in the art. [Table 17-1] [Table 17-2] [Table 17-3] 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 [ka]

[0265] (A) N-Cyclopropyl-1H-imidazole-1-carboxamide 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 the mixture was stirred at room temperature overnight. The reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of dichloromethane / methanol = 100:0 to 0:100) to give 907 mg of a white solid product. MS (m / z): 152.1 [M+H] + .

[0266] (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 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) were added to a reaction flask, and the mixture was stirred at room temperature overnight. The reaction solution was then concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 50 mg of a white solid product. MS (m / z): 609.4 [M+H] + .

[0267] 1H NMR(400MHz,CD3OD)δ 8.38(s,1H),8.34(s,1H),7.38-7.35(m,1H),7.28-7.20(m,1H),7.18-7.12(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,1 H),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).

[0268] The following compounds were prepared according to the procedure for preparing compound 26 using the corresponding intermediates and reagents under appropriate conditions recognized by one skilled in the art. [Table 18-1] [Table 18-2] [Table 18-3] 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 [ka]

[0269] (A) 1-Fluoro-2-isocyanatobenzene A reaction flask was charged with 2-fluoroaniline (200 mg, 1.78 mmol), pyridine (570 mg, 7.21 mmol), and dichloromethane (20 ml). Triphosgene (540 mg, 1.82 mmol) was added dropwise under nitrogen protection. The mixture was stirred and reacted at room temperature for 15 hours. After the reaction was completed, the reaction solution was washed with 1 mol / L dilute hydrochloric acid and saturated aqueous sodium chloride solution. The organic phase was concentrated to obtain the crude product, which was used directly in the next reaction. MS (m / z): 241.1 [2M+H] + .

[0270] (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 The crude product 1-fluoro-2-isocyanatobenzene (150 mg), intermediate 10-1 (50 mg, 0.095 mmol), triethylamine (19 mg, 0.19 mmol), and dichloromethane (20 mL) were added to a sealed tube. The mixture was then heated to 80 °C, stirred, and reacted for 15 h. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 30 mg of a white solid. MS (m / z): 663.4 [M+H] + .

[0271] 1H NMR(400MHz,CD3OD)δ 8.35(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),3.5 5-3.33(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).

[0272] The following compounds were prepared according to the procedure for preparing compound 36 using the corresponding intermediates and reagents under appropriate conditions recognized by one skilled in the art. [Table 19] 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 [ka]

[0273] 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) were added sequentially to a reaction flask, and the mixture was heated to 120 °C and reacted for 3 hours. After the reaction was complete, the reaction solution was cooled to room temperature and purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 35 mg of a white solid. MS (m / z): 672.4 [M+H] + .

[0274] 1 H NMR(400MHz,CD3OD)δ 8.45(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),3.27-3.1 7(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,4 H),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).

[0275] The following compounds were prepared according to the procedure for preparing compound 38 using the corresponding intermediates and reagents under appropriate conditions recognized by one skilled in the art. [Table 20-1] [Table 20-2] [Table 20-3] [Table 20-4] 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 [ka]

[0276] 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) were sequentially added to a reaction flask. The mixture was heated to 100 °C and reacted under nitrogen protection for 15 h. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 25 mg of a white solid. MS (m / z): 643.4 [M+H] + .

[0277] 1 H NMR(400MHz,CD3OD)δ 8.45-8.42(m,2H),8.32(s,1H),8.15(s,1H),7.43-7.38(m,1H),7.33-7.20(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),3.5 6-3.42(m,1H),3.28-3.08(br,4H),3.02-2.95(m,4H),2.20-2.11(m,5H),1.94(d,J=12.5H z,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).

[0278] The following compounds were prepared according to the procedure for preparing compound 55 using the corresponding intermediates and reagents under appropriate conditions recognized by one skilled in the art. [Table 21] 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 [ka]

[0279] 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. 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 (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 19 mg of product. MS (m / z): 603.4 [M+H] + .

[0280] 1H NMR(400MHz,CD3OD)δ 8.38(s,1H),8.34(s,1H),7.38-7.35(m,1H),7.28-7.20(m,1H),7.18-7.12(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),1.75(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).

[0281] The following compounds were prepared according to the procedure for preparing compound 57 using the corresponding intermediates and reagents under appropriate conditions recognized by one skilled in the art. [Table 22-1] [Table 22-2] [Table 22-3] [Table 22-4] [Table 22-5] [Table 22-6] [Table 22-7] [Table 22-8] [Table 22-9] [Table 22-10] [Table 22-11] [Table 22-12] [Table 22-13] [Table 22-14] [Table 22-15] [Table 22-16] [Table 22-17] [Table 22-18] 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 [ka]

[0282] (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 To a reaction flask were added 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), and the mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (99 mg, 0.47 mmol) was then added, and the mixture was stirred for an additional 15 hours. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 38 mg of a yellow solid. MS (m / z): 779.4 [M+H] + .

[0283] (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 To a reaction flask, 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 (60 mg, 0.077 mmol) and a solution of hydrochloric acid in methanol (5 mL, 6 mol / L) were added, and the mixture was reacted at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of dichloromethane / methanol = 100:0 to 0:100) to give 40 mg of a white solid. MS (m / z): 679.3 [M+H] + .

[0284] 1H NMR(400MHz,CD3OD)δ 12.20(s,1H),8.43(s,1H),8.14(s,1H),7.45-7.38(m,1H),7.37-7.29(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,3H),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). Compound 132: 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 [ka]

[0285] (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 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) were added to a reaction flask in this order, and the mixture was 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 (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 40 mg of a white solid. MS (m / z): 747.5 [M+H] + .

[0286] (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 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 (40 mg, 0.05 mmol), tetrabutylammonium fluoride (30 mg, 0.12 mmol), and tetrahydrofuran (5 mL) were added to the reaction flask, and the mixture was 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 (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 7 mg of a white solid. MS (m / z): 633.3 [M+H] + .

[0287] 1 H NMR(400MHz,DMSO-d6)δ 8.43(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,2 H),5.13(t,J=5.9Hz,1H),4.34(d,J=5.9Hz,2H),4.25-4.18(m,4H),3.78(s,2H),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). 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 [ka]

[0288] (A) 2-((5-(7-((1-(6-cyclopyridazin-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 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) were added to a reaction flask, and the mixture was heated to 120 °C, stirred, and reacted for 2 hours. After the reaction was completed, the reaction solution was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 260 mg of a yellow solid. MS (m / z): 638.3, 640.3 [M+H] + .

[0289] (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 To a reaction flask was added 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)Cl.CH.sub.2Cl.sub.2 (13 mg, 0.018 mmol), dioxane (20 ml), and water (3 ml). The mixture was then heated to 100°C, stirred, and reacted for 15 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 15 mg of a white solid. MS (m / z): 630.6 [M+H] + .

[0290] 1 H NMR(400MHz,CD3OD)δ 8.38(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),3.5 8-3.45(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).

[0291] The following compounds were prepared according to the procedure for preparing compound 133 using the corresponding intermediates and reagents under appropriate conditions recognized by one skilled in the art. [Table 23] 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 [ka]

[0292] Compound 123 (100 mg, 0.167 mmol), palladium on carbon (15 mg), and methanol (15 mL) were added to a reaction flask, and the mixture was reacted at room temperature for 15 hours under a hydrogen balloon. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 80 mg of a white solid. MS (m / z): 602.4 [M+H] + .

[0293] 1 H NMR(400MHz,CD3OD)δ 8.48-8.43(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),1.7 2-1.61(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). 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-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)nicotinonitrile [ka]

[0294] (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 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) were added sequentially to a reaction flask, and the mixture was allowed to react at room temperature for 2 hours. The reaction solution was quenched with saturated aqueous ammonium chloride (2 mL), extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give a residue. This was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 49 mg of a yellow solid. MS (m / z): 627.8 [M+H] + .

[0295] (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 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 (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 sequentially to a reaction flask, and the mixture was reacted in an ice bath for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride (2 ml), extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give a residue, which was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 15.6 mg of a yellow solid. MS (m / z): 629.8 [M+H] + .

[0296] 1 H NMR(400MHz,CD3OD)δ 8.35(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). Compound 137: N-ethyl-5-fluoro-N-isopropyl-2-((5-(7-((1-(oxetan-3-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide [ka]

[0297] Intermediate 10-1 (45 mg, 0.086 mmol), oxetan-3-one (12 mg, 0.17 mmol), sodium cyanoborohydride (11 mg, 0.18 mmol), methanol (5 mL), and acetic acid (0.5 mL) were added sequentially to a reaction flask, and the mixture was 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 (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 12.4 mg of an oily liquid. MS (m / z): 582.4 [M+H] + .

[0298] 1 H NMR(400MHz,DMSO-d6)δ 8.43(d,J=0.9Hz,1H),7.43-7.39(m,1H),7.35-7.31(m,2H),4.48(t,J=6.2Hz,2 H),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).

[0299] The following compounds were prepared according to the procedure for preparing compound 137 using the corresponding intermediates and reagents under appropriate conditions recognized by one skilled in the art. [Table 24] 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 [ka]

[0300] (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 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 triacetoxyborohydride (112 mg, 0.53 mmol), and dichloromethane (8 mL) were added to a reaction flask, and the mixture was reacted at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 28 mg of a white solid. MS (m / z): 583.3 [M+H] + .

[0301] (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 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 (10 mg, 0.017 mmol), aqueous carbaldehyde solution (0.2 mL), sodium cyanoborohydride (2 mg, 0.032 mmol), methanol (5 mL), and acetic acid (0.5 mL) were added to a reaction flask, and the mixture was reacted at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 7.4 mg of a white solid. MS (m / z): 597.3 [M+H] + .

[0302] 1 H NMR(400MHz,DMSO-d6)δ 12.23(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,2H),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).

[0303] The following compounds were prepared according to the procedure for preparing compound 139 using the corresponding intermediates and reagents under appropriate conditions recognized by one skilled in the art. [Table 25] Compound 144: N-ethyl-5-fluoro-N-isopropyl-2-((5-(7-((1-(2-methoxy-N-methylacetamido)cyclopropyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide [ka]

[0304] (A) N-ethyl-5-fluoro-N-isopropyl-2-((5-(7-((1-(2-methoxyacetamido)cyclopropyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide To a reaction flask, 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) were added. The mixture was stirred and reacted at room temperature for 15 hours. After completion of the reaction, the reaction solution was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 40 mg of a yellow solid. MS (m / z): 570.4 [M+H] + .

[0305] (B) N-ethyl-5-fluoro-N-isopropyl-2-((5-(7-((1-(2-methoxy-N-methylacetamido)cyclopropyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide To a reaction flask were added N-ethyl-5-fluoro-N-isopropyl-2-((5-(7-((1-(2-methoxyacetamido)cyclopropyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide (40 mg, 0.07 mmol) and N,N-dimethylformamide (5 mL). Sodium hydride (4.2 mg, 0.105 mmol) was added at room temperature, and the mixture was stirred and reacted at room temperature for 30 minutes. Iodomethane (10 mg, 0.07 mmol) was then added, and the mixture was stirred for an additional 15 hours. After the reaction was complete, the reaction solution was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 25 mg of a white solid. MS (m / z): 584.4 [M+H] + .

[0306] 1H NMR(400MHz,DMSO-d6)δ 8.46(s,1H),8.40-8.37(m,1H),7.44-7.36(m,1H),7.32-7.17(m,2H),4.51-4.16(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,1H),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). 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 [ka]

[0307] (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 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) were added sequentially to a reaction flask, and the mixture was reacted at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 90 mg of a solid. MS (m / z): 552.2 [M+H] + .

[0308] (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 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 (80 mg, 0.15 mmol), aqueous carbaldehyde solution (1 mL), sodium cyanoborohydride (45 mg, 0.72 mmol), and methanol (5 mL) were added to a reaction flask in this order, and the mixture was reacted at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 63 mg of a white solid. MS (m / z): 566.8 [M+H] + .

[0309] 1 H NMR(400MHz,CD3OD)δ 8.37(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),3.86-3.74(m,2H),3 .72-3.56(m,4H),3.54-3.42(m,1H),2.26(s,3H),1.32-2.26(m,2H),1.23-1.11(m,7H),1.05(t,J=7.1Hz,1H),0.81-0.76(m,5H). 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 [ka]

[0310] Compound 145 (50 mg, 0.088 mmol) and pyridine (2 mL) were added sequentially to a reaction flask, and two drops of phosphorus oxychloride were added at 0°C. The mixture was allowed to react 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 (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 19 mg of a white solid. MS (m / z): 548.6 [M+H] + .

[0311] 1 H NMR(400MHz,CD3OD)δ 8.39(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),3.72-2.6 4(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). Compound 147: 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 [ka]

[0312] (A) Ethyl 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-hydroxypropanoate Intermediate 10-1 (100 mg, 0.19 mmol), ethyl oxirane-2-carboxylate (44 mg, 0.38 mmol), triethylamine (38 mg, 0.38 mmol), and methanol (5 mL) were added sequentially to a reaction flask, and the mixture was 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 (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 40 mg of an oily liquid. MS (m / z): 642.4 [M+H] + .

[0313] (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 Ethyl 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-hydroxypropanoate (40 mg, 0.062 mmol) in methanol (10 ml) and ammonia were added sequentially to a reaction flask, and the mixture was 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 (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 6 mg of a white solid. MS (m / z): 613.4 [M+H] + .

[0314] 1H NMR(400MHz,CD3OD)δ 8.36(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).

[0315] The following compounds were prepared according to the procedure for preparing compound 147 using the corresponding intermediates and reagents under appropriate conditions recognized by one skilled in the art. [Table 26] 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 [ka]

[0316] (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 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) were added sequentially to a reaction flask, and the mixture was heated to 60 °C and reacted for 3 hours. The reaction solution was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 72 mg of a white solid. MS (m / z): 628.3 [M+H] + .

[0317] (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 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 (72 mg, 0.12 mmol), potassium carbonate (30 mg, 0.22 mmol), and DMSO (3 mL) were added sequentially to a reaction flask. Hydrogen peroxide (0.1 mL) was added dropwise, and the mixture was reacted at room temperature for 3 hours. The reaction solution was quenched with saturated aqueous ammonium chloride (5 mL), extracted three times with ethyl acetate, washed with saturated aqueous sodium hydrogen sulfate and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a residue. This was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 32.5 mg of a pale yellow solid. MS(m / z):646.4[M+H] + .

[0318] 1H NMR(400MHz,CD3OD)δ 8.62-8.59(m,1H),8.41(s,1H),8.38(s,1H),7.96-7.93(m,1H),7.42-7.39(m,1H),7.3 2-7.19(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,1 H),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). 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 [ka]

[0319] (A) Methyl 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 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) were added sequentially to a reaction flask, and the mixture was allowed to react at room temperature for 2 hours. The reaction solution was quenched with saturated aqueous ammonium chloride (2 mL), extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give a residue. This was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 72 mg of a yellow solid. MS (m / z): 661.4 [M+H] + .

[0320] (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 Methyl 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 (72 mg, 0.11 mmol) and 7 mol / L ammonia in methanol (8 mL, 0.56 mmol) were added sequentially to a sealed tube, and the mixture was heated to 80 °C and reacted for 40 hours. After the reaction was completed, the reaction solution was concentrated to give the crude product, which was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 32.5 mg of a pale yellow solid. MS (m / z): 646.4 [M+H] + .

[0321] 1 H NMR(400MHz,CD3OD)δ 8.41(s,1H),8.36(s,1H),8.26-8.23(m,1H),7.39-7.36(m,1H),7.26-7.23(m,1H),7.1 8-7.11(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,2 H),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).

[0322] The following compounds were prepared according to the procedure for preparing compound 150 using the corresponding intermediates and reagents under appropriate conditions recognized by one skilled in the art. [Table 27] 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 [ka]

[0323] (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 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-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 procedure for preparing Compound 57), methanamine 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 sequentially to a reaction flask, and the mixture was 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 (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 20 mg of a solid. MS (m / z): 757.4 [M+H] + .

[0324] (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 In a reaction flask, 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) (20 mg, 0.026 mmol) was dissolved in methanol (5 mL), two drops of concentrated hydrochloric acid were added, and the mixture was reacted 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 (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 11 mg of a white solid. MS (m / z): 673.4 [M+H] + .

[0325] 1 H NMR(400MHz,DMSO-d6)δ 8.43(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),3.63(t,J=5.5H z,2H),3.58(d,J=6.7Hz,1H),3.47(s,3H),3.06-3.00(m,3H),2.75(d,J=4.4Hz,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).

[0326] The following compounds were prepared according to the procedure for preparing compound 152 using the corresponding intermediates and reagents under appropriate conditions recognized by one skilled in the art. [Table 28-1] [Table 28-2] [Table 28-3] 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 [ka]

[0327] (A) tert-Butyl (tert-butoxycarbonyl) (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 Intermediate 10-1 (50 mg, 0.10 mmol), tert-butyl (6-bromopyridin-2-yl)(tert-butoxycarbonyl)carbamate (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) were sequentially added to a reaction flask. The mixture was heated to 100 °C and reacted under nitrogen protection for 15 h. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 14 mg of a yellow solid. MS (m / z): 818.5 [M+H] + .

[0328] (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 To a reaction flask, tert-butyl (tert-butoxycarbonyl) (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 (14 mg, 0.017 mmol), concentrated hydrochloric acid (0.25 mL), and methanol (2 mL) were added sequentially, and the mixture was allowed to react at room temperature for 30 minutes. The reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 4.5 mg of a yellow solid. MS (m / z): 618.4 [M+H] + .

[0329] 1 H NMR (400MHz, mixture of CDCl3 and CD3OD) δ 8.36(s,1H),7.38-7.35(m,1H),7.26-7.19(m,2H),7.13-7.10(m,1H),6.00-5.9 7(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). 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 [ka]

[0330] (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 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) were added to a reaction flask, and the mixture was stirred and reacted 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 (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 30 mg of a yellow solid. MS (m / z): 638.3 [M+H] + .

[0331] (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 To a reaction flask were added 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 (30 mg, 0.047 mmol), palladium on carbon (6 mg), and methanol (10 ml), and the mixture was reacted under hydrogen at room temperature for 15 hours. After completion of the reaction, the reaction solution was filtered, the filtrate was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 20 mg of a white solid. MS (m / z): 604.4 [M+H] + .

[0332] 1H NMR(400MHz,DMSO-d6)δ 8.43(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),2.1 0(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).

[0333] The following compounds were prepared according to the procedure for preparing compound 165 using the corresponding intermediates and reagents under appropriate conditions recognized by one skilled in the art. [Table 29] 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 [ka]

[0334] (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 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) were added sequentially to a reaction flask, and the mixture was allowed to react at room temperature for 1 h. The reaction solution was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 61 mg of a pale yellow solid. MS (m / z): 749.2 [M+H] + .

[0335] (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 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 (61 mg, 0.081 mmol), palladium on carbon (6 mg), and methanol (6 mL) were added sequentially to a reaction flask, and the mixture was reacted under hydrogen for 2 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 16.5 mg of product. MS (m / z): 671.4 [M+H] + .

[0336] 1H NMR(400MHz,CD3OD)δ 9.02-8.99(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). Compound 170: methyl 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 [ka]

[0337] (A) 4-Nitrophenyl 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 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) were added sequentially to a reaction flask, and the mixture was reacted at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 50 mg of a solid. MS (m / z): 691.4 [M+H] + .

[0338] (B) Methyl 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 4-Nitrophenyl 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 (30 mg, 0.043 mmol), sodium methoxide (5 mg, 0.093 mmol), and methanol (5 mL) were added sequentially to a reaction flask, and the mixture was heated to 80 °C and reacted for 5 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 6 mg of a white solid. MS (m / z): 584.4 [M+H] + .

[0339] 1 H NMR(400MHz,DMSO-d6)δ 8.42(s,1H),7.43-7.38(m,1H),7.32(dd,J=9.9,5.8Hz,2H),4.17(s,2 H),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). Compound 171: 2-((5-(7-((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 [ka]

[0340] (A) 1-(1-(5,6-dimethoxypyridazin-3-yl)piperidin-4-yl)ethan-1-one To a reaction flask, 6-chloro-3,4-dimethoxypyridazine (523 mg, 3 mmol), 1-(piperidin-4-yl)ethan-1-one (572 mg, 4.5 mmol), Pd2(dba)3 (137 mg, 0.15 mmol), BINAP (187 mg, 0.3 mmol), sodium methoxide (324 mg, 6 mmol), and toluene (30 mL) were sequentially added. The mixture was heated to 110 °C and reacted under nitrogen protection for 16 h. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 110 mg of a solid. MS (m / z): 266.2 [M+H] + .

[0341] (B) 1-(1-(5,6-dimethoxypyridazin-3-yl)piperidin-4-yl)ethan-1-ol 1-(1-(5,6-Dimethoxypyridazin-3-yl)piperidin-4-yl)ethan-1-one (110 mg, 0.42 mmol) and methanol (10 ml) were added sequentially to the reaction flask, and the mixture was cooled to 0°C. Sodium borohydride (46 mg, 1.22 mmol) was added, and the mixture was 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 (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 80 mg of a solid. MS (m / z): 268.4 [M+H] + .

[0342] (C) 1-(1-(5,6-dimethoxypyridazin-3-yl)piperidin-4-yl)ethyl methanesulfonate 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) were added to the reaction flask, and the mixture was cooled to 0°C. Methanesulfonyl chloride (52 mg, 0.45 mmol) was added, and the mixture was reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 50 mg of a solid. MS (m / z): 346.1 [M+H] + .

[0343] (D) 2-((5-(7-((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 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) were added sequentially to a reaction flask, and the mixture was heated to 100 °C and reacted for 15 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 10 mg of a white solid. MS (m / z): 678.4 [M+H] + .

[0344] 1H NMR(400MHz,CD3OD)δ 8.41(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). 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 [ka]

[0345] 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) were added sequentially to a reaction flask, and the mixture was allowed to react at room temperature for 1 hour. The reaction solution was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 24.6 mg of a pale yellow solid. MS (m / z): 617.4 [M+H] + .

[0346] 1H NMR(400MHz,CD3OD)δ 8.38(s,1H),7.43-7.40(m,1H),7.33-7.23(m,1H),7.21-7.18(m,1H),6.68(s,1 H),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,3 H),2.24-2.20(m,2H),1.88-1.83(m,7H),1.37-1.00(m,11H),0.83-0.79(m,2H). 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 [ka]

[0347] (A) tert-Butyl 7-(4-(pyridin-2-yl)piperazine-1-carbonyl)-2-azaspiro[3.5]nonane-2-carboxylate 1-(pyridin-2-yl)piperazine (480 mg, 2.9 mmol), 2-(tert-butoxycarbonyl)-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 sequentially to a reaction flask, and the mixture was reacted at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 500 mg of a solid. MS (m / z): 415.1 [M+H] + .

[0348] (B) (4-(pyridin-2-yl)piperazin-1-yl)(2-azaspiro[3.5]nonan-7-yl)methanone To 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 sequentially, and the mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, the reaction solution was neutralized with aqueous sodium bicarbonate and concentrated. The residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 300 mg of a solid. MS (m / z): 315.2 [M+H] + .

[0349] (C) 7-((4-(pyridin-2-yl)piperazin-1-yl)methyl)-2-azaspiro[3.5]nonane To the reaction flask, (4-(pyridin-2-yl)piperazin-1-yl)(2-azaspiro[3.5]nonan-7-yl)methanone (300 mg, 0.95 mmol), tetrahydrofuran (10 mL), and lithium aluminum hydride (72 mg, 1.90 mmol) were added sequentially, and the mixture was heated to 70 °C and reacted for 3 days. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 150 mg of a solid. MS (m / z): 301.2 [M+H] + .

[0350] (D) 2-(3,6-dichloro-1,2,4-triazin-5-yl)-7-((4-(pyridin-2-yl)piperazin-1-yl)methyl)-2-azaspiro[3.5]nonane 7-((4-(pyridin-2-yl)piperazin-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 sequentially to the reaction flask, and the mixture was reacted 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 (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 120 mg of a solid. MS (m / z): 448.2 [M+H] + .

[0351] (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 2-(3,6-Dichloro-1,2,4-triazin-5-yl)-7-((4-(pyridin-2-yl)piperazin-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 to the reaction flask, and the mixture was reacted at 40 °C for 16 h. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 30 mg of a solid. MS (m / z): 637.4 [M+H] + .

[0352] (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 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 (20 mg, 0.03 mmol), palladium on carbon (10 mg), and methanol (5 mL) were added sequentially to the reaction flask, and the mixture was reacted under hydrogen at room temperature for 5 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 6 mg of a solid. MS (m / z): 603.4 [M+H] + .

[0353] 1 H NMR(400MHz,DMSO-d6)δ 8.41(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),3.6 2-3.54(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). Compound 175: 2-((5-(7-((2-cyano-4-methyl-1H-indol-5-yl)methyl-d-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide [ka]

[0354] 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) were added sequentially to a reaction flask, and the mixture was allowed to react at room temperature for 3 days. The reaction solution was quenched with 0.2 mL of saturated ammonium chloride solution and concentrated to give the crude product, which was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 24.3 mg of a white solid. MS (m / z): 598.3 [M+H] + 1 H NMR(400MHz,CD3OD)δ 8.36(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),3.5 4(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).

[0355] The following compounds were prepared according to the procedure for preparing compound 175 using the corresponding intermediates and reagents under appropriate conditions recognized by one skilled in the art. [Table 30] 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 [ka]

[0356] (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 Compound 106 (300 mg, 0.47 mmol), sodium hydroxide (57 mg, 1.41 mmol), THF (8 mL), and water (2 mL) were added sequentially to a reaction flask, and the mixture was reacted at 50 °C for 15 h. The reaction solution was adjusted to pH 5-6 with 1N dilute hydrochloric acid, concentrated, and then purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 30 mg of a white solid. MS (m / z): 595.2 [M+H] +

[0357] (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 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 (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 sequentially to a reaction flask, and the mixture was reacted at room temperature for 2 hours. The reaction solution was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to obtain 7 mg of a pale yellow solid. MS (m / z): 636.6 [M+H] + 1H NMR(400MHz,CD3OD)δ 8.33(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). 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-fluorobenzimidic acid [ka]

[0358] Intermediate 7-26 (72 mg, 0.19 mmol), intermediate 24-3 (81 mg, 0.32 mmol), NaBH(OAc) (81 mg, 0.38 mmol), and THF (5 mL) were added to a reaction flask, and the mixture was reacted at room temperature for 5 h. The reaction solution was quenched with 0.5 mL of saturated ammonium chloride, concentrated, and purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give two pale yellow solid products, compound 178 (26.6 mg) and compound 179 (14.2 mg).

[0359] Compound 178:MS(m / z):622.4[M+H] + 1H NMR(400MHz,CD3OD)δ 8.86(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).

[0360] Compound 179:MS(m / z):622.4[M+H] + 1 H NMR (400 MHz, CD3OD) δ 8.51(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,3 H),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). 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 [ka]

[0361] Methyl 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-fluorobenzoate (250 mg, 0.41 mmol, prepared from Intermediates 7-24 and 24-3 according to the procedure for preparing Compound 57), NaOH (33 mg, 0.82 mmol), THF (4 mL), and water (1 mL) were added sequentially to a reaction flask, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was neutralized with dilute hydrochloric acid and concentrated. The residue was purified by flash column chromatography (eluting with a gradient of water / methanol = 100:0 to 0:100) to give 4 mg of a white solid. MS (m / z): 595.3 [M+H] + 1 H NMR(400MHz,CD3OD)δ 8.41(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),4.07(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). Example 3: Determination of the activity of compounds of the invention on menin and MLL protein binding at the molecular level (fluorescence polarization)

[0362] 1. Reagents, materials and equipment: Recombinant human menin protein (2-610): ChemPartner, CP2021020801; MLL polypeptide (6-FAM-Ahx-SG-40): GL Biochem, 865700; Trizma® Hydrochloric Acid Buffer (Tris): Sigma, T2194-1L; NaCl: Invitrogen, AM9760G; TCEP:Sigma,646547; DMSO: Sigma, D4540; 384-well plate: Corning, 4514; Envision: PerkinElmer.

[0363] 2. Preparation of Reaction Solutions 1) Buffer solution: 20 mL of Tris and 4 mL of NaCl were added to 376 ml of ddH2O, respectively, and the pH was adjusted to 7.5. TCEP was added at a dilution ratio of 1:500 before testing.

[0364] 2) 5x test compound: Test compounds were diluted in a gradient of 5x the reaction concentration with buffer to final compound concentrations of 1.000, 0.333, 0.111, 0.037, 0.012, 0.004, 0.001 and 0.0005 µM, respectively.

[0365] 3) 2.5x menin protein reaction solution: Menin protein was diluted to 5 nM with buffer.

[0366] 4) 2.5×MLL polypeptide reaction solution: MLL polypeptide was diluted with buffer to 5 nM.

[0367] 3. Method 1) Binding reaction (20 μL system) 4 μL of 5× test compound was added to each reaction well of a 384-well plate, and a corresponding volume of 10% DMSO was added to the control wells. Except for the control wells, 8 μL of menin protein reaction solution was added to each well. After incubating the reaction solution at room temperature for 30 minutes, 8 μL of MLL polypeptide reaction solution was added to each well. The final concentration of DMSO in the test compound wells and control wells was all 2%. The 384-well plate was sealed and incubated in the dark at room temperature for 30 hours.

[0368] Three control groups were established: a blank control group containing buffer only; a negative control group containing only the MLL polypeptide reaction solution; and A positive control group containing a menin protein reaction solution and an MLL polypeptide reaction solution.

[0369] 2) Detection Vertically polarized S and horizontally polarized P values ​​(excitation wavelength 480 nm and emission wavelength 535 nm) were measured using an Envison.

[0370] 4. Data Analysis Calculating G-factor: G = ((1000-mP) x Corrected S) / ((1000+mP) x Corrected P) The corrected S is the S value of the negative control group minus the S value of the blank control group. The corrected P is the P value of the negative control group minus the P value of the blank control group. Fluorescence polarization value mP: mP = [(SP × G) / (S + P × G)] × 1000 Inhibition rate % (IR) = [(mP 陽性対照 -mP 試験試料 ) / (mP 陽性対照 -mP 陰性対照 )] × 100%

[0371] 5. G.I. 50 Calculations: Calculations were made by using the software XL-Fit™ (version 5.3) supplied by ID Business Solutions (Guildford, UK), which is additional software for Microsoft Excel.

[0372] 6. Test Results [Table 31-1] [Table 31-2] Example 4 Cell proliferation assay

[0373] 1. Cell lines MV-4-11 (ATCC, CRL-9591), a human acute myeloid leukemia cell line harboring the MLL-AF4 mutation, was cultured in IMDM medium containing 10% heat-inactivated fetal bovine serum (HIFBS) and supplemented with 50 μM β-mercaptoethanol.

[0374] 2. Reagents, materials and equipment: IMDM culture solution: GIBCO, 12440-053; HIFBS:GIBCO, 10100-147; β-mercaptoethanol: Sigma, M3148; CellTiter-Glo® 2.0 Assay Kit (CTG): Promega, G9243; DMSO: Sigma, D4540; 96-well cell culture plate: Corning, 3903; Envision: PerkinElmer.

[0375] 3. Method MV-4-11 cells were resuspended in medium and added to a 96-well plate at a density of 3000 cells / well in a volume of 100 μL / well. Cultured for 4 hours in a cell incubator at 5% CO2 and 37°C. Gradient-diluted test compounds were added to the cell culture plate, with final compound concentrations of 1.100, 0.367, 0.122, 0.041, 0.014, 0.005, 0.002, and 0.001 μM, respectively. Corresponding volumes of DMSO dilutions were added to blank control wells, resulting in a final DMSO concentration of 0.1% in both the experimental and control groups. The cell plate was placed in a cell incubator at 5% CO2 and 37°C and cultured for 3 days.

[0376] 4. Detection On days 0 and 3 of treatment, 50 μL / well of CTG reagent was added to the cell plate, and the plate was shaken in the dark at room temperature for 10 minutes, after which the chemiluminescence value of each well was measured using Envision.

[0377] 5. Data Analysis Inhibition rate % = 100 - (luminescence value試験試料 - Luminous value 0日目 ) / (luminous value 細胞ウェル - Luminous value 0日目 ) x 100 During the ceremony, Luminous value 試験試料 : Chemiluminescence values ​​of cell wells treated with test compounds for 3 days.

[0378] Luminous value 0日目 : Chemiluminescence value of cell well on day 0.

[0379] Luminous value 細胞ウェル : Chemiluminescence values ​​on day 3 of cell wells not treated with compound.

[0380] 6. G.I. 50 Calculation: Calculations were made by using the software XL-Fit™ (version 5.3) supplied by ID Business Solutions (Guildford, UK), which is a supplement to Microsoft Excel.

[0381] 7. Test Results [Table 32-1] [Table 32-2]

Claims

1. Compound of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated thereof, wherein, R １ However, hydrogen, halogen, -CN, -OH, -NH ２ , C １～６ Alkyl, C １～６ Haloalkyl, -O-(C) １～６ Alkyl) and -O-(C １～６ Selected from haloalkyl, R ２ is selected from hydrogen, halogen, -CN, -OH, -NH ２ , 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- to 8-membered heterocyclyl), C ３～８ cycloalkyl, 4- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, -S-(C １～６ alkyl), -S-(C ３～８ cycloalkyl), -S-(4- to 8-membered heterocyclyl), -NH(C １～６ alkyl), -N(C １～６ alkyl) ２ , -NHCONH ２ , -NHCO(C １～６ alkyl), -CONR ａ R ｂ , -CSNR ａ R ｂ , -COR ｃ and -COOR ｅ is selected from the group, and said C ３～８ cycloalkyl, 4- to 8-membered heterocyclyl, phenyl and 5- to 12-membered heteroaryl are each optionally substituted with halogen, -OH, oxo, -CN, -NH ２ , -CONH ２ , 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 Substituted with one or more elements independently selected from, R ３ However, hydrogen, halogen, -CN, -OH, -NH ２ , C １～６ Alkyl, C １～６ Haloalkyl, -O-(C) １～６ Alkyl) and -O-(C １～６ Selected from haloalkyl, or R ２ and R ３ However, together with the carbon atoms to which they are bonded, they form a 5-6 member heteroaryl or a 4-6 member heterocycline, and the 5-6 member heteroaryl and 4-6 member heterocycline can be optionally composed of halogen, -OH, oxo, -CN, or -NH. ２ , -CONH ２ , C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, 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 Substituted with one or more groups independently selected from haloalkyl groups, R ５ However, 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 Cycloalkyl, 4-8 membered heterocyclyl, -S-(C １～６ Alkyl), -NHCONH ２ , - NHCO (C １～６ Alkyl) and -NR ａ R ｂ Selected from, Cy １ is a 4- to 12-membered heterocyclyl, optionally substituted with halogen, -OH, oxo, -CN, -NH ２ , -CONH ２ , 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), substituted with one or more groups independently selected from Cy ２ However, C ３～８ Selected from cycloalkyl, 4-9 membered heterocyclyl, aryl, and 5-14 membered heteroaryl, R ４ However, independently, halogen, -CN, -OH, oxo, -SH, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, -O-(C １～６ Alkyl), -O-(C １～６ Haloalkyl), -O-(C ３～８ Cycloalkyl), -O- (4-8 membered heterocyclyl), -(C １～６ Alkyl) ｍ - (C ３～８ Cycloalkyl), - (C １～６ Alkyl) ｍ - (4-8 member heterocyclyl), - (C １～６ Alkyl) ｍ -phenyl, -(C １～６ Alkyl) ｍ - (5-12 member heteroaryl), -S- (C １～６ Alkyl), -S-(C ３～８ Cycloalkyl), -S- (4-8 membered heterocyclyl), -NHCONH ２ , -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 Selected from, the C １～６ Alkyl, C ３～８ Cycloalkyl, 4-8 membered heterocyclyl, phenyl, and 5-12 membered heteroaryl are each optionally associated with halogen, -OH, oxo, -SH, -CN, and -NH. ２ , -CONH ２ , C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, 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 heterocyclyl), -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 Alkinyl), -CONH(C １～６ Alkyl), -CON(C １～６ Alkyl) ２ , C ３～８ Substituted with one or more groups independently selected from cycloalkyl and 4- to 8-membered heterocyclines, L does not exist, or L is CH ２ And, R ａ , R ｂ , R ｃ , R ｄ and R ｅ However, each independently, hydrogen, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, -(C １～６ Alkyl) ｍ - (C ３～８ Cycloalkyl), - (C １～６ Alkyl) ｍ - (4-8 member heterocyclyl), - (C １～６ Alkyl) ｍ -Phenyl and -(C １～６ Alkyl) ｍ - Selected from (5-12 member heteroaryl), the C １～６ Alkyl, C ３～８ Cycloalkyl, 4-8 membered heterocyclyl, phenyl, and 5-12 membered heteroaryl are each optionally associated with halogen, -OH, oxo, -SH, -CN, and -NH. ２ , -CONH ２ , C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, 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 heterocyclyl), -S- (C １～６ Alkyl), -NH(C １～６ Alkyl), -N(C １～６ Alkyl) ２ ,-NH(C ３～８ Cycloalkyl), -NH (4-8 membered heterocyclyl), -CO (C １～６ Alkyl), -CO(C ２～６ Alkenyl), -CO(C) ２～６ Alkinyl), -CO(C ３～８ Cycloalkyl), -CO (4-8 membered heterocyclyl), -CONH (C １～６ Alkyl), -CONH(C ３～８ Cycloalkyl), -CONH (4-8 member heterocyclyl) and -CON (C １～６ Alkyl) ２ Substituted with one or more elements independently selected from, R ｆ However, -CH ３ And, p is 0, 1, 2, 3, 4, or 5. m is 0 or 1, n is 1 or 2, However, R ４ A compound, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated thereof, provided that it is not -NH (a six-membered nitrogen-containing heteroaryl) or -NH (a phenyl substituted with F).

2. R １ However, halogen, CN or C １～６ It is a haloalkyl, R ２ However, hydrogen, -O-(C １～６ Alkyl), C ３～８ Cycloalkyl, 4-8 membered heterocyclyl, 5-12 membered heteroaryl, -CONR ａ R ｂ , -CSNR ａ R ｂ , -COR ｃ and -COOR ｅ Selected from, the C ３～８ Cycloalkyl, 4-8 membered heterocyclyl, and 5-12 membered heteroaryl are each optionally associated with halogen, -OH, oxo, -CN, and -NH. ２ , -CONH ２ , 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 Substituted with one or more groups independently selected from haloalkyl groups, R ３ But is it hydrogen? or R ２ and R ３ However, together with the carbon atoms to which they are bonded, they form a 5-6 member heteroaryl group, and the 5-6 member heteroaryl group can optionally be C １～６ Substituted with one or more groups independently selected from alkyl, R ５ However, hydrogen, C １～６ Alkyl and -NR ａ R ｂ Selected from, Cy １ However, they are 4-12 member heterocyclines. Cy ２ However, C ３～８ Selected from cycloalkyl, 4-9 membered heterocyclyl, aryl, and 5-14 membered heteroaryl, R ４ However, independently, 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 member heterocyclyl), - (C １～６ Alkyl) ｍ -phenyl, -(C １～６ Alkyl) ｍ - (5-12 member 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 Selected from, the C １～６ Alkyl, C ３～８ Cycloalkyl, 4-8 membered heterocyclyl, phenyl, and 5-12 membered heteroaryl are each optionally associated with halogen, -OH, oxo, -CN, and -NH. ２ , -CONH ２ , C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, 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 Substituted with one or more groups independently selected from cycloalkyl and 4- to 8-membered heterocyclines, L does not exist, or L is CH ２ And, R ａ , R ｂ , R ｃ , R ｄ and R ｅ However, each independently, hydrogen, C １～６ Alkyl, C ２～６ Alkenil, - (C １～６ Alkyl) ｍ - (C ３～８ Cycloalkyl), - (C １～６ Alkyl) ｍ - (4-8 member heterocyclyl), - (C １～６ Alkyl) ｍ -Phenyl and -(C １～６ Alkyl) ｍ - Selected from (5-12 member heteroaryl), the C １～６ Alkyl, C ３～８ Cycloalkyl, 4-8 membered heterocyclyl, phenyl, and 5-12 membered heteroaryl are each optionally associated with halogen, -OH, -CN, and -CONH. ２ , C １～６ Alkyl, C １～６ Haloalkyl, -(C) １～６ Alkyl)-OH,-O-(C １～６ Alkyl), -NH(C ３～８ Cycloalkyl), -CO(C ２～６ Alkenyl) and -CON(C １～６ Alkyl) ２ Substituted with one or more elements independently selected from, R ｆ However, -CH ３ And, p is 0, 1, 2, or 3, m is 0 or 1, n is 1 or 2, However, R ４ The compound according to claim 1, provided that it is not -NH (a six-membered nitrogen-containing heteroaryl) or -NH (a phenyl substituted with F), or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated thereof.

3. The aforementioned compound is the compound of formula (I-1), 【Chemistry 2】 During the ceremony, Z is N or CH, preferably Z is N. A compound according to claim 1 or 2, wherein n1, n2, n3, and n4 are each independently selected from 1 and 2, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated thereof.

4. The aforementioned compound is the compound of formula (I-2), 【Transformation 3】 A compound according to claim 1 or 2, wherein n5 and n6 are each independently selected from 1 and 2, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated thereof.

5. R １ However, it is a halogen, preferably R １ However, it is F or Cl, more preferably R １ The compound according to claim 1 or 2, wherein F is present, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated thereof.

6. R ２ However, hydrogen, -O-(C １～６ Alkyl), C ３～８ Cycloalkyl, 4-8 membered heterocyclyl, 5-12 membered heteroaryl, -CONR ａ R ｂ , -CSNR ａ R ｂ , -COR ｃ and -COOR ｅ Selected from, R ａ , R ｂ , R ｃ and R ｅ However, each independently, 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 Selected from cycloalkyl and 4-8 membered heterocyclyl, the C ３～８ Cycloalkyl, 4-8 membered heterocyclyl, and 5-12 membered heteroaryl are each optionally associated with halogen, -OH, oxo, -CN, and -NH. ２ , -CONH ２ , 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 Substituted with one or more groups independently selected from haloalkyl groups, Preferably, R ２ However, hydrogen, -O-(C １～６ Alkyl), C ３～６ Cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, -CONR ａ R ｂ , -CSNR ａ R ｂ , -COR ｃ and -COOR ｅ Selected from, R ａ , R ｂ , R ｃ and R ｅ However, each is independent of C １～６ Alkyl, C ３～６ Selected from cycloalkyl and 4-6 membered heterocyclyl, the C ３～６ Cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl are each optionally composed of a halogen, -OH, and C １～６ Substituted with one or more groups independently selected from alkyl, More specifically, R ２ However, -COO(C １～６ Alkyl) and -CON(C １～６ Alkyl) ２ Selected from, Most preferably, R ２ However, -CON(C １～６ Alkyl) ２ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated thereof.

7. R ３ The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated thereof, wherein the compound is hydrogen.

8. R ２ and R ３ However, together with the carbon atoms to which they are bonded, they form a 5-6 member heteroaryl group, and the 5-6 member heteroaryl group can optionally be C １～６ Substituted with one or more groups independently selected from alkyl groups, preferably R ２ and R ３ However, together with the carbon atoms to which they are bonded, they form a pyrazolyl, and the pyrazolyl is optionally C １～６ A compound according to claim 1 or 2, substituted with one or more groups independently selected from alkyl groups, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated thereof.

9. R ５ However, hydrogen, C １～６ Alkyl, -NH ２ ,-NH(C １～６ Alkyl) and -N(C １～６ Alkyl) ２ Selected from, preferably R ５ However, hydrogen, C １～６ Alkyl and -NH(C) １～６ Selected from alkyl, more preferably R ５ The compound according to claim 1 or 2, wherein the compound is hydrogen, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated thereof.

10. L is CH ２ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated thereof.

11. Cy ２ However, C ３～８ Selected from cycloalkyl, 4-8 membered heterocyclyl, phenyl, and 5-12 membered heteroaryl, preferably Cy ２ However, C ３～６ A compound according to claim 1 or 2, selected from cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, and 8-10 membered heteroaryl, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated thereof.

12. Cy ２ The compound according to claim 11, selected from cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl, pyrrolidyl, piperidyl, piperazinyl, phenyl, pyridyl, pyridinonyl, pyrimidyl, indolyl, indazolyl, benzofuranyl, benzoxazolyl, imidazopyridyl, quinolinyl, quinolinonyl, quinazolinyl and dihydro-[1,4]dioxynopyridyl, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated thereof.

13. Cy ２ but, 【Chemistry 4】 Selected from, Preferably, Cy ２ but, 【Transformation 5】 Selected from, Comfortable, Cy ２ but, 【Transformation 6】 is or Cy ２ but, 【Transformation 7】 is or Cy ２ but, 【Transformation 8】 The compound according to claim 12, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated thereof.

14. R ４ However, independently, 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 member heterocyclyl), - (C １～６ Alkyl) ｍ -phenyl, -(C １～６ Alkyl) ｍ - (5-12 member 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 Selected from, the C １～６ Alkyl, C ３～８ Cycloalkyl, 4-8 membered heterocyclyl, phenyl, and 5-12 membered heteroaryl are each optionally associated with halogen, -OH, oxo, -CN, and -NH. ２ , -CONH ２ , C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, 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 Substituted with one or more groups independently selected from cycloalkyl and 4- to 8-membered heterocyclines, Preferably, R ４ However, independently, halogen, -CN, -OH, oxo, C １～６ Alkyl, -O-(C １～６ Alkyl), -(C １～６ Alkyl) ｍ - (4-8 member heterocyclyl), - (C １～６ Alkyl) ｍ -phenyl, -(C １～６ Alkyl) ｍ - (5-12 member 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 Selected from, the C １～６ Alkyl, 4-8 membered heterocyclyl, phenyl, and 5-12 membered heteroaryl are each optionally selected as halogen, -OH, oxo, -CN, and -NH. ２ , -CONH ２ , C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Haloalkyl, -(C) １～６ Alkyl)-OH,-O-(C １～６ Alkyl) and C ３～８ Substituted with one or more groups independently selected from cycloalkyl groups, However, R ４ The compound according to claim 1 or 2, provided that it is not -NH (a six-membered nitrogen-containing heteroaryl) or -NH (a phenyl substituted with F), or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated thereof.

15. R ４ However, they became independent, 1) Halogen, 2) -CN, 3) -OH, 4) Oxo, 5) C １～６ Alkyl, optionally comprising -OH, -CN, and -CONH ２ Substituted with one or more groups independently selected from C １～６ Alkyl, 6) -O-(C １～６ Alkyl), 7) - (C １～６ Alkyl) ｍ - (4-6 member heterocyclil), preferably the 4-6 member heterocyclil is selected from oxetanil and dihydropyranil, - (C １～６ Alkyl) ｍ - (4-6 member heterocycline), 8) - (C １～６ Alkyl) ｍ -Phenyl, wherein the phenyl is optionally substituted with one or more groups independently selected from -CN, -(C １～６ Alkyl) ｍ - Phenyl, 9) - (C １～６ Alkyl) ｍ - (5-12 member heteroaryl), preferably the 5-12 member heteroaryl is selected from 5-6 member heteroaryls and 8-10 member heteroaryls, more preferably the 5-12 member heteroaryl is selected from pyrazolyl, oxazolyl, pyridyl, pyridinonyl, pyrimidyl, pyridadinyl, pyridadinyl, pyrazinyl, 1,2,4-triazinyl, indolyl, imidazopyridazinyl, [1,2,4]triazolopyridyl, pyrazolopyridyl, dihydropyrimidopyridazinyl and dihydro-[1,4]dioxynopyridazinyl, most preferably the 5-12 member heteroaryl is selected from pyridyl and pyridadinyl. The aforementioned 5- to 12-membered heteroaryls may be optionally halogen, -OH, oxo, -CN, -NH ２ , -CONH ２ , C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Haloalkyl, -(C) １～６ Alkyl)-OH,-O-(C １～６ Alkyl) and C ３～８ Substituted with one or more groups independently selected from cycloalkyl groups, preferably the 5-12 membered heteroaryl is optionally a halogen, -OH, -CN, -CONH ２ , C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Haloalkyl, -(C) １～６ Alkyl)-OH,-O-(C １～６ Alkyl) and C ３～８ Substituted with one or more groups independently selected from cycloalkyl groups, -(C １～６ Alkyl) m-(5-12 member heteroaryl), 10) - CONR ａ R ｂ And R ａ and R ｂ However, each independently, hydrogen, C １～６ Alkyl, -(C １～６ Alkyl) ｍ - (C ３～６ Cycloalkyl), - (C １～６ Alkyl) ｍ - (4-6 member heterocyclyl), - (C １～６ Alkyl) ｍ -Phenyl and -(C １～６ Alkyl) ｍ - (5-6 member heteroaryl), and the above C １～６ Alkyl, C ３～６ Cycloalkyls, 4-6 membered heterocyclines, phenyls, and 5-6 membered heteroaryls are each optionally associated with halogens and -O-(C) １～６ Substituted with one or more groups independently selected from alkyl groups, -CONR ａ R ｂ , 11) -COR ｃ And R ｃ However, C １～６ Alkyl, C ２～６ Alkenil, - (C １～６ Alkyl) ｍ - (C ３～８ Cycloalkyl), - (C １～６ Alkyl) ｍ - (4-6 member heterocyclyl), - (C １～６ Alkyl) ｍ -Phenyl and -(C １～６ Alkyl) ｍ - Selected from (5-10 member heteroaryl), the C １～６ Alkyl, C ３～８ Cycloalkyl, 4-6 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl are each optionally associated with halogen, -OH, -CN, and C. １～６ Alkyl, C １～６ Haloalkyl, -O-(C) １～６ Alkyl), -NH(C ３～６ Cycloalkyl), -CO(C ２～６ Alkenyl) and -CON(C １～６ Alkyl) ２ -COR is substituted with one or more groups independently selected from ｃ , 12) - COOR ｅ And R ｅ However, hydrogen and C １～６ Selected from alkyl groups, -COOR ｅ , 13) -NR ａ R ｂ And R ａ and R ｂ However, each independently, hydrogen, C １～６ Alkyl and -(C １～６ Alkyl) ｍ - Selected from (5-10 member heteroaryl), the C １～６ Alkyl and 5-10 membered heteroaryls are each optionally selected as halogen, -OH, -CN, and -CONH. ２ , C １～６ Alkyl, -(C １～６ Alkyl)-OH and -O-(C １～６ Substituted with one or more groups independently selected from alkyl, provided that R ４ However, the condition is that it is not -NH (a six-membered nitrogen-containing heteroaryl), -NR ａ R ｂ , 14) -NR ｄ COR ｃ And R ｄ However, hydrogen and C １～６ Selected from alkyl groups, R ｃ However, optionally, -CN and -O-(C １～６ C substituted with one or more groups independently selected from alkyl groups １～６ Alkyl, -NR ｄ COR ｃ , 15) -NR ｄ S(O) ｎ R ｆ And R ｄ However, it is hydrogen, R ｆ However, -CH ３ -NR ｄ S(O) ｎ R ｆ , 16) -S(O) ｎ R ｆ And R ｆ However, -CH ３ -S(O) ｎ R ｆ A compound according to claim 14, selected from, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated thereof.

16. The aforementioned compound is the compound of formula (I-3), 【Chemistry 9】 During the ceremony, n1, n2, n3, and n4 are each independently selected from 1 and 2, preferably both n1 and n2 are 1, and both n3 and n4 are 2. R １ However, it is a halogen, preferably R １ However, it is F or Cl, more preferably R １ However, it is F, R ２ However, hydrogen, -O-(C １～６ Alkyl), C ３～８ Cycloalkyl, 4-8 membered heterocyclyl, 5-12 membered heteroaryl, -CONR ａ R ｂ , -CSNR ａ R ｂ , -COR ｃ and -COOR ｅ Selected from, R ａ , R ｂ , R ｃ and R ｅ However, each independently, 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 Selected from cycloalkyl and 4-8 membered heterocyclyl, the C ３～８ Cycloalkyl, 4-8 membered heterocyclyl, and 5-12 membered heteroaryl are each optionally associated with halogen, -OH, oxo, -CN, and -NH. ２ , -CONH ２ , 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 Substituted with one or more groups independently selected from haloalkyl groups, preferably R ２ However, hydrogen, -O-(C １～６ Alkyl), C ３～６ Cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, -CONR ａ R ｂ , -CSNR ａ R ｂ , -COR ｃ and -COOR ｅ Selected from, R ａ , R ｂ , R ｃ and R ｅ However, each is independent of C １～６ Alkyl, C ３～６ Selected from cycloalkyl and 4-6 membered heterocyclyl, the C ３～６ Cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl are each optionally composed of a halogen, -OH, and C １～６ Substituted with one or more groups independently selected from alkyl, more preferably R ２ However, -COO(C １～６ Alkyl) and -CON(C １～６ Alkyl) ２ Selected from, most preferably R ２ However, -CON(C １～６ Alkyl) ２ And, R ３ But is it hydrogen? or R ２ and R ３ However, together with the carbon atoms to which they are bonded, they form a 5-6 member heteroaryl group, and the 5-6 member heteroaryl group can optionally be C １～６ Substituted with one or more groups independently selected from alkyl groups, preferably R ２ and R ３ However, together with the carbon atoms to which they are bonded, they form a pyrazolyl, and the pyrazolyl is optionally C １～６ Substituted with one or more groups independently selected from alkyl, R ５ However, hydrogen, C １～６ Alkyl, -NH ２ ,-NH(C １～６ Alkyl) and -N(C １～６ Alkyl) ２ Selected from, preferably R ５ However, hydrogen, C １～６ Alkyl and -NH(C) １～６ Selected from alkyl, more preferably R ５ However, it is hydrogen, Cy ２ However, C ３～６ Selected from cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, and 8-10 membered heteroaryl, preferably Cy ２ The compound is selected from cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl, pyrrolidyl, piperidyl, piperazinyl, phenyl, pyridyl, pyridinonyl, pyrimidyl, indolyl, indazolyl, benzofuranyl, benzoxazolyl, imidazopyridyl, quinolinyl, quinolinonyl, quinazolinyl and dihydro-[1,4]dioxynopyridyl, and more preferably Cy ２ but, 【Chemistry 10】 Selected from, most preferably Cy ２ but, 【Chemistry 11】 And, R ４ However, independently, halogen, -CN, -OH, oxo, C １～６ Alkyl, -O-(C １～６ Alkyl), -(C １～６ Alkyl) ｍ - (4-8 member heterocyclyl), - (C １～６ Alkyl) ｍ -phenyl, -(C １～６ Alkyl) ｍ - (5-12 member 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 Selected from, the C １～６ Alkyl, 4-8 membered heterocyclyl, phenyl, and 5-12 membered heteroaryl are each optionally selected as halogen, -OH, oxo, -CN, and -NH. ２ , -CONH ２ , C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Haloalkyl, -(C) １～６ Alkyl)-OH,-O-(C １～６ Alkyl) and C ３～８ Substituted with one or more groups independently selected from cycloalkyl groups, preferably R ４ However, they became independent, 1) Halogen, 2) -CN, 3) -OH, 4) Oxo, 5) C １～６ Alkyl, optionally comprising -OH, -CN, and -CONH ２ Substituted with one or more groups independently selected from C １～６ Alkyl, 6) -O-(C １～６ Alkyl), 7) - (C １～６ Alkyl) ｍ - (4-6 member heterocyclil), preferably the 4-6 member heterocyclil is selected from oxetanil and dihydropyranil, - (C １～６ Alkyl) ｍ - (4-6 member heterocycline), 8) - (C １～６ Alkyl) ｍ -Phenyl, wherein the phenyl is optionally substituted with one or more groups independently selected from -CN, -(C １～６ Alkyl) ｍ - Phenyl, 9) - (C １～６ Alkyl) ｍ - (5-12 member heteroaryl), preferably the 5-12 member heteroaryl is selected from 5-6 member heteroaryls and 8-10 member heteroaryls, more preferably the 5-12 member heteroaryl is selected from pyrazolyl, oxazolyl, pyridyl, pyridinonyl, pyrimidyl, pyridadinyl, pyridadinyl, pyrazinyl, 1,2,4-triazinyl, indolyl, imidazopyridazinyl, [1,2,4]triazolopyridyl, pyrazolopyridyl, dihydropyrimidopyridazinyl and dihydro-[1,4]dioxynopyridazinyl, most preferably the 5-12 member heteroaryl is selected from pyridyl and pyridadinyl. The aforementioned 5- to 12-membered heteroaryls may be optionally halogen, -OH, oxo, -CN, -NH ２ , -CONH ２ , C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Haloalkyl, -(C) １～６ Alkyl)-OH,-O-(C １～６ Alkyl) and C ３～８ Substituted with one or more groups independently selected from cycloalkyl groups, preferably the 5-12 membered heteroaryl is optionally a halogen, -OH, -CN, -CONH ２ , C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Haloalkyl, -(C) １～６ Alkyl)-OH,-O-(C １～６ Alkyl) and C ３～８ Substituted with one or more groups independently selected from cycloalkyl groups, -(C １～６ Alkyl) ｍ - (5-12 member heteroaryl), 10) - CONR ａ R ｂ And R ａ and R ｂ However, each independently, hydrogen, C １～６ Alkyl, -(C １～６ Alkyl) ｍ - (C ３～６ Cycloalkyl), - (C １～６ Alkyl) ｍ - (4-6 member heterocyclyl), - (C １～６ Alkyl) ｍ -Phenyl and -(C １～６ Alkyl) ｍ - Selected from (5-6 member heteroaryl), the C １～６ Alkyl, C ３～６ Cycloalkyls, 4-6 membered heterocyclines, phenyls, and 5-6 membered heteroaryls are each optionally associated with halogens and -O-(C) １～６ Substituted with one or more groups independently selected from alkyl groups, -CONR ａ R ｂ , 11) -COR ｃ And R ｃ However, C １～６ Alkyl, C ２～６ Alkenil, - (C １～６ Alkyl) ｍ - (C ３～８ Cycloalkyl), - (C １～６ Alkyl) ｍ - (4-6 member heterocyclyl), - (C １～６ Alkyl) ｍ -Phenyl and -(C １～６ Alkyl) ｍ - Selected from (5-10 member heteroaryl), the C １～６ Alkyl, C ３～８ Cycloalkyl, 4-6 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl are each optionally associated with halogen, -OH, -CN, and C. １～６ Alkyl, C １～６ Haloalkyl, -O-(C) １～６ Alkyl), -NH(C ３～６ Cycloalkyl), -CO(C ２～６ Alkenyl) and -CON(C １～６ Alkyl) ２ -COR is substituted with one or more groups independently selected from ｃ , 12) - COOR ｅ And R ｅ However, hydrogen and C １～６ Selected from alkyl groups, -COOR ｅ , 13) -NR ａ R ｂ And R ａ and R ｂ However, each independently, hydrogen and C １～６ Selected from alkyl, the C １～６ Alkyl is optionally -CN and -O-(C １～６ Substituted with one or more groups independently selected from alkyl groups, -NR ａ R ｂ , 14) -NR ｄ COR ｃ And R ｄ However, hydrogen and C １～６ Selected from alkyl groups, R ｃ However, optionally, -CN and -O-(C １～６ C substituted with one or more groups independently selected from alkyl groups １～６ Alkyl, -NR ｄ COR ｃ , 15) -NR ｄ S(O) ｎ R ｆ And R ｄ However, it is hydrogen, R ｆ However, -CH ３ -NR ｄ S(O) ｎ R ｆ , 16) -S(O) ｎ R ｆ And R ｆ However, -CH ３ -S(O) ｎ R ｆ , selected from, L is CH ２ And, p is 0, 1, 2, or 3, m is 0 or 1, The compound according to claim 1, wherein n is 1 or 2, preferably n is 2, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated thereof.

17. The aforementioned compound is the compound of formula (I-4), 【Chemistry 12】 During the ceremony, n5 and n6 are each independently selected from 1 and 2, preferably both n5 and n6 are 1. R １ However, it is a halogen, preferably R １ However, it is F, R ２ However, -CON(C １～６ Alkyl) ２ And, R ３ However, it is hydrogen, R ５ However, it is hydrogen, Cy ２ However, C ３～８ Selected from cycloalkyl and 4- to 8-membered heterocyclyl, preferably Cy ２ However, it is selected from cyclopropyl and pyrrolidyl, more preferably Cy ２ but, 【Chemistry 13】 Selected from, most preferably Cy ２ but, 【Chemistry 14】 And, R ４ However, independently, -(C １～６ Alkyl) ｍ - (5-12 member heteroaryl) and -NR ａ R ｂ Selected from, the 5-12 member heteroaryl is optionally -CN and C １～６ Substituted with one or more groups independently selected from alkyl groups, preferably R ４ However, they became independent, 1) - (C １～６ Alkyl)-indolyl, wherein the indolyl is optionally -CN and C １～６ Substituted with one or more groups independently selected from alkyl, -(C １～６ Alkyl)-Indolyl, 2) -NR ａ R ｂ And R ａ and R ｂ However, each independently, hydrogen, C １～６ Alkyl and -(C １～６ Alkyl) ｍ - Selected from (5-10 member heteroaryl), the C １～６ Alkyl and 5-10 member heteroaryl groups are each optionally represented by -OH, -CN, and C. １～６ Alkyl and -(C １～６ Substituted with one or more groups independently selected from alkyl)-OH, provided that R ４ However, the condition is that it is not -NH (a six-membered nitrogen-containing heteroaryl), -NR ａ R ｂ , selected from, p is 0, 1, or 2, preferably p is 1. The compound according to claim 1, wherein m is 0 or 1, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated thereof.

18. A compound, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated thereof, selected from the following: Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10

19. A pharmaceutical composition comprising the compound and / or a pharmaceutically acceptable salt thereof according to claim 1 or 2, and optionally comprising a pharmaceutically acceptable excipient.

20. A method for inhibiting menin-MLL interaction in vivo or in vitro, comprising contacting menin with an effective amount of the compound and / or a pharmaceutically acceptable salt thereof according to claim 1 or 2.

21. Use of the compound and / or a pharmaceutically acceptable salt thereof according to claim 1 or 2 in the manufacture of a medicament for treating or preventing a disease mediated by, or at least partially by, the menin-MLL interaction, wherein the disease mediated by, or at least partially by, the menin-MLL interaction is preferably cancer, wherein the cancer is preferably a hematological malignancy or solid tumor, including leukemia, lymphoma and myeloma, and wherein the cancer is more preferably acute leukemia, chronic leukemia, myeloid leukemia, myeloid leukemia, lymphocytic leukemia, lymphoblastic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), B-cell acute lymphoblastic leukemia (B-ALL), T-cell prolymphoblastic leukemia Leukemia (T-PLL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia, large granular lymphocytic leukemia, hairy cell leukemia (HCL), mixed lineage leukemia (MLL), MLL-associated leukemia, MLL-rearranged leukemia (MLL-r), MLL-PTD leukemia, MLL-positive leukemia, NPM1 mutation leukemia, leukemia showing HOX / MEIS1 gene expression signature, myelodysplastic syndrome (MDS), myeloproliferative disorders Use is selected from the following: multiple myeloma (MPN), Hodgkin lymphoma, non-Hodgkin lymphoma, diffuse large B-cell lymphoma (DLBCL), B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, follicular lymphoma (FL), Waldenström macroglobulinemia, prostate cancer, breast cancer, lung cancer, liver cancer, colon cancer, colorectal cancer, pancreatic cancer, melanoma, and glioblastoma (GBM).

22. A pharmaceutical composition according to claim 19 for treating or preventing a disease in a subject, wherein the disease is a disease mediated by, or at least partially mediated by, menin-MLL interaction, the disease is preferably cancer, the cancer is preferably a hematological malignancy or solid tumor including leukemia, lymphoma and myeloma, and the cancer is more preferably acute leukemia, chronic leukemia, myeloid leukemia, myeloid leukemia, lymphocytic leukemia, lymphoblastic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), B-cell acute lymphoblastic leukemia (B-ALL), T-cell prelymphoblastic leukemia (T-PLL), chronic lymphocytic leukemia (CLL), chronic myeloid Leukemia, large granular lymphocytic leukemia, hairy cell leukemia (HCL), mixed lineage leukemia (MLL), MLL-associated leukemia, MLL-rearranged leukemia (MLL-r), MLL-PTD leukemia, MLL-positive leukemia, NPM1 mutation leukemia, leukemia showing HOX / MEIS1 gene expression signature, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), multiple myeloma (M A pharmaceutical composition selected from M), Hodgkin lymphoma, non-Hodgkin lymphoma, diffuse large B-cell lymphoma (DLBCL), B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, follicular lymphoma (FL), Waldenström macroglobulinemia, prostate cancer, breast cancer, lung cancer, liver cancer, colon cancer, colorectal cancer, pancreatic cancer, melanoma, and glioblastoma (GBM).

23. A compound and / or a pharmaceutically acceptable salt thereof, as described in claim 1 or 2, for use as a pharmaceutical.

24. A compound and / or a pharmaceutically acceptable salt thereof according to claim 1 or 2 for use in the treatment or prevention of a disease mediated by, or at least partially mediated by, menin-MLL interaction, wherein the disease is preferably cancer, and the cancer is preferably a hematological malignancy or solid tumor, including leukemia, lymphoma and myeloma, and the cancer is more preferably acute leukemia, chronic leukemia, myeloid leukemia, myeloid leukemia, lymphocytic leukemia, lymphoblastic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), B-cell acute lymphoblastic leukemia (B-ALL), T-cell prelymphocytic leukemia (T-PLL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia, macrogranuloma Granular lymphocytic leukemia, hairy cell leukemia (HCL), mixed lineage leukemia (MLL), MLL-associated leukemia, MLL rearrangement leukemia (MLL-r), MLL-PTD leukemia, MLL-positive leukemia, NPM1 mutation leukemia, leukemia showing HOX / MEIS1 gene expression signature, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), multiple myeloma (MM), Hodgkin lymphoma Compounds and / or pharmaceutically acceptable salts thereof selected from tumors, non-Hodgkin lymphoma, diffuse large B-cell lymphoma (DLBCL), B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, follicular lymphoma (FL), Waldenström macroglobulinemia, prostate cancer, breast cancer, lung cancer, liver cancer, colon cancer, colorectal cancer, pancreatic cancer, melanoma, and glioblastoma (GBM).

25. A pharmaceutical combination comprising a compound and / or a pharmaceutically acceptable salt thereof according to claim 1 or 2, and at least one additional therapeutic agent, wherein the additional therapeutic agent is preferably selected from an antitumor agent, an anti-inflammatory agent, or an immunomodulator, and the antitumor agent comprises a chemotherapeutic agent, an immune checkpoint inhibitor, or an agonist, and a targeted therapeutic agent.

26. Compound of formula (III): 【Chemistry 15】 or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated thereof, wherein, R １ , R ２ , R ３ and R ５ However, as defined in claim 1 or 2, R ７ However, it is a hydrogen or amino protecting group, preferably R ７ However, R is an amino protecting group selected from hydrogen, or Boc(tert-butoxycarbonyl), benzyl, Pmb(p-methoxybenzyl), and Cbz(benzyloxycarbonyl), and more preferably R ７ However, it is hydrogen or Boc(tert-butoxycarbonyl), Provided that when R ５ is H or Cl, R ２ is selected from -C(O)N(CH(CH ３ ) ２ ) ２ , -C(O)N(CH(CH ３ ) ２ )(CH ３ ), -C(O)N(CH(CH ３ ) ２ )(CH ２ CH ３ ), -C(O)N(CH(CH ３ ) ２ )(CH ２ CHF ２ ), -C(O)N(CH(CH ３ ) ２ )(CH ２ CF ３ ), -C(O)N(CH(CH ３ ) ２ )(CH ２ CH ２ OH), -C(O)N(cyclopropyl) ２ , -C(O)N(CH(CH ３ ) ２ )(cyclopropyl), -C(O)N(CH ２ CH ３ )(cyclopropyl), -C(O)N(CH(CH ３ ) ２ )(cyclobutyl), pyrimidyl substituted with isopropyl, and pyrazolyl substituted with isopropyl and / or Cl, with the proviso that the compound is not any of the aforementioned groups; a compound, or a pharmaceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, or a deuterated derivative thereof.

27. A compound selected from the following: Table 2 or its pharmaceutically acceptable salts, solvates, racemic mixtures, enantiomers, diastereomers or tautomers, or deuterated compounds thereof.

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