Substituted heterocyclic compounds and their applications

Abstract

This application relates to a class of substituted heterocyclic compounds of formula (III) that have inhibitory activity against cell proliferation, as well as their preparation methods and uses. The uses include the use of compounds of formula (III) in the preparation of medicaments for treating diseases related to MLL. In the preparation process, the compounds of this invention are obtained through a series of reactions including substitution, cyclization, and deprotection.

Description

[0001] Cross-references

[0002] This application claims Chinese Patent Application No. 202110617682.0, filed June 3, 2021, entitled "Substituted Heterocyclic Compounds as Menin-MLL Inhibitors"; Chinese Patent Application No. 202111066260.5, filed September 9, 2021, also entitled "Substituted Heterocyclic Compounds as Menin-MLL Inhibitors"; and Chinese Patent Application No. 202111066260.5, filed December 24, 2021, entitled "Substituted Heterocyclic Compounds as Menin-MLL Inhibitors". The entire disclosure of Chinese Patent Application No. 202111607724.9 entitled “Substituted Heterocyclic Compounds as Menin-MLL Inhibitors”, filed on February 7, 2022, and Chinese Patent Application No. 202210110663.3 entitled “Substituted Heterocyclic Compounds as Menin-MLL Inhibitors”, filed on April 2, 2022, is incorporated herein by reference. Technical Field

[0003] This invention generally relates to novel substituted heterocyclic compounds having Menin-MLL interaction inhibitory activity, methods of their preparation, pharmaceutical compositions thereof, and also to the use of such compounds and pharmaceutical compositions thereof in treating diseases that benefit from inhibition of Menin-MLL interactions, such as acute leukemia. Background Technology

[0004] Acute leukemia is typically caused by acquired mutations in hematopoietic progenitor cells. In these leukemias, chromosomal abnormalities are often a discrete mutational feature. Many chromosomal abnormalities result from specific translocations leading to the formation of fusion genes, which can become drivers of tumorigenesis.

[0005] Acute leukemia in both adults and children can be caused by rearrangements of the MLL gene located on chromosome 11q23. These rearrangements produce a chimeric gene encoding an oncogenic fusion protein formed by the fusion of the N-terminus of MLL with the C-terminus of one of more than 80 known fusion partners (Meyer et al., 2018). The MLL fusion protein binds to DNA / chromatin and induces leukemic transformation of hematopoietic stem cells and progenitor cells by releasing transcriptional regulation of the fusion protein's target genes. Depending on the progenitor cell of origin, MLLr can present as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), or, in rare cases, mixed phenotype acute leukemia (MPAL). Furthermore, MLL translocations are observed in approximately 33% of treatment-related acute leukemias, typically occurring after treatment with topoisomerase II inhibitors (Winters 2017).

[0006] MLL gene rearrangements occur in 5-10% of acute leukemias, particularly prevalent in infantile acute leukemia (up to 70% of cases) (Krivtsov 2007). The incidence of MLLr-ALL peaks in the first two years, declines during childhood and adolescence, and then steadily increases with age. A similar pattern has been observed in MLLr AML patients, with this pattern seen in nine cases, except for the postnatal peak observed in infantile ALL (Meyer 2018). The MLLr leukemia subtype is characterized by its aggressiveness, treatment resistance, and high frequency of early relapse, even after initial complete remission (Armstrong 2002; Krivtsov 2007; Pieters 2007; Muntean 2012; Sanjuan Pla, 2015). MLLr in childhood ALL is a strong predictor of adverse outcomes (Inaba 2013; Zhang 2019). In the Interfant-06 study, the 6-year event-free survival (EFS) for children with MLLr ALL was 36.4% (Pieters 2019). In a large cohort of pediatric AML patients with various MLL rearrangements, the 5-year EFS and overall survival (OS) were worse (38% EFS and 58% OS) compared to the overall pediatric AML population (55% EFS and 70% OS) (Guest 2016) (Zwaan 2015). Due to the high-risk classification of MLLr leukemia, clinical chemotherapy regimens are aggressive, with significant short-term toxicities and serious long-term health effects on surviving patients. Childhood MLLr acute leukemia is a poorly prognostic disease, and there is an urgent need for new treatment approaches to improve outcomes.

[0007] Menin, encoded by the multiple endocrine tumor (MEN) gene, is a widely expressed nuclear protein that interacts with DNA processing and repair proteins, chromatin modification proteins, and various transcription factors. The binding of Menin to MLL fusion proteins is mediated by amino acid residues 9-13 at the N-terminus of MLL1. Binding to Menin localizes these fusions to chromatin and is essential for the oncogenic activity of MLL fusion proteins (Yokoyama 2005; Kaslini 2007). This association has been shown to constitutively upregulate the expression of HOX and MESI oncogenes and impair hematopoietic cell proliferation and differentiation, leading to leukemia development. Since Menin is a common oncogenic cofactor in MLL-related leukemia, the interaction between Menin and MLL fusion proteins, or MLL itself, is a potential therapeutic target.

[0008] Recent studies have shown that nucleophosphoprotein 1 (NPM1c) cells also rely on the interaction between Menin and wtMLL to maintain the development of this leukemia, and these cells are sensitive to the blockage of Menin-MLL binding (Uckelmann 2020). MLLr and NPM1c target in the same way because the MLL fusion protein and wt-MLL share an N-terminal domain. Therefore, NPM1c acute myeloid leukemia is also a focus of clinical development programs for adult acute leukemia.

[0009] Menin-MLL interaction inhibitors have shown activity in a range of cell lines containing MLLr fusions, disrupting the interaction between Menin and the MLL1 fusion protein required for leukemia formation activity, thereby affecting the expression of key oncogenes and leading to growth arrest and cell proliferation inhibition. These inhibitors have demonstrated strong single-agent activity in various leukemia xenograft models and good survival benefits after oral administration in non-clinical models (Cierpicki 2014; Bojin 2015). In conclusion, these data suggest that drug inhibition of the Menin-MLL interaction is a potential targeted strategy for the treatment of MLLr acute leukemia.

[0010] Currently, no Menin-MLL inhibitors have been approved for marketing, but three inhibitors have recently entered clinical trials. Syndax's inhibitor SNDX-5613 first entered a Phase I / II clinical trial (NCT04065399) on August 22, 2019, targeting acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), mixed lineage acute leukemia (MLAL), mixed phenotype acute leukemia (MPAL), and undetermined lineage acute leukemia (ALAL) with MLL rearrangements or NPM1 mutations. Following closely behind, Kura's inhibitor KO-539 began a Phase I / II clinical trial (NCT04067336) on August 26, 2019, targeting advanced malignancies, AML, mixed lineage leukemia (MLL), MLAL, MPAL, and ALAL. Janssen recently initiated a Phase I clinical trial (NCT04065399) of JNJ-75276617 on March 21, 2021, targeting acute leukemia, AML, and ALL. The molecular structures of the first two inhibitors have been disclosed, while the structure of the latter has not yet been disclosed. Bayer, Agios, the University of Michigan, the University of Pennsylvania, Sumitomo, and others also have patents related to this.

[0011] Inhibiting the interaction between small molecule inhibitors and the MLL fusion protein has been shown to be a potential therapeutic strategy for MLL-r leukemia, demonstrating its clinical translational value. More effective and selective small molecule inhibitors are crucial for in vivo studies. We utilize computer-aided drug design to discover structurally novel compounds and modify their structures to achieve the desired enhanced potency and improved drug properties. Summary of the Invention

[0012] This invention provides a compound represented by formula (III) or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite, or prodrug thereof.

[0013]

[0014] in,

[0015] Y3 is NR6 or

[0016] X is

[0017] L represents a bond, -(CO)-, or -CH2-.

[0018] V is either N or CH.

[0019] U is N or CR 16 ,

[0020] Ring A is a 3-12 membered carbon ring or a 3-12 membered hetero ring.

[0021] Ring B is a benzene ring or a 5-6 membered heteroaryl ring.

[0022] The C ring is a 3-12 member nitrogen-containing heterocycle.

[0023] Y1 is -O-, -S-, -NR 13 -、or-CR 11 R 12 -,

[0024] Y2 is a key, -O-, -S-, or -NR. 13 -,

[0025] R6 is -CN, C 1-6 Alkyl, 6-10 aryl, 5-12 heteroaryl, -(CO)-CH=CH2, or The alkyl, aryl, and heteroaryl groups may optionally be converted by halogens, CF3, C 1-6 Alkyl, -NR 13 R 14 Alternatively, -OR1 can be used instead.

[0026] R7 is hydrogen, -OR 13 -NR 13 R 14 C 1-6 Alkyl, or C 3-8 cycloalkyl, the C 1-6 Alkyl or C 3-8 The cycloalkyl group may optionally be replaced by a halogen.

[0027] Z is -(CO)-NR 13 R 14 Or -(CO)-OR 13 ,

[0028] R1 is hydrogen, halogen, CN, NO2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, CF3, -NR 13 R 14 -OR 13 -(CO)-R 15 -O-(CO)-R 15 -NR 13 -(CO)-R 15 -(CO)-OR 13 -(CO)-NR 13 R 14-S(O)R 15 -S(O)2R 15 -S(O)2NR 13 R 14 -S(O)2OR 13 -OS(O)2R 15 -NR 13 -S(O)2R 15 , or

[0029] R2 can be hydrogen, halogen, CN, NO2, or C independently. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, CF3, -NR 13 R 14 -OR 13 -(CO)-R 15 -O-(CO)-R 15 -NR 13 -(CO)-R 15 -(CO)-OR 13 -(CO)-NR 13 R 14 -S(O)R 15 -S(O)2R 15 -S(O)2NR 13 R 14 -S(O)2OR 13 -OS(O)2R 15 -NR 13 -S(O)2R 15 , or

[0030] R3 is a halogen.

[0031] R4 represents hydrogen, halogen, CN, NO2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, CF3, -NR 13 R 14 -OR 13 -(CO)-R 15 -O-(CO)-R 15 -NR 13 -(CO)-R 15 -(CO)-OR13 -(CO)-NR 13 R 14 -S(O)R 15 -S(O)2R 15 -S(O)2NR 13 R 14 -S(O)2OR 13 -OS(O)2R 15 -NR 13 -S(O)2R 15 , or

[0032] R5 can be independently represented by hydrogen, halogen, CN, NO2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, CF3, -NR 13 R 14 -OR 13 -(CO)-R 15 -O-(CO)-R 15 -NR 13 -(CO)-R 15 -(CO)-OR 13 -(CO)-NR 13 R 14 -S(O)R 15 -S(O)2R 15 -S(O)2NR 13 R 14 -S(O)2OR 13 -OS(O)2R 15 -NR 13 -S(O)2R 15 , or

[0033] R 11 and R 12 Each is independently selected from H, halogen, CN, OH, C 1-6 Alkyl, C 1-6 Alkyl-O-, C 3-8 Cycloalkyl, amino, C 1-6 Alkylamino or C 2-8 Dialkylamino; the C 1-6 Alkyl, C 3-8 cycloalkyl, C 1-6 Alkylamino or C 2-8 Dialkylamino groups may optionally be substituted with halogens.

[0034] R 15 Each is independently selected from H and C. 1-6 Alkyl, C 3-8 Cycloalkyl, 3-12-membered heterocycloalkyl, 6-10-membered aryl, 5-12-membered heteroaryl, C 2-6 alkenyl and C 2-6 alkynyl group, the C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-12-membered heterocycloalkyl, 6-10-membered aryl, 5-12-membered heteroaryl, C 2-6 alkenyl or C 2-6 The alkynyl group can optionally be replaced by halogen, -CN, C 1-6 Alkyl, -(CO)-R 41 -(CO)-NR 13 R 14 -(CO)-C≡CR 41 Or -(CO)-CR 42 =CR 43 R 41 replace,

[0035] R 41 For H or C 1-6 Alkyl groups, which may optionally be converted to halogen, -CN, or -NR. 13 R 14 Or -OR 13 replace,

[0036] R 42 and R 43 Each is independently selected from H and halogens.

[0037] R 13 and R 14 Each is independently selected from hydrogen and C. 1-6 Alkyl and C 3-8 cycloalkyl, the C 1-6 Alkyl or C 3-8 The cycloalkyl group may optionally be replaced by a halogen.

[0038] R 16 Selected from H, halogens, CN, OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, amino, C 1-6 Alkylamino or C 2-8 Dialkylamino; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 1-6 Alkylamino or C 2-8 Dialkylamino groups may optionally be substituted with halogens.

[0039] R 30 and R 31 Each is independently selected from hydrogen and C. 1-6 Alkyl and C 3-8 cycloalkyl,

[0040] R 40 Selected from hydrogen, -CN, -(CO)-CH=CH2, C 1-6 Alkyl and C 3-8 cycloalkyl, the C 1-6 Alkyl or C 3-8 The cycloalkyl group may optionally be replaced by a halogen.

[0041] m can be 0, 1, or 2 independently.

[0042] n can be 0, 1, 2, or 3 independently.

[0043] p is independently 0 or 1.

[0044] In some implementations, Y3 is

[0045] In some implementations, the C ring is a 3-6 member nitrogen-containing heterocycle.

[0046] In some implementations, ring C is

[0047] In some implementations, L stands for key.

[0048] In some implementations, V is N.

[0049] In some implementations, p is 1.

[0050] In some implementations, m is independently 0 or 1.

[0051] In some implementations, n is independently 0 or 1.

[0052] In some implementations, Z is -(CO)-NR 13 R 14 .

[0053] In some implementations, Y2 is a key or -NR 13 -

[0054] In some implementations, Y1 is -NR 13 -

[0055] In some implementations, U is N.

[0056] In some implementations, R6 is

[0057] In some implementations, Z is -(CO)-NR 13 R 14 .

[0058] In some embodiments, R1 is hydrogen, halogen, CN, NO2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, or C 2-6 Alkyne group.

[0059] In some embodiments, R2 is independently hydrogen, halogen, CN, NO2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, CF3, -NR 13 R 14 、or -OR 13 .

[0060] In some implementations, R3 is fluorine.

[0061] In some embodiments, R4 is hydrogen, halogen, CN, NO2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, CF3, -NR 13 R 14 、or -OR 13 .

[0062] In some implementations, R5 is independently hydrogen, halogen, CN, NO2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, CF3, -NR 13 R 14 、or -OR 13 .

[0063] In some implementations, R 11 and R 12 It is hydrogen.

[0064] In some implementations, R 13 and R 14 Each is independently selected from hydrogen and C.1-6 Alkyl groups, preferably hydrogen and C 1-3 alkyl;

[0065] In some implementations, R 15 Selected from C 1-6 Alkyl and C 3-8 Cycloalkyl, preferably C 1-6 alkyl.

[0066] In some implementations, R 42 and R 43 For H.

[0067] In another aspect, the present invention provides a compound represented by formula (III) or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite, or prodrug thereof.

[0068]

[0069] in,

[0070] Y3 is NR6 or

[0071] X is

[0072] L represents a bond, -(CO)-, or -CH2-.

[0073] V is either N or CH.

[0074] U is N or CR 16 ,

[0075] Ring A is a 3-12 membered carbon ring or a 3-12 membered hetero ring.

[0076] Ring B is a benzene ring or a 5-6 membered heteroaryl ring.

[0077] The C ring is a 3-12 member nitrogen-containing heterocycle.

[0078] Y1 is -O-, -S-, -NR 13 -、or-CR 11 R 12 -,

[0079] Y2 is a key, -O-, -S-, or -NR. 13 -,

[0080] R6 is -CN, C 1-6 Alkyl, 5-12 membered heteroaryl, -(CO)-CH=CH2, or The alkyl group may optionally be replaced by a halogen.

[0081] R7 is hydrogen, -OR13 -NR 13 R 14 C 1-6 Alkyl, or C 3-8 cycloalkyl, the C 1-6 Alkyl or C 3-8 The cycloalkyl group may optionally be replaced by a halogen.

[0082] Z is -(CO)-NR 13 R 14 Or -(CO)-OR 13 ,

[0083] R1 is hydrogen, halogen, CN, NO2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, CF3, -NR 13 R 14 -OR 13 -(CO)-R 15 -O-(CO)-R 15 -NR 13 -(CO)-R 15 -(CO)-OR 13 -(CO)-NR 13 R 14 -S(O)R 15 -S(O)2R 15 -S(O)2NR 13 R 14 -S(O)2OR 13 -OS(O)2R 15 -NR 13 -S(O)2R 15 , or

[0084] R2 can be hydrogen, halogen, CN, NO2, or C independently. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, CF3, -NR 13 R 14 -OR 13 -(CO)-R 15 -O-(CO)-R 15 -NR 13 -(CO)-R 15 -(CO)-OR13 -(CO)-NR 13 R 14 -S(O)R 15 -S(O)2R 15 -S(O)2NR 13 R 14 -S(O)2OR 13 -OS(O)2R 15 -NR 13 -S(O)2R 15 , or

[0085] R3 is a halogen.

[0086] R4 represents hydrogen, halogen, CN, NO2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, CF3, -NR 13 R 14 -OR 13 -(CO)-R 15 -O-(CO)-R 15 -NR 13 -(CO)-R 15 -(CO)-OR 13 -(CO)-NR 13 R 14 -S(O)R 15 -S(O)2R 15 -S(O)2NR 13 R 14 -S(O)2OR 13 -OS(O)2R 15 -NR 13 -S(O)2R 15 , or

[0087] R5 can be independently represented by hydrogen, halogen, CN, NO2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, CF3, -NR 13 R 14 -OR 13 -(CO)-R 15 -O-(CO)-R 15-NR 13 -(CO)-R 15 -(CO)-OR 13 -(CO)-NR 13 R 14 -S(O)R 15 -S(O)2R 15 -S(O)2NR 13 R 14 -S(O)2OR 13 -OS(O)2R 15 -NR 13 -S(O)2R 15 , or

[0088] R 11 and R 12 Each is independently selected from H, halogen, CN, OH, C 1-6 Alkyl, C 1-6 Alkyl-O-, C 3-8 Cycloalkyl, amino, C 1-6 Alkylamino or C 2-8 Dialkylamino; the C 1-6 Alkyl, C 3-8 cycloalkyl, C 1-6 Alkylamino or C 2-8 Dialkylamino groups may optionally be substituted with halogens.

[0089] R 15 Each is independently selected from H and C. 1-6 Alkyl, C 3-8 Cycloalkyl, 3-12 membered heterocycloalkyl, C 2-6 alkenyl and C 2-6 alkynyl group, the C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-12 membered heterocycloalkyl, C 2-6 alkenyl or C 2-6 The alkynyl group can optionally be replaced by halogen, -(CO)-R 41 Or -(CO)-CH=CHR 41 replace,

[0090] R 41 For H or C 1-6 Alkyl group, wherein the alkyl group may optionally be -NR 13 R 14 Or -OR 13 replace,

[0091] R 13 and R 14 Each is independently selected from hydrogen and C. 1-6Alkyl and C 3-8 cycloalkyl, the C 1-6 Alkyl or C 3-8 The cycloalkyl group may optionally be replaced by a halogen.

[0092] R 16 Selected from H, halogens, CN, OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, amino, C 1-6 Alkylamino or C 2-8 Dialkylamino; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 1-6 Alkylamino or C 2-8 Dialkylamino groups may optionally be substituted with halogens.

[0093] R 30 and R 31 Each is independently selected from hydrogen and C. 1-6 Alkyl and C 3-8 cycloalkyl,

[0094] R 40 Selected from hydrogen, -CN, -(CO)-CH=CH2, C 1-6 Alkyl and C 3-8 cycloalkyl, the C 1-6 Alkyl or C 3-8 The cycloalkyl group may optionally be replaced by a halogen.

[0095] m can be 0, 1, or 2 independently.

[0096] n can be 0, 1, 2, or 3 independently.

[0097] p is independently 0 or 1.

[0098] In some implementations, Y3 is

[0099] In some implementations, the C ring is a 3-6 member nitrogen-containing heterocycle.

[0100] In some implementations, L stands for key.

[0101] In some implementations, V is N.

[0102] In some implementations, p is 1.

[0103] In some implementations, m is independently 0 or 1.

[0104] In some implementations, n is independently 0 or 1.

[0105] In some implementations, Z is -(CO)-NR 13 R 14 .

[0106] In some implementations, Y2 is a key or -NR 13 -

[0107] In some implementations, Y1 is -NR 13 -

[0108] In some implementations, U is N.

[0109] In some implementations, R6 is

[0110] In some implementations, Z is -(CO)-NR 13 R 14 .

[0111] In some embodiments, R1 is hydrogen, halogen, CN, NO2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, or C 2-6 Alkyne group.

[0112] In some embodiments, R2 is independently hydrogen, halogen, CN, NO2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, CF3, -NR 13 R 14 、or -OR 13 .

[0113] In some implementations, R3 is fluorine.

[0114] In some embodiments, R4 is hydrogen, halogen, CN, NO2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, CF3, -NR 13 R 14 、or -OR 13 .

[0115] In some implementations, R5 is independently hydrogen, halogen, CN, NO2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, CF3, -NR 13 R 14 、or -OR 13 .

[0116] In some implementations, R 11 and R 12 It is hydrogen.

[0117] In some implementations, R 13 and R 14 Each is independently selected from hydrogen and C. 1-6 Alkyl groups, preferably hydrogen and C 1-3 alkyl;

[0118] In some implementations, R 15 Selected from C 1-6 Alkyl and C 3-8 Cycloalkyl, preferably C 1-6 alkyl.

[0119] In another aspect, the present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite, or prodrug thereof.

[0120]

[0121] in,

[0122] X is

[0123] L represents a bond or -CH2-.

[0124] V is either N or CH.

[0125] U is N or CR 16 ,

[0126] Ring A is a 3-12 membered carbon ring or a 3-12 membered hetero ring.

[0127] Ring B is a benzene ring or a 5-6 membered heteroaryl ring.

[0128] The C ring is a 3-12 member nitrogen-containing heterocycle.

[0129] Y1 is -O-, -S-, -NR 13 -、or-CR 11 R 12 -,

[0130] Y2 is a key, -O-, -S-, or -NR. 13 -,

[0131] R6 is C 1-6 alkyl, or The alkyl group may optionally be replaced by a halogen.

[0132] R7 is hydrogen, -OR 13 -NR 13 R 14 C 1-6 Alkyl, or C 3-8 cycloalkyl, the C 1-6 Alkyl or C 3-8 The cycloalkyl group may optionally be replaced by a halogen.

[0133] Z is -(CO)-NR 13 R 14 Or -(CO)-OR 13 ,

[0134] R1 is hydrogen, halogen, CN, NO2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, CF3, -NR 13 R 14 -OR 13 -(CO)-R 15 -O-(CO)-R 15 -NR 13 -(CO)-R 15 -(CO)-OR 13 -(CO)-NR 13 R 14 -S(O)R 15 -S(O)2R 15 -S(O)2NR 13 R 14 -S(O)2OR 13 -OS(O)2R 15 -NR 13 -S(O)2R 15 , or

[0135] R2 can be hydrogen, halogen, CN, NO2, or C independently. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, CF3, -NR 13 R 14 -OR 13-(CO)-R 15 -O-(CO)-R 15 -NR 13 -(CO)-R 15 -(CO)-OR 13 -(CO)-NR 13 R 14 -S(O)R 15 -S(O)2R 15 -S(O)2NR 13 R 14 -S(O)2OR 13 -OS(O)2R 15 -NR 13 -S(O)2R 15 , or

[0136] R3 is a halogen.

[0137] R4 represents hydrogen, halogen, CN, NO2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, CF3, -NR 13 R 14 -OR 13 -(CO)-R 15 -O-(CO)-R 15 -NR 13 -(CO)-R 15 -(CO)-OR 13 -(CO)-NR 13 R 14 -S(O)R 15 -S(O)2R 15 -S(O)2NR 13 R 14 -S(O)2OR 13 -OS(O)2R 15 -NR 13 -S(O)2R 15 , or

[0138] R5 can be independently represented by hydrogen, halogen, CN, NO2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6Alkyne group, CF3, -NR 13 R 14 -OR 13 -(CO)-R 15 -O-(CO)-R 15 -NR 13 -(CO)-R 15 -(CO)-OR 13 -(CO)-NR 13 R 14 -S(O)R 15 -S(O)2R 15 -S(O)2NR 13 R 14 -S(O)2OR 13 -OS(O)2R 15 -NR 13 -S(O)2R 15 , or

[0139] R 11 and R 12 Each is independently selected from H, halogen, CN, OH, C 1-6 Alkyl, C 1-6 Alkyl-O-, C 3-8 Cycloalkyl, amino, C 1-6 Alkylamino or C 2-8 Dialkylamino; the C 1-6 Alkyl, C 3-8 cycloalkyl, C 1-6 Alkylamino or C 2-8 Dialkylamino groups may optionally be substituted with halogens.

[0140] R 13 and R 14 Each is independently selected from hydrogen and C. 1-6 Alkyl and C 3-8 cycloalkyl, the C 1-6 Alkyl or C 3-8 The cycloalkyl group may optionally be replaced by a halogen.

[0141] R 15 Each is independently selected from H and C. 1-6 Alkyl, C 3-8 cycloalkyl, C 2-6 alkenyl and C 2-6 alkynyl group, the C 1-6 Alkyl, C 3-8 cycloalkyl, C 2-6 alkenyl or C 2-6 The alkynyl group may optionally be replaced by a halogen.

[0142] R 16 Selected from H, halogens, CN, OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, amino, C 1-6 Alkylamino or C 2-8 Dialkylamino; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 1-6 Alkylamino or C 2-8 Dialkylamino groups may optionally be substituted with halogens.

[0143] R 30 and R 31 Each is independently selected from hydrogen and C. 1-6 Alkyl and C 3-8 cycloalkyl,

[0144] m can be 0, 1, or 2 independently.

[0145] n can be 0, 1, 2, or 3 independently.

[0146] p is independently 0 or 1.

[0147] In some implementations, L stands for key.

[0148] In some implementations, V is N.

[0149] In some implementations, p is 1.

[0150] In some implementations, m is independently 0 or 1.

[0151] In some implementations, n is independently 0 or 1.

[0152] In some implementations, Z is -(CO)-NR 13 R 14 .

[0153] In some implementations, Y2 is a key or -NR 13 -

[0154] In some implementations, Y1 is -NR 13 -

[0155] In some implementations, U is N.

[0156] In some implementations, R6 is

[0157] In some implementations, Z is -(CO)-NR 13 R14 .

[0158] In some embodiments, R1 is hydrogen, halogen, CN, NO2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, or C 2-6 Alkyne group.

[0159] In some embodiments, R2 is independently hydrogen, halogen, CN, NO2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, CF3, -NR 13 R 14 、or -OR 13 .

[0160] In some implementations, R3 is fluorine.

[0161] In some embodiments, R4 is hydrogen, halogen, CN, NO2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, CF3, -NR 13 R 14 、or -OR 13 .

[0162] In some implementations, R5 is independently hydrogen, halogen, CN, NO2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, CF3, -NR 13 R 14 、or -OR 13 .

[0163] In some implementations, R 11 and R 12 It is hydrogen.

[0164] In some implementations, R 13 and R 14 Each is independently selected from hydrogen and C. 1-6 Alkyl groups, preferably hydrogen and C 1-3 alkyl;

[0165] In some implementations, R15 Selected from C 1-6 Alkyl and C 3-8 Cycloalkyl, preferably C 1-6 alkyl.

[0166] In another aspect, the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite, or prodrug thereof.

[0167]

[0168] in,

[0169] X is

[0170] U is N or CR 16 ,

[0171] Ring A is a 3-12 membered carbon ring or a 3-12 membered hetero ring.

[0172] Ring B is a benzene ring or a 5-6 membered heteroaryl ring.

[0173] The C ring is a 3-12 member nitrogen-containing heterocycle.

[0174] Y1 is -O-, -S-, -NR 13 -、or-CR 11 R 12 -,

[0175] Y2 is a key, -O-, -S-, or -NR. 13 -,

[0176] R6 is or

[0177] R7 is hydrogen, -OR 13 -NR 13 R 14 C 1-6 Alkyl, or C 3-8 cycloalkyl, the C 1-6 Alkyl or C 3-8 The cycloalkyl group may optionally be replaced by a halogen.

[0178] Z is -(CO)-NR 13 R 14 Or -(CO)-OR 13 ,

[0179] R1 is hydrogen, halogen, CN, NO2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C2-6 Alkyne group, CF3, -NR 13 R 14 -OR 13 -(CO)-R 15 -O-(CO)-R 15 -NR 13 -(CO)-R 15 -(CO)-OR 13 -(CO)-NR 13 R 14 -S(O)R 15 -S(O)2R 15 -S(O)2NR 13 R 14 -S(O)2OR 13 -OS(O)2R 15 -NR 13 -S(O)2R 15 , or

[0180] R2 can be hydrogen, halogen, CN, NO2, or C independently. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, CF3, -NR 13 R 14 -OR 13 -(CO)-R 15 -O-(CO)-R 15 -NR 13 -(CO)-R 15 -(CO)-OR 13 -(CO)-NR 13 R 14 -S(O)R 15 -S(O)2R 15 -S(O)2NR 13 R 14 -S(O)2OR 13 -OS(O)2R 15 -NR 13 -S(O)2R 15 , or

[0181] R3 is a halogen.

[0182] R4 represents hydrogen, halogen, CN, NO2, or C. 1-6 Alkyl, C1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, CF3, -NR 13 R 14 -OR 13 -(CO)-R 15 -O-(CO)-R 15 -NR 13 -(CO)-R 15 -(CO)-OR 13 -(CO)-NR 13 R 14 -S(O)R 15 -S(O)2R 15 -S(O)2NR 13 R 14 -S(O)2OR 13 -OS(O)2R 15 -NR 13 -S(O)2R 15 , or

[0183] R5 can be independently represented by hydrogen, halogen, CN, NO2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, CF3, -NR 13 R 14 -OR 13 -(CO)-R 15 -O-(CO)-R 15 -NR 13 -(CO)-R 15 -(CO)-OR 13 -(CO)-NR 13 R 14 -S(O)R 15 -S(O)2R 15 -S(O)2NR 13 R 14 -S(O)2OR 13 -OS(O)2R 15 -NR 13 -S(O)2R 15 , or

[0184] R 11 and R12 Each is independently selected from H, halogen, CN, OH, C 1-6 Alkyl, C 1-6 Alkyl-O-, C 3-8 Cycloalkyl, amino, C 1-6 Alkylamino or C 2-8 Dialkylamino; the C 1-6 Alkyl, C 3-8 cycloalkyl, C 1-6 Alkylamino or C 2-8 Dialkylamino groups may optionally be substituted with halogens.

[0185] R 13 and R 14 Each is independently selected from hydrogen and C. 1-6 Alkyl and C 3-8 cycloalkyl, the C 1-6 Alkyl or C 3-8 The cycloalkyl group may optionally be replaced by a halogen.

[0186] R 15 Selected from H, C 1-6 Alkyl, C 3-8 cycloalkyl, C 2-6 alkenyl and C 2-6 alkynyl group, the C 1-6 Alkyl, C 3-8 cycloalkyl, C 2-6 alkenyl or C 2-6 The alkynyl group may optionally be replaced by a halogen.

[0187] R 16 Selected from H, halogens, CN, OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, amino, C 1-6 Alkylamino or C 2-8 Dialkylamino; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 1-6 Alkylamino or C 2-8 Dialkylamino groups may optionally be substituted with halogens.

[0188] m can be 0, 1, or 2 independently.

[0189] n can be 0, 1, 2, or 3 independently.

[0190] p is independently 0 or 1.

[0191] In some implementations, p is 1.

[0192] In some implementations, m is independently 0 or 1.

[0193] In some implementations, n is independently 0 or 1.

[0194] In some implementations, Z is -(CO)-NR 13 R 14 .

[0195] In some implementations, Y2 is a key or -NR 13 -

[0196] In some implementations, Y1 is -NR 13 -

[0197] In some implementations, U is N.

[0198] In some implementations, R6 is

[0199] In some implementations, Z is -(CO)-NR 13 R 14 .

[0200] In some embodiments, R1 is hydrogen, halogen, CN, NO2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, or C 2-6 Alkyne group.

[0201] In some embodiments, R2 is independently hydrogen, halogen, CN, NO2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, CF3, -NR 13 R 14 、or -OR 13 .

[0202] In some implementations, R3 is fluorine.

[0203] In some embodiments, R4 is hydrogen, halogen, CN, NO2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, CF3, -NR 13 R 14 、or -OR 13 .

[0204] In some implementations, R5 is independently hydrogen, halogen, CN, NO2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, CF3, -NR 13 R 14 、or -OR 13 .

[0205] In some implementations, R 11 and R 12 It is hydrogen.

[0206] In some implementations, R 13 and R 14 Each is independently selected from hydrogen and C. 1-6 Alkyl groups, preferably hydrogen and C 1-3 alkyl;

[0207] In some implementations, R 15 Selected from C 1-6 Alkyl and C 3-8 Cycloalkyl, preferably C 1-6 alkyl.

[0208] In another aspect, the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite, or prodrug thereof.

[0209]

[0210] in,

[0211] X is

[0212] U is N or CR 16 ,

[0213] Ring A is a 3-12 membered carbon ring or a 3-12 membered hetero ring.

[0214] Ring B is a benzene ring or a 5-6 membered heteroaryl ring.

[0215] The C ring is a 3-8 member nitrogen-containing heterocycle.

[0216] Y1 is -O-, -S-, -NR 13 -、or-CR 11 R 12 -,

[0217] Y2 is -O-, -S-, or -NR 13 -,

[0218] R6 is or

[0219] R7 is hydrogen, -OR 13 -NR 13 R 14 C 1-6 Alkyl, or C 3-8 cycloalkyl, the C 1-6 Alkyl or C 3-8 The cycloalkyl group may optionally be replaced by a halogen.

[0220] Z is -(CO)-NR 13 R 14 Or -(CO)-OR 13 ,

[0221] R1 is hydrogen, halogen, CN, NO2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, CF3, -NR 13 R 14 -OR 13 -(CO)-R 15 -O-(CO)-R 15 -NR 13 -(CO)-R 15 -(CO)-OR 13 -(CO)-NR 13 R 14 -S(O)R 15 -S(O)2R 15 -S(O)2NR 13 R 14 -S(O)2OR 13 -OS(O)2R 15 -NR 13 -S(O)2R 15 , or

[0222] R2 can be hydrogen, halogen, CN, NO2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, CF3, -NR 13 R 14 -OR 13 -(CO)-R 15 -O-(CO)-R15 -NR 13 -(CO)-R 15 -(CO)-OR 13 -(CO)-NR 13 R 14 -S(O)R 15 -S(O)2R 15 -S(O)2NR 13 R 14 -S(O)2OR 13 -OS(O)2R 15 -NR 13 -S(O)2R 15 , or

[0223] R3 is a halogen.

[0224] R4 represents hydrogen, halogen, CN, NO2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, CF3, -NR 13 R 14 -OR 13 -(CO)-R 15 -O-(CO)-R 15 -NR 13 -(CO)-R 15 -(CO)-OR 13 -(CO)-NR 13 R 14 -S(O)R 15 -S(O)2R 15 -S(O)2NR 13 R 14 -S(O)2OR 13 -OS(O)2R 15 -NR 13 -S(O)2R 15 , or

[0225] R5 represents hydrogen, halogen, CN, NO2, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, CF3, -NR 13 R 14 -OR13 -(CO)-R 15 -O-(CO)-R 15 -NR 13 -(CO)-R 15 -(CO)-OR 13 -(CO)-NR 13 R 14 -S(O)R 15 -S(O)2R 15 -S(O)2NR 13 R 14 -S(O)2OR 13 -OS(O)2R 15 -NR 13 -S(O)2R 15 , or

[0226] R 11 and R 12 Each is independently selected from H, halogen, CN, OH, C 1-6 Alkyl, C 1-6 Alkyl-O-, C 3-8 Cycloalkyl, amino, C 1-6 Alkylamino or C 2-8 Dialkylamino; the C 1-6 Alkyl, C 3-8 cycloalkyl, C 1-6 Alkylamino or C 2-8 Dialkylamino groups may optionally be substituted with halogens.

[0227] R 13 and R 14 Each is independently selected from hydrogen and C. 1-6 Alkyl and C 3-8 cycloalkyl, the C 1-6 Alkyl or C 3-8 The cycloalkyl group may optionally be replaced by a halogen.

[0228] R 15 Selected from H, C 1-6 Alkyl, C 3-8 cycloalkyl, C 2-6 alkenyl and C 2-6 alkynyl group, the C 1-6 Alkyl, C 3-8 cycloalkyl, C 2-6 alkenyl or C 2-6 The alkynyl group may optionally be replaced by a halogen.

[0229] R 16 Selected from H, halogens, CN, OH, C 1-6 Alkyl, C1-6 Alkoxy, C 3-8 Cycloalkyl, amino, C 1-6 Alkylamino or C 2-8 Dialkylamino; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 1-6 Alkylamino or C 2-8 Dialkylamino groups may optionally be substituted with halogens.

[0230] m can be 0, 1, or 2 independently.

[0231] n can be 0, 1, 2, or 3 independently.

[0232] p is independently 0 or 1.

[0233] In some implementations, p is 1.

[0234] In some implementations, m is independently 0 or 1.

[0235] In some implementations, n is independently 0 or 1.

[0236] In some implementations, Z is -(CO)-NR 13 R 14 .

[0237] In some implementations, Y2 is -NR 13 -

[0238] In some implementations, Y1 is -NR 13 -

[0239] In some implementations, U is N.

[0240] In some implementations, R6 is

[0241] In some implementations, Z is -(CO)-NR 13 R 14 .

[0242] In some embodiments, R1 is hydrogen, halogen, CN, NO2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, or C 2-6 Alkyne group.

[0243] In some embodiments, R2 is hydrogen, halogen, CN, NO2, or C. 1-6 Alkyl, C 1-6Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, CF3, -NR 13 R 14 、or -OR 13 .

[0244] In some implementations, R3 is fluorine.

[0245] In some embodiments, R4 is hydrogen, halogen, CN, NO2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, CF3, -NR 13 R 14 、or -OR 13 .

[0246] In some embodiments, R5 is hydrogen, halogen, CN, NO2, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, CF3, -NR 13 R 14 、or -OR 13 .

[0247] In some implementations, R 11 and R 12 It is hydrogen.

[0248] In some implementations, R 13 and R 14 Each is independently selected from hydrogen and C. 1-6 Alkyl groups, preferably hydrogen and C 1-3 alkyl;

[0249] In some implementations, R 15 Selected from C 1-6 Alkyl and C 3-8 Cycloalkyl, preferably C 1-6 alkyl.

[0250] In another aspect, the present invention provides the following compounds or pharmaceutically acceptable salts, solvates, polymorphs, tautomers, metabolites, or prodrugs thereof:

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, and optionally comprising a pharmaceutically acceptable carrier.

[0263] On another front, the present invention provides a method for treating diseases associated with MLL activity, comprising administering to a subject a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite, or prodrug of the present invention, or a pharmaceutical composition of the present invention; in some embodiments, the disease associated with MLL activity is cancer, preferably acute leukemia (including MLL acute leukemia, MLL partial tandem repeat acute leukemia, NPM mutant acute leukemia, MOZ acute leukemia, NUP98 acute leukemia, and CALM acute leukemia), chronic lymphocytic leukemia, chronic myeloid leukemia, or myelodysplastic syndromes. Syndrome, polycythemia vera, malignant lymphoma (including B-cell lymphoma), myeloma (including multiple myeloma), brain tumor, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, gastric cancer, gallbladder and bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, anal cancer, choriocarcinoma, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, urothelial carcinoma, kidney cancer, renal cell carcinoma, prostate cancer, testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms' tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue sarcoma, or skin cancer.

[0264] The compounds of the present invention, or their pharmaceutically acceptable salts, solvates, polymorphs, tautomers, metabolites, or prodrugs, or the pharmaceutical compositions of the present invention, are used in combination with at least one different agent, wherein the different agent is selected from at least one agent selected from antitumor alkylating agents, antitumor antibiotics, plant-derived antitumor drugs, antitumor platinum coordination compounds, antitumor camptothecin derivatives, antitumor tyrosine kinase inhibitors, antitumor serine / threonine kinase inhibitors, antitumor phospholipid kinase inhibitors, antitumor monoclonal antibodies, interferons, biological response modifiers, hormone preparations, angiogenesis inhibitors, immune checkpoint inhibitors, epigenetic-related molecule inhibitors, protein post-translational modification inhibitors, proteasome inhibitors, and other antitumor drugs.

[0265] In another aspect, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts, solvates, polymorphs, tautomers, metabolites or prodrugs thereof, or pharmaceutical compositions of the present invention, in the preparation of a medicament for treating diseases associated with MLL activity; in some embodiments, the diseases associated with MLL activity are cancers, preferably acute leukemia (including MLL acute leukemia, MLL partial tandem repeat acute leukemia, NPM mutant acute leukemia, MOZ acute leukemia, NUP98 acute leukemia, and CALM acute leukemia), chronic lymphocytic leukemia, chronic myeloid leukemia, and myelodysplastic syndromes. Polycythemia vera, malignant lymphoma (including B-cell lymphoma), myeloma (including multiple myeloma), brain tumors, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, gastric cancer, gallbladder and bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, anal cancer, choriocarcinoma, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, urothelial carcinoma, kidney cancer, renal cell carcinoma, prostate cancer, testicular tumors, testicular germ cell tumors, ovarian germ cell tumors, Wilms' tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue sarcoma, or skin cancer. Invention Details

[0267] Exemplary embodiments utilizing the principles of the invention are set forth in the following detailed description of the invention. The features and advantages of the invention can be better understood by referring to the following summary of the invention.

[0268] It should be understood that the scope of protection of each aspect of the present invention is determined by the claims, and the methods and structures within the scope of these claims, as well as their equivalents, are all within the scope of these claims.

[0269] Unless otherwise defined, all technical terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains. Unless otherwise stated, all patents, patent applications, and publications cited in this document are incorporated herein in their entirety through reference.

[0270] It should be understood that the above summary and the following detailed description are exemplary and explanatory, and not intended to limit any subject matter of the invention. Unless otherwise specified, the singular form includes the plural form. Unless otherwise specified, the use of "or" or "or" means "and / or". Furthermore, the use of the term "comprising" and other forms such as "including," "containing," and "containing" are not limiting.

[0271] Some chemical terms

[0272] The terms “optional,” “optional,” or “optionally” mean that the event or condition described below may or may not occur, including both the occurrence and non-occurrence of the event or condition. For example, “optionally substituted alkyl” means “unsubstituted alkyl” or “substituted alkyl.” Furthermore, the optionally substituted group can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or any level between monosubstituted and fully substituted (e.g., -CH2CHF2, -CF2CH3, -CFHCHF2, etc.). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution mode that is spatially impossible and / or cannot be synthesized is introduced.

[0273] Unless otherwise stated, conventional methods within the scope of the art, such as mass spectrometry, nuclear magnetic resonance, high-performance liquid chromatography, infrared and ultraviolet / visible spectroscopy, and pharmacological methods, are employed. Unless specifically defined herein, the terminology, experimental procedures, and techniques used herein in analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and patient treatment. For example, reactions and purifications can be carried out using the manufacturer's instructions for use of reagent kits, or in accordance with methods known in the art or the description of this invention. The techniques and methods described herein are generally carried out according to conventional methods well known in the art, based on descriptions in several summary and more specific documents cited and discussed herein. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0274] When a substituent is described using a conventional chemical formula written from left to right, it also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0275] As used in this article, the terms "group" and "chemical group" refer to a specific part or functional group of a molecule. Chemical groups are often considered as chemical entities that are embedded in or attached to a molecule.

[0276] Some chemical groups named herein may be indicated by abbreviations to represent the total number of carbon atoms. For example, C1-C6 alkyl describes an alkyl group having a total of 1 to 6 carbon atoms, as defined below. The total number of carbon atoms indicated by the abbreviations does not include carbon atoms on possible substituents.

[0277] The terms “halogen,” “halogenated,” or “halogenated” refer to bromine, chlorine, fluorine, or iodine.

[0278] As used herein, the terms "aromatic," "aromatic ring," "aromatic," "aromatic," and "aromatic ring" refer to a planar ring or ring portion of one or more rings having a delocalized electronic conjugated system containing 4n+2 electrons, where n is an integer. An aromatic ring can be formed from 5, 6, 7, 8, 9, or more atoms. Aromatic compounds can be optionally substituted and can be monocyclic or polycyclic with fused rings. The term aromatic compound includes all carbocyclic rings (such as benzene rings) and rings containing one or more heteroatoms (such as pyridine).

[0279] The term "heteroatom" or "heteroatom" as used herein, alone or as part of other components, refers to an atom other than carbon and hydrogen. Heteroatoms are independently selected from, but not limited to, oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may be identical to each other, or some or all of the two or more heteroatoms may be different from each other.

[0280] The term “dense” or “dense ring” as used alone or in combination in this article refers to a ring structure in which two or more rings share one or more bonds.

[0281] The term “spiral” or “spiral ring” as used alone or in combination in this article refers to a ring structure in which two or more rings share one or more atoms.

[0282] The term "alkyl" as used hereby, either alone or as part of other components (e.g., monoalkylamino), refers to a monovalent saturated hydrocarbon with optional substituted straight or optional substituted branched chains having 1-12 carbon atoms, preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms, and connected to other parts of the molecule by single bonds, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, n-nonyl, n-decyl, etc.

[0283] The term "alkenyl" as used alone or in combination herein refers to a monovalent hydrocarbon group of optional substituted straight or optional branched form, having one or more C=C double bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. The double bonds in these groups may be in cis or trans conformations and should be understood to include both isomers. Examples include, but are not limited to, vinyl (CH=CH2), 1-propenyl (CH2CH=CH2), isopropenyl (C(CH3)=CH2), butenyl, and 1,3-butadienyl. When alkenyl as defined herein includes a numerical range, such as "C2-C6 alkenyl" or "C2-6 alkenyl," it refers to an alkenyl group that can consist of 2, 3, 4, 5, or 6 carbon atoms. The use of alkenyl herein also includes cases where no numerical range is specified.

[0284] The term "alkynyl" as used alone or in combination herein refers to an optionally substituted straight-chain or branched monovalent hydrocarbon group having one or more C≡C triple bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1,3-butadiynyl. When a numerical range is specified for alkynyl as defined herein, such as "C2-C6 alkynyl" or "C2-6 alkynyl", it refers to an alkynyl group that can consist of 2, 3, 4, 5, or 6 carbon atoms. The use of alkynyl herein also includes cases where no numerical range is specified.

[0285] The term "aryl" refers to a fully carbon monocyclic or fused ring having a fully conjugated π-electron system, having 6-14 carbon atoms, preferably 6-12 carbon atoms, and most preferably 6 carbon atoms. The aryl group can be unsubstituted or substituted with one or more substituents, examples of which include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxyl, sulfonyl, sulfinyl, phosphoryl, and heterocyclic groups. Non-limiting examples of unsubstituted aryl groups include, but are not limited to, phenyl, naphthyl, and anthraceneyl.

[0286] The terms "heteroaryl" and "heteroary ring" refer to a monocyclic or fused ring with 5-12 ring atoms, having 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, of which 1, 2, 3, or 4 are selected from N, O, and S, and the remaining ring atoms are C, and possessing a fully conjugated π-electron system. Heteroaryl groups can be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxyl, cyano, nitro, carbonyl, and heterocyclic groups. Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrole, furanyl, thiophene, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, and triazineyl.

[0287] The term "cycloalkyl" as used alone or in combination herein refers to a stable, monovalent, non-aromatic monocyclic or polycyclic hydrocarbon group containing only carbon and hydrogen atoms. It may include fused ring, spirocyclic, or bridged ring systems, containing 3-15 cyclic carbon atoms, preferably 3-10 cyclic carbon atoms, more preferably 3-8 cyclic carbon atoms, and may be saturated or unsaturated, linked to other parts of the molecule by single bonds. Non-limiting examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0288] The terms "heterocyclic group," "heterocyclic alkyl group," and "heterocycle" as used alone or as part of other components herein refer to a stable 3-18 member monovalent non-aromatic ring comprising 2-12 carbon atoms and 1-6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise stated, the heterocyclic group can be a monocyclic, bicyclic, tricyclic, or tetracyclic system, which may contain fused rings, spirocyclic, or bridged ring systems. The nitrogen, carbon, or sulfur on the heterocyclic group may be selectively oxidized, the nitrogen atom may be selectively quaternized, and the heterocyclic group may be partially or completely saturated. A heterocyclic group can be connected to the rest of the molecule by a single bond via a carbon atom or heteroatom on the ring. Heterocyclic groups containing fused rings may contain one or more aromatic or heteroaromatic rings, provided that the atoms connected to the rest of the molecule are atoms from non-aromatic rings. For the purposes of this application, the heterocyclic group is preferably a stable 4-11 monovalent non-aromatic monocyclic or bicyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; more preferably, it is a stable 4-8 monovalent non-aromatic monocyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur. Non-limiting examples of heterocyclic groups include azirheptanyl, azirheptanyl, decahydroisoquinolinyl, dihydrofuranyl, dihydroindolyl, dioxopentyl, 1,1-dioxo-thiomorpholinyl, imidazoalkyl, imidazolinyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, piperazinyl, piperidinyl, 4-piperidinoneyl, pyranyl, pyrazolyl, pyrrolidinyl, quinazinyl, quininecycloyl, tetrahydrofuranyl, tetrahydropyranyl, etc.

[0289] The term "carbon ring" refers to a structure consisting of a covalently closed ring of carbon, which can be saturated or partially unsaturated. A carbon ring can be formed by 3, 4, 5, 6, 7, 8, 9, or more atoms. The distinction between a carbon ring and a heterocycle lies in the fact that the ring skeleton of a heterocycle contains at least one atom different from carbon. The term "carbon ring" as used herein can refer to a monocyclic or polycyclic ring, including spirocyclic, fused, and bridged rings. Carbon rings can be arbitrarily substituted. Preferably, a "carbon ring" as used herein contains about 5 to about 20, 5 to 10, 5-8, or 5-6 cyclic atoms in its skeleton.

[0290] The term "polymorph" or "polymorphism" as used in this invention refers to the fact that the compounds of this invention have multiple crystal lattice forms. Some compounds of this invention may have more than one crystal form, and this invention covers all polymorphs or mixtures thereof.

[0291] Intermediate compounds and polymorphs of the compounds of this invention are also within the scope of this invention.

[0292] Unless otherwise specified, the olefin double bonds contained in the compounds of this invention include E and Z isomers.

[0293] The compounds of this invention include compounds having one or more isotopic substitutions, and references to a specific element include all isotopes of that element within their scope. For example, references to hydrogen within their scope include... 1 H, 2 H(D) and 3 H(T). Similarly, references to carbon and oxygen within their scope include, respectively, 12 C 13 C and 14 C and 16 O and 18 O.

[0294] It should be understood that the compounds of the present invention may contain asymmetric centers. These asymmetric centers may independently be R or S configurations. Some compounds of the present invention may also exhibit cis-trans isomerism, which will be apparent to those skilled in the art. It should be understood that the compounds of the present invention include their individual geometric isomers and stereoisomers, as well as mixtures thereof, including racemic mixtures. These isomers can be isolated from mixtures thereof by implementing or modifying known methods, such as chromatography and recrystallization techniques, or they can be prepared separately from suitable isomers of their intermediates.

[0295] The term “pharmaceutically acceptable salt” as used in this article includes both salts with added acid salts and salts with added alkali salts.

[0296] "Pharmaceutically acceptable salts" refer to salts that retain the biological potency and properties of the free base of a compound, are not biologically or otherwise undesirable, and are formed with inorganic acids, such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or organic acids, such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, decanoic acid, hexanoic acid, carbonic acid, cinnamic acid, citric acid, etc. "Pharmaceutically acceptable base salts" refer to salts that retain the biological potency and properties of the free acid of a compound, and are not biologically or otherwise undesirable. These salts are prepared by reacting a free acid with an inorganic or organic base. Salts formed by reacting with an inorganic base include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, etc. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts, and manganese salts.

[0297] Organic bases that form salts include, but are not limited to, primary amines, secondary amines, tertiary amines, and cyclic amines, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purines, piperazine, piperidine, choline, and caffeine. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0298] Crystallization often produces solvates of the compounds of this invention. As used herein, the term "solvate" refers to a combination of one or more molecules of the compounds of this invention and one or more solvent molecules.

[0299] The solvent can be water, in which case the solvate is a hydrate. Alternatively, it can be an organic solvent. Therefore, the compounds of this invention can exist as hydrates, including monohydrates, dihydrates, hemihydrates, trihydrates, tetrahydrates, etc., and the corresponding solvated forms. The compounds of this invention can be true solvates, but in other cases, they may simply retain water or a mixture of water and some other solvents by chance. The compounds of this invention can react in a solvent or precipitate or crystallize in a solvent. The solvates of the compounds of this invention are also included within the scope of this invention.

[0300] As used herein, the term "pharmaceutical composition" refers to a formulation containing the compounds of the present invention and a medium generally accepted in the art for delivering biologically active compounds to mammals, such as humans. This medium includes all pharmaceutically acceptable carriers.

[0301] As used in this article, the term "acceptable" in relation to formulations, compositions, or ingredients means that it does not have a lasting harmful effect on the overall health of the treated subject.

[0302] As used herein, the term "pharmaceutically acceptable" means a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., that the substance can be administered to an individual without causing an adverse biological reaction or interacting adversely with any component contained in the composition.

[0303] "Pharmaceutically acceptable carriers" include, but are not limited to, adjuvants, carriers, excipients, auxiliaries, deodorants, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants and wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the relevant government administrative departments for use in humans and domesticated animals.

[0304] As used herein, the terms “subject,” “patient,” “object,” or “individual” refer to an individual suffering from a disease, disorder, or symptom, including both mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans; non-human primates (e.g., chimpanzees and other apes and monkeys); livestock such as cattle, horses, sheep, goats, and pigs; domesticated animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. Examples of non-human mammals include, but are not limited to, birds and fish. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0305] The term "treatment" as used in this article refers to the treatment of relevant diseases or conditions in mammals, particularly humans, including...

[0306] (i) To prevent mammals, especially those previously exposed to a disease or condition but not yet diagnosed with it, from developing the corresponding disease or condition.

[0307] (ii) To suppress a disease or symptom, that is, to control its development;

[0308] (iii) To alleviate the disease or symptom, that is, to make the disease or symptom subside;

[0309] (iv) Relieve symptoms caused by disease or illness.

[0310] The terms “disease” and “symptom” used in this article may be used interchangeably or have different meanings, because some specific diseases or symptoms do not yet have known causative factors (so the cause of the disease is still unclear), so they cannot be recognized as diseases but can only be regarded as unwanted conditions or syndromes. These syndromes have more or less some specific symptoms that have been confirmed by clinical researchers.

[0311] As used herein, the terms "effective amount," "therapeutic effective amount," or "pharmaceutical effective amount" refer to an amount of at least one drug or compound that, when taken, is sufficient to alleviate, to some extent, one or more symptoms of the disease or condition being treated. The result may be a reduction and / or relief of signs, symptoms, or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition containing the compounds disclosed herein that is clinically necessary to provide significant symptom relief. Effective amounts suitable for any individual case can be determined using techniques such as dose escalation testing.

[0312] As used herein, the terms “administration,” “application,” “dosage,” etc., refer to methods that deliver a compound or composition to the desired site for biological action. These methods include, but are not limited to, oral administration, duodenal administration, parenteral administration (including intravenous, subcutaneous, intraperitoneal, intramuscular, intra-arterial injection or infusion), local administration, and rectal administration. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.

[0313] Preparation of the compounds of the present invention

[0314] The specific embodiments described below are intended to enable those skilled in the art to better understand and implement the present invention. They should not be considered as limiting the scope of the invention, but merely as exemplary illustrations and typical representatives. Those skilled in the art should understand that there are other synthetic routes for forming the compounds of the present invention; the examples provided below are non-limiting.

[0315] All operations involving easily oxidized or hydrolyzed raw materials are performed under nitrogen protection. Unless otherwise stated, the raw materials used in this invention are commercially available and used directly without further purification.

[0316] Column chromatography used silica gel (200-300 mesh) manufactured by Qingdao Chemical Co., Ltd. Thin-layer chromatography used pre-prepared plates (60 PF silica gel) manufactured by E. Merck. 254 Chiral compound separation and enantiomeric excess (ee) determination were performed using an Agilent LC 1200 series column (CHIRALPAK AD-H). (mm, 5 μm, 30℃). Nuclear magnetic resonance chromatography (NMR) was performed using a Varian VNMRS-400 NMR spectrometer; liquid chromatography-mass spectrometry (LC / MS) was performed using a FINNIGAN Thermo LCQ Advantage MAX, Agilent LC 1200 series (column: Waters Symmetry C18). (millimeter, 5 micrometer, 35℃), using ESI(+) ion mode.

[0317] Experimental Section

[0318] Intermediate 1: 2-((4-chloropyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0319]

[0320] 2-((4-chloropyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide was synthesized using the same intermediate method as in Example 253 of Patent WO2017214367.

[0321] Intermediate 2: (trans-4-(methanesulfonyl)cyclohexyl)methyl-4-methylbenzenesulfonate

[0322]

[0323] (trans-4-(methanesulfonamide)cyclohexyl)methyl 4-methylbenzenesulfonate was synthesized using the same method as intermediate 50 in patent WO2017214367.

[0324] Intermediate 3: (trans-4-(ethanesulfonamido)cyclohexyl)methyl-4-methylbenzenesulfonate

[0325]

[0326] (trans-4-(ethanesulfonamide)cyclohexyl)methyl 4-methylbenzenesulfonate was synthesized according to the method of intermediate 50 in patent WO2017214367.

[0327] Intermediate 4: N-(trans-4-formylcyclohexyl)methanesulfonamide

[0328]

[0329] N-(trans-4-formylcyclohexyl)methanesulfonamide was synthesized according to the method of intermediate 47 in patent WO2017214367.

[0330] Intermediate 5: 2-((4-(2,7-diazaspiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5- Fluoro-N-isopropylbenzamide

[0331]

[0332] 2-((4-(2,7-diazaspiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide was synthesized using the same intermediate as described in Example 253 of patent WO2017214367.

[0333] Intermediate 6: N-Ethyl-5-fluoro-N-isopropyl-2-((4-((piperidin-4-ylmethyl)amino)pyrimidin-5-yl)oxy (Bento) benzamide

[0334]

[0335] Step 1: 4-(((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester

[0336] Intermediate 1 (675 mg), tert-butyl 4-aminomethylpiperidine-1-carboxylate (642 mg), and diisopropylethylamine (774 mg) were added to isopropanol (10 mL) and reacted at 80 °C for 18 hours with stirring. After cooling to room temperature, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether / ethyl acetate, 1:2) to give tert-butyl 4-(((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)piperidine-1-carboxylate (880 mg). MS m / z [LC-MS]: 516.30 [M+1].

[0337] Step 2: N-Ethyl-5-fluoro-N-isopropyl-2-((4-((piperidin-4-ylmethyl)amino)pyrimidin-5-yl)oxy)benzamide

[0338] 880 mg of 4-(((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)piperidin-1-carboxylic acid tert-butyl ester was added to 10 mL of 4N hydrogen chloride methanol solution and stirred at room temperature for 2 hours. After concentration under reduced pressure, the pH was adjusted to 11-12 with 10% sodium hydroxide solution. The solution was extracted with a 4:1 mixture of dichloromethane and isopropanol. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give N-ethyl-5-fluoro-N-isopropyl-2-((4-((piperidin-4-ylmethyl)amino)pyrimidin-5-yl)oxy)benzamide (645 mg). MS m / z [LC-MS]: 416.25 [M+1].

[0339] Intermediate 7: 2-((4-((((1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)amino)pyrimidine (Pyridine-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0340]

[0341] Step 1: (1R,5S,6s)-6-(((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

[0342] Following the method in step 1 of intermediate 6, 4-aminomethylpiperidine-1-carboxylic acid tert-butyl ester was replaced with (1R,5S,6s)-6-(((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 514.29 [M+1].

[0343] Step 2: 2-((4-((((1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)amino)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0344] Following the method in step 2 of intermediate 6, 4-(((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester was substituted for 4-(((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester to obtain 2-((4-((((1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)amino)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide. MS m / z [LC-MS]: 414.23 [M+1].

[0345] Intermediate 8: 2-((4-(((1R,5S,6S)-3-azabicyclo[3.1.0]hexane-6-yl)amino)pyrimidin-5-yl) (Oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0346]

[0347] Step 1: (1R,5S,6S)-6-((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

[0348] Following the method in step 1 of intermediate 6, 4-aminomethylpiperidine-1-carboxylic acid tert-butyl ester was replaced with (1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester to obtain (1R,5S,6s)-6-((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 500.27 [M+1].

[0349] Step 2: 2-((4-(((1R,5S,6S)-3-azabicyclo[3.1.0]hexane-6-yl)amino)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0350] Following the method in step 2 of intermediate 6, 4-(((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester was substituted for 4-(((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester to obtain 2-((4-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexane-6-yl)amino)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide. MS m / z [LC-MS]: 400.22 [M+1].

[0351] Intermediate 9: 2-((4-(3-(aminomethyl)azacyclobutane-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5- Fluoro-N-isopropylbenzamide

[0352]

[0353] Step 1: ((1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)azacyclobutane-3-yl)methyl)tert-butyl carbamate

[0354] Following the method in step 1 of intermediate 6, tert-butyl carbamate was substituted for tert-butyl 4-aminomethylpiperidin-1-carboxylic acid to obtain ((1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)azacyclobutane-3-yl)methyl)carbamate. MS m / z [LC-MS]: 488.27 [M+1].

[0355] Step 2: 2-((4-(3-(aminomethyl)azacyclobutane-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0356] Following the method in step 2 of intermediate 6, 4-(((5-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)azacyclobutane-3-yl)methyl)carbamate tert-butyl ester was replaced with ((1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)piperidin-1-carboxylic acid tert-butyl ester to obtain 2-((4-(3-(aminomethyl)azacyclobutane-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide. MS m / z [LC-MS]: 388.22 [M+1].

[0357] Intermediate 10: 2-((4-(4-aminopiperidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropyl benzamide

[0358]

[0359] Step 1: (1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)piperidin-4-yl)tert-butyl carbamate

[0360] Following the method in step 1 of intermediate 6, tert-butyl piperidin-4-ylcarbamate was used instead of tert-butyl 4-aminomethylpiperidin-1-carboxylic acid to obtain (1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)piperidin-4-yl)carbamate tert-butyl. MS m / z [LC-MS]: 502.29 [M+1].

[0361] Step 2: 2-((4-(4-aminopiperidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0362] Following the method in step 2 of intermediate 6, 4-(((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)piperidin-4-yl)tert-butyl carbamate was replaced with tert-butyl (1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)piperidin-1-carboxylic acid to obtain 2-((4-(4-aminopiperidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide. MS m / z [LC-MS]: 402.23 [M+1].

[0363] Intermediate 11: (R)-2-((4-(3-aminopyrrolidone-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N- Isopropylbenzamide

[0364]

[0365] Step 1: (R)-(1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)tert-butyl carbamate

[0366] Following the method in step 1 of intermediate 6, (R)-pyrrolidine-3-ylcarbamate tert-butyl ester was used instead of 4-aminomethylpiperidine-1-carboxylic acid tert-butyl ester to obtain (R)-(1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)carbamate tert-butyl ester. MS m / z [LC-MS]: 488.27 [M+1].

[0367] Step 2: (R)-2-((4-(3-aminopyrrolidone-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0368] Following the method in step 2 of intermediate 6, 4-(((5-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)carbamate tert-butyl ester was replaced with (R)-(R)-(1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)piperidin-1-carboxylic acid tert-butyl ester to obtain (R)-2-((4-(3-aminopyrrolidine-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide. MS m / z [LC-MS]: 388.22 [M+1].

[0369] Intermediate 12: N-Ethyl-5-fluoro-2-((4-(3-(hydroxymethyl)azacyclobutane-1-yl)pyrimidin-5-yl)oxy )-N-isopropylbenzamide

[0370]

[0371] Following the method in step 1 of intermediate 6, tert-butyl 4-aminomethylpiperidin-1-carboxylic acid was replaced with aziridine-3-ylmethanol to obtain N-ethyl-5-fluoro-2-((4-(3-(hydroxymethyl)aziridine-1-yl)pyrimidin-5-yl)oxy)-N-isopropylbenzamide. MS m / z [LC-MS]: 389.20 [M+1].

[0372] Intermediate 13: N-Ethyl-5-fluoro-2-((4-((((4-fluoropiperidin-4-yl)methyl)amino)pyrimidin-5-yl)oxy )-N-isopropylbenzamide

[0373]

[0374] Step 1: 4-(((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester

[0375] Following the method in step 1 of intermediate 6, 4-aminomethyl-4-fluoropiperidine-1-carboxylic acid tert-butyl ester was used instead of 4-aminomethylpiperidine-1-carboxylic acid tert-butyl ester to obtain (4-(((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 534.29 [M+1].

[0376] Step 2: N-Ethyl-5-fluoro-2-((4-(((4-fluoropiperidin-4-yl)methyl)amino)pyrimidin-5-yl)oxy)-N-isopropylbenzamide

[0377] Following the method in step 2 of intermediate 6, 4-(((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-carboxylic acid tert-butyl ester was substituted for 4-(((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)piperidin-1-carboxylic acid tert-butyl ester to obtain N-ethyl-5-fluoro-2-((4-((((4-fluoropiperidin-4-yl)methyl)amino)pyrimidin-5-yl)oxy)-N-isopropylbenzamide. MS m / z [LC-MS]: 434.24 [M+1].

[0378] Intermediate 14: (R)-2-((4-(3-aminopyrrolidone-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N- Isopropylbenzamide

[0379]

[0380] Step 1: (S)-((1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)tert-butyl carbamate

[0381] Following the method in step 1 of intermediate 6, (R)-pyrrolidine-3-ylmethylcarbamate tert-butyl ester was used instead of 4-aminomethylpiperidin-1-carboxylic acid tert-butyl ester to obtain (S)-((1-(5-(2-(ethyl(isopropyl)aminocarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)carbamate tert-butyl ester. MS m / z [LC-MS]: 502.29 [M+1].

[0382] Step 2: (R)-2-((4-(3-aminopyrrolidone-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0383] Following the method in step 2 of intermediate 6, tert-butyl carbamate was used instead of 4-(((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)carbamate to obtain (S)-2-((4-(3-aminomethylpyrrolidine-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide. MS m / z [LC-MS]: 402.23 [M+1].

[0384] Intermediate 15: 2-((4-(4-(aminomethyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N- Isopropylbenzamide

[0385]

[0386] Step 1: ((1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)piperidin-4-yl)methyl)tert-butyl carbamate

[0387] Following the method in step 1 of intermediate 6, 4-aminomethyl-4-fluoropiperidine-1-carboxylic acid tert-butyl ester was used instead of 4-aminomethylpiperidine-1-carboxylic acid tert-butyl ester to obtain ((1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)piperidine-4-yl)methyl)carbamate tert-butyl ester. MS m / z [LC-MS]: 516.30 [M+1].

[0388] Step 2: 2-((4-(4-(aminomethyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0389] Following the method in step 2 of intermediate 6, 4-(((5-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)piperidin-4-yl)methyl)tert-butyl carbamate was replaced with tert-butyl carbamate to obtain 2-((4-(4-(aminomethyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide. MS m / z [LC-MS]: 416.25 [M+1].

[0390] Intermediate 16: 2-((4-(3-(aminomethyl)-3-fluorozacriane-1-yl)pyrimidin-5-yl)oxy)-N-ethyl 5-Fluoro-N-isopropylbenzamide

[0391]

[0392] Step 1: ((1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-fluorozahexacyclobutane-3-yl)methyl)tert-butyl carbamate

[0393] Following the method in step 1 of intermediate 6, tert-butyl carbamate was replaced with ((3-fluorozacricyclobutane-3-yl)methyl)carbamate to obtain ((1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-fluorozacricyclobutane-3-yl)methyl)carbamate. MS m / z [LC-MS]: 506.26 [M+1].

[0394] Step 2: 2-((4-(3-(aminomethyl)-3-fluorozacriane-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0395] Following the method in step 2 of intermediate 6, 4-(((5-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-fluoroazacyclobutane-3-yl)methyl)carbamate tert-butyl ester was replaced with ((1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)piperidin-1-carboxylic acid tert-butyl ester to obtain 2-((4-(3-(aminomethyl)-3-fluoroazacyclobutane-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide. MS m / z [LC-MS]: 406.21 [M+1].

[0396] Intermediate 17: (R)-2-((4-(3-(aminomethyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5- Fluoro-N-isopropylbenzamide

[0397]

[0398] Step 1: (R)-((1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)tert-butyl carbamate

[0399] Following the method in step 1 of intermediate 6, (S)-(pyrrolidine-3-ylmethyl)carbamate tert-butyl ester was used instead of 4-aminomethylpiperidin-1-carboxylic acid tert-butyl ester to obtain (R)-((1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)carbamate tert-butyl ester. MS m / z [LC-MS]: 502.29 [M+1].

[0400] Step 2: (R)-2-((4-(3-(aminomethyl)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0401] Following the method in step 2 of intermediate 6, 4-(((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)tert-butyl carbamate was replaced with (R)-((1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)piperidin-1-carboxylic acid tert-butyl ester to obtain (R)-2-((4-(3-(aminomethyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide. MS m / z [LC-MS]: 402.23 [M+1].

[0402] Intermediate 18: 2-((4-(6-amino-3-azabicyclo[3.1.0]hexane-3-yl)pyrimidin-5-yl)oxy)-N- Ethyl-5-fluoro-N-isopropylbenzamide

[0403]

[0404] Step 1: (3-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-yl)tert-butyl carbamate

[0405] Following the method in step 1 of intermediate 6, tert-butyl 3-(3-azabicyclo[3.1.0]hexane-6-yl)carbamate was substituted for tert-butyl 4-aminomethylpiperidin-1-carboxylic acid to obtain (3-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-yl)carbamate. MS m / z [LC-MS]: 500.27 [M+1].

[0406] Step 2: 2-((4-(6-amino-3-azabicyclo[3.1.0]hexane-3-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0407] Following the method in step 2 of intermediate 6, tert-butyl carbamate was used instead of 4-(((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-yl)carbamate to yield 2-((4-(6-amino-3-azabicyclo[3.1.0]hexane-3-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide. MS m / z [LC-MS]: 400.22 [M+1].

[0408] Intermediate 19: 2-((4-(3-aminoazacyclobutane-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N- Isopropylbenzamide

[0409]

[0410] Step 1: (1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)azacyclobutane-3-yl)tert-butyl carbamate

[0411] Following the method in step 1 of intermediate 6, tert-butyl aziridine-3-ylcarbamate was used instead of tert-butyl 4-aminomethylpiperidine-1-carboxylic acid to obtain (1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)aziridine-3-yl)carbamate. MS m / z [LC-MS]: 474.25 [M+1].

[0412] Step 2: 2-((4-(3-aminoazacyclobutane-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0413] Following the method in step 2 of intermediate 6, 4-(((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)azacyclobutane-3-yl)carbamate tert-butyl ester was replaced with (1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)piperidin-1-carboxylic acid tert-butyl ester to obtain 2-((4-(3-aminoazacyclobutane-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide. MS m / z [LC-MS]: 374.20 [M+1].

[0414] Intermediate 20: N-Ethyl-5-fluoro-N-isopropyl-2-((4-((morpholin-2-ylmethyl)amino)pyrimidin-5-yl)oxy (Bento) benzamide

[0415]

[0416] Step 1: 2-(((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester

[0417] Following the method in step 1 of intermediate 6, 2-(aminomethyl)morpholine-4-carboxylic acid tert-butyl ester was used instead of 4-aminomethylpiperidine-1-carboxylic acid tert-butyl ester to obtain ((1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)piperidine-4-yl)methyl)morpholine-4-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 518.28 [M+1].

[0418] Step 2: N-Ethyl-5-fluoro-N-isopropyl-2-((4-((morpholin-2-ylmethyl)amino)pyrimidin-5-yl)oxy)benzamide

[0419] Following the method in step 2 of intermediate 6, 4-(((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester was substituted for 2-(((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester to obtain N-ethyl-5-fluoro-N-isopropyl-2-((4-(((morpholine-2-ylmethyl)amino)pyrimidin-5-yl)oxy)benzamide. MS m / z [LC-MS]: 418.23 [M+1].

[0420] Intermediate 21: (S)-2-((4-(3-aminopyrrolidone-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N- Isopropylbenzamide

[0421]

[0422] Step 1: (S)-(1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)tert-butyl carbamate

[0423] Following the method in step 1 of intermediate 6, (S)-pyrrolidine-3-ylcarbamate tert-butyl ester was used instead of 4-aminomethylpiperidin-1-carboxylic acid tert-butyl ester to obtain (S)-(1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)carbamate tert-butyl ester. MS m / z [LC-MS]: 488.27 [M+1].

[0424] Step 2: (S)-2-((4-(3-aminopyrrolidone-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0425] Following the method in step 2 of intermediate 6, 4-(((5-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)carbamate tert-butyl ester was replaced with (S)-(1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)piperidin-1-carboxylic acid tert-butyl ester to obtain (S)-2-((4-(3-aminopyrrolidine-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide. MS m / z [LC-MS]: 388.22 [M+1].

[0426] Intermediate 22: 2-((4-(3-(aminomethyl)-3-methylazacyclobutane-1-yl)pyrimidin-5-yl)oxy)-N- Ethyl-5-fluoro-N-isopropylbenzamide

[0427]

[0428] Step 1: ((1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-methylazacyclobutane-3-yl)methyl)tert-butyl carbamate

[0429] Following the method in step 1 of intermediate 6, tert-butyl carbamate was substituted with ((3-methylazacyclobutane-3-yl)methyl)carbamate to obtain ((1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-methylazacyclobutane-3-yl)methyl)carbamate. MS m / z [LC-MS]: 502.29 [M+1].

[0430] Step 2: 2-((4-(3-(aminomethyl)-3-methylazacyclobutane-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0431] Following the method in step 2 of intermediate 6, 4-(((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-methylazacyclobutane-3-yl)methyl)carbamate tert-butyl ester was substituted for 4-(((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)piperidin-1-carboxylic acid tert-butyl ester to obtain 2-((4-(3-(aminomethyl)-3-methylazacyclobutane-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide. MS m / z [LC-MS]: 402.23 [M+1].

[0432] Intermediate 23: 2-((4-(4-aminomethyl)-4-hydroxypiperidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5- Fluoro-N-isopropylbenzamide

[0433]

[0434] Step 1: ((1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)-4-hydroxypiperidin-4-yl)methyl)tert-butyl carbamate

[0435] Following the method in step 1 of intermediate 6, tert-butyl carbamate was substituted with ((4-hydroxypiperidin-4-yl)methyl)carbamate to obtain ((1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)-4-hydroxypiperidin-4-yl)methyl)carbamate. MS m / z [LC-MS]: 532.30 [M+1].

[0436] Step 2: 2-((4-(4-aminomethyl)-4-hydroxypiperidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0437] Following the method in step 2 of intermediate 6, 4-(((5-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)-4-hydroxypiperidin-4-yl)methyl)tert-butyl carbamate was replaced with tert-butyl carbamate to obtain 2-((4-(4-aminomethyl)-4-hydroxypiperidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide. MS m / z [LC-MS]: 432.24 [M+1].

[0438] Intermediate 24: 2-((4-(6-(aminomethyl)-3-azabicyclo[3.1.0]hexane-3-yl)pyrimidin-5-yl)oxy 5-(N-ethyl-5-fluoro-N-isopropylbenzamide)

[0439]

[0440] Step 1: ((3-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)tert-butyl carbamate

[0441] Following the method in step 1 of intermediate 6, tert-butyl carbamate was replaced with ((3-azabicyclo[3.1.0]hexane-6-yl)methyl)carbamate to obtain ((3-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)carbamate. MS m / z [LC-MS]: 514.29 [M+1].

[0442] Step 2: 2-((4-(6-(aminomethyl)-3-azabicyclo[3.1.0]hexane-3-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0443] Following the method in step 2 of intermediate 6, 4-(((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)carbamate tert-butyl ester was substituted for 4-(((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester to obtain 2-((4-(6-(aminomethyl)-3-azabicyclo[3.1.0]hexane-3-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide. MS m / z [LC-MS]: 414.23 [M+1].

[0444] Intermediate 25: N-(trans-4-formylcyclohexyl)ethanesulfonamide

[0445]

[0446] N-(trans-4-formylcyclohexyl)ethanesulfonamide was synthesized according to the method of intermediate 47 in patent WO2017214367.

[0447] Intermediate 26: 2-((4-chloropyridin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[0448]

[0449] 2-((4-chloropyridin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide was synthesized according to the method of intermediate 41 in patent WO2017214367.

[0450] Intermediate 27: (S)-N-ethyl-5-fluoro-N-isopropyl-2-((4-((pyrrolid-3-ylmethyl)amino)pyrimidine- 5-yl)oxy)benzamide

[0451]

[0452] Step 1: (R)-3-(((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0453] The target compound was obtained from (R)-3-(aminomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester starting material, following the method in step 1 of intermediate 6. MS m / z [LC-MS]: 502.28 [M+1].

[0454] Step 2: (S)-N-ethyl-5-fluoro-N-isopropyl-2-((4-((pyrrolidone-3-ylmethyl)amino)pyrimidin-5-yl)oxy)benzamide

[0455] Following the method in step 2 of intermediate 6, the target compound was obtained from (R)-3-(((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 402.23 [M+1].

[0456] Intermediate 28: (R)-N-ethyl-5-fluoro-N-isopropyl-2-((4-((pyrrolid-3-ylmethyl)amino)pyrimidine- 5-yl)oxy)benzamide

[0457]

[0458] Step 1: (S)-3-(((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0459] Following the method in step 1 of intermediate 6, the target compound was obtained from (S)-3-(aminomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 502.28 [M+1].

[0460] Step 2: (R)-N-ethyl-5-fluoro-N-isopropyl-2-((4-((pyrrolidone-3-ylmethyl)amino)pyrimidin-5-yl)oxy)benzamide

[0461] Following the method in step 2 of intermediate 6, the target compound was obtained from (S)-3-(((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 402.23 [M+1].

[0462] Intermediate 29: N-((1r,4r)-4-((((3-hydroxypyrrolidone-3-yl)methyl)amino)methyl)cyclohexyl)methyl sulfonamide

[0463]

[0464] Step 1: 3-(aminomethyl)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester

[0465] 1-oxa-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (1.0 g) and concentrated ammonia (25%, 10 mL) were added to a sealed tube, heated to 70 °C and stirred for 4 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to obtain the target compound (1.05 g), which was used directly in the next step. MS m / z [LC-MS]: 217.16 [M+1].

[0466] Step 2: 3-Hydroxy-3-(((((1r,4r)-4-(methanesulfonamide)cyclohexyl)methyl)amino)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0467] 1.05 g of 3-(aminomethyl)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester, 1.02 g of N-((1r,4r)-4-formylcyclohexyl)methanesulfonamide, and 50 mg of glacial acetic acid were added to 20 mL of 1,2-dichloroethane and stirred at room temperature for 1 hour. Then, 3.18 g of sodium triacetoxyborohydride was added and stirred overnight at room temperature. The reaction was quenched with saturated sodium bicarbonate solution, filtered, and the filtrate was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (dichloromethane / methanol, 15:1) to obtain the target compound (1.35 g). MS m / z [LC-MS]: 406.24 [M+1].

[0468] Step 3: N-((1r,4r)-4-((((3-hydroxypyrrolidone-3-yl)methyl)amino)methyl)cyclohexyl)methanesulfonamide

[0469] 1.35 g of 3-hydroxy-3-(((((1r,4r)-4-(methanesulfonamide)cyclohexyl)methyl)amino)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester was added to 20 mL of 4 mol / L hydrogen chloride methanol solution and stirred at room temperature for 2 hours. After concentration under reduced pressure, the pH was adjusted to 11-12 with 10% sodium hydroxide solution. The extract was extracted with a 4:1 mixture of dichloromethane and isopropanol. The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (900 mg). MS m / z [LC-MS]: 306.19 [M+1].

[0470] Intermediate 30: (S)-2-((4-(3-(aminomethyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro- N-Isopropylbenzamide

[0471]

[0472] Step 1: (S)-((1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)piperidin-3-yl)methyl)tert-butyl carbamate

[0473] Following the method in step 1 of intermediate 6, the target compound was obtained from (R)-(piperidin-3-ylmethyl)carbamate tert-butyl ester. MS m / z [LC-MS]: 516.30 [M+1].

[0474] Step 2: (S)-2-((4-(3-(aminomethyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0475] Following the method in step 2 of intermediate 6, the target compound was obtained from (S)-((1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)piperidin-3-yl)methyl)tert-butyl carbamate. MS m / z [LC-MS]: 416.25 [M+1].

[0476] Intermediate 31: N-(4-fluoro-4-formylcyclohexyl)methanesulfonamide

[0477]

[0478] Step 1: 4-Amino-1-fluorocyclohexane-1-carboxaldehyde hydrochloride

[0479] 500 mg of (4-fluoro-4-formylcyclohexyl)carbamate tert-butyl ester was added to 5 mL of 4 mol / L dioxane hydrochloride solution and stirred at room temperature for 2 hours. 40 mL of diethyl ether was added and stirred for 1 hour. The mixture was filtered, the filter cake was washed with diethyl ether, and dried to obtain 350 mg of the target compound, which was used directly in the next step. MS m / z [LC-MS]: 146.10 [M+1].

[0480] Step 2: N-(4-fluoro-4-formylcyclohexyl)methanesulfonamide

[0481] 4-Amino-1-fluorocyclohexane-1-carboxaldehyde hydrochloride (350 mg) and diisopropylethylamine (780 mg) were added to dichloromethane (20 mL), cooled to 0 °C, and then methanesulfonyl chloride (225 mg) was added dropwise. The mixture was stirred for 1 hour. The reaction solution was washed successively with 1 mol / L dilute hydrochloric acid, saturated sodium bicarbonate aqueous solution, water, and saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (400 mg).

[0482] Intermediate 32: (R)-2-((4-(3-(aminomethyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro- N-Isopropylbenzamide

[0483]

[0484] Step 1: (R)-((1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)piperidin-3-yl)methyl)tert-butyl carbamate

[0485] Following the method in step 1 of intermediate 6, the target compound was obtained from (S)-(piperidin-3-ylmethyl)carbamate tert-butyl ester. MS m / z [LC-MS]: 516.30 [M+1].

[0486] Step 2: (R)-2-((4-(3-(aminomethyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0487] Following the method in step 2 of intermediate 6, the target compound was obtained from (R)-((1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)piperidin-3-yl)methyl)tert-butyl carbamate. MS m / z [LC-MS]: 416.25 [M+1].

[0488] Intermediate 33: (R)-2-((4-(3-(aminomethyl)-3-methylpyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl 5-Fluoro-N-isopropylbenzamide

[0489]

[0490] Step 1: (R)-((1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-methylpyrrolidine-3-yl)methyl)tert-butyl carbamate

[0491] Following the method in step 1 of intermediate 6, the target compound was obtained from (S)-((3-methylpyrrolidone-3-yl)methyl)carbamate tert-butyl ester. MS m / z [LC-MS]: 516.30 [M+1].

[0492] Step 2: (R)-2-((4-(3-(aminomethyl)-3-methylpyrrolidone-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0493] Following the method in step 2 of intermediate 6, the target compound was obtained from (R)-((1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-methylpyrrolidine-3-yl)methyl)tert-butyl carbamate. MS m / z [LC-MS]: 416.25 [M+1].

[0494] Intermediate 34: (S)-2-((4-(3-(aminomethyl)-3-methylpyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl 5-Fluoro-N-isopropylbenzamide

[0495]

[0496] Step 1: (S)-((1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-methylpyrrolidine-3-yl)methyl)tert-butyl carbamate

[0497] Following the method in step 1 of intermediate 6, the target compound was obtained from (R)-((3-methylpyrrolidone-3-yl)methyl)carbamate tert-butyl ester. MS m / z [LC-MS]: 516.30 [M+1].

[0498] Step 2: (S)-2-((4-(3-(aminomethyl)-3-methylpyrrolidone-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0499] Following the method in step 2 of intermediate 6, the target compound was obtained from (S)-((1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-methylpyrrolidine-3-yl)methyl)tert-butyl carbamate. MS m / z [LC-MS]: 416.25 [M+1].

[0500] Intermediate 35: N-(2-(pyrrolidone-3-ylmethyl)-2-azaspiro[3.5]nonane-7-yl)ethanesulfonamide hydrochloride

[0501]

[0502] Step 1: 3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0503] 3-Formylpyrrolidine-1-carboxylic acid tert-butyl ester (500 mg), N-(2-azaspiro[3.5]nonane-7-yl)ethanesulfonamide (464 mg), and glacial acetic acid (20 mg) were added to 1,2-dichloroethane (10 mL) and stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (1.27 g) was added and stirred at room temperature overnight. The reaction was quenched by adding saturated sodium bicarbonate aqueous solution, filtered, and the filtrate was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (dichloromethane / methanol, 20:1) to obtain the target compound (490 mg). MS m / z [LC-MS]: 416.26 [M+1].

[0504] Step 2: N-(2-(pyrrolidone-3-ylmethyl)-2-azaspiro[3.5]nonane-7-yl)ethanesulfonamide hydrochloride

[0505] 490 mg of 3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester was added to 5 mL of 4 mol / L dioxane hydrochloride solution and stirred at room temperature for 2 hours. Then, 40 mL of diethyl ether was added and stirred for 1 hour. The mixture was filtered, the filter cake was washed with diethyl ether, and dried to obtain the target compound (400 mg), which was used directly in the next step. MS m / z [LC-MS]: 316.21 [M+1].

[0506] Intermediate 36: 2-((4-(3-(aminomethyl)-3-ethylazonobutan-1-yl)pyrimidin-5-yl)oxy)-N-ethyl 5-Fluoro-N-isopropylbenzamide

[0507]

[0508] Step 1: ((3-ethyl-1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)azacyclobutane-3-yl)methyl)tert-butyl carbamate

[0509] Following the method in step 1 of intermediate 6, the target compound was obtained from tert-butyl ((3-ethylazacyclobutane-3-yl)methyl)carbamate. MS m / z [LC-MS]: 516.30 [M+1].

[0510] Step 2: 2-((4-(3-(aminomethyl)-3-ethylazacyclobutane-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0511] Following the method in step 2 of intermediate 6, the target compound was obtained from ((3-ethyl-1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)azacyclobutane-3-yl)methyl)tert-butyl carbamate. MS m / z [LC-MS]: 416.25 [M+1].

[0512] Intermediate 37: 2-((4-((3R,4S)-3-(aminomethyl)-4-fluoropyrrolidine-1-yl)pyrimidin-5-yl)oxy)-N- Ethyl-5-fluoro-N-isopropylbenzamide

[0513]

[0514] Step 1: (((3R,4S)-1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidine-4- 4-Fluoropyrrolidone-3-yl)methyl)tert-butyl carbamate

[0515] Following the method in step 1 of intermediate 6, the target compound was obtained from tert-butyl (((3S,4S)-4-fluoropyrrolidine-3-yl)methyl)carbamate. MS m / z [LC-MS]: 520.27 [M+1].

[0516] Step 2: 2-((4-((3R,4S)-3-(aminomethyl)-4-fluoropyrrolidone-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0517] Following the method in step 2 of intermediate 6, the target compound was obtained from tert-butyl carbamate (((3R,4S)-1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)-4-fluoropyrrolidine-3-yl)methyl)carbamate. MS m / z [LC-MS]: 420.22 [M+1].

[0518] Intermediate 38: 2-((4-((3S,4S)-3-(aminomethyl)-4-fluoropyrrolidine-1-yl)pyrimidin-5-yl)oxy)-N- Ethyl-5-fluoro-N-isopropylbenzamide

[0519]

[0520] Step 1: (((3S,4S)-1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidine-4- 4-Fluoropyrrolidone-3-yl)methyl)tert-butyl carbamate

[0521] Following the method in step 1 of intermediate 6, the target compound was obtained from tert-butyl (((3R,4S)-4-fluoropyrrolidine-3-yl)methyl)carbamate. MS m / z [LC-MS]: 520.27 [M+1].

[0522] Step 2: 2-((4-((3S,4S)-3-(aminomethyl)-4-fluoropyrrolidone-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0523] Following the method in step 2 of intermediate 6, the target compound was obtained from tert-butyl carbamate (((3S,4S)-1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)-4-fluoropyrrolidine-3-yl)methyl)carbamate. MS m / z [LC-MS]: 420.22 [M+1].

[0524] Intermediate 39: (S)-2-((4-(2-(aminomethyl)morpholinyl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isocyano Propylbenzamide

[0525]

[0526] Step 1: (S)-((4-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)morpholino-2-yl)methyl)tert-butyl carbamate

[0527] Following the method in step 1 of intermediate 6, the target compound was obtained from (S)-(piperidin-3-ylmethyl)carbamate tert-butyl ester. MS m / z [LC-MS]: 518.28 [M+1].

[0528] Step 2: (S)-2-((4-(2-(aminomethyl)morpholinyl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0529] Following the method in step 2 of intermediate 6, the target compound was obtained from (S)-((4-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)morpholino-2-yl)methyl)tert-butyl carbamate. MS m / z [LC-MS]: 418.23 [M+1].

[0530] Intermediate 40: (S)-2-((4-(3-aminomethylpyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-di Isopropylbenzamide

[0531]

[0532] Step 1: (S)-((1-(5-(2-(diisopropylaminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)tert-butyl carbamate

[0533] Following the method in step 1 of intermediate 6, the target compound was obtained from intermediate 26 and (R)-pyrrolidine-3-ylmethylcarbamate tert-butyl ester. MS m / z [LC-MS]: 516.30 [M+1].

[0534] Step 2: (S)-2-((4-(3-aminomethylpyrrolidone-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[0535] Following the method in step 2 of intermediate 6, the target compound was obtained from (S)-((1-(5-(2-(diisopropylaminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)tert-butyl carbamate. MS m / z [LC-MS]: 416.25 [M+1].

[0536] Intermediate 41: 2-((4-(3-(aminomethyl)-3-methylazacyclobutane-1-yl)pyrimidin-5-yl)oxy)-5- Fluoro-N,N-diisopropylbenzamide

[0537]

[0538] Step 1: ((1-(5-(2-(diisopropylaminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-methylazacyclobutane-3-yl)methyl)tert-butyl carbamate

[0539] Following the method in step 1 of intermediate 6, the target compound was obtained from intermediate 26 and ((3-methylazacyclobutane-3-yl)methyl)carbamate tert-butyl ester. MS m / z [LC-MS]: 516.30 [M+1].

[0540] Step 2: 2-((4-(3-(aminomethyl)-3-methylazacyclobutane-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[0541] Following the method in step 2 of intermediate 6, the target compound was obtained from ((1-(5-(2-(diisopropylaminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-methylazacyclobutane-3-yl)methyl)tert-butyl carbamate. MS m / z [LC-MS]: 416.25 [M+1].

[0542] Intermediate 42: N-(2-(azacyclobutane-3-ylmethyl)-2-azaspiro[3.3]heptane-6-yl)ethanesulfonamide salt Salt

[0543]

[0544] Step 1: 3-((6-(ethanesulfonamido)-2-azaspiro[3.3]heptane-2-yl)methyl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0545] Following the method in step 1 of intermediate 35, the target compound was obtained from tert-butyl 3-formylazacyclobutane-1-carboxylate and N-(2-azaspiro[3.3]heptane-6-yl)ethanesulfonamide. MS m / z [LC-MS]: 374.21 [M+1].

[0546] Step 2: N-(2-(azacyclobutane-3-ylmethyl)-2-azaspiro[3.3]heptane-6-yl)ethanesulfonamide hydrochloride

[0547] Following the method in step 2 of intermediate 35, the target compound was obtained from tert-butyl 3-((6-(ethanesulfonamido)-2-azaspiro[3.3]heptane-2-yl)methyl)azacyclobutane-1-carboxylic acid. MS m / z [LC-MS]: 274.16 [M+1].

[0548] Intermediate 43: (S)-3-((6-(ethanesulfonamido)-2-azaspiro[3.3]heptane-2-yl)methyl)pyrrolidine-1- tert-butyl carboxylate

[0549]

[0550] Step 1: (R)-3-((6-(ethanesulfonamido)-2-azaspiro[3.3]heptane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0551] Following the method in step 1 of intermediate 35, the target compound was obtained from (S)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester and N-(2-azaspiro[3.3]heptane-6-yl)ethanesulfonamide. MS m / z [LC-MS]: 388.23 [M+1].

[0552] Step 2: (S)-N-(2-(pyrrolidone-3-yl)methyl)-2-azaspiro[3.3]heptane-6-yl)ethanesulfonamide hydrochloride

[0553] Following the method in step 2 of intermediate 35, the target compound was obtained from (R)-3-((6-(ethanesulfonamido)-2-azaspiro[3.3]heptane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 288.18 [M+1].

[0554] Intermediate 44: (R)-3-((6-(ethanesulfonamido)-2-azaspiro[3.3]heptane-2-yl)methyl)pyrrolidine-1- tert-butyl carboxylate

[0555]

[0556] Step 1: (S)-3-((6-(ethanesulfonamido)-2-azaspiro[3.3]heptane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0557] Following the method in step 1 of intermediate 35, the target compound was obtained from (R)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester and N-(2-azaspiro[3.3]heptane-6-yl)ethanesulfonamide. MS m / z [LC-MS]: 388.23 [M+1].

[0558] Step 2: (R)-N-(2-(pyrrolidone-3-yl)methyl)-2-azaspiro[3.3]heptane-6-yl)ethanesulfonamide hydrochloride

[0559] Following the method in step 2 of intermediate 35, the target compound was obtained from (S)-3-((6-(ethanesulfonamido)-2-azaspiro[3.3]heptane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 288.18 [M+1].

[0560] Intermediate 45: N-(2-(azacyclobutane-3-ylmethyl)-2-azaspiro[3.5]nonane-7-yl)ethanesulfonamide salt Salt

[0561]

[0562] Step 1: 3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0563] The target compound was obtained from tert-butyl 3-formylazetane-1-carboxylic acid using the method described in step 1 of intermediate 35. MS m / z [LC-MS]: 402.24 [M+1].

[0564] Step 2: N-(2-(azacyclobutane-3-ylmethyl)-2-azaspiro[3.5]nonane-7-yl)ethanesulfonamide hydrochloride

[0565] Following the method in step 2 of intermediate 35, the target compound was obtained from tert-butyl 3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)azacyclobutane-1-carboxylic acid. MS m / z [LC-MS]: 302.19 [M+1].

[0566] Intermediate 46: (R)-N-(2-(pyrrolidone-3-ylmethyl)-2-azaspiro[3.5]nonane-7-yl)ethanesulfonamide salt Salt

[0567]

[0568] Step 1: (S)-3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0569] Following the method in step 1 of intermediate 35, the target compound was obtained from (R)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 416.26 [M+1].

[0570] Step 2: (R)-N-(2-(pyrrolidone-3-ylmethyl)-2-azaspiro[3.5]nonane-7-yl)ethanesulfonamide hydrochloride

[0571] Following the method in step 2 of intermediate 35, the target compound was obtained from (S)-3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 316.21 [M+1].

[0572] Intermediate 47: (S)-N-(2-(pyrrolidone-3-ylmethyl)-2-azaspiro[3.5]nonane-7-yl)ethanesulfonamide salt Salt

[0573]

[0574] Step 1: (R)-3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0575] Following the method in step 1 of intermediate 35, the target compound was obtained from (S)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 416.26 [M+1].

[0576] Step 2: (S)-N-(2-(pyrrolidone-3-ylmethyl)-2-azaspiro[3.5]nonane-7-yl)ethanesulfonamide hydrochloride

[0577] Following the method in step 2 of intermediate 35, the target compound was obtained from (R)-3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 316.21 [M+1].

[0578] Intermediate 48: (R)-N-(2-(pyrrolidone-3-ylmethyl)-2-azaspiro[3.5]nonane-7-yl)methanesulfonamide salt Salt

[0579]

[0580] Step 1: (S)-3-((7-(methanesulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0581] Following the method in step 1 of intermediate 35, the target compound was obtained from (R)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 402.24 [M+1].

[0582] Step 2: (R)-N-(2-(pyrrolidone-3-ylmethyl)-2-azaspiro[3.5]nonane-7-yl)methanesulfonamide hydrochloride

[0583] Following the method in step 2 of intermediate 35, the target compound was obtained from (S)-3-((7-(methanesulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 302.19 [M+1].

[0584] Intermediate 49: (S)-N-(2-(pyrrolidone-3-ylmethyl)-2-azaspiro[3.5]nonane-7-yl)methanesulfonamide salt Salt

[0585]

[0586] Step 1: (R)-3-((7-(methanesulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0587] Following the method in step 1 of intermediate 35, (S)-3-formylpyrrolidine-1-carboxylate tert-butyl ester was used instead of 3-formylpyrrolidine-1-carboxylate tert-butyl ester, and N-(2-azaspiro[3.5]nonane-7-yl)methanesulfonamide was used instead of N-(2-azaspiro[3.5]nonane-7-yl)ethanesulfonamide to obtain (R)-3-((7-(methanesulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylate tert-butyl ester. MS m / z [LC-MS]: 402.24 [M+1].

[0588] Step 2: (S)-N-(2-(pyrrolidone-3-ylmethyl)-2-azaspiro[3.5]nonane-7-yl)methanesulfonamide hydrochloride

[0589] Following the method in step 2 of intermediate 35, tert-butyl pyrrolidine-1-carboxylate was substituted with (R)-3-((7-(methanesulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylate to obtain (S)-N-(2-(pyrrolidine-3-ylmethyl)-2-azaspiro[3.5]nonane-7-yl)methanesulfonamide hydrochloride. MS m / z [LC-MS]: 302.19 [M+1].

[0590] Intermediate 50: (R)-1,1,1-trifluoro-N-(2-(pyrrolidine-3-ylmethyl)-2-azaspiro[3.5]nonane-7- (Base) Methanesulfonamide hydrochloride

[0591]

[0592] Step 1: (S)-3-((7-(trifluoromethanesulfonamide)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0593] Following the method in step 1 of intermediate 35, (R)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester was used instead of 3-formylpyrrolidine-1-carboxylic acid tert-butyl ester, and 1,1,1-trifluoro-N-(2-azaspiro[3.5]nonane-7-yl)methanesulfonamide was used instead of N-(2-azaspiro[3.5]nonane-7-yl)ethanesulfonamide to obtain (S)-3-((7-(trifluoromethanesulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 456.21 [M+1].

[0594] Step 2: (R)-1,1,1-trifluoro-N-(2-(pyrrolidone-3-ylmethyl)-2-azaspiro[3.5]nonane-7-yl)methanesulfonamide hydrochloride

[0595] Following the method in step 2 of intermediate 35, tert-butyl pyrrolidine-1-carboxylate was substituted with (S)-3-((7-(trifluoromethanesulfonyl)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylate to obtain (R)-1,1,1-trifluoro-N-(2-(pyrrolidine-3-ylmethyl)-2-azaspiro[3.5]nonane-7-yl)methanesulfonamide hydrochloride. MS m / z [LC-MS]: 356.16 [M+1].

[0596] Intermediate 51: N-(3-(((R)-pyrrolidine-3-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-yl)ethanesulfonate Amide hydrochloride

[0597]

[0598] Step 1: (3S)-3-((6-(ethanesulfonamido)-3-azabicyclo[3.1.0]hexane-3-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0599] Following the method in step 1 of intermediate 35, (R)-3-formylpyrrolidine-1-carboxylate tert-butyl ester was used instead of 3-formylpyrrolidine-1-carboxylate tert-butyl ester, and N-(3-azabicyclo[3.1.0]hexan-6-yl)ethanesulfonamide was used instead of N-(2-azaspiro[3.5]nonane-7-yl)ethanesulfonamide to obtain (3S)-3-((6-(ethanesulfonamido)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)pyrrolidine-1-carboxylate tert-butyl ester. MS m / z [LC-MS]: 374.21 [M+1].

[0600] Step 2: N-(3-(((R)-pyrrolidine-3-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-yl)ethanesulfonamide hydrochloride

[0601] Following the method in step 2 of intermediate 35, tert-butyl pyrrolidine-1-carboxylate was substituted with (3S)-3-((6-(ethanesulfonamido)-3-azabicyclo[3.1.0]hexane-3-yl)methyl)pyrrolidine-1-carboxylate to obtain N-(3-(((R)-pyrrolidine-3-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-yl)ethanesulfonamide hydrochloride. MS m / z [LC-MS]: 274.16 [M+1].

[0602] Intermediate 52: N-(2-(((R)-pyrrolidine-3-yl)methyl)-2-azaspiro[3.5]nonane-7-yl)-N',N'- Dimethylsulfonylurea hydrochloride

[0603]

[0604] Step 1: 7-((N,N-dimethylaminosulfonyl)amino)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester

[0605] 480 mg of 7-amino-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester was added to pyridine (10 mL), and dimethylaminosulfonyl chloride (340 mg) was added dropwise under ice bath. After the addition was complete, the mixture was heated to 60 °C and stirred for 2 hours. The solvent was removed by concentration under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed successively with 1 mol / L dilute hydrochloric acid, water, and saturated brine. The residue was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether / ethyl acetate, 3:1) to obtain 550 mg of 7-((N,N-dimethylaminosulfonyl)amino)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 348.20 [M+1].

[0606] Step 2: N-(2-azaspiro[3.5]nonane-7-yl)-N',N'-dimethylsulfonylurea hydrochloride

[0607] 550 mg of 7-((N,N-dimethylaminosulfonyl)amino)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester was added to 10 mL of 4 mol / L dioxane hydrochloride solution and stirred at room temperature for 1 hour. 40 mL of diethyl ether was added, and the mixture was stirred for another 1 hour. The mixture was filtered, the filter cake was washed with diethyl ether, and dried to obtain N-(2-azaspiro[3.5]nonane-7-yl)-N',N'-dimethylsulfonylurea hydrochloride (400 mg), which was used directly in the next step. MS m / z [LC-MS]: 248.14 [M+1].

[0608] Step 3: (S)-3-((7-((N,N-dimethylaminosulfonyl)amino)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0609] (R)-3-carboxypyrrolidine-1-carboxylic acid tert-butyl ester (385 mg), N-(2-azaspiro[3.5]nonane-7-yl)-N',N'-dimethylsulfonylurea hydrochloride (400 mg), and sodium acetate (115 mg) were added to 1,2-dichloroethane (10 mL) and stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (0.91 g) was added and stirred at room temperature overnight. The reaction was quenched by adding saturated sodium bicarbonate aqueous solution. The mixture was filtered, and the filtrate was extracted with dichloromethane. The extracts were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (dichloromethane / methanol, 20:1) to obtain (S)-3-((7-((N,N-dimethylaminosulfonyl)amino)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (420 mg). MS m / z[LC-MS]:431.27[M+1].

[0610] Step 4: N-(2-(((R)-pyrrolidine-3-yl)methyl)-2-azaspiro[3.5]nonane-7-yl)-N',N'-dimethylsulfonylurea hydrochloride

[0611] (S)-3-((7-((N,N-dimethylaminosulfonyl)amino)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (420 mg) was added to a 4 mol / L dioxane solution (10 mL), stirred at room temperature for 2 hours, then ether (40 mL) was added, stirred for 1 hour, filtered, the filter cake was washed with ether, and dried to obtain N-(2-(((R)-pyrrolidine-3-yl)methyl)-2-azaspiro[3.5]nonane-7-yl)-N',N'-dimethylsulfonylurea hydrochloride (320 mg). MS m / z [LC-MS]: 331.22 [M+1].

[0612] Intermediate 53: (R)-N-(2-(pyrrolidone-3-ylmethyl)-2-azaspiro[3.5]nonane-7-yl)cyclopropylsulfonyl Amino hydrochloride

[0613]

[0614] Step 1: (S)-3-((7-(cyclopropylsulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0615] Following the method in step 1 of intermediate 35, (R)-3-formylpyrrolidine-1-carboxylate tert-butyl ester was used instead of 3-formylpyrrolidine-1-carboxylate tert-butyl ester, and N-(2-azaspiro[3.5]nonane-7-yl)cyclopropylsulfonamide was used instead of N-(2-azaspiro[3.5]nonane-7-yl)ethanesulfonamide to obtain (S)-3-((7-(cyclopropylsulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylate tert-butyl ester. MS m / z [LC-MS]: 428.26 [M+1].

[0616] Step 2: (R)-N-(2-(pyrrolidone-3-ylmethyl)-2-azaspiro[3.5]nonane-7-yl)cyclopropylsulfonamide hydrochloride

[0617] Following the method in step 2 of intermediate 35, tert-butyl pyrrolidine-1-carboxylate was substituted with (S)-3-((7-(cyclopropylsulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylate to obtain (R)-N-(2-(pyrrolidine-3-ylmethyl)-2-azaspiro[3.5]nonane-7-yl)cyclopropylsulfonamide hydrochloride. MS m / z [LC-MS]: 328.21 [M+1].

[0618] Intermediate 54: (R)-N-(2-(pyrrolidine-3-ylmethyl)-2-azaspiro[3.5]nonane-7-yl)propane-1-sulfonyl Amide hydrochloride

[0619]

[0620] Step 1: (S)-3-((7-(propylsulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0621] Following the method in step 1 of intermediate 35, (R)-3-formylpyrrolidine-1-carboxylate tert-butyl ester was used instead of 3-formylpyrrolidine-1-carboxylate tert-butyl ester, and N-(2-azaspiro[3.5]nonane-7-yl)propane-1-sulfonamide was used instead of N-(2-azaspiro[3.5]nonane-7-yl)ethanesulfonamide to obtain (S)-3-((7-(propylsulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylate tert-butyl ester. MS m / z [LC-MS]: 430.27 [M+1].

[0622] Step 2: (R)-N-(2-(pyrrolidone-3-ylmethyl)-2-azaspiro[3.5]nonane-7-yl)propane-1-sulfonamide hydrochloride

[0623] Following the method in step 2 of intermediate 35, tert-butyl pyrrolidine-1-carboxylate was substituted with (S)-3-((7-(propylsulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylate to obtain (R)-N-(2-(pyrrolidine-3-ylmethyl)-2-azaspiro[3.5]nonane-7-yl)propane-1-sulfonamide hydrochloride. MS m / z [LC-MS]: 330.22 [M+1].

[0624] Intermediate 55: (R)-N-((1-(pyrrolidone-3-ylmethyl)piperidin-4-yl)methyl)ethanesulfonamide hydrochloride

[0625]

[0626] Step 1: tert-butyl 4-(ethanesulfonamide methyl)piperidine-1-carboxylate

[0627] 500 mg of 4-(aminomethyl)piperidin-1-carboxylic acid tert-butyl ester and 300 mg of diisopropylethylamine were added to 10 mL of 1,2-dichloroethane. Ethylsulfonyl chloride (360 mg) was added dropwise under ice bath conditions. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated sodium bicarbonate solution. The aqueous phase was removed by separation. The organic phase was washed successively with 1 mol / L dilute hydrochloric acid, water, and saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether / ethyl acetate, 3:1) to obtain 610 mg of 4-(ethanesulfonamide methyl)piperidin-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 307.17 [M+1].

[0628] Step 2: N-(piperidin-4-ylmethyl)ethanesulfonamide hydrochloride

[0629] 600 mg of 4-(ethanesulfonamide methyl)piperidine-1-carboxylic acid tert-butyl ester was added to 10 mL of 4 mol / L dioxane hydrochloride solution and stirred at room temperature for 2 hours. 40 mL of diethyl ether was added, and the mixture was stirred for 1 hour. The mixture was filtered, the filter cake was washed with diethyl ether, and dried to obtain 450 mg of N-(piperidine-4-ylmethyl)ethanesulfonamide hydrochloride, which was used directly in the next step. MS m / z [LC-MS]: 207.12 [M+1].

[0630] Step 3: (S)-3-((4-(ethanesulfonamide methyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0631] (R)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester (500 mg), N-(piperidin-4-ylmethyl)ethanesulfonamide hydrochloride (450 mg), and sodium acetate (150 mg) were added to 1,2-dichloroethane (10 mL) and stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (1.18 g) was added and stirred overnight at room temperature. The reaction was quenched with saturated sodium bicarbonate aqueous solution, filtered, and the filtrate was extracted with dichloromethane. The extracts were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (dichloromethane / methanol, 20:1) to obtain (S)-3-((4-(ethanesulfonamide methyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (570 mg). MS m / z [LC-MS]: 390.24 [M+1].

[0632] Step 4: (R)-N-((1-(pyrrolidone-3-ylmethyl)piperidin-4-yl)methyl)ethanesulfonamide hydrochloride

[0633] (S)-3-((4-(ethanesulfonamide methyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (570 mg) was added to a 4 mol / L dioxane solution (10 mL), stirred at room temperature for 2 hours, then ether (40 mL) was added, stirred for 2 hours, filtered, the filter cake was washed with ether, and dried to obtain (R)-N-((1-(pyrrolidine-3-ylmethyl)piperidin-4-yl)methyl)ethanesulfonamide hydrochloride (480 mg), which was used directly for the next step. MS m / z [LC-MS]: 290.19 [M+1].

[0634] Intermediate 56: (R)-7-(ethanesulfonyl)-2-(pyrrolidine-3-ylmethyl)-2,7-diazaspiro[3.5]nonane salt Salt

[0635]

[0636] Step 1: tert-butyl 7-(ethanesulfonyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0637] Following the method in step 1 of intermediate 55, tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate was substituted for tert-butyl 4-(aminomethyl)piperidine-1-carboxylate to obtain tert-butyl 7-(ethanesulfonyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate. MS m / z [LC-MS]: 319.17 [M+1].

[0638] Step 2: 7-(ethanesulfonyl)-2,7-diazaspiro[3.5]nonane hydrochloride

[0639] Following the method in step 2 of intermediate 55, tert-butyl 7-(ethanesulfonyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate was substituted for tert-butyl 4-(ethanesulfonamide methyl)piperidine-1-carboxylate to obtain 7-(ethanesulfonyl)-2,7-diazaspiro[3.5]nonane hydrochloride. MS m / z [LC-MS]: 219.12 [M+1].

[0640] Step 3: (S)-3-((7-(ethanesulfonyl)-2,7-diazaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0641] Following the method in step 3 of intermediate 55, N-(piperidin-4-ylmethyl)ethanesulfonamide hydrochloride was replaced with 7-(ethanesulfonyl)-2,7-diazaspiro[3.5]nonane hydrochloride to obtain (S)-3-((7-(ethanesulfonyl)-2,7-diazaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 402.24 [M+1].

[0642] Step 4: (R)-7-(ethanesulfonyl)-2-(pyrrolidine-3-ylmethyl)-2,7-diazaspiro[3.5]nonane hydrochloride

[0643] Following the method in step 4 of intermediate 55, (S)-3-((7-(ethanesulfonyl)-2,7-diazaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester was used instead of (S)-3-((4-(ethanesulfonamide methyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain (R)-7-(ethanesulfonyl)-2-(pyrrolidine-3-ylmethyl)-2,7-diazaspiro[3.5]nonane hydrochloride. MS m / z [LC-MS]: 302.19 [M+1].

[0644] Intermediate 57: (R)-2-(pyrrolidine-3-ylmethyl)-2,7-diazaspiro[3.5]nonane-7-sulfonamide hydrochloride

[0645]

[0646] Step 1: tert-butyl 7-aminosulfonyl-2,7-diazaspiro[3,5]nonane-2-carboxylate

[0647] Following the method in step 1 of intermediate 55, tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate was used instead of tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, and aminosulfonyl chloride was used instead of ethylsulfonyl chloride to obtain 7-aminosulfonyl-2,7-diazaspiro[3.5]nonane-2-carboxylate. MS m / z [LC-MS]: 306.15 [M+1].

[0648] Step 2: 2,7-diazaspiro[3.5]nonane-7-sulfonamide hydrochloride

[0649] Following the method in step 2 of intermediate 55, tert-butyl 7-aminosulfonyl-2,7-diazaspiro[3.5]nonane-2-carboxylate was substituted for tert-butyl 4-(ethanesulfonamide methyl)piperidine-1-carboxylate to obtain 2,7-diazaspiro[3.5]nonane-7-sulfonamide hydrochloride. MS m / z [LC-MS]: 206.10 [M+1].

[0650] Step 3: (S)-3-((7-aminosulfonyl-2,7-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0651] Following the method in step 3 of intermediate 55, N-(piperidin-4-ylmethyl)ethanesulfonamide hydrochloride was replaced with 2,7-diazaspiro[3.5]nonane-7-sulfonamide hydrochloride to obtain (S)-3-((7-aminosulfonyl-2,7-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 389.22 [M+1].

[0652] Step 4: (R)-2-(pyrrolidine-3-ylmethyl)-2,7-diazaspiro[3.5]nonane-7-sulfonamide hydrochloride

[0653] Following the method in step 4 of intermediate 55, (S)-3-((4-(ethanesulfonylmethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate tert-butyl ester was substituted with (S)-3-((7-aminosulfonyl-2,7-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylate to obtain (R)-2-(pyrrolidine-3-ylmethyl)-2,7-diazaspiro[3.5]nonane-7-sulfonamide hydrochloride. MS m / z [LC-MS]: 289.17 [M+1].

[0654] Intermediate 58: (R)-N-(7-(pyrrolidine-3-ylmethyl)-7-azaspiro[3.5]nonane-2-yl)ethanesulfonamide salt Salt

[0655]

[0656] Step 1: 2-(ethanesulfonamide)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester

[0657] Following the method in step 1 of intermediate 55, tert-butyl 2-amino-7-azaspiro[3.5]nonane-7-carboxylate was substituted for tert-butyl 4-(aminomethyl)piperidine-1-carboxylate to obtain tert-butyl 2-(ethanesulfonamide)-7-azaspiro[3.5]nonane-7-carboxylate. MS m / z [LC-MS]: 333.18 [M+1].

[0658] Step 2: N-(7-azaspiro[3.5]nonane-2-yl)ethanesulfonamide hydrochloride

[0659] Following the method in step 2 of intermediate 55, tert-butyl 2-(ethanesulfonamido)-7-azaspiro[3.5]nonane-7-carboxylate was substituted for tert-butyl 4-(ethanesulfonamidomethyl)piperidine-1-carboxylate to obtain N-(7-azaspiro[3.5]nonane-2-yl)ethanesulfonamide hydrochloride. MS m / z [LC-MS]: 233.13 [M+1].

[0660] Step 3: (S)-3-((2-(ethanesulfonamido)-7-azaspiro[3.5]nonane-7-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0661] Following the method in step 3 of intermediate 55, N-(7-azaspiro[3.5]nonane-2-yl)ethanesulfonamide hydrochloride was substituted for N-(piperidin-4-ylmethyl)ethanesulfonamide hydrochloride to obtain (S)-3-((2-(ethanesulfonamido)-7-azaspiro[3.5]nonane-7-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 416.26 [M+1].

[0662] Step 4: (R)-N-(7-(pyrrolidone-3-ylmethyl)-7-azaspiro[3.5]nonane-2-yl)ethanesulfonamide hydrochloride

[0663] Following the method in step 4 of intermediate 55, (S)-3-((2-(ethanesulfonamido)-7-azaspiro[3.5]nonane-7-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester was used instead of (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain (R)-N-(7-(pyrrolidine-3-ylmethyl)-7-azaspiro[3.5]nonane-2-yl)ethanesulfonamide hydrochloride. MS m / z [LC-MS]: 316.21 [M+1].

[0664] Intermediate 59: (R)-N-(3-(pyrrolidine-3-ylmethyl)-3-azaspiro[5.5]undecane-9-yl)ethanesulfonamide hydrochloride

[0665]

[0666] Step 1: 9-(ethanesulfonamido)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester

[0667] Following the method in step 1 of intermediate 55, tert-butyl 9-amino-3-azaspiro[5.5]undecane-3-carboxylate was substituted for tert-butyl 4-(aminomethyl)piperidine-1-carboxylate to obtain tert-butyl 9-(ethanesulfonamide)-3-azaspiro[5.5]undecane-3-carboxylate. MS m / z [LC-MS]: 361.22 [M+1].

[0668] Step 2: N-(3-azaspiro[5.5]undecane-9-yl)ethanesulfonamide hydrochloride

[0669] Following the method in step 2 of intermediate 55, tert-butyl 9-(ethanesulfonamido)-3-azaspiro[5.5]undecane-3-carboxylate was substituted for tert-butyl 4-(ethanesulfonamidomethyl)piperidine-1-carboxylate to obtain N-(3-azaspiro[5.5]undecane-9-yl)ethanesulfonamide hydrochloride. MS m / z [LC-MS]: 261.16 [M+1].

[0670] Step 3: (S)-3-((9-(ethanesulfonamido)-3-azaspiro[5.5]undecane-3-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0671] Following the method in step 3 of intermediate 55, N-(3-azaspiro[5.5]undecane-9-yl)ethanesulfonamide hydrochloride was substituted for N-(piperidin-4-ylmethyl)ethanesulfonamide hydrochloride to obtain (S)-3-((9-(ethanesulfonamido)-3-azaspiro[5.5]undecane-3-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 444.29 [M+1].

[0672] Step 4: (R)-N-(3-(pyrrolidine-3-ylmethyl)-3-azaspiro[5.5]undecane-9-yl)ethanesulfonamide hydrochloride

[0673] Following the method in step 4 of intermediate 55, (S)-3-((9-(ethanesulfonamido)-3-azaspiro[5.5]undecane-3-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester was used instead of (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain (R)-N-(3-(pyrrolidine-3-ylmethyl)-3-azaspiro[5.5]undecane-9-yl)ethanesulfonamide hydrochloride. MS m / z [LC-MS]: 344.24 [M+1].

[0674] Intermediate 60: N-((S)-8-(((R)-pyrrolidine-3-yl)methyl)-8-azaspiro[4.5]decane-1-yl)ethanesulfonate Amide hydrochloride

[0675]

[0676] Step 1: (S)-1-(ethanesulfonamido)-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester

[0677] Following the method in step 1 of intermediate 55, tert-butyl (S)-1-amino-8-azaspiro[4.5]decane-8-carboxylate was substituted for tert-butyl 4-(aminomethyl)piperidine-1-carboxylate to obtain (S)-1-(ethanesulfonamido)-8-azaspiro[4.5]decane-8-carboxylate. MS m / z [LC-MS]: 347.20 [M+1].

[0678] Step 2: (S)-N-(8-azaspiro[4.5]decane-1-yl)ethanesulfonamide hydrochloride

[0679] Following the method in step 2 of intermediate 55, tert-butyl (S)-1-(ethanesulfonamido)-8-azaspiro[4.5]decane-8-carboxylate was substituted for tert-butyl (4-(ethanesulfonamidomethyl)piperidine-1-carboxylate) to obtain (S)-N-(8-azaspiro[4.5]decane-1-yl)ethanesulfonamide hydrochloride. MS m / z [LC-MS]: 247.15 [M+1].

[0680] Step 3: (S)-3-(((S)-1-(ethanesulfonamido)-8-azaspiro[4.5]decane-8-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0681] Following the method in step 3 of intermediate 55, (S)-N-(8-azaspiro[4.5]decane-1-yl)ethanesulfonamide hydrochloride was substituted for N-(piperidin-4-ylmethyl)ethanesulfonamide hydrochloride to obtain (S)-3-(((S)-1-(ethanesulfonamide)-8-azaspiro[4.5]decane-8-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 430.27 [M+1].

[0682] Step 4: N-((S)-8-(((R)-pyrrolidine-3-yl)methyl)-8-azaspiro[4.5]decane-1-yl)ethanesulfonamide hydrochloride

[0683] Following the method in step 4 of intermediate 55, (S)-3-(((S)-1-(ethanesulfonamido)-8-azaspiro[4.5]decane-8-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester was used instead of (S)-3-(((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain N-((S)-8-(((R)-pyrrolidine-3-yl)methyl)-8-azaspiro[4.5]decane-1-yl)ethanesulfonamide hydrochloride. MS m / z [LC-MS]: 330.22 [M+1].

[0684] Intermediate 61: N-(8-(((R)-pyrrolidine-3-yl)methyl)-1-oxa-8-azaspiro[4.5]decane-3-yl) Ethylsulfonamide hydrochloride

[0685]

[0686] Step 1: tert-butyl 3-(ethanesulfonamide)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

[0687] Following the method in step 1 of intermediate 55, tert-butyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate was substituted for tert-butyl 4-(aminomethyl)piperidine-1-carboxylate to obtain tert-butyl 3-(ethanesulfonamido)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate. MS m / z [LC-MS]: 349.18 [M+1].

[0688] Step 2: N-(1-oxa-8-azaspiro[4.5]decane-3-yl)ethanesulfonamide hydrochloride

[0689] Following the method in step 2 of intermediate 55, tert-butyl 3-(ethanesulfonamido)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate was substituted for tert-butyl 4-(ethanesulfonamidomethyl)piperidine-1-carboxylate to obtain N-(1-oxa-8-azaspiro[4.5]decane-3-yl)ethanesulfonamide hydrochloride. MS m / z [LC-MS]: 249.13 [M+1].

[0690] Step 3: (3S)-3-((3-(ethanesulfonamido)-1-oxa-8-azaspiro[4.5]decane-8-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0691] Following the method in step 3 of intermediate 55, N-(1-oxa-8-azaspiro[4.5]decane-3-yl)ethanesulfonamide hydrochloride was substituted for N-(piperidin-4-ylmethyl)ethanesulfonamide hydrochloride to obtain (3S)-3-((3-(ethanesulfonamide)-1-oxa-8-azaspiro[4.5]decane-8-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 432.25 [M+1].

[0692] Step 4: N-(8-(((R)-pyrrolidine-3-yl)methyl)-1-oxa-8-azaspiro[4.5]decane-3-yl)ethanesulfonamide hydrochloride

[0693] Following the method in step 4 of intermediate 55, (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-methyl)pyrrolidine-1-carboxylate tert-butyl ester was substituted with (3S)-3-((3-(ethanesulfonamido)-1-oxa-8-azaspiro[4.5]decane-8-yl)methyl)pyrrolidine-1-carboxylate tert-butyl ester to obtain N-(8-((((R)-pyrrolidine-3-yl)methyl)-1-oxa-8-azaspiro[4.5]decane-3-yl)ethanesulfonamide hydrochloride. MS m / z [LC-MS]: 332.20 [M+1].

[0694] Intermediate 62: N-((3-(((R)-pyrrolidine-3-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-yl)methyl 2-(2-ethyl)sulfonamide hydrochloride

[0695]

[0696] Step 1: 6-(ethanesulfonamide methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

[0697] Following the method in step 1 of intermediate 55, 6-(aminomethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester was substituted for 4-(aminomethyl)piperidine-1-carboxylic acid tert-butyl ester to obtain 6-(ethanesulfonamidomethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 305.15 [M+1].

[0698] Step 2: N-((3-azabicyclo[3.1.0]hexane-6-yl)methyl)ethanesulfonamide hydrochloride

[0699] Following the method in step 2 of intermediate 55, tert-butyl 6-(ethanesulfonamide methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate was substituted for tert-butyl 4-(ethanesulfonamide methyl)piperidine-1-carboxylate to obtain N-((3-azabicyclo[3.1.0]hexane-6-yl)methyl)ethanesulfonamide hydrochloride. MS m / z [LC-MS]: 205.10 [M+1].

[0700] Step 3: (3S)-3-((6-(ethanesulfonamidomethyl)-3-azabicyclo[3.1.0]hexane-3-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0701] Following the method in step 3 of intermediate 55, N-((3-azabicyclo[3.1.0]hexane-6-yl)methyl)ethanesulfonamide hydrochloride was substituted for N-(piperidin-4-ylmethyl)ethanesulfonamide hydrochloride to obtain (3S)-3-((6-(ethanesulfonamide methyl)-3-azabicyclo[3.1.0]hexane-3-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 388.23 [M+1].

[0702] Step 4: N-((3-(((R)-pyrrolidine-3-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)ethanesulfonamide hydrochloride

[0703] Following the method in step 4 of intermediate 55, (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-methyl)pyrrolidine-1-carboxylate was substituted with (3S)-3-((6-(ethanesulfonamidomethyl)-3-azabicyclo[3.1.0]hexane-3-yl)methyl)pyrrolidine-1-carboxylate to obtain N-((3-((((R)-pyrrolidine-3-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)ethanesulfonamide hydrochloride. MS m / z [LC-MS]: 288.17 [M+1].

[0704] Intermediate 63: (R)-2-methyl-1-((2-(pyrrolidine-3-ylmethyl)-2-azaspiro[3.5]nonane-7-yl)amino 2-propane-2-ol hydrochloride

[0705]

[0706] Step 1: 7-((2-hydroxy-2-methylpropyl)amino)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester

[0707] 480 mg of 7-oxo-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester, 1-amino-2-methylprop-2-ol (260 mg), and acetic acid (24 mg) were added to 10 mL of 1,2-dichloroethane and stirred at room temperature for 1 hour. Then, 1.27 g of sodium triacetoxyborohydride was added and stirred overnight at room temperature. The reaction was quenched with saturated sodium bicarbonate solution, filtered, and the filtrate was extracted with dichloromethane. The extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The filtrate was then separated by silica gel column chromatography (dichloromethane / methanol, 15:1) to obtain 420 mg of 7-((2-hydroxy-2-methylpropyl)amino)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 313.25 [M+1].

[0708] Step 2: 1-((2-azaspiro[3.5]nonane-7-yl)amino)-2-methylprop-2-ol hydrochloride

[0709] Following the method in step 2 of intermediate 55, tert-butyl 7-((2-hydroxy-2-methylpropyl)amino)-2-azaspiro[3.5]nonane-2-carboxylate was substituted for tert-butyl 4-(ethanesulfonamide methyl)piperidine-1-carboxylate to obtain 1-((2-azaspiro[3.5]nonane-7-yl)amino)-2-methylprop-2-ol hydrochloride. MS m / z [LC-MS]: 213.10 [M+1].

[0710] Step 3: (S)-3-((7-((2-hydroxy-2-methylpropyl)amino)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0711] Following the method in step 3 of intermediate 55, N-(piperidin-4-ylmethyl)ethanesulfonamide hydrochloride was replaced with 1-((2-azaspiro[3.5]nonane-7-yl)amino)-2-methylprop-2-ol hydrochloride to obtain (S)-3-((7-(((2-hydroxy-2-methylpropyl)amino)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 396.32 [M+1].

[0712] Step 4: (R)-2-methyl-1-((2-(pyrrolidone-3-ylmethyl)-2-azaspiro[3.5]nonane-7-yl)amino)prop-2-ol hydrochloride

[0713] Following the method in step 4 of intermediate 55, (S)-3-((7-(((2-hydroxy-2-methylpropyl)amino)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylate tert-butyl ester was used instead of (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate tert-butyl ester to obtain (R)-2-methyl-1-((2-(pyrrolidine-3-ylmethyl)-2-azaspiro[3.5]nonane-7-yl)amino)prop-2-ol hydrochloride. MS m / z [LC-MS]: 296.27 [M+1].

[0714] Intermediate 64: N-(2-(((R)-pyrrolidine-3-yl)methyl)-2-azaspiro[3.5]nonane-7-yl)sulfonylurea Salt

[0715]

[0716] Step 1: 7-((aminosulfonyl)amino)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester

[0717] Following the method in step 1 of intermediate 52, 7-((aminosulfonyl)amino)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester was obtained by replacing dimethylaminosulfonyl chloride with aminosulfonyl chloride. MS m / z [LC-MS]: 320.16 [M+1].

[0718] Step 2: N-(2-azaspiro[3.5]nonane-7-yl)sulfonylurea hydrochloride

[0719] Following the method in step 2 of intermediate 52, 7-((N,N-dimethylaminosulfonyl)amino)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester was substituted for 7-((N,N-dimethylaminosulfonyl)amino)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester to obtain N-(2-azaspiro[3.5]nonane-7-yl)sulfonylurea hydrochloride. MS m / z [LC-MS]: 220.11 [M+1].

[0720] Step 3: (S)-3-((7-((aminosulfonyl)amino)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0721] Following the method in step 3 of intermediate 52, N-(2-azaspiro[3.5]nonane-7-yl)sulfonylurea hydrochloride was substituted for N-(2-azaspiro[3.5]nonane-7-yl)-N',N'-dimethylsulfonylurea hydrochloride to obtain (S)-3-((7-(((aminosulfonyl)amino)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 403.24 [M+1].

[0722] Step 4: N-(2-(((R)-pyrrolidine-3-yl)methyl)-2-azaspiro[3.5]nonane-7-yl)sulfonylurea hydrochloride

[0723] Following the method in step 4 of intermediate 52, (S)-3-((7-((N,N-dimethylaminosulfonyl)amino)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester was used instead of (S)-3-((7-((N,N-dimethylaminosulfonyl)amino)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain N-(2-((((R)-pyrrolidine-3-yl)methyl)-2-azaspiro[3.5]nonane-7-yl)sulfonylurea hydrochloride. MS m / z [LC-MS]: 303.19 [M+1].

[0724] Intermediate 65: (R)-N-(2-(pyrrolidine-3-ylmethyl)-2-azaspiro[3.5]nonane-7-yl)propane-2-sulfonyl Amide hydrochloride

[0725]

[0726] Step 1: 6-(ethanesulfonamide methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

[0727] Following the method in step 1 of intermediate 55, tert-butyl 7-amino-2-azaspiro[3.5]nonane-2-carboxylate was substituted for tert-butyl 4-(aminomethyl)piperidine-1-carboxylate to obtain tert-butyl 7-(isopropylsulfonamido)-2-azaspiro[3.5]nonane-2-carboxylate. MS m / z [LC-MS]: 347.20 [M+1].

[0728] Step 2: N-(2-azaspiro[3.5]nonane-7-yl)propane-2-sulfonamide hydrochloride

[0729] Following the method in step 2 of intermediate 55, tert-butyl 7-(isopropylsulfonamido)-2-azaspiro[3.5]nonane-2-carboxylate was substituted for tert-butyl 4-(ethanesulfonamidomethyl)piperidine-1-carboxylate to obtain N-(2-azaspiro[3.5]nonane-7-yl)propane-2-sulfonamide hydrochloride. MS m / z [LC-MS]: 247.15 [M+1].

[0730] Step 3: (S)-3-((7-(isopropylsulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0731] Following the method in step 3 of intermediate 55, N-(piperidin-4-ylmethyl)ethanesulfonamide hydrochloride was substituted for N-(2-azaspiro[3.5]nonane-7-yl)propane-2-sulfonamide hydrochloride to obtain (S)-3-((7-(isopropylsulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 430.27 [M+1].

[0732] Step 4: (R)-N-(2-(pyrrolidone-3-ylmethyl)-2-azaspiro[3.5]nonane-7-yl)propane-2-sulfonamide hydrochloride

[0733] Following the method in step 4 of intermediate 55, (S)-3-((7-(isopropylsulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester was used instead of (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain (R)-N-(2-(pyrrolidine-3-ylmethyl)-2-azaspiro[3.5]nonane-7-yl)propane-2-sulfonamide hydrochloride. MS m / z [LC-MS]: 330.22 [M+1].

[0734] Intermediate 66: (S)-2-((4-(3-((7-amino-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1- (5-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[0735]

[0736] Step 1: 7-(((benzyloxy)carbonyl)amino)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester

[0737] Following the method in step 1 of intermediate 55, tert-butyl 7-amino-2-azaspiro[3.5]nonane-2-carboxylate was used instead of tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, and benzyl chloroformate was used instead of ethylsulfonyl chloride to obtain the target compound. MS m / z [LC-MS]: 375.23 [M+1].

[0738] Step 2: (2-azaspiro[3.5]nonane-7-yl)carbamate hydrochloride

[0739] Following the method in step 2 of intermediate 55, the target compound was obtained by replacing 4-(ethanesulfonamide methyl)piperidine-1-carboxylic acid tert-butyl ester with 7-(((benzyloxy)carbonyl)amino)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 275.18 [M+1].

[0740] Step 3: (S)-3-((7-(((benzyloxy)carbonyl)amino)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0741] Following the method in step 3 of intermediate 55, the target compound was obtained by replacing N-(piperidin-4-ylmethyl)ethanesulfonamide hydrochloride with (2-azaspiro[3.5]nonane-7-yl)carbamate benzyl ester hydrochloride. MS m / z [LC-MS]: 458.30 [M+1].

[0742] Step 4: (R)-(2-(pyrrolidone-3-ylmethyl)-2-azaspiro[3.5]nonane-7-yl)carbamate hydrochloride

[0743] Following the method in step 4 of intermediate 55, the target compound was obtained by replacing (S)-3-((4-(ethanesulfonamide methyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester with (S)-3-((7-((((benzyloxy)carbonyl)amino)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 358.25 [M+1].

[0744] Step 5: (S)-(2-((1-(5-(2-(diisopropylaminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)-2-azaspiro[3.5]nonane-7-yl)benzyl carbamate

[0745] Following the method in Example 36, intermediate 1 was replaced with intermediate 26, and intermediate 29 was replaced with (R)-(2-(pyrrolidone-3-ylmethyl)-2-azaspiro[3.5]nonane-7-yl)carbamate hydrochloride to obtain the target compound. MSm / z [LC-MS]: 673.39 [M+1].

[0746] Step 6: (S)-2-((4-(3-((7-amino-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[0747] (S)-(2-((1-(5-(2-(diisopropylaminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)-2-azaspiro[3.5]nonane-7-yl)carbamate (700 mg) and 10% palladium on carbon (70 mg) were added to methanol (20 mL). The air in the reactor was replaced with hydrogen. The mixture was stirred at room temperature for 4 hours under hydrogen at 3 atmospheres. After filtration, the filtrate was concentrated under reduced pressure to obtain the target compound (550 mg), which was used directly in the next step. MS m / z [LC-MS]: 539.35 [M+1].

[0748] Intermediate 67: (R)-N-((2-(pyrrolidine-3-ylmethyl)-2-azaspiro[3.5]nonane-7-yl)methyl)ethanesulfonate Amide hydrochloride

[0749]

[0750] Step 1: 7-(ethanesulfonamide methyl)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester

[0751] Following the method in step 1 of intermediate 55, tert-butyl 7-(aminomethyl)-2-azaspiro[3.5]nonane-2-carboxylic acid was substituted for tert-butyl 4-(aminomethyl)piperidine-1-carboxylic acid to obtain the target compound. MS m / z [LC-MS]: 333.18 [M+1].

[0752] Step 2: N-((2-azaspiro[3.5]nonane-7-yl)methyl)ethanesulfonamide hydrochloride

[0753] Following the method in step 2 of intermediate 55, 4-(ethanesulfonamide methyl)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester was replaced with 7-(ethanesulfonamide methyl)piperidine-1-carboxylic acid tert-butyl ester to obtain the target compound. MS m / z [LC-MS]: 233.13 [M+1].

[0754] Step 3: (S)-3-((7-(ethanesulfonamidomethyl)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0755] Following the method in step 3 of intermediate 55, the target compound was obtained by replacing N-(piperidin-4-ylmethyl)ethanesulfonamide hydrochloride with N-((2-azaspiro[3.5]nonane-7-yl)methyl)ethanesulfonamide hydrochloride. MS m / z [LC-MS]: 416.26 [M+1].

[0756] Step 4: (R)-N-((2-(pyrrolidone-3-ylmethyl)-2-azaspiro[3.5]nonane-7-yl)methyl)ethanesulfonamide hydrochloride

[0757] Following the method in step 4 of intermediate 55, the target compound was obtained by replacing (S)-3-((4-((ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester with (S)-3-((7-(ethanesulfonamidomethyl)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 316.21 [M+1].

[0758] Intermediate 68: N-Ethyl-5-fluoro-N-isopropyl-2-((4-(7-(prop-2-yn-1-yl)-2,7-diazaspiro) [3.5]Nonan-2-yl)pyrimidin-5-yl)oxy)benzamide

[0759]

[0760] Intermediate 5 (428 mg) was added to dry tetrahydrofuran (20 mL), sodium hydride (48 mg) was added under ice bath conditions, and the mixture was stirred for 0.5 hours. Propylbromine (131 mg) was added dropwise, and after the addition was complete, the mixture was slowly brought to room temperature and stirred for 2 hours. The solvent was removed by concentration under reduced pressure. Ethyl acetate (30 mL) was added to the residue, and the residue was washed successively with water and saturated brine. The residue was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (dichloromethane / methanol, 15:1) to obtain the target compound (410 mg). MS m / z [LC-MS]: 466.26 [M+1].

[0761] Intermediate 69: (1S,4S)-5-((4-bromophenyl)sulfonyll)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[0762]

[0763] (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (396 mg) was added to pyridine (10 mL), and 4-bromobenzenesulfonyl chloride (613 mg) was added under ice bath. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The solvent was removed by concentration under reduced pressure. Ethyl acetate (30 mL) was added to the residue, and the mixture was washed successively with 1 mol / L dilute hydrochloric acid, water, and saturated brine. The residue was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 3:1) to obtain the target compound (790 mg). MS m / z [LC-MS]: 417.05 [M+1].

[0764] Intermediate 70: (S)-2-((4-(3-((2,7-diazaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl) Pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[0765]

[0766] Step 1: 7-((benzyloxy)carbonyl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester

[0767] Following the method in step 1 of intermediate 55, tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate was used instead of tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, and benzyl chloroformate was used instead of ethylsulfonyl chloride to obtain the target compound. MS m / z [LC-MS]: 361.21 [M+1].

[0768] Step 2: 2,7-diazaspiro[3.5]nonane-7-carboxylic acid benzyl ester hydrochloride

[0769] Following the method in step 2 of intermediate 55, the target compound was obtained by replacing 4-(ethanesulfonamide methyl)piperidine-1-carboxylic acid tert-butyl ester with 7-((benzyloxy)carbonyl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 261.16 [M+1].

[0770] Step 3: (S)-2-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid benzyl ester

[0771] Following the method in step 3 of intermediate 55, the target compound was obtained by replacing N-(piperidin-4-ylmethyl)ethanesulfonamide hydrochloride with 2,7-diazaspiro[3.5]nonane-7-carboxylic acid benzyl ester hydrochloride. MS m / z [LC-MS]: 444.28 [M+1].

[0772] Step 4: (R)-(2-(pyrrolidone-3-ylmethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid benzyl ester hydrochloride

[0773] Following the method in step 4 of intermediate 55, the target compound was obtained by replacing (S)-3-((4-(ethanesulfonamide methyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester with (S)-2-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid benzyl ester. MS m / z [LC-MS]: 344.23 [M+1].

[0774] Step 5: (S)-(2-((1-(5-(2-(diisopropylaminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid benzyl ester

[0775] Following the method in Example 36, intermediate 1 was replaced with intermediate 26, and intermediate 29 was replaced with (R)-(2-(pyrrolidone-3-ylmethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid benzyl ester hydrochloride) to obtain the target compound. MS m / z [LC-MS]: 659.37 [M+1].

[0776] Step 6: (S)-2-((4-(3-((2,7-diazaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[0777] Following the method in step 6 of intermediate 66, the target compound was obtained by replacing (S)-(2-((1-(5-(2-(diisopropylaminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-7-yl)carbamate with (S)-(2-((1-(5-(2-(diisopropylaminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)-2-diazaspiro[3.5]nonane-7-yl)carbamate. MS m / z [LC-MS]: 525.33 [M+1].

[0778] Intermediate 71: 2-(chlorosulfonyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester

[0779]

[0780] 453 mg of 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester and 404 mg of triethylamine were added to 10 mL of dichloromethane. Sulfonyl chloride (297 mg) was added dropwise under ice bath conditions. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction solution was washed successively with 1 mol / L dilute hydrochloric acid, water, and saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 4:1) to obtain the target compound (550 mg). MS m / z [LC-MS]: 325.10 [M+1].

[0781] Intermediate 72: 5-(chlorosulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester

[0782]

[0783] Following the method described in Intermediate 71, the target compound was obtained by replacing 2,7-diazaspiro[3,4-c]pyrrolo-2(1H)-carboxylic acid tert-butyl ester with hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 311.09 [M+1].

[0784] Intermediate 73: 7-(chlorosulfonyl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester

[0785]

[0786] Following the method described in Intermediate 71, the target compound was obtained by replacing 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester with 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 325.10 [M+1].

[0787] Intermediate 74: 7-(chlorosulfonyl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester

[0788]

[0789] Following the method described in Intermediate 71, the target compound was obtained by replacing 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester with 1,4-diazacycloheptan-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 299.09 [M+1].

[0790] Intermediate 75: (S)-5-Fluoro-N,N-Diisopropyl-2-((4-(3-((9-oxo-3-azaspiro[5.5]undecane- 3-yl)methyl)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)benzamide

[0791]

[0792] Step 1: (S)-3-((9-oxo-3-azaspiro[5.5]undecane-3-)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0793] 3-azaspiro[5.5]undecane-9-one hydrochloride (611 mg), (R)-3-((((methanesulfonyl)oxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (840 mg), and potassium carbonate (1242 mg) were added to acetonitrile (30 mL), heated to 80 °C and refluxed for 6 hours. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (dichloromethane / methanol, 20:1) to obtain the target compound (530 mg). MS m / z [LC-MS]: 351.27 [M+1].

[0794] Step 2: (R)-3-(pyrrolidine-3-ylmethyl)-3-azaspiro[5.5]undecane-9-one hydrochloride

[0795] Following the method in step 4 of intermediate 55, (S)-3-((9-oxo-3-azaspiro[5.5]undecane-3-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester was substituted for (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain the target compound. MS m / z [LC-MS]: 251.21 [M+1].

[0796] Step 3: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-oxo-3-azaspiro[5.5]undecane-3-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)benzamide

[0797] Following the method in Example 36, intermediate 1 was replaced with intermediate 26, and intermediate 29 was replaced with (R)-3-(pyrrolidine-3-ylmethyl)-3-azaspiro[5.5]undecane-9-one hydrochloride to obtain the target compound. MS m / z [LC-MS]: 566.35 [M+1].

[0798] Intermediate 76: (S)-2-((4-(3-((9-amino-3-azaspiro[5.5]undecane-3-yl)methyl)pyrrolidine- 1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[0799]

[0800] Following the method described in Example 92, ammonium acetate was used instead of 2,2,2-trifluoroethylamine to obtain the target compound. MSm / z [LC-MS]: 567.38 [M+1].

[0801] Intermediate 77: (R)-N-(2-(pyrrolidone-3-ylmethyl)-2-azaspiro[4.5]decane-8-yl)ethanesulfonamide salt Salt

[0802]

[0803] Step 1: 8-(ethanesulfonamido)-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester

[0804] Following the method in step 1 of intermediate 55, the target compound was obtained by replacing 4-(aminomethyl)piperidine-1-carboxylic acid tert-butyl ester with 8-amino-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 347.20 [M+1].

[0805] Step 2: N-(2-azaspiro[4.5]decane-8-yl)ethanesulfonamide hydrochloride

[0806] Following the method in step 2 of intermediate 55, tert-butyl 8-(ethanesulfonamido)-2-azaspiro[4.5]decane-2-carboxylic acid was substituted for tert-butyl 4-(ethanesulfonamidomethyl)piperidine-1-carboxylic acid to obtain the target compound. MS m / z [LC-MS]: 247.15 [M+1].

[0807] Step 3: (S)-3-((8-(ethanesulfonamido)-2-azaspiro[4.5]decane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0808] Following the method in step 3 of intermediate 55, N-(2-azaspiro[4.5]decane-8-yl)ethanesulfonamide hydrochloride was substituted for N-(piperidin-4-ylmethyl)ethanesulfonamide hydrochloride to obtain the target compound. MS m / z [LC-MS]: 430.28 [M+1].

[0809] Step 4: (R)-N-(2-(pyrrolidone-3-ylmethyl)-2-azaspiro[4.5]decane-8-yl)ethanesulfonamide hydrochloride

[0810] Following the method in step 4 of intermediate 55, the target compound was obtained by replacing (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester with (S)-3-((8-(ethanesulfonamido)-2-azaspiro[4.5]decane-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 330.22 [M+1].

[0811] Intermediate 78: (R)-N-(3-(pyrrolidine-3-ylmethyl)-3-azaspiro[5.5]undecane-9-yl)ethanesulfonamide hydrochloride

[0812]

[0813] Step 1: 9-(ethanesulfonamido)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester

[0814] Following the method in step 1 of intermediate 55, the target compound was obtained by replacing 4-(aminomethyl)piperidine-1-carboxylic acid tert-butyl ester with 9-amino-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 361.22 [M+1].

[0815] Step 2: N-(3-azaspiro[5.5]undecane-9-yl)ethanesulfonamide hydrochloride

[0816] Following the method in step 2 of intermediate 55, 4-(ethanesulfonamido)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester was substituted for 4-(ethanesulfonamidomethyl)piperidine-1-carboxylic acid tert-butyl ester to obtain the target compound. MS m / z [LC-MS]: 261.17 [M+1].

[0817] Step 3: (S)-3-((9-(ethanesulfonamido)-3-azaspiro[5.5]undecane-3-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0818] Following the method in step 3 of intermediate 55, the target compound was obtained by replacing N-(piperidin-4-ylmethyl)ethanesulfonamide hydrochloride with N-(3-azaspiro[5.5]undecane-9-yl)ethanesulfonamide hydrochloride. MS m / z [LC-MS]: 444.29 [M+1].

[0819] Step 4: (R)-N-(3-(pyrrolidine-3-ylmethyl)-3-azaspiro[5.5]undecane-9-yl)ethanesulfonamide hydrochloride

[0820] Following the method in step 4 of intermediate 55, the target compound was obtained by replacing (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester with (S)-3-((9-(ethanesulfonamido)-3-azaspiro[5.5]undecane-3-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 344.24 [M+1].

[0821] Intermediate 79: (S)-2-((4-(3-((3,9-diazaspiro[5.5]undecane-3-yl)methyl)pyrrolidine-1- (5-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[0822]

[0823] Step 1: 3-Benzyl9-(tert-butyl)3,9-diazaspiro[5.5]undecane-3,9-dicarboxylic acid ester

[0824] Following the method in step 1 of intermediate 55, the target compound was obtained by replacing 4-(aminomethyl)piperidine-1-carboxylic acid tert-butyl ester with 3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester and benzyl chloroformate with ethylsulfonyl chloride. MS m / z [LC-MS]: 389.25 [M+1].

[0825] Step 2: 3,9-diazaspiro[5.5]undecane-3-carboxylic acid benzyl ester hydrochloride

[0826] Following the method in step 2 of intermediate 55, the target compound was obtained by replacing 4-(ethanesulfonamide methyl)piperidine-1-carboxylic acid tert-butyl ester with 3-benzyl9-(tert-butyl)3,9-diazaspiro[5.5]undecane-3,9-dicarboxylic acid ester. MS m / z [LC-MS]: 289.19 [M+1].

[0827] Step 3: (S)-9-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)methyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid benzyl ester

[0828] Following the method in step 3 of intermediate 55, the target compound was obtained by replacing N-(piperidin-4-ylmethyl)ethanesulfonamide hydrochloride with 3,9-diazaspiro[5.5]undecane-3-carboxylic acid benzyl ester hydrochloride. MS m / z [LC-MS]: 472.32 [M+1].

[0829] Step 4: (R)-9-(pyrrolidine-3-ylmethyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid benzyl ester hydrochloride

[0830] Following the method in step 4 of intermediate 55, the target compound was obtained by replacing (S)-3-((4-(ethanesulfonamide methyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester with (S)-9-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)methyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid benzyl ester. MS m / z [LC-MS]: 372.27 [M+1].

[0831] Step 5: (S)-9-((1-(5-(2-(diisopropylaminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid benzyl ester

[0832] Following the method in Example 36, intermediate 1 was replaced with intermediate 26, and intermediate 29 was replaced with (R)-9-(pyrrolidine-3-ylmethyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid benzyl ester hydrochloride to obtain the target compound. MS m / z [LC-MS]: 687.41 [M+1].

[0833] Step 6: (S)-2-((4-(3-((3,9-diazaspiro[5.5]undecane-3-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[0834] Following the method in step 6 of intermediate 66, the target compound was obtained by replacing (S)-(2-((1-(5-(2-(diisopropylaminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid benzyl ester. MS m / z [LC-MS]: 553.37 [M+1].

[0835] Intermediate 80: (R)-N-((3-(pyrrolidine-3-ylmethyl)-3-azaspiro[5.5]undecane-9-yl)methyl)ethyl sulfonamide hydrochloride

[0836]

[0837] Step 1: 9-(ethanesulfonamide methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester

[0838] Following the method in step 1 of intermediate 55, tert-butyl 9-(aminomethyl)-3-azaspiro[5.5]undecane-3-carboxylic acid was substituted for tert-butyl 4-(aminomethyl)piperidine-1-carboxylic acid to obtain the target compound. MS m / z [LC-MS]: 375.23 [M+1].

[0839] Step 2: N-((3-azaspiro[5.5]undecane-9-yl)methyl)ethanesulfonamide hydrochloride

[0840] Following the method in step 2 of intermediate 55, 4-(ethanesulfonamide methyl)piperidine-1-carboxylic acid tert-butyl ester was replaced with 9-(ethanesulfonamide methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester to obtain the target compound. MS m / z [LC-MS]: 275.18 [M+1].

[0841] Step 3: (S)-3-((9-(ethanesulfonamidomethyl)-3-azaspiro[5.5]undecane-3-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0842] Following the method in step 3 of intermediate 55, the target compound was obtained using N-((3-azaspiro[5.5]undecane-9-yl)methyl)ethanesulfonamide hydrochloride. MS m / z [LC-MS]: 458.31 [M+1].

[0843] Step 4: (R)-N-((3-(pyrrolidine-3-ylmethyl)-3-azaspiro[5.5]undecane-9-yl)methyl)ethanesulfonamide hydrochloride

[0844] Following the method in step 4 of intermediate 55, the target compound was obtained by replacing (S)-3-((4-((ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester with (S)-3-((9-(ethanesulfonamidomethyl)-3-azaspiro[5.5]undecane-3-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 358.25 [M+1].

[0845] Intermediate 81: (R)-N-(ethanesulfonyl)-3-(pyrrolidine-3-ylmethyl)-3-azaspiro[5.5]undecane-9- Formamide hydrochloride

[0846]

[0847] Step 1: 9-(chloroformyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester

[0848] 1.50 g of 3-(tert-butoxycarbonyl)-3-azaspiro[5.5]undecane-9-carboxylic acid and 1 drop of N,N-dimethylformamide were dissolved in 15 mL of dichloromethane. Oxaloyl chloride (1.27 g) was added dropwise under ice bath cooling. After the addition was complete, the mixture was slowly heated to room temperature and stirred for 2 hours. The solvent and oxaloyl chloride were removed by concentration under reduced pressure to obtain the target compound (1.60 g), which was used directly in the next step.

[0849] Step 2: 9-((ethanesulfonyl)carbamoyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester

[0850] 790 mg of 9-(chloroformyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester, ethanesulfonamide (545 mg), triethylamine (758 mg), and 4-dimethylaminopyridine (61 mg) were added to dichloromethane (15 mL) and stirred at room temperature for 6 hours. The reaction solution was washed successively with 1 mol / L dilute hydrochloric acid, water, and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 3:1) to obtain the target compound (580 mg). MS m / z [LC-MS]: 389.21 [M+1].

[0851] Step 3: N-(ethanesulfonyl)-3-azaspiro[5.5]undecane-9-carboxamide hydrochloride

[0852] Following the method in step 2 of intermediate 55, the target compound was obtained by replacing 4-(ethanesulfonamide methyl)piperidine-1-carboxylic acid tert-butyl ester with 9-(ethanesulfonamide methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 289.16 [M+1].

[0853] Step 4: (S)-3-((9-((ethanesulfonyl)carbamoyl)-3-azaspiro[5.5]undecane-3-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0854] Following the method in step 3 of intermediate 55, the target compound was obtained using N-(ethanesulfonyl)-3-azaspiro[5.5]undecane-9-carboxamide hydrochloride. MS m / z [LC-MS]: 472.29 [M+1].

[0855] Step 5: (R)-N-(ethanesulfonyl)-3-(pyrrolidine-3-ylmethyl)-3-azaspiro[5.5]undecane-9-carboxamide hydrochloride

[0856] Following the method in step 4 of intermediate 55, the target compound was obtained by replacing (S)-3-((9-(((ethanesulfonyl)carbamoyl)-3-azaspiro[5.5]undecane-3-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester with (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 372.23 [M+1].

[0857] Intermediate 82: 2-((4-(7-((4-aminocyclohexyl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)pyrimidine (Pyridine-5-yl)oxy-5-fluoro-N,N-diisopropylbenzamide hydrochloride

[0858]

[0859] 2-((4-(2,7-diazaspiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide was synthesized using the same intermediate as described in Example 6A of Patent WO2017214367.

[0860] Step 1: (4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)cyclohexyl)tert-butyl carbamate

[0861] Following the method in step 1 of intermediate 63, the target compound was obtained by replacing 1-amino-2-methylprop-2-ol with 2-((4-(2,7-diazaspiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide and 7-oxo-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester with (4-formylcyclohexyl)carbamate. MS m / z [LC-MS]: 653.42 [M+1].

[0862] Step 2: 2-((4-(7-((4-aminocyclohexyl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride

[0863] Following the method in step 2 of intermediate 55, the target compound was obtained by replacing 4-(ethanesulfonamide methyl)piperidine-1-carboxylic acid tert-butyl ester with (4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)cyclohexyl)carbamate tert-butyl ester. MS m / z [LC-MS]: 553.37 [M+1].

[0864] Intermediate 83: N-Ethyl-5-fluoro-N-isopropyl-2-((4-(7-(piperidin-4-ylmethyl)-2,7-diazaspiro) [3.5]Nonane-2-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

[0865]

[0866] Step 1: 4-((2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester

[0867] Following the method in step 1 of intermediate 63, 1-amino-2-methylprop-2-ol was replaced with intermediate 5, and tert-butyl 4-formylpiperidin-1-carboxylate was replaced with tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylic acid to obtain the target compound. MS m / z [LC-MS]: 625.39 [M+1].

[0868] Step 2: N-Ethyl-5-fluoro-N-isopropyl-2-((4-(7-(piperidin-4-ylmethyl)-2,7-diazaspiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

[0869] Following the method in step 2 of intermediate 55, the target compound was obtained by replacing 4-(ethanesulfonamide methyl)piperidine-1-carboxylic acid tert-butyl ester with 4-((2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 525.34 [M+1].

[0870] Intermediate 84: 6-(chlorosulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0871]

[0872] The target compound was obtained from tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate, following the method described in intermediate 71. MS m / z [LC-MS]: 297.07 [M+1].

[0873] Intermediate 85: 3-(chlorosulfonyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0874]

[0875] The target compound was obtained from tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate, following the method described in intermediate 71. MS m / z [LC-MS]: 311.08 [M+1].

[0876] Intermediate 86: (S)-4-(chlorosulfonyl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

[0877]

[0878] The target compound was obtained from (S)-3-methylpiperazine-1-carboxylic acid tert-butyl ester, following the method described in intermediate 71. MS m / z [LC-MS]: 299.08 [M+1].

[0879] Intermediate 87: (S)-4-(chlorosulfonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester

[0880]

[0881] The target compound was obtained from (S)-2-methylpiperazine-1-carboxylic acid tert-butyl ester, following the method described in intermediate 71. MS m / z [LC-MS]: 299.08 [M+1].

[0882] Intermediate 88: (3aR,6aS)-5-(chlorosulfonyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-tert-butyl carboxylate

[0883]

[0884] The target compound was obtained from (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester, following the method described in intermediate 71. MS m / z [LC-MS]: 311.08 [M+1].

[0885] Intermediate 89: (S)-2-((5-(3-((2,7-diazaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)- 1,2,4-Triazine-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[0886]

[0887] Step 1: (S)-2-((1-(3,6-dichloro-1,2,4-triazin-5-yl)pyrrolidine-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid benzyl ester

[0888] Following the method in step 1 of Example 82, the target compound was obtained using the product of step 4 in intermediate 70 as a starting material. MS m / z [LC-MS]: 491.17 [M+1].

[0889] Step 2: (S)-2-((1-(3-chloro-6-(2-(diisopropylaminoformyl)-4-fluorophenoxy)-1,2,4-triazine-5-yl)pyrrolidine-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid benzyl ester

[0890] Following the method in step 2 of Example 82, the target compound was obtained from (S)-2-((1-(3,6-dichloro-1,2,4-triazine-5-yl)pyrrolidine-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid benzyl ester. MS m / z [LC-MS]: 694.33 [M+1].

[0891] Step 3: (S)-2-((5-(3-((2,7-diazaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[0892] Following the method in step 3 of Example 82, the target compound was obtained from (S)-2-((1-(3-chloro-6-(2-(diisopropylaminoformyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)pyrrolidine-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid benzyl ester. MS m / z [LC-MS]: 526.33 [M+1].

[0893] Intermediate 90: (R)-1-(pyrrolidone-3-ylmethyl)-3'-(trifluoromethyl)-5',6'-dihydro-8'H-spirop[piperazine] Pyridine-4,7'-[1,2,4]triazolo[4,3-a]pyridine]hydrochloride

[0894]

[0895] Step 1: tert-butyl 8-thio-3,9-diazaspiro[5.5]undecane-3-carboxylate

[0896] 268 mg of tert-butyl 8-oxo-3,9-diazaspiro[5.5]undecane-3-carboxylate and Lawson's reagent (424 mg) were added to toluene (10 mL), stirred overnight at 100 °C, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether / ethyl acetate, 3:1-1:1) to obtain the target compound (255 mg). MS m / z [LC-MS]: 285.16 [M+1].

[0897] Step 2: 3'-(trifluoromethyl)-5',6'-dihydro-8'H-spiro[piperidine-4,7'-[1,2,4]triazolo[4,3-a]pyridine]-1-carboxylic acid tert-butyl ester

[0898] 250 mg of tert-butyl 8-thio-3,9-diazaspiro[5.5]undecane-3-carboxylate, 460 mg of trifluoroacetylhydrazine, 630 mg of mercuric acetate, and 10 mL of tetrahydrofuran were added to a sealed tube and stirred at 80 °C for two days. The mixture was then filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (dichloromethane / methanol, 100:1) to obtain the target compound. MS m / z [LC-MS]: 361.18 [M+1].

[0899] Step 3: 3'-(trifluoromethyl)-5',6'-dihydro-8'H-spiro[piperidine-4,7'-[1,2,4]triazolo[4,3-a]pyridine] hydrochloride

[0900] Following the method in step 2 of intermediate 55, the target compound was obtained from tert-butyl 3'-(trifluoromethyl)-5',6'-dihydro-8'H-spiro[piperidine-4,7'-[1,2,4]triazolo[4,3-a]pyridine]-1-carboxylate. MS m / z [LC-MS]: 261.13 [M+1].

[0901] Step 4: (S)-3-((3'-(trifluoromethyl)-5',6'-dihydro-8'H-spiro[piperidine-4,7'-[1,2,4]triazolo[4,3-a]pyridin]-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0902] Following the method in step 3 of intermediate 55, the target compound was obtained from 3'-(trifluoromethyl)-5',6'-dihydro-8'H-spiro[piperidine-4,7'-[1,2,4]triazolo[4,3-a]pyridine] hydrochloride. MS m / z [LC-MS]: 444.26 [M+1].

[0903] Step 5: (R)-1-(pyrrolidine-3-ylmethyl)-3'-(trifluoromethyl)-5',6'-dihydro-8'H-spiro[piperidine-4,7'-[1,2,4]triazolo[4,3-a]pyridine] hydrochloride

[0904] Following the method in step 4 of intermediate 55, the target compound was obtained from (S)-3-((3'-(trifluoromethyl)-5',6'-dihydro-8'H-spiro[piperidin-4,7'-[1,2,4]triazolo[4,3-a]pyridin]-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 344.21 [M+1].

[0905] Intermediate 91: 9-(chlorosulfonyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester

[0906]

[0907] The target compound was obtained from tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate as a starting material, following the method described in intermediate 71. MS m / z [LC-MS]: 353.13 [M+1].

[0908] Intermediate 92: (R)-(3-(pyrrolidine-3-ylmethyl)-3-azaspiro[5.5]undecane-9-yl)benzyl carbamate Ester hydrochloride

[0909]

[0910] Step 1: 9-(((benzyloxy)carbonyl)amino)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester

[0911] Following the method in step 1 of intermediate 55, the target compound was obtained from tert-butyl 9-amino-3-azaspiro[5.5]undecane-3-carboxylate and benzyl chloroformate. MS m / z [LC-MS]: 403.26 [M+1].

[0912] Step 2: (3-azaspiro[5.5]undecane-9-yl)carbamate hydrochloride

[0913] Following the method in step 2 of intermediate 55, the target compound was obtained from tert-butyl 9-(((benzyloxy)carbonyl)amino)-3-azaspiro[5.5]undecane-3-carboxylate. MS m / z [LC-MS]: 303.21 [M+1].

[0914] Step 3: (S)-3-((9-(((benzyloxy)carbonyl)amino)-3-azaspiro[5.5]undecane-3-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0915] Following the method in step 3 of intermediate 55, the target compound was obtained from (3-azaspiro[5.5]undecane-9-yl)carbamate hydrochloride. MS m / z [LC-MS]: 486.33 [M+1].

[0916] Step 4: (R)-(3-(pyrrolidine-3-ylmethyl)-3-azaspiro[5.5]undecane-9-yl)carbamate hydrochloride

[0917] Following the method in step 4 of intermediate 55, the target compound was obtained from (S)-3-((9-((((benzyloxy)carbonyl)amino)-3-azaspiro[5.5]undecane-3-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 386.28 [M+1].

[0918] Intermediate 93: (S)-2-((5-(3-((9-amino-3-azaspiro[5.5]undecane-3-yl)methyl)pyrrolidine- 1-yl)-1,2,4-triazine-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[0919]

[0920] Step 1: (S)-(3-((1-(3,6-dichloro-1,2,4-triazin-5-yl)pyrrolidine-3-yl)methyl)-3-azaspiro[5.5]undecane-9-yl)benzyl carbamate

[0921] Following the method in step 1 of Example 82, the target compound was obtained using intermediate 92 as the starting material. MS m / z [LC-MS]: 533.22 [M+1].

[0922] Step 2: (S)-(3-((1-(3-chloro-6-(2-(diisopropylaminoformyl)-4-fluorophenoxy)-1,2,4-triazine-5-yl)pyrrolidine-3-yl)methyl)-3-azaspiro[5.5]undecane-9-yl)benzyl carbamate

[0923] Following the method in step 2 of Example 82, the target compound was obtained from (S)-(3-((1-(3,6-dichloro-1,2,4-triazin-5-yl)pyrrolidine-3-yl)methyl)-3-azaspiro[5.5]undecane-9-yl)carbamate. MS m / z [LC-MS]: 736.38 [M+1].

[0924] Step 3: (S)-2-((5-(3-((9-amino-3-azaspiro[5.5]undecane-3-yl)methyl)pyrrolidine-1-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[0925] Following the method in step 3 of Example 82, the target compound was obtained from (S)-(3-((1-(3-chloro-6-(2-(diisopropylaminoformyl)-4-fluorophenoxy)-1,2,4-triazine-5-yl)pyrrolidine-3-yl)methyl)-3-azaspiro[5.5]undecane-9-yl)carbamate. MS m / z [LC-MS]: 568.38 [M+1].

[0926] Intermediate 94: 5-Fluoro-N,N-Diisopropyl-2-((4-(7-(piperidin-4-ylmethyl)-2,7-diazaspiro[3.5]) Nonane-2-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

[0927]

[0928] Step 1: 4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester

[0929] Following the method in step 1 of intermediate 63, the target compound was obtained from 2-((4-(2,7-diazaspiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide and tert-butyl 4-formylpiperidine-1-carboxylate. MS m / z [LC-MS]: 639.40 [M+1].

[0930] Step 2: 5-Fluoro-N,N-Diisopropyl-2-((4-(7-(piperidin-4-ylmethyl)-2,7-diazaspiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

[0931] Following the method in step 2 of intermediate 55, the target compound was obtained from tert-butyl 4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)piperidine-1-carboxylate. MS m / z [LC-MS]: 539.35 [M+1].

[0932] Intermediate 95: (1-(chlorosulfonyl)piperidin-4-yl)tert-butyl carbamate

[0933]

[0934] The target compound was obtained from piperidine-4-ylcarbamate tert-butyl ester using the method described in intermediate 71. MS m / z [LC-MS]: 299.08 [M+1].

[0935] Intermediate 96: (R)-(1-(chlorosulfonyl)piperidin-3-yl)tert-butyl carbamate

[0936]

[0937] The target compound was obtained from (R)-piperidin-3-ylcarbamate tert-butyl ester using the method described in intermediate 71. MS m / z [LC-MS]: 299.08 [M+1].

[0938] Intermediate 97: (S)-2-((4-(3-((9-amino-3-azaspiro[5.5]undecane-3-yl)methyl)pyrrolidine- 1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0939]

[0940] Step 1: (S)-(3-((1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)-3-azaspiro[5.5]undecane-9-yl)benzyl carbamate

[0941] The target compound was obtained using intermediate 92 as a starting material, following the method described in Example 36. MS m / z [LC-MS]: 687.40 [M+1].

[0942] Step 2: (S)-2-((4-(3-((9-amino-3-azaspiro[5.5]undecane-3-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0943] Following the method in step 6 of intermediate 66, the target compound was obtained from (S)-(3-((1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)-3-azaspiro[5.5]undecane-9-yl)carbamate. MS m / z [LC-MS]: 553.37 [M+1].

[0944] Intermediate 98: (1-(chlorosulfonyl)azacyclobutane-3-yl)tert-butyl carbamate

[0945]

[0946] The target compound was obtained from tert-butyl aziridine-3-ylcarbamate as a starting material, following the method described in intermediate 71. MS m / z [LC-MS]: 271.05 [M+1].

[0947] Intermediate 99: (R)-(1-(chlorosulfonyl)pyrrolidone-3-yl)tert-butyl carbamate

[0948]

[0949] The target compound was obtained from (R)-pyrrolidine-3-ylcarbamate tert-butyl ester, following the method described in intermediate 71. MS m / z [LC-MS]: 285.07 [M+1].

[0950] Intermediate 100: 4-((2,7-diazaspiro[3.5]nonane-7-yl)methyl)piperidine-1-carboxylic acid benzyl ester hydrochloride

[0951]

[0952] Step 1: 7-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester

[0953] The target compound was obtained from 4-formylpiperidine-1-carboxylic acid benzyl ester and 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester, following the method in step 1 of intermediate 35. MS m / z [LC-MS]: 458.30 [M+1].

[0954] Step 2: 4-((2,7-diazaspiro[3.5]nonane-7-yl)methyl)piperidine-1-carboxylic acid benzyl ester hydrochloride

[0955] Following the method in step 2 of intermediate 35, the target compound was obtained from tert-butyl 7-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate. MS m / z [LC-MS]: 358.25 [M+1].

[0956] Intermediate 101: 5-Fluoro-N,N-Diisopropyl-2-((5-(7-(piperidin-4-ylmethyl)-2,7-diazaspiro) [3.5]Nonane-2-yl)-1,2,4-triazine-6-yl)oxy)benzamide

[0957]

[0958] Step 1: 4-((2-(3,6-dichloro-1,2,4-triazin-5-yl)pyrrolidine-3-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)piperidine-1-carboxylic acid benzyl ester

[0959] Following the method in step 1 of Example 82, the target compound was obtained using intermediate 100 as the starting material. MS m / z [LC-MS]: 505.19 [M+1].

[0960] Step 2: 4-((2-(3-chloro-6-(2-(diisopropylaminoformyl)-4-fluorophenoxy)-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)piperidine-1-carboxylic acid benzyl ester

[0961] Following the method in step 2 of Example 82, the target compound was obtained from benzyl 4-((2-(3,6-dichloro-1,2,4-triazine-5-yl)pyrrolidine-3-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)piperidine-1-carboxylic acid. MS m / z [LC-MS]: 708.34 [M+1].

[0962] Step 3: 5-Fluoro-N,N-Diisopropyl-2-((5-(7-(piperidin-4-ylmethyl)-2,7-diazaspiro[3.5]nonane-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide

[0963] Following the method in step 3 of Example 82, the target compound was obtained from benzyl 4-((2-(3-chloro-6-(2-(diisopropylaminoformyl)-4-fluorophenoxy)-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)piperidine-1-carboxylic acid ester. MS m / z [LC-MS]: 540.35 [M+1].

[0964] Intermediate 102: (S)-5-Fluoro-N,N-Diisopropyl-2-((4-(7-(pyrrolid-3-ylmethyl)-2,7-diaza) Spiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

[0965]

[0966] Step 1: (R)-3-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0967] Following the method in step 1 of intermediate 63, the target compound was obtained from 2-((4-(2,7-diazaspiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide and (S)-3-carboxypyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 625.39 [M+1].

[0968] Step 2: (S)-5-fluoro-N,N-diisopropyl-2-((4-(7-(pyrrolidine-3-ylmethyl)-2,7-diazaspiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

[0969] Following the method in step 2 of intermediate 55, the target compound was obtained from (R)-3-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 525.34 [M+1].

[0970] Intermediate 103: (R)-5-Fluoro-N,N-Diisopropyl-2-((4-(7-(pyrrolid-3-ylmethyl)-2,7-diaza) Spiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

[0971]

[0972] Step 1: (S)-3-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0973] Following the method in step 1 of intermediate 63, the target compound was obtained from 2-((4-(2,7-diazaspiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide. MS m / z [LC-MS]: 625.39 [M+1].

[0974] Step 2: (R)-5-fluoro-N,N-diisopropyl-2-((4-(7-(pyrrolidine-3-ylmethyl)-2,7-diazaspiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

[0975] Following the method in step 2 of intermediate 55, the target compound was obtained from (S)-3-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 525.34 [M+1].

[0976] Intermediate 104: 4-((4-(bromomethyl)phenyl)sulfonyl)-1,4-diazacycloheptan-1-carboxylic acid tert-butyl ester

[0977]

[0978] Following the method described in Intermediate 71, the target compound was obtained from tert-butyl 1,4-diazacycloheptan-1-carboxylate and 4-(bromomethyl)benzenesulfonyl chloride. MS m / z [LC-MS]: 433.08 [M+1].

[0979] Intermediate 105: (R)-(1-((4-(bromomethyl)phenyl)sulfonyl)piperidin-3-yl)tert-butyl carbamate

[0980]

[0981] Following the method described in intermediate 71, the target compound was obtained from (R)-piperidin-3-ylcarbamate tert-butyl ester and 4-(bromomethyl)benzenesulfonyl chloride. MS m / z [LC-MS]: 433.08 [M+1].

[0982] Intermediate 106: (1S,4S)-5-((4-(bromomethyl)phenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane tert-butyl alkyl-2-carboxylic acid

[0983]

[0984] Following the method described in Intermediate 71, the target compound was obtained from (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester and 4-(bromomethyl)benzenesulfonyl chloride. MS m / z [LC-MS]: 431.06 [M+1].

[0985] Intermediate 107: (1R,5R)-3-(chlorosulfonyl)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylic acid tert-butyl ester

[0986]

[0987] Following the method described in Intermediate 71, the target compound was obtained from (1S,5R)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 297.07 [M+1].

[0988] Intermediate 108: 5-Fluoro-N,N-Diisopropyl-2-((4-(7-((1,2,3,6-tetrahydropyridin-4-yl)methyl)-2, 7-Diazaspiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

[0989]

[0990] Step 1: 4-(((methanesulfonyl)oxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0991] 426 mg of 4-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester and 774 mg of diisopropylethylamine were added to 10 mL of dichloromethane. The mixture was cooled to -5 °C in an ice-salt bath, and a solution of 620 mg of trifluoromethanesulfonic anhydride in 5 mL of dichloromethane was slowly added dropwise. After the addition was complete, the mixture was stirred at -5 °C to 0 °C for 1 hour. The reaction solution was washed successively with 0.5 mol / L dilute hydrochloric acid, saturated sodium bicarbonate solution, and saturated brine. After concentration under reduced pressure, the solution was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 4:1) to obtain the target compound (495 mg). MS m / z [LC-MS]: 292.12 [M+1].

[0992] Step 2: 4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0993] 4-(((methanesulfonyl)oxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (437 mg), 2-((4-(2,7-diazaspiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide (660 mg) and potassium carbonate (620 mg) were added to acetonitrile (10 mL), stirred at 60 °C for 4 hours, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (dichloromethane / methanol, 15:1) to obtain the target compound (763 mg). MS m / z [LC-MS]: 637.39 [M+1].

[0994] Step 3: 5-Fluoro-N,N-Diisopropyl-2-((4-(7-((1,2,3,6-tetrahydropyridin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

[0995] Following the method in step 2 of intermediate 55, the target compound was obtained from 4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 537.34 [M+1].

[0996] Intermediate 109: (R)-5-Fluoro-N,N-Diisopropyl-2-((4-(7-(pyrrolid-3-ylmethyl)-2,7-diaza) Spiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

[0997]

[0998] Step 1: 4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester

[0999] Following the method in step 1 of intermediate 63, the target compound was obtained from 2-((4-(2,7-diazaspiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide and 4-fluoro-4-formylpiperidin-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 657.39 [M+1].

[1000] Step 2: 5-Fluoro-2-((4-(7-((4-fluoropiperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide hydrochloride

[1001] Following the method in step 2 of intermediate 55, the target compound was obtained from 4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 557.34 [M+1].

[1002] Intermediate 110: 2-((5-(2,7-diazaspiro[3.5]nonane-2-yl)-1,2,4-triazine-6-yl)oxy)-5- Fluoro-N,N-diisopropylbenzamide

[1003]

[1004] Step 1: 2-(3,6-dichloro-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid benzyl ester

[1005] Following the method in step 1 of Example 82, the target compound was obtained from benzyl 2,7-diazaspiro[3.5]nonane-7-carboxylate. MS m / z [LC-MS]: 408.10 [M+1].

[1006] Step 2: 2-(3-chloro-6-(2-(diisopropylaminoformyl)-4-fluorophenoxy)-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid benzyl ester

[1007] Following the method in step 2 of Example 82, the target compound was obtained from 2-(3,6-dichloro-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid benzyl ester. MS m / z [LC-MS]: 611.25 [M+1].

[1008] Step 3: 2-((5-(2,7-diazaspiro[3.5]nonane-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1009] Following the method in step 3 of Example 82, the target compound was obtained from 2-(3-chloro-6-(2-(diisopropylaminoformyl)-4-fluorophenoxy)-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid benzyl ester. MS m / z [LC-MS]: 443.26 [M+1].

[1010] Intermediate 111: (R)-5-Fluoro-N,N-Diisopropyl-2-((5-(7-(pyrrolid-3-ylmethyl)-2,7-diaza) Spiro[3.5]nonane-2-yl)-1,2,4-triazine-6-yl)oxy)benzamide hydrochloride

[1011]

[1012] Step 1: (S)-3-((2-(6-(2-(diisopropylaminoformyl)-4-fluorophenoxy)-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[1013] Following the method in step 1 of intermediate 63, the target compound was obtained from intermediate 110 and (R)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 626.38 [M+1].

[1014] Step 2: (R)-5-fluoro-N,N-diisopropyl-2-((5-(7-(pyrrolidin-3-ylmethyl)-2,7-diazaspiro[3.5]nonane-2-yl)-1,2,4-triazine-6-yl)oxy)benzamide hydrochloride

[1015] Following the method in step 2 of intermediate 55, the target compound was obtained from (S)-3-((2-(6-(2-(diisopropylaminoformyl)-4-fluorophenoxy)-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 526.33 [M+1].

[1016] Intermediate 112: (S)-5-Fluoro-N,N-Diisopropyl-2-((5-(7-(pyrrolid-3-ylmethyl)-2,7-diaza) Spiro[3.5]nonane-2-yl)-1,2,4-triazine-6-yl)oxy)benzamide hydrochloride

[1017]

[1018] Step 1: (R)-3-((2-(6-(2-(diisopropylaminoformyl)-4-fluorophenoxy)-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[1019] Following the method in step 1 of intermediate 63, the target compound was obtained from intermediate 110 and (S)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 626.38 [M+1].

[1020] Step 2: (S)-5-fluoro-N,N-diisopropyl-2-((5-(7-(pyrrolidin-3-ylmethyl)-2,7-diazaspiro[3.5]nonane-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide hydrochloride

[1021] Following the method in step 2 of intermediate 55, the target compound was obtained from (R)-3-((2-(6-(2-(diisopropylaminoformyl)-4-fluorophenoxy)-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 526.33 [M+1].

[1022] Intermediate 113: (1S,5S)-3-(chlorosulfonyl)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylic acid tert-butyl ester

[1023]

[1024] Following the method described in Intermediate 71, the target compound was obtained from (1R,5S)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 297.07 [M+1].

[1025] Intermediate 114: (S)-5-Fluoro-N,N-Diisopropyl-2-((4-(7-(pyrrolid-3-ylmethyl)-2,7-diaza) Spiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

[1026]

[1027] Step 1: (R)-3-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[1028] Following the method in step 1 of intermediate 63, the target compound was obtained from 2-((4-(2,7-diazaspiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide and (S)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 625.39 [M+1].

[1029] Step 2: (S)-5-fluoro-N,N-diisopropyl-2-((4-(7-(pyrrolidine-3-ylmethyl)-2,7-diazaspiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

[1030] Following the method in step 2 of intermediate 55, the target compound was obtained from (R)-3-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 525.34 [M+1].

[1031] Intermediate 115: 5-Fluoro-N,N-Diisopropyl-2-((5-(7-((1,2,3,6-tetrahydropyridin-4-yl)methyl)-2, 7-Diazaspiro[3.5]nonane-2-yl)-1,2,4-triazine-6-yl)oxy)benzamide hydrochloride

[1032]

[1033] Step 1: 4-((2-(6-(2-(diisopropylaminoformyl)-4-fluorophenoxy)-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[1034] Following the method in step 1 of intermediate 108, the target compound was obtained from intermediate 110 and 4-(((methanesulfonyl)oxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 638.38 [M+1].

[1035] Step 2: 5-Fluoro-N,N-Diisopropyl-2-((5-(7-((1,2,3,6-tetrahydropyridin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide hydrochloride

[1036] Following the method in step 2 of intermediate 55, the target compound was obtained from 4-((2-(6-(2-(diisopropylaminoformyl)-4-fluorophenoxy)-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 538.33 [M+1].

[1037] Intermediate 116: 5-Fluoro-2-((4-(7-((4-fluoropiperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane- 2-yl)-1,2,4-triazine-6-yl)oxy)benzamide hydrochloride

[1038]

[1039] Step 1: 4-((2-(6-(2-(diisopropylaminoformyl)-4-fluorophenoxy)-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester

[1040] Following the method in step 1 of intermediate 63, the target compound was obtained from intermediate 110 and tert-butyl 4-fluoro-4-formylpiperidine-1-carboxylate. MS m / z [LC-MS]: 658.39 [M+1].

[1041] Step 2: 5-Fluoro-2-((4-(7-((4-fluoropiperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide hydrochloride

[1042] Following the method in step 2 of intermediate 55, the target compound was obtained from 4-((2-(6-(2-(diisopropylaminoformyl)-4-fluorophenoxy)-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 558.34 [M+1].

[1043] Intermediate 117: (S)-2-((5-(3-((7-amino-2-diazaspiro[3.5]nonane-2-yl)methyl)pyrrolidine- 1-yl)-1,2,4-triazine-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[1044]

[1045] Step 1: (S)-(2-((1-(3,6-dichloro-1,2,4-triazin-5-yl)pyrrolidine-3-yl)methyl)-2-diazaspiro[3,5]nonane-7-yl)carbamate

[1046] Following the method in step 1 of Example 82, the target compound was obtained from (R)-(2-(pyrrolidone-3-ylmethyl)-2-azaspiro[3.5]nonane-7-yl)carbamate hydrochloride and 3,5,6-trichloro-1,2,4-triazine. MS m / z [LC-MS]: 505.19 [M+1].

[1047] Step 2: (S)-(2-((1-(3-chloro-6-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)-1,2,4-triazine-5-yl)pyrrolidine-3-yl)methyl)-2-diazaspiro[3.5]nonane-7-yl)carbamate

[1048] Following the method in step 2 of Example 82, the target compound was obtained using (S)-(2-((1-(3,6-dichloro-1,2,4-triazine-5-yl)pyrrolidine-3-yl)methyl)-2-diazaspiro[3.5]nonane-7-yl)carbamate and N-ethyl-5-fluoro-2-hydroxy-N-isopropylbenzamide as raw materials. MS m / z [LC-MS]: 694.33 [M+1].

[1049] Step 3: (S)-2-((5-(3-((7-amino-2-diazaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[1050] Following the method in step 3 of Example 82, the target compound was obtained from (S)-(2-((1-(3-chloro-6-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)pyrrolidine-3-yl)methyl)-2-diazaspiro[3.5]nonane-7-yl)carbamate. MS m / z [LC-MS]: 526.33 [M+1].

[1051] Example 1: N-Ethyl-5-fluoro-N-isopropyl-2-((4-(7-((trans-4-((2-methoxy-3,4-dioxocyclohexane) But-1-en-1-yl)amino)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)benzyl amide

[1052]

[1053] Step 1: ((trans-4-((2-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)cyclohexyl)tert-butyl carbamate

[1054] Intermediate 5 (214 mg), tert-butyl 4-formylcyclohexylcarbamate (136 mg), and tetraethyl titanate (138 mg) were added to 1,2-dichloroethane (10 mL) and stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (212 mg) was added and stirred at room temperature overnight. The reaction was quenched with saturated sodium bicarbonate solution, filtered, and the filtrate was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (dichloromethane / methanol, 20:1) to obtain ((trans-4-((2-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)cyclohexyl)carbamate (190 mg). MS m / z[LC-MS]:639.41[M+1].

[1055] Step 2: 2-((4-(7-((trans-4-aminocyclohexyl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[1056] 190 mg of ((trans-4-((2-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)cyclohexyl)tert-butyl carbamate was added to 5 mL of 4N hydrogen chloride methanol solution and stirred at room temperature for 2 hours. After concentration under reduced pressure, the pH was adjusted to 11-12 with 10% sodium hydroxide solution. The solution was extracted with a 4:1 mixture of dichloromethane and isopropanol. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 140 mg of 2-((4-(7-((trans-4-aminocyclohexyl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide. MS m / z[LC-MS]:539.35[M+1].

[1057] Step 3: N-ethyl-5-fluoro-N-isopropyl-2-((4-(7-((trans-4-((2-methoxy-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)benzamide

[1058] 2-((4-(7-((trans-4-aminocyclohexyl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (54 mg), 3,4-dimethoxycyclobut-3-ene-1,2-dione (28 mg) and diisopropylethylamine (26 mg) were added to ethanol (2 mL) and stirred at 80 °C for 6 hours. The mixture was then poured into water (20 mL) and diluted with ethyl acetate (3 × 10 mL). Extraction was performed, the organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. N-ethyl-5-fluoro-N-isopropyl-2-((4-(7-((trans-4-((2-methoxy-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)benzamide (30 mg) was obtained by silica gel column chromatography (dichloromethane / methanol, 15:1). MS m / z [LC-MS]: 649.35 [M+1]. 1H NMR (400MHz, DMSO-d6): δ = 8.79 (d, J = 8.4Hz, 0.6H), 8.59 (d, J = 8.4Hz, 0.4H), 8.23 ​​(s, 0.6H), 8.22 (s ,0.4H),7.69(s,0.6H),7.63(s,0.4H),7.19-7.29(m,2H),6.98-7.04(m,1H),4.26(s,1.8H),4.24(s ,1.2H),3.66-3.87(m,5H),3.08-3.39(m,3H),2.08-2.26(m,3H),1.95-2.00(m,2H),1.70-1.85(m, 4H),1.60-1.68(m,3H),1.12-1.44(m,6H),1.03-1.10(m,5H),0.93-1.10(m,3H),0.77-0.89(m,2H).

[1059] Example 2: N-Ethyl-5-fluoro-N-isopropyl-2-((4-(7-((trans-4-((2-methylamino-3,4-dioxocyclohexane) But-1-en-1-yl)amino)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)benzyl amide

[1060]

[1061] Following the method in step 3 of Example 1, 3-methoxy-4-(methylamino)cyclobut-3-ene-1,2-dione was used instead of 3,4-dimethoxycyclobut-3-ene-1,2-dione, and the reaction was carried out at 100°C for 6 hours to obtain the target compound. MS m / z [LC-MS]: 648.37 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ = 8.24 (s, 0.7H), 8.23 ​​(s, 0.3H), 7.72-8.12 (br, 2H), 7. 69(s,0.7H),7.63(s,0.3H),7.20-7.29(m,2H),6.99-7.08(m,1H),3.56-3.96(m, 6H),3.30-3.40(m,1H),3.14-3.22(m,1H),3.08(d,J=5.2Hz,3H),2.62-2.96(m,2 H),1.40-2.08(m,10H),1.11-1.31(m,6H),1.04-1.07(m,5H),0.94-1.01(m,5H).

[1062] Example 3: N-Ethyl-5-fluoro-N-isopropyl-2-((4-((1-((trans-4-((2-methoxy-3,4-dioxocyclohexane) But-1-en-1-yl)amino)cyclohexyl)methyl)piperidin-4-yl)amino)pyrimidin-5-yl)oxy)benzamide

[1063]

[1064] Step 1: 4-((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[1065] Intermediate 1 (675 mg), 4-aminopiperidine-1-carboxylic acid tert-butyl ester (600 mg), and diisopropylethylamine (774 mg) were added to isopropanol (10 mL) and stirred at 80 °C for 18 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether / ethyl acetate, 1:2) to obtain 4-((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (900 mg). MS m / z [LC-MS]: 502.29 [M+1].

[1066] Step 2: N-Ethyl-5-fluoro-N-isopropyl-2-((4-(piperidin-4-ylamino)pyrimidin-5-yl)oxy)benzamide

[1067] 900 mg of 4-((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)piperidine-1-carboxylic acid tert-butyl ester was added to 10 mL of 4N hydrogen chloride methanol solution and stirred at room temperature for 2 hours. After concentration under reduced pressure, the pH was adjusted to 11-12 with 10% sodium hydroxide solution. The solution was extracted with a 4:1 mixture of dichloromethane and isopropanol. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 650 mg of N-ethyl-5-fluoro-N-isopropyl-2-((4-(piperidine-4-ylamino)pyrimidin-5-yl)oxy)benzamide. MS m / z [LC-MS]: 402.23 [M+1].

[1068] Step 3: (trans-4-((4-((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)piperidin-1-yl)methyl)cyclohexyl)tert-butyl carbamate

[1069] N-ethyl-5-fluoro-N-isopropyl-2-((4-(piperidin-4-ylamino)pyrimidin-5-yl)oxy)benzamide (201 mg), tert-butyl 4-formylcyclohexylcarbamate (136 mg), and tetraethyl titanate (138 mg) were added to 1,2-dichloroethane (10 mL) and stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (212 mg) was added, and the mixture was stirred overnight at room temperature. Finally, saturated sodium triacetoxyborohydride was added. The reaction was quenched with sodium bicarbonate solution, filtered, and the filtrate was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (dichloromethane / methanol, 20:1) to obtain (trans-4-((4-((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)piperidin-1-yl)methyl)cyclohexyl)tert-butyl carbamate (160 mg). MS m / z [LC-MS]: 613.39 [M+1].

[1070] Step 4: 2-((4-((1-((trans-4-aminocyclohexyl)methyl)piperidin-4-yl)amino)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[1071] 160 mg of (trans-4-((4-(((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)piperidin-1-yl)methyl)cyclohexyl)tert-butyl carbamate was added to 5 mL of 4N hydrogen chloride methanol solution and stirred at room temperature for 2 hours. After concentration under reduced pressure, the pH was adjusted to 11-12 with 10% sodium hydroxide solution. The solution was extracted with a 4:1 mixture of dichloromethane and isopropanol. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 120 mg of 2-((4-((1-((trans-4-aminocyclohexyl)methyl)piperidin-4-yl)amino)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide. MS m / z [LC-MS]: 513.34 [M+1].

[1072] Step 5: N-Ethyl-5-fluoro-N-isopropyl-2-((4-((1-((trans-4-((2-methoxy-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)methyl)piperidin-4-yl)amino)pyrimidin-5-yl)oxy)benzamide

[1073] 2-((4-((1-((trans-4-aminocyclohexyl)methyl)piperidin-4-yl)amino)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (52 mg), 3,4-dimethoxycyclobut-3-ene-1,2-dione (28 mg), and diisopropylethylamine (26 mg) were added to ethanol (2 mL) and stirred at 80 °C for 6 hours. The mixture was then poured into water (20 mL) and diluted with ethyl acetate (3 × 10 mL). Extraction was performed, the organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. N-ethyl-5-fluoro-N-isopropyl-2-((4-((1-((trans-4-((2-methoxy-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)methyl)piperidin-4-yl)amino)pyrimidin-5-yl)oxy)benzamide (26 mg) was obtained by silica gel column chromatography (dichloromethane / methanol, 15:1). MS m / z [LC-MS]: 623.34 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ = 8.78 (d, J = 7.6Hz, 0.6H), 8.58 (d, J = 7.6Hz, 0.4H), 8.25 (s,1H),7.93(s,1H),7.27-7.33(m,1H),7.18-7.23(m,1H),7.04-7.10(m,2H),4. 27(s,1.8H),4.25(s,1.2H),3.66-3.88(m,2H),3.24-3.38(m,1H),2.56-2.78(m, 2H),1.70-2.08(m,10H),1.24-1.66(m,7H),0.98-1.14(m,9H),0.77-0.91(m,2H).

[1074] Example 4: N-Ethyl-5-fluoro-N-isopropyl-2-((4-((1-((trans-4-(methanesulfonyl)cyclohexyl)methyl) (4-yl)piperidine-amino)pyrimidine-5-yl)oxy)benzamide

[1075]

[1076] Intermediate N-ethyl-5-fluoro-N-isopropyl-2-((4-(piperidin-4-ylamino)pyrimidin-5-yl)oxy)benzamide (40 mg), potassium carbonate (40 mg), and potassium iodide (7 mg) were added to a solution of intermediate 2 (43 mg) in N,N-dimethylformamide (2 mL). The mixture was stirred at 80 °C for 4 hours, poured into water (20 mL), and extracted with ethyl acetate (3 × 10 mL). The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was separated by silica gel column chromatography (dichloromethane / methanol, 15:1) to obtain N-ethyl-5-fluoro-N-isopropyl-2-((4-((1-((trans-4-(methanesulfonyl)cyclohexyl)methyl)piperidin-4-yl)amino)pyrimidin-5-yl)oxy)benzamide (35 mg). MS m / z[LC-MS]:591.32[M+1]. 1 H NMR (400MHz, CD3OD): δ = 8.34 (s, 1H), 7.99 (s, 1H), 7.14-7.19 (m, 2H), 7.02-7.08 (m, 1H), 4.22-4.33 (m, 1H), 3 .58-3.69(m,1H),3.42-3.49(m,1H),3.03-3.22(m,2H),2.93(s,3H),1.72-2.36(m,12H),1.08-1.40(m,16H).

[1077] Example 5: N-Ethyl-2-((4-(((1-((trans-4-(ethylsulfonamido)cyclohexyl)methyl)piperidin-4-yl) Methylaminopyrimidin-5-yloxy-5-fluoro-N-isopropylbenzamide

[1078]

[1079] Referring to the method in Example 4, intermediate 6 was used instead of N-ethyl-5-fluoro-N-isopropyl-2-((4-(piperidin-4-ylamino)pyrimidin-5-yl)oxy)benzamide, and intermediate 3 was used instead of intermediate 2 to obtain N-ethyl-2-((4-(((1-((trans-4-(ethylsulfonamido)cyclohexyl)methyl)piperidin-4-yl)methyl)amino)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide. MS m / z [LC-MS]: 619.35 [M+1]. 1 H NMR (400MHz, CDCl3): δ=8.39(s,1H),8.03(s,1H),6.88-7.01(m,3H),3.90-4.06(m,1H),3.13- 3.52(m,5H),3.01(q,J=7.2Hz,2H),2.60-2.90(m,2H),1.40-2.14(m,12H),0.92-1.39(m,20H).

[1080] Example 6: N-Ethyl-5-fluoro-N-isopropyl-2-((4-(((1-((trans-4-((2-methoxy-3,4-dioxo) Cyclobut-1-en-1-yl)amino)cyclohexyl)methyl)piperidin-4-yl)methyl)amino)pyrimidin-5-yl)oxy)benzamide

[1081]

[1082] Step 1: (trans-4-((4-(((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)methyl)cyclohexyl)tert-butyl carbamate

[1083] Referring to the method in step 1 of Example 1, intermediate 5 was replaced with intermediate 6 to obtain (trans-4-((4-(((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)methyl)cyclohexyl)tert-butyl carbamate. MS m / z [LC-MS]: 627.41 [M+1].

[1084] Step 2: 2-((4-(((1-((trans-4-aminocyclohexyl)methyl)piperidin-4-yl)methyl)amino)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[1085] Referring to step 2 of Example 1, (trans-4-((4-(((5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)methyl)cyclohexyl)tert-butyl carbamate was used instead of ((trans-4-((2-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)cyclohexyl)tert-butyl carbamate to obtain 2-((4-(((1-((trans-4-aminocyclohexyl)methyl)piperidin-4-yl)methyl)amino)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide. MS m / z [LC-MS]: 527.35 [M+1].

[1086] Step 3: N-Ethyl-5-fluoro-N-isopropyl-2-((4-(((1-((trans-4-((2-methoxy-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)methyl)piperidin-4-yl)methyl)amino)pyrimidin-5-yl)oxy)benzamide

[1087] Referring to step 3 of Example 1, 2-((4-(((1-((trans-4-aminocyclohexyl)methyl)piperidin-4-yl)methyl)amino)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide was substituted for 2-((4-(7-(((trans-4-aminocyclohexyl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide to obtain N-ethyl-5-fluoro-N-isopropyl-2-((4-(((1-((trans-4-((2-methoxy-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)methyl)piperidin-4-yl)methyl)amino)pyrimidin-5-yl)oxy)benzamide. MSm / z[LC-MS]:637.35[M+1]. 1 H NMR (400MHz, DMSO-d6): δ = 8.78 (d, J = 7.6Hz, 0.6H), 8.57 (d, J = 7.6Hz, 0.4H), 8.24 (s, 1 H),7.88(s,1H),7.33-7.41(br,1H),7.27-7.30(m,1H),7.18-7.23(m,1H),7.03-7.08( m,1H),4.27(s,1.8H),4.25(s,1.2H),3.10-3.34(m,4H),2.62-2.73(m,2H),1.93-1.9 9(m,2H),1.62-1.86(m,8H),1.39-1.52(m,4H),0.96-1.37(m,13H),0.76-0.88(m,2H).

[1088] Example 7: N-Ethyl-5-fluoro-N-isopropyl-2-((4-((((1R,5S,6S)-3-((trans-4-(methanesulfonamide)) [3.1.0]hexane-6-yl)methyl)amino)pyrimidin-5-yl)oxy)benzamide

[1089]

[1090] Referring to the method in Example 4, intermediate 7 was used instead of N-ethyl-5-fluoro-N-isopropyl-2-((4-(piperidin-4-ylamino)pyrimidin-5-yl)oxy)benzamide to obtain N-ethyl-5-fluoro-N-isopropyl-2-((4-((((1R,5S,6S)-3-((trans-4-(methanesulfonyl)cyclohexyl)methyl)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)amino)pyrimidin-5-yl)oxy)benzamide. MS m / z [LC-MS]: 603.32 [M+1]. 1H NMR (400MHz, CDCl3): δ = 8.08 (s, 2H), 6.94-7.02 (m, 2H), 6.74-6.79 (m, 1H), 5.22-5.40(br,1H),4.18-4.34(br,1H),3.81-3.88(m,1H),3.31-3.48(m,2 H),3.16-3.30(m,3H),2.96(s,3H),2.26-2.78(m,3H),1.88-2.12(m,5H),1 .44-1.84(m,6H),1.21-1.26(m,6H),0.94-1.13(m,5H),0.78-0.90(m,2H).

[1091] Example 8: N-Ethyl-5-fluoro-N-isopropyl-2-((4-(((1R,5S,6S)-3-((trans-4-(methanesulfonamide)) Cyclohexyl)methyl)-3-azabicyclo[3.1.0]hexane-6-yl)amino)pyrimidin-5-yl)oxy)benzamide

[1092]

[1093] Referring to the method in Example 4, intermediate 8 was used instead of N-ethyl-5-fluoro-N-isopropyl-2-((4-(piperidin-4-ylamino)pyrimidin-5-yl)oxy)benzamide to obtain N-ethyl-5-fluoro-N-isopropyl-2-((4-(((1R,5S,6S)-3-((trans-4-(methanesulfonyl)cyclohexyl)methyl)-3-azabicyclo[3.1.0]hexane-6-yl)amino)pyrimidin-5-yl)oxy)benzamide. MS m / z [LC-MS]: 589.30 [M+1]. 1 H NMR (400MHz, CDCl3): δ=8.45(s,1H),8.06(s,1H),7.12-7.41(br,1H),6.83-6.99(m,3H),4.55-4.76(m,1H),3.88-3.95(m,1H), 3.45-3.54(m,1H),3.14-3.39(m,3H),2.95(s,3H),2.34-2.75(m,3H),1.46-2.10(m,8H),1.18-1.33(m,10H),0.92-1.17(m,5H).

[1094] Example 9: N-Ethyl-5-fluoro-N-isopropyl-2-((4-(3-(((((trans-4-(methanesulfonyl)cyclohexyl)methyl) (1-yl)amino)methyl)azacyclobutane-1-yl)pyrimidin-5-yl)oxy)benzamide

[1095]

[1096] Intermediate 9 (97 mg), intermediate 4 (66 mg), and tetraethyl titanate (70 mg) were added to 1,2-dichloroethane (5 mL) and stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (106 mg) was added, and the mixture was stirred overnight at room temperature. The reaction was quenched with saturated sodium bicarbonate solution, filtered, and the filtrate was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (dichloromethane / methanol, 15:1) to give N-ethyl-5-fluoro-N-isopropyl-2-((4-(3-(((((trans-4-(methanesulfonyl)cyclohexyl)methyl)amino)methyl)azacyclobutane-1-yl)pyrimidin-5-yl)oxy)benzamide (55 mg). MS m / z [LC-MS]: 577.30 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=8.42-8.60(s,1H),7.86(s,1H),7.26-7.35(m,2H),7.13-7.20(m,1H),6.98(d,J=7.6Hz,1H),4.24-4.50(m,3H),4.02 -4.17(m,2H),2.96-3.24(m,5H),2.88(s,3H),2.66-2.75(m,2H),1.86- 1.93(m,2H),1.72-1.80(m,2H),1.38-1.61(m,3H),0.92-1.22(m,13H).

[1097] Example 10: N-Ethyl-5-fluoro-N-isopropyl-2-((4-(3-(((((trans-4-(methanesulfonyl)cyclohexyl)methyl) (1-yl)amino)methyl)azacyclobutane-1-yl)pyrimidin-5-yl)oxy)benzamide

[1098]

[1099] Referring to the method in Example 9, intermediate 9 was replaced with N-ethyl-5-fluoro-N-isopropyl-2-((4-(3-((((trans-4-(methanesulfonyl)cyclohexyl)methyl)amino)methyl)azacyclobutane-1-yl)pyrimidin-5-yl)oxy)benzamide to obtain N-ethyl-5-fluoro-N-isopropyl-2-((4-(3-((methyl((trans-4-(methanesulfonyl)cyclohexyl)methyl)amino)methyl)azacyclobutane-1-yl)pyrimidin-5-yl)oxy)benzamide. MS m / z [LC-MS]: 591.32 [M+1]. 1H NMR (400MHz, CDCl3): δ=8.42(s,1H),7.85(s,1H),6.95-7.03(m,2H),6.62-6.71(m,1H),4.20-4.48(m,3H),3 .76-4.06(m,2H),3.15-3.54(m,4H),2.97(s,3H),2.56-2.90(m,3H),1.92-2.16(m,7H),0.88-1.80(m,16H).

[1100] Example 11: N-Ethyl-5-fluoro-N-isopropyl-2-((4-(4-((((trans-4-(methanesulfonyl)cyclohexyl)methyl) (I)amino)piperidin-1-yl)pyrimidin-5-yl)oxy)benzamide

[1101]

[1102] Referring to the method in Example 9, intermediate 10 was used instead of intermediate 9 to obtain N-ethyl-5-fluoro-N-isopropyl-2-((4-(4-(((trans-4-(methanesulfonyl)cyclohexyl)methyl)amino)piperidin-1-yl)pyrimidin-5-yl)oxy)benzamide. MS m / z [LC-MS]: 591.32 [M+1].

[1103] Example 12: N-Ethyl-5-fluoro-N-isopropyl-2-((4-((R)-3-(((trans-4-(methanesulfonamide)cyclohexane) 1-yl)methyl)amino)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)benzamide

[1104]

[1105] Referring to the method in Example 9, intermediate 11 was used instead of intermediate 9 to obtain N-ethyl-5-fluoro-N-isopropyl-2-((4-((R)-3-(((trans-4-(methanesulfonyl)cyclohexyl)methyl)amino)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)benzamide. MS m / z [LC-MS]: 577.30 [M+1]. 1 H NMR (400MHz, CD3OD): δ=8.47(s,1H),8.01(s,1H),7.15-7.25(m,2H),6.88-7.04(m,1H),4.50-4.57(m,1H),3.89-3.98(m,1H),3.68-3.81(m ,1H),3.39-3.64(m,2H),3.12-3.23(m,1H),2.85-3.07(m,5H),2.41-2 .52(m,2H),1.84-2.22(m,8H),1.50-1.74(m,3H),1.08-1.38(m,10H).

[1106] Example 13: N-Ethyl-5-fluoro-N-isopropyl-2-((4-(3-(((trans-4-(methanesulfonyl)cyclohexyl)methyl) (Oxy)methyl)azacyclobutane-1-yl)pyrimidin-5-yl)oxy)benzamide

[1107]

[1108] Referring to the method in Example 4, intermediate 12 was used instead of N-ethyl-5-fluoro-N-isopropyl-2-((4-(piperidin-4-ylamino)pyrimidin-5-yl)oxy)benzamide to obtain N-ethyl-5-fluoro-N-isopropyl-2-((4-(3-(((trans-4-(methanesulfonyl)cyclohexyl)methoxy)methyl)azacyclobutane-1-yl)pyrimidin-5-yl)oxy)benzamide. MS m / z [LC-MS]: 578.28 [M+1]. 1 H NMR (400MHz, CDCl3): δ = 8.38 (s, 1H), 7.37 (s, 1H), 6.96-7.04 (m, 2H), 6.67-6.85 (m ,1H),4.14-4.42(m,3H),3.88-4.07(m,2H),3.80-3.86(m,1H),3.43-3.53(m,2H),3 .27-3.36(m,1H),3.14-3.26(m,3H),2.97(s,3H),2.82-2.93(m,1H),2.01-2.08(m ,2H),1.74-1.82(m,2H),1.42-1.53(m,1H),1.10-1.34(m,11H),0.93-1.09(m,3H).

[1109] Example 14: N-Ethyl-5-fluoro-2-((4-(((4-fluoro-1-((trans-4-(methanesulfonyl)cyclohexyl)methyl) Piperidin-4-yl)methyl)amino)pyrimidin-5-yl)oxy)-N-isopropylbenzamide

[1110]

[1111] Referring to the method in Example 4, intermediate 13 was used instead of N-ethyl-5-fluoro-N-isopropyl-2-((4-(piperidin-4-ylamino)pyrimidin-5-yl)oxy)benzamide to obtain N-ethyl-5-fluoro-2-((4-(((4-fluoro-1-((trans-4-(methanesulfonyl)cyclohexyl)methyl)piperidin-4-yl)methyl)amino)pyrimidin-5-yl)oxy)-N-isopropylbenzamide. MS m / z [LC-MS]: 623.32 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=8.27(s,1H),7.91(m,1H),7.26-7.42(m,2H),7.18-7.25(m,1H),6.92-7.09(m ,2H),3.57-3.81(m,2H),3.10-3.54(m,2H),2.80-3.07(m,5H),1.39-2.12(m,12H),0.76-1.36(m,16H).

[1112] Example 15: N-Ethyl-5-fluoro-N-isopropyl-2-((4-((S)-3-((((cis-4-(methanesulfonyl)cyclohexane) 1-ylpyrrolidone-5-ylpyrimidinyloxybenzamide

[1113] Example 16: N-Ethyl-5-fluoro-N-isopropyl-2-((4-((S)-3-((((trans-4-(methanesulfonyl)cyclohexane) 1-ylpyrrolidone-5-ylpyrimidinyloxybenzamide

[1114]

[1115] Referring to the method in Example 9, intermediate 14 was used instead of intermediate 9. The product was separated by thin-layer silica gel chromatography to obtain a relatively less polar product, N-ethyl-5-fluoro-N-isopropyl-2-((4-((S)-3-((((cis-4-(methanesulfonyl)cyclohexyl)methyl)amino)methyl)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)benzamide. MS m / z [LC-MS]: 591.32 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=8.30-8.34(m,1H),7.80-7.85(m,1H),7.16-7.29(m,2H),6.81-6.93(m,2H),3.69-3.94(m,2H),3.55-3.66(m,1H),3.1 0-3.46(m,4H),2.90-3.01(m,2H),2.88(s,3H),2.73-2.82(m,2H),2.54- 2.65(m,1H),2.02-2.12(m,1H),1.33-1.83(m,11H),0.97-1.22(m,10H).

[1116] Simultaneously, a relatively polar product was obtained: N-ethyl-5-fluoro-N-isopropyl-2-((4-((S)-3-((((trans-4-(methanesulfonyl)cyclohexyl)methyl)amino)methyl)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)benzamide. MS m / z [LC-MS]: 591.32 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=8.30-8.32(m,1H),7.80-7.84(m,1H),7.17-7. 28(m,2H),6.97-7.02(m,1H),6.81-6.91(m,1H),3.68-3.93(m,2H),3.55- 3.67(m,1H),3.10-3.47(m,4H),2.84-2.99(m,5H),2.69-2.78(m,2H),2.5 3-2.62(m,1H),2.01-2.11(m,1H),1.54-1.94(m,6H),0.93-1.21(m,15H).

[1117] Example 17: N-Ethyl-5-fluoro-N-isopropyl-2-((4-(4-(((((trans-4-(methanesulfonyl)cyclohexyl)methyl) (I)amino)methyl)piperidin-1-yl)pyrimidin-5-yl)oxy)benzamide

[1118] Example 18: N-Ethyl-5-fluoro-N-isopropyl-2-((4-(4-((((cis-4-(methanesulfonyl)cyclohexyl)methyl) (I)amino)methyl)piperidin-1-yl)pyrimidin-5-yl)oxy)benzamide

[1119]

[1120] Referring to the method in Example 9, intermediate 15 was used instead of intermediate 9. The product was separated by thin-layer silica gel chromatography to obtain a relatively polar product, N-ethyl-5-fluoro-N-isopropyl-2-((4-(4-(((((trans-4-(methanesulfonyl)cyclohexyl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-5-yl)oxy)benzamide. MS m / z [LC-MS]: 605.33 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ = 8.40 (s, 1H), 7.90 (s, 1H), 7.25-7.30 (m, 1H), 7.16-7.2 1(m,1H),6.91(d,J=6.4Hz,1H),6.77-6.82(m,1H),4.38-4.50(m,2H),3.12-3.42 (m,4H),2.84-2.94(m,5H),2.71-2.80(m,4H),1.87-1.99(m,2H),1.66-1.78(m,3 H),1.56-1.65(m,2H),1.44-1.54(m,4H),1.30-1.42(m,2H),0.96-1.29(m,11H).

[1121] Simultaneously, a product with relatively low polarity was obtained: N-ethyl-5-fluoro-N-isopropyl-2-((4-(4-((((cis-4-(methanesulfonyl)cyclohexyl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-5-yl)oxy)benzamide. MS m / z [LC-MS]: 591.32 [M+1]. 1H NMR (400MHz, DMSO-d6): δ = 8.40 (s, 1H), 17.89 (s, 1H), 17.25-7.30 (m, 1H), 7. 16-7.21(m,1H),6.97(d,J=7.6Hz,1H),6.77-6.82(m,1H),4.38-4.50(m,2H), 3.10-3.42(m,3H),2.97-3.09(m,1H),2.84-2.94(m,5H),2.67-2.78(m,4H), 1.84-1.99(m,4H),1.67-1.78(m,4H),1.38-1.61(m,2H),0.91-1.20(m,14H).

[1122] Example 19: N-Ethyl-5-fluoro-2-((4-(3-fluoro-3-((((trans-4-(methanesulfonyl)cyclohexyl)methyl) (amino)methyl)azacyclobutane-1-yl)pyrimidin-5-yl)oxy)-N-isopropylbenzamide

[1123]

[1124] Referring to the method in Example 9, intermediate 16 was used instead of intermediate 9 to obtain N-ethyl-5-fluoro-2-((4-(3-fluoro-3-((((trans-4-(methanesulfonyl)cyclohexyl)methyl)amino)methyl)azacyclobutane-1-yl)pyrimidin-5-yl)oxy)-N-isopropylbenzamide. MS m / z [LC-MS]: 595.29 [M+1]. 1 H NMR (400MHz, CDCl3): δ=8.41(s,1H),7.85(s,1H),6.97-7.07(m,2H),6.74-6.82(m,1H),4.23-4.64(m,4H),3 .76-3.87(m,1H),3.12-3.53(m,4H),2.95(s,3H),2.69-2.81(m,1H),1.46-2.17(m,9H),1.01-1.36(m,13H).

[1125] Example 20: N-Ethyl-5-fluoro-N-isopropyl-2-((4-((R)-3-((((trans-4-(methanesulfonamide)cyclohexane) 1-ylpyrrolidone-5-ylpyrimidinyloxybenzamide

[1126]

[1127] Referring to the method in Example 9, intermediate 17 was used instead of intermediate 9 to obtain N-ethyl-5-fluoro-N-isopropyl-2-((4-(((R)-3-((((trans-4-(methanesulfonyl)cyclohexyl)methyl)amino)methyl)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)benzamide. MS m / z [LC-MS]: 591.32 [M+1]. 1H NMR (400MHz, CDCl3): δ = 8.51 (s, 1H), 7.95 (s, 1H), 6.87-7.14 (m, 3H), 6.46-6.64 (br,1H),3.06-4.36(m,6H),2.97(s,3H),2.50-2.94(m,2H),0.99-2.28(m,26H).

[1128] Example 21: N-Ethyl-5-fluoro-N-isopropyl-2-((4-(6-(((trans-4-(methanesulfonyl)cyclohexyl)methyl) (3.1.0)hexane-3-yl)pyrimidin-5-yl)oxy)benzamide

[1129] Example 22: N-Ethyl-5-fluoro-N-isopropyl-2-((4-(6-(((cis-4-(methanesulfonyl)cyclohexyl)methyl) (3.1.0)hexane-3-yl)pyrimidin-5-yl)oxy)benzamide

[1130]

[1131] Following the method described in Example 9, intermediate 18 was used instead of intermediate 9. The product was separated by thin-layer silica gel chromatography to obtain a relatively polar product, N-ethyl-5-fluoro-N-isopropyl-2-((4-(6-(((trans-4-(methanesulfonyl)cyclohexyl)methyl)amino)-3-azabicyclo[3.1.0]hexane-3-yl)pyrimidin-5-yl)oxy)benzamide. MS m / z [LC-MS]: 589.30 [M+1]. 1 H NMR (400MHz, CDCl3: δ = 8.37 (s, 1H), 7.80 (s, 1H), 6.98-7.11 (m, 2H), 6.66 -6.74(m,1H),5.12-5.93(br,1H),4.01-4.14(m,2H),3.70-3.84(m,2H),3 .54-3.60(m,1H),3.43-3.52(m,1H),3.10-3.34(m,3H),2.86(s,3H),2.6 8-2.79(m,2H),1.94-2.35(m,8H),1.60-1.84(m,2H),0.98-1.36(m,11H).

[1132] Simultaneously, a product with relatively low polarity was obtained: N-ethyl-5-fluoro-N-isopropyl-2-((4-(6-(((cis-4-(methanesulfonyl)cyclohexyl)methyl)amino)-3-azabicyclo[3.1.0]hexane-3-yl)pyrimidin-5-yl)oxy)benzamide. MS m / z [LC-MS]: 589.30 [M+1]. 1H NMR (400MHz, CDCl3): δ=8.40(s,1H),7.85(s,1H),6.98-7.05(m,2H),6.63-6.72(m,1 H),5.90-6.01(br,1H),4.03-4.16(m,2H),3.81-3.88(m,1H),3.54-3.72(m,3H),3.3 9-3.49(m,1H),3.26-3.37(m,1H),3.10-3.21(m,1H),2.91-3.03(m,5H),2.38-2.41( m,3H),1.95-2.08(m,1H),1.73-1.90(m,3H),1.54-1.70(m,3H),1.01-1.27(m,11H).

[1133] Example 23: N-Ethyl-5-fluoro-N-isopropyl-2-((4-(3-(((trans-4-(methanesulfonyl)cyclohexyl)methyl) (1-yl)amino)azacyclobutane-1-yl)pyrimidin-5-yl)oxy)benzamide

[1134]

[1135] Referring to the method in Example 9, intermediate 19 was used instead of intermediate 9 to obtain N-ethyl-5-fluoro-N-isopropyl-2-((4-(3-(((trans-4-(methanesulfonyl)cyclohexyl)methyl)amino)azacyclobutane-1-yl)pyrimidin-5-yl)oxy)benzamide. MS m / z [LC-MS]: 563.28 [M+1].

[1136] Example 24: N-Ethyl-5-fluoro-N-isopropyl-2-((4-(((4-((trans-4-(methanesulfonyl)cyclohexyl)methyl) (Methyl)morpholino-2-yl)methyl)amino)pyrimidin-5-yl)oxy)benzamide

[1137]

[1138] Referring to the method in Example 4, intermediate 20 was used instead of N-ethyl-5-fluoro-N-isopropyl-2-((4-(piperidin-4-ylamino)pyrimidin-5-yl)oxy)benzamide to obtain N-ethyl-5-fluoro-N-isopropyl-2-((4-(((4-((trans-4-(methanesulfonyl)cyclohexyl)methyl)morpholin-2-yl)methyl)amino)pyrimidin-5-yl)oxy)benzamide. MS m / z [LC-MS]: 607.31 [M+1]. 1H NMR (400MHz, CDCl3): δ = 8.39 (s, 1H), 7.99 (s, 1H), 6.82-7.02 (m, 4H), 4.31 (d, J = 6.4Hz, 1H), 3.86-3.94 (m, 1H), 3.74-3.80 (m, 1H), 3.57-3. 64(m,5H),3.18-3.30(m,2H),2.96(s,3H),2.42-2.78(m,2H),1.94-2 .26(m,5H),1.70-1.92(m,3H),1.09-1.30(m,12H),0.88-1.04(m,2H).

[1139] Example 25: N-Ethyl-5-fluoro-N-isopropyl-2-((4-((S)-3-(((cis-4-(methanesulfonyl)cyclohexane) (methyl)amino ) pyrrolidine-1-yl)pyrimidin-5-yl)oxy)benzamide

[1140] Example 26: N-Ethyl-5-fluoro-N-isopropyl-2-((4-((S)-3-(((trans-4-(methanesulfonamide)cyclohexane) (methyl)amino ) pyrrolidine-1-yl)pyrimidin-5-yl)oxy)benzamide

[1141]

[1142] Referring to the method in Example 9, intermediate 21 was used instead of intermediate 9. The product was separated by thin-layer silica gel chromatography to obtain a relatively less polar product, N-ethyl-5-fluoro-N-isopropyl-2-((4-((S)-3-(((cis-4-(methanesulfonyl)cyclohexyl)methyl)amino)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)benzamide. MS m / z [LC-MS]: 577.30 [M+1]. 1 HNMR (400MHz, DMSO-d6): δ=8.35-8.37(m,1H),7.86-7.91(m,1H),7.16-7.30(m,2H),6.79-6.90(m,2H),3.44- 4.02(m,5H),3.10-3.42(m,4H),2.66-2.92(m,5H),1.84-2.31(m,2H),1.30-1.82(m,8H),0.90-1.28(m,11H).

[1143] The product with relatively high polarity was N-ethyl-5-fluoro-N-isopropyl-2-((4-((S)-3-(((trans-4-(methanesulfonyl)cyclohexyl)methyl)amino)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)benzamide. MS m / z [LC-MS]: 577.30 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=8.36-8.38(m,1H),7.88-7.93(m,1H),7.16-7.30(m,2H),6.98(d,J=7.2Hz,1H),6.78-6.90(m,1H),3.44-4.02(m,5H),3 .12-3.41(m,3H),2.96-3.08(m,1H),2.88(s,3H),2.68-2.85(m,2H),1.9 6-2.28(m,2H),1.74-1.93(m,4H),1.47-1.62(m,2H),0.90-1.30(m,13H).

[1144] Example 27: N-Ethyl-5-fluoro-2-((4-(3-((((1-hydroxy-4-(methanesulfonyl)cyclohexyl)methyl)amino (1-yl)-methyl)azonyl-1-yl)pyrimidin-5-yl)oxy)-N-isopropylbenzamide

[1145]

[1146] Intermediate 9 (97 mg), N-(1-oxaspiro[2.5]octane-6-yl)methanesulfonamide (63 mg), and tetrahydrofuran (1 mL) were added to a sealed tube and reacted at 90 °C for 6 hours with stirring. After cooling to room temperature, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography (dichloromethane / methanol, 15:1) to obtain N-ethyl-5-fluoro-2-((4-(3-((((1-hydroxy-4-(methanesulfonyl)cyclohexyl)methyl)amino)methyl)azacyclobutane-1-yl)pyrimidin-5-yl)oxy)-N-isopropylbenzamide (85 mg). MS m / z [LC-MS]: 593.29 [M+1]. 1 H NMR (400MHz, CD3OD): δ = 8.30 (s, 1H), 7.85 (s, 1H), 7.10-7.24 (m, 2H), 6.86-6.72 (m, 1H), 4.28-4.50 (m ,2H),3.83-4.02(m,3H),3.26-3.55(m,5H),3.10-3.24(m,5H),1.39-1.89(m,7H),1.08-1.26(m,11H).

[1147] Example 28: N-Ethyl-5-fluoro-N-isopropyl-2-((4-(3-methyl-3-((((trans-4-(methanesulfonyl)cyclo) Hexyl)methyl)amino)methyl)azacyclobutane-1-yl)pyrimidin-5-yl)oxy)benzamide

[1148]

[1149] Referring to the method in Example 9, intermediate 22 was used instead of intermediate 9 to obtain N-ethyl-5-fluoro-N-isopropyl-2-((4-(3-methyl-3-((((trans-4-(methanesulfonyl)cyclohexyl)methyl)amino)methyl)azacyclobutane-1-yl)pyrimidin-5-yl)oxy)benzamide. MS m / z [LC-MS]: 591.32 [M+1]. 1 H NMR (400MHz, CDCl3): δ = 8.48 (s, 1H), 7.73 (s, 1H), 6.82-7.12 (m, 3H), 5.14-5.30 (br, 1H), 4.18-4.58 (m, 2H), 3.88-4.10 (m,2H),3.75-3.86(m,2H),3.06-3.50(m,5H),2.94(s,3H),2.74-2.87(m,2H),1.50-2.10(m,10H),1.01-1.40(m,11H).

[1150] Example 29: N-Ethyl-5-fluoro-2-((4-(4-hydroxy-4-((((trans-4-(methanesulfonyl)cyclohexyl)methyl) (B)amino)methyl ) Piperidin-1-yl)pyrimidin-5-yl)oxy)-N-isopropylbenzamide

[1151]

[1152] Referring to the method in Example 9, intermediate 23 was used instead of intermediate 9 to obtain N-ethyl-5-fluoro-2-((4-(4-hydroxy-4-((((trans-4-(methanesulfonyl)cyclohexyl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-N-isopropylbenzamide. MS m / z [LC-MS]: 621.33 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ = 8.40 (s, 1H), 7.89 (s, 1H), 7.25-7.30 (m, 1H), 7.16-7.21 (m, 1H), 6.99 (d, J = 7.2Hz, 1H), 6.80-6.84(m,1H),4.03-4.15(m,2H),3.74-3.80(m,1H),3.10-3.42(m,4H),2.96-3.08(m,2H),2.82-2.95(m,5H), 2.66-2.81(m,2H),1.84-1.92(m,2H),1.69-1.80(m,2H),1.42-1.68(m,6H),0.90-1.28(m,13H).

[1153] Example 30: N-Ethyl-5-fluoro-N-isopropyl-2-((4-(6-(((((trans-4-(methanesulfonyl)cyclohexyl)methyl) [3.1.0]hexane-3-yl)pyrimidin-5-yl)oxy)benzamide

[1154]

[1155] Referring to the method in Example 9, intermediate 24 was used instead of intermediate 9 to obtain N-ethyl-5-fluoro-N-isopropyl-2-((4-(6-((((trans-4-(methanesulfonyl)cyclohexyl)methyl)amino)methyl)-3-azabicyclo[3.1.0]hexane-3-yl)pyrimidin-5-yl)oxy)benzamide. MS m / z [LC-MS]: 603.32 [M+1].

[1156] Example 31: N-Ethyl-5-fluoro-N-isopropyl-2-((4-(3-(((((trans-4-(ethanesulfonamido)cyclohexyl)methyl) (1-yl)amino)methyl)azacyclobutane-1-yl)pyrimidin-5-yl)oxy)benzamide

[1157]

[1158] Referring to the method in Example 9, intermediate 4 was replaced with intermediate 25 to obtain N-ethyl-5-fluoro-N-isopropyl-2-((4-(3-((((trans-4-(ethanesulfonamido)cyclohexyl)methyl)amino)methyl)azacyclobutane-1-yl)pyrimidin-5-yl)oxy)benzamide. MS m / z [LC-MS]: 591.32 [M+1]. 1 H NMR (400MHz, CD3OD): δ = 8.31 (s, 1H), 7.73-7.86 (m, 1H), 7.16-7.22 (m, 2H), 6.92-6.99 (m,1H),4.32-4.52(m,1H),3.97-4.16(m,2H),3.85-3.91(m,1H),3.45-3.54(m,2H),3. 22-3.42(m,2H),3.07-3.18(m,2H),3.02(q,J=7.2Hz,2H),2.86-2.95(m,2H),1.98-2.0 6(m,2H),1.82-1.90(m,2H),1.60-1.72(m,2H),1.41-1.52(m,1H),1.07-1.37(m,15H).

[1159] Example 32: N-Ethyl-5-fluoro-N-isopropyl-2-((4-((R)-3-(((trans-4-(methanesulfonamide)cyclohexane) 1-yl)methyl)amino)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)benzamide

[1160]

[1161] Referring to the method in Example 9, intermediate 22 was used instead of intermediate 9, and intermediate 25 was used instead of intermediate 4 to obtain N-ethyl-2-((4-(3-((((trans-4-(ethanesulfonyl)cyclohexyl)methyl)amino)methyl)-3-methylazacyclobutane-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide. MS m / z [LC-MS]: 605.33 [M+1]. 1H NMR (400MHz, CDCl3): δ = 8.45 (s, 1H), 7.78 (s, 1H), 6.98-7.10 (m, 2H), 6.79-6.96 (m, 1H), 4.93-5.06 (m, 1H), 4.13-4.58 (m, 3H), 3.6 8-4.08(m,3H),3.28-3.67(m,2H),3.08-3.26(m,3H),2.75-3.05(m,4H),1.50-2.10(m,9H),1.20-1.39(m,10H),1.02-1.17(m,5H).

[1162] Example 33: N-Ethyl-2-((4-((S)-3-((((trans-4-(ethanesulfonamido)cyclohexyl)methyl)amino)methyl 1-(1-yl)pyrrolidine-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

[1163]

[1164] Referring to the method in Example 9, intermediate 14 was used instead of intermediate 9, and intermediate 25 was used instead of intermediate 4 to obtain N-ethyl-2-((4-((S)-3-((((trans-4-(ethanesulfonamido)cyclohexyl)methyl)amino)methyl)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide. MS m / z [LC-MS]: 605.33 [M+1]. 1 H NMR (400MHz, CDCl3): δ=8.44(s,1H),7.89(s,1H),6.92-7.03(m,2H),6.52-6.64(m,1H),3.98-4.24(m,2H),3.72-3.92(m,2H),3.32-3.70(m,3H) ),3.13-3.28(m,2H),3.02(q,J=7.2Hz,2H),2.42-2.70(m,4H),1.99-2. 11(m,4H),1.48-1.94(m,4H),1.35(t,J=7.2Hz,3H),0.94-1.31(m,14H).

[1165] Example 34: N-Ethyl-5-fluoro-N-isopropyl-2-((4-((((R)-1-(((1r,4R)-4-(methanesulfonamide)) Cyclohexyl)methyl)pyrrolidone-3-yl)methyl)amino)pyrimidin-5-yl)oxy)benzamide

[1166]

[1167] The target compound was obtained using intermediate 27 as a starting material, following the method described in Example 9. MS m / z [LC-MS]: 591.32 [M+1]. 1H NMR (400MHz, CDCl3): δ=8.41(s,1H),8.11(brs,1H),7.55(m,1H),6.85-7.02(m,2H),4.76(m,1H),3.47-3.97( m,5H),3.15-3.41(m,2H),3.10(m,1H),2.96(s,3H),2.45-2.90(m,4H),1.95-2.35(m,4H),1.05-1.40(m,18H).

[1168] Example 35: N-Ethyl-5-fluoro-N-isopropyl-2-((4-((((S)-1-(((1r,4S)-4-(methanesulfonamide)) Cyclohexyl)methyl)pyrrolidone-3-yl)methyl)amino)pyrimidin-5-yl)oxy)benzamide

[1169]

[1170] The target compound was obtained using intermediate 28 as a starting material, following the method described in Example 9. MS m / z [LC-MS]: 591.32 [M+1]. 1 H NMR (400MHz, CDCl3): δ=8.41(s,1H),8.15(brs,1H),7.55(s,1H),6.90-7.02(m,2H),4.61(m,1H),3.47- 3.98(m,5H),3.15-3.40(m,2H),2.96(s,3H),2.45-2.85(m,4H),1.95-2.35(m,5H),0.95-1.35(m,18H).

[1171] Example 36: N-Ethyl-5-fluoro-2-((4-(3-hydroxy-3-(((((1r,4r)-4-(methanesulfonamide)cyclohexane) (1-yl) pyrrolidone-1-yl) pyrimidin-5-yl) oxy)-N-isopropylbenzamide

[1172]

[1173] Intermediate 1 (68 mg), intermediate 29 (61 mg), and diisopropylethylamine (77 mg) were added to isopropanol (3 mL), heated to 80 °C and stirred for 18 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (dichloromethane / methanol, 20:1) to obtain the target compound (84 mg). MS m / z [LC-MS]: 607.31 [M+1].

[1174] Example 37: N-Ethyl-5-fluoro-N-isopropyl-2-((4-((S)-3-(((((1r,4S)-4-(methanesulfonamide)) Cyclohexyl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-5-yl)oxy)benzamide

[1175]

[1176] The target compound was obtained using intermediate 30 as a starting material, following the method described in Example 9. MS m / z [LC-MS]: 605.33 [M+1].1 H NMR (400MHz, CDCl3): δ=9.89-10.06(br,0.4H),9.51-9.70(br,0.6H),9.16-9.36(br,0.6H),8.84- 8.98(br,0.4H),8.46(s,1H),7.89(s,1H),7.03-7.16(m,1H),6.88-7.01(m,1.6H),6.60-6.67(m,0 .4H),4.48-4.66(m,1H),4.26-4.44(m,2H),3.82-3.93(m,1H),3.34-3.46(m,2H),3.13-3.30(m,2H ),2.92-3.08(m,4H),2.60-2.84(m,4H),2.26-2.41(m,1H),1.52-2.13(m,12H),1.10-1.32(m,9H).

[1177] Example 38: N-Ethyl-5-fluoro-2-((4-(3-((((1-fluoro-4-(methanesulfonyl)cyclohexyl)methyl)amino (1-yl)-methyl)azonyl-1-yl)pyrimidin-5-yl)oxy)-N-isopropylbenzamide

[1178]

[1179] The target compound was obtained using intermediate 31 as a starting material, following the method described in Example 9. MS m / z [LC-MS]: 595.29 [M+1]. 1 H NMR (400MHz, CDCl3): δ = 8.41 (s, 1H), 7.81 (s, 1H), 6.94-7.08 (m, 2H), 6.64-6.79 (m, 1H), 6.43-6.52 (m, 1H), 4.24-4.72(m,3H),3.58-4.15(m,4H),3.03-3.52(m,6H),2.96(s,3H),1.50-2.38(m,9H),1.02-1.18(m,9H).

[1180] Example 39: N-Ethyl-5-fluoro-N-isopropyl-2-((4-((R)-3-(((((1r,4R)-4-(methanesulfonamide)) Cyclohexyl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-5-yl)oxy)benzamide

[1181]

[1182] The target compound was obtained using intermediate 32 as a starting material, following the method described in Example 9. MS m / z [LC-MS]: 605.33 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=8.36-8.74(m,2H),7.90(s,1H),7.17-7.32(m,2H),7.01(d,J=8.0Hz,1H),6.80-6.86(m,1H),4.45(s,1H),4.08-4.26 (m,2H),3.72-3.81(m,1H),3.10-3.22(m,1H),2.96-3.07(m,2H),2.61- 2.90(m,8H),1.70-1.92(m,6H),1.52-1.65(m,2H),1.03-1.30(m,15H).

[1183] Example 40: N-Ethyl-2-((4-((R)-3-(((((1r,4R)-4-(ethanesulfonamide)cyclohexyl)methyl)amino (3-methylpyrrolidone-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

[1184]

[1185] The target compound was obtained using intermediates 33 and 25 as starting materials, following the method described in Example 9. MS m / z [LC-MS]: 619.35 [M+1]. 1 H NMR (400MHz, CDCl3): δ=8.51(s,1H),7.95(s,1H),6.90-7.13(m,2H),6.51-6.81(m,1H),5.16- 5.59(br,1H),4.28-4.62(br,1H),2.62-3.98(m,14H),1.50-2.18(m,11H),1.02-1.40(m,15H).

[1186] Example 41: N-Ethyl-2-((4-((S)-3-(((((1r,4S)-4-(ethanesulfonamido)cyclohexyl)methyl)amino (3-methylpyrrolidone-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

[1187]

[1188] The target compound was obtained using intermediates 34 and 25 as starting materials, following the method described in Example 9. MS m / z [LC-MS]: 619.35 [M+1]. 1H NMR (400MHz, CDCl3): δ=8.50(s,1H),7.97(s,1H),6.91-7.08(m,2H),6.55-6.75(m,1H),4.74-4.94(m,1H),3.58-3.92(m,2H),3.34- 3.48(m,1H),3.08-3.33(m,2H),3.01(q,J=7.2Hz,2H),2.24-2.94(m,7H),1.88-2.14(m,6H),1.46-1.88(m,5H),0.98-1.42(m,16H).

[1189] Example 42: N-Ethyl-2-((4-(3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl 1-(1-yl)pyrrolidine-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

[1190]

[1191] The target compound was obtained using intermediate 35 as a starting material, following the method described in Example 36. MS m / z [LC-MS]: 617.33 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ = 8.29 (s, 0.6H), 8.28 (s, 0.4H), 7.79 (s, 0.6H), 7. 74(s,0.4H),7.14-7.30(m,2H),6.93(d,J=7.6Hz,1H),6.79-6.89(m,1H),4. 36-4.45(m,1H),3.46-3.82(m,4H),3.07-3.44(m,6H),2.80-3.06(m,5H),2 .08-2.28(m,1H),1.74-2.01(m,4H),1.32-1.73(m,6H),0.96-1.27(m,12H).

[1192] Example 43: N-Ethyl-2-((4-(3-Ethyl-3-(((((1r,4r)-4-(ethanesulfonamide)cyclohexyl)methyl (1-yl)amino)methyl)azacyclobutane-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzoyl

[1193]

[1194] The target compound was obtained using intermediates 36 and 25 as starting materials, following the method described in Example 9. MS m / z [LC-MS]: 619.35 [M+1]. 1H NMR (400MHz, CDCl3): δ=8.35(s,1H),7.76(s,1H),6.95-7.04(m,2H),6.65-6.76(m,1H),4.39(d,J=7.6Hz,1H),3.72-4.05(m,5H),3.40- 3.59(m,2H),3.10-3.36(m,2H),2.95-3.04(m,2H),2.68(m,2H),2.42(m,2H),1.98-2.07(m,2H),1.44-1.84(m,8H),1.10-1.38(m,16H).

[1195] Example 44: N-Ethyl-2-((4-((3R,4S)-3-(((((1r,4R)-4-(ethanesulfonamide)cyclohexyl)methyl (I)amino)methyl)-4-fluoropyrrolidone-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

[1196]

[1197] The target compound was obtained using intermediates 37 and 25 as starting materials, following the method described in Example 9. MS m / z [LC-MS]: 623.32 [M+1]. 1 H NMR (400MHz, CDCl3): δ = 8.50 (s, 0.5H), 8.46 (s, 0.5H), 7.89-7.97 (m, 1H), 6.93-7.10 (m, 2H), 6.49-6.85 (m, 1H), 4.80-5.38 (m, 1H), 4. 24-4.69(m,1H),3.58-4.20(m,4H),3.10-3.52(m,5H),2.96-3.06(m,2H),2.60-2.92(m,3H),1.50-2.16(m,10H),0.99-1.40(m,12H).

[1198] Example 45: N-Ethyl-2-((4-((3S,4S)-3-(((((1r,4S)-4-(ethanesulfonamide)cyclohexyl)methyl (I)amino)methyl)-4-fluoropyrrolidone-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

[1199]

[1200] The target compound was obtained using intermediates 38 and 25 as starting materials, following the method described in Example 9. MS m / z [LC-MS]: 623.32 [M+1]. 1H NMR (400MHz, CDCl3): δ=8.52(s,0.5H),8.40(s,0.5H),7.86-7.99(m,1H),6.94-7.08(m,2H),6.50-6.83(m,1H),4.98-5.62( m,1H),3.54-4.35(m,6H),3.12-3.49(m,4H),2.98-3.10(m,2H),2.63-2.96(m,3H),1.54-2.12(m,10H),0.98-1.40(m,12H).

[1201] Example 46: N-Ethyl-2-((4-((S)-2-(((((1r,4S)-4-(ethanesulfonamide)cyclohexyl)methyl)amino 5-methyl-5-morpholino-5-pyrimidin-5-yl-oxy-5-fluoro-N-isopropylbenzamide

[1202]

[1203] The target compound was obtained using intermediates 39 and 25 as starting materials, following the method described in Example 9. MS m / z [LC-MS]: 621.33 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=8.62-9.26(brs,1H),8.45(s,1H),7.95(s,1H),7.17-7.31(m,2H),6.98-7.06(m,1H),6.83-6.89(m,1H),4.12-4.33( m,2H),3.70-3.80(m,2H),3.40-3.65(m,1H),2.77-3.30(m,10H),2.57- 2.74(m,2H),1.72-1.87(m,4H),1.38-1.66(m,3H),0.88-1.26(m,14H).

[1204] Example 47: 2-((4-((S)-3-(((((1r,4S)-4-(ethanesulfonamide)cyclohexyl)methyl)amino)methyl 1-(1-)pyrrolidine-5-)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1205]

[1206] The target compound was obtained using intermediates 40 and 25 as starting materials, following the method described in Example 9. MS m / z [LC-MS]: 619.35 [M+1]. 1H NMR (400MHz, CDCl3): δ = 8.42 (s, 0.5H), 8.40 (s, 0.5H), 7.86 (s, 1H), 6.90-7.01 (m, 2H), 6. 64-6.68(m,0.5H),6.48-6.53(m,0.5H),4.88-5.07(br,0.5H),4.44(d,7.6Hz,0.5H),4.39 (d,J=7.6Hz,0.5H),3.98-4.12(br,0.5H),3.36-3.88(m,4H),2.72-3.32(m,5H),2.44-2.6 8(m,4H),1.98-2.10(m,3H),1.37-1.94(m,12H),1.34(t,J=7.2Hz,3H),0.92-1.29(m,9H).

[1207] Example 48: 2-((4-(3-(((((1r,4r)-4-(ethanesulfonamide)cyclohexyl)methyl)amino)methyl)-3- Methylazacyclobutane-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1208]

[1209] The target compound was obtained using intermediate 41 and intermediate 25 as starting materials, following the method described in Example 9. MS m / z [LC-MS]: 619.35 [M+1]. 1 H NMR (400MHz, CDCl3): δ=8.25(s,1H),7.76(s,1H),6.92-7.01(m,2H),6.66-6.73(m,1 H),4.26(d,J=8.0Hz,1H),3.97-4.11(m,1H),3.58-3.96(m,6H),3.42-3.52(m,1H),3. 11-3.22(m,1H),3.00(q,J=7.2Hz,2H),2.65-2.70(m,2H),2.42(m,2H),1.96-2.08(m, 2H), 1.74-1.86 (m, 2H), 1.44-1.71 (m, 10H), 1.24-1.37 (m, 6H), 1.11 (d, J = 6.8Hz, 6H).

[1210] Example 49: N-Ethyl-2-((4-(3-((6-(ethanesulfonamido)-2-azaspiro[3.3]heptane-2-yl)methyl (1-yl)azonyl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

[1211]

[1212] The target compound was obtained using intermediate 42 as a starting material, following the method described in Example 36. MS m / z [LC-MS]: 575.28 [M+1]. 1H NMR (400MHz, CD3OD): δ=8.24(s,1H),7.76(s,1H),7.12-7.22(m,2H),6.90- 7.01(m,1H),4.54-4.68(m,1H),4.23-4.41(m,2H),3.82-4.02(m,2H),3.66- 3.75(m,1H),3.22-3.57(m,5H),2.96(q,J=7.2Hz,2H),2.84-2.92(m,2H),2 .72-2.83(m,2H),2.50-2.58(m,2H),2.08-2.18(m,2H),1.06-1.30(m,12H).

[1213] Example 50: (R)-N-ethyl-2-((4-(3-((6-(ethanesulfonamido)-2-azaspiro[3.3]heptane-2-yl) Methylpyrrolidone-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

[1214]

[1215] The target compound was obtained using intermediate 43 as a starting material, following the method described in Example 36. MS m / z [LC-MS]: 589.30 [M+1]. 1 H NMR (400MHz, CD3OD): δ = 8.32 (s, 1H), 7.76 (s, 1H), 7.18-7.20 (m, 2H), 6.77-6.90 (m, 1H), 3.35-4.03 (m, 10H), 3.12-3.32 (m, 1H), 2.96 (q,J=7.6Hz,2H),2.76-2.88(m,2H),2.53-2.63(m,2H),2.25-2.38(m,1H),2.01-2.22(m,3H),1.53-1.67(m,2H),1.08-1.34(m,12H).

[1216] Example 51: (S)-N-ethyl-2-((4-(3-((6-(ethanesulfonamido)-2-azaspiro[3.3]heptane-2-yl) Methylpyrrolidone-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

[1217]

[1218] The target compound was obtained using intermediate 44 as a starting material, following the method described in Example 36. MS m / z [LC-MS]: 589.30 [M+1]. 1H NMR (400MHz, CD3OD): δ = 8.24 (s, 1H), 7.78 (s, 1H), 7.12-7.20 (m, 2H), 6.77-6.90 (m, 1H), 3.10-4.04 (m, 10H), 2.8 2-3.01(m,4H),2.52-2.66(m,2H),2.26-2.40(m,1H),2.04-2.23(m,4H),1.52-1.68(m,2H),1.08-1.36(m,12H).

[1219] Example 52: N-Ethyl-2-((4-(3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl (1-yl)azonyl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

[1220]

[1221] The target compound was obtained using intermediate 45 as a starting material, following the method described in Example 36. MS m / z [LC-MS]: 603.32 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=8.25(s,1H),7.73(s,1H),7.18-7.28(m,2H),6.90-6.98(m,2H),4.34-4.51(m,1H),4.03-4.24(m ,2H),3.67-3.89(m,3H),2.62-3.30(m,11H),1.74-1.86(m,2H),1.61-1.72(m,2H),1.32-1.44(m,2H),0.94-1.24(m,14H).

[1222] Example 53: (S)-N-ethyl-2-((4-(3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonane-2-yl) Methylpyrrolidone-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

[1223]

[1224] The target compound was obtained using intermediate 46 as a starting material, following the method described in Example 36. MS m / z [LC-MS]: 617.33 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=8.29(s,1H),7.79(s,1H),7.16-7.24(m,2H),6.85-6.94(m,2H),4.34-4.48(m,1H),4.03-4.24(m,2H),3.45-3.80( m,4H),2.65-3.20(m,7H),2.16-2.30(m,1H),1.78-1.98(m,3H),1.61- 1.72(m,2H),1.45-1.60(m,1H),1.35-1.45(m,2H),0.95-1.24(m,14H).

[1225] Example 54: (R)-N-ethyl-2-((4-(3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonane-2-yl) Methylpyrrolidone-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

[1226]

[1227] The target compound was obtained using intermediate 47 as a starting material, following the method described in Example 36. MS m / z [LC-MS]: 617.33 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ = 8.30 (s, 1H), 7.81 (s, 1H), 7.16-7.28 (m, 2H), 6.78-7.00 (m, 2H), 4.35-4.50 (m, 1H), 3.45-3.85 (m, 7H), 2. 85-3.20(m,6H),2.22-2.38(m,1H),1.82-2.02(m,3H),1.62-1.74(m,2H),1.50-1.62(m,1H),1.38-1.50(m,2H),0.95-1.25(m,14H).

[1228] Example 55: 2-((4-(3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)aza-heterocycle (butane-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1229]

[1230] The target compound was obtained using intermediates 26 and 45 as starting materials, following the method described in Example 36. MS m / z [LC-MS]: 617.33 [M+1]. 1H NMR (400MHz, CDCl3): δ=8.33(s,1H),7.74(s,1H),6.90-6.97(m,2H),6.60-6.65(m,1H),4.58(d ,J=7.2Hz,1H),4.21-4.33(m,1H),4.11-4.19(m,1H),3.86-3.96(m,1H),3.70-3.80(m,2H),3.4 2-3.50(m,1H),3.11-3.23(m,1H),2.92-3.04(m,6H),2.67(m,3H),1.78-1.92(m,4H),1.59(d,J =6.8Hz,3H),1.39-1.47(m,5H),1.30(t,J=7.2Hz,3H),1.16-1.27(m,2H),1.09(d,J=6.8Hz,6H).

[1231] Example 56: (S)-2-((4-(3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyridine (Pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1232]

[1233] The target compound was obtained using intermediates 26 and 46 as starting materials, following the method described in Example 36. MS m / z [LC-MS]: 631.35 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ = 8.28 (s, 1H), 7.78 (s, 1H), 7.13-7.20 (m, 2H), 6.94 (d, J = 7.6Hz, 1H), 6.8 0-6.88(m,1H),3.10-3.84(m,12H),2.90-3.04(m,3H),2.70-2.88(m,1H),2.17-2.28(m,1H),1.90 -2.00(m,1H),1.78-1.90(m,2H),1.63-1.72(m,2H),1.49-1.61(m,1H),1.35-1.47(m,4H),1.31(d ,J=6.8Hz,3H),1.17-1.26(m,2H),1.14(t,J=7.2Hz,3H),1.06(d,J=6.8Hz,3H),0.98-1.02(m,3H).

[1234] Example 57: (S)-2-((4-(3-((7-(methanesulfonyl)-2-azaspiro[3.5]nonane-2-yl)methyl)pyridine (Pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1235]

[1236] The target compound was obtained using intermediates 26 and 48 as starting materials, following the method described in Example 36. MS m / z [LC-MS]: 617.33 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ = 8.31 (s, 1H), 7.82 (s, 1H), 7.13-7.24 (m, 2H), 6.78-6.97 (m, 2H), 4.38-4.46 (m, 1H), 3.46-3.95 (m, 9H) ,2.90-3.25(m,3H),2.87(s,3H),2.27-2.41(m,1H),1.80-2.05(m,3H),1.40-1.80(m,8H),1.28-1.35(m,3H),0.95-1.25(m,8H).

[1237] Example 58: 2-((4-((S)-3-(((((1r,4S)-4-(methanesulfonamide)cyclohexyl)methyl)amino)methyl 1-(1-)pyrrolidine-5-)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1238]

[1239] The target compound was obtained using intermediate 40 as a starting material, following the method described in Example 9. MS m / z [LC-MS]: 605.33 [M+1]. 1 H NMR (400MHz, CDCl3): δ = 8.47 (s, 0.5H), 8.44 (s, 0.5H), 7.93 (s, 1H), 6.86-7.07 (m, 2.5H) ),6.66-6.73(m,1H),6.43-6.49(m,0.5H),4.84-4.91(m,0.5H),4.72-4.80(m,0.5H),4. 10-4.18(m,0.5H),3.74-3.94(m,1.5H),3.51-3.73(m,2H),3.02-3.51(m,3H),2.82-3. 07(m,4H),2.62-2.81(m,2H),2.43-2.58(m,1H),1.76-2.20(m,6H),1.05-1.66(m,18H).

[1240] Example 59: 2-((4-(3-(((((1r,4r)-4-(methanesulfonamide)cyclohexyl)methyl)amino)methyl)-3- Methylazacyclobutane-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1241]

[1242] The target compound was obtained using intermediate 41 as a starting material, following the method described in Example 9. MS m / z [LC-MS]: 605.33 [M+1]. 1H NMR (400MHz, CDCl3): δ = 8.33 (s, 1H), 7.79 (s, 1H), 6.91-7.00 (m, 2H), 6.63-6.69 (m, 1H), 5.4 4-5.69(m,1H),4.01-4.11(m,1H),3.88-3.98(m,2H),3.68-3.80(m,2H),3.41-3.50(m,1H),3 .04-3.19(m,3H),2.88(s,3H),2.72-2.83(m,1H),1.91-2.02(m,2H),1.76-1.90(m,2H),1.5 1-1.63(m,2H),1.47(d,J=6.8Hz,3H),1.41(d,J=6.8Hz,3H),1.36(s,3H),0.94-1.14(m,9H).

[1243] Example 60: (S)-N-ethyl-5-fluoro-N-isopropyl-2-((4-(3-((7-(methanesulfonyl)-2-azaspiro) [3.5]Nonane-2-yl)methyl)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)benzamide

[1244]

[1245] Referring to the method in Example 36, intermediate 29 was replaced with intermediate 48 to obtain (S)-N-ethyl-5-fluoro-N-isopropyl-2-((4-(3-((7-(methanesulfonyl)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)benzamide. MS m / z [LC-MS]: 603.31 [M+1]. 1 H NMR (400MHz, CDCl3): δ = 8.38-8.41 (m, 1H), 7.79-7.83(m,1H),6.93-7.02(m,2H),6.65-6.70(m,0.5H),6.56-6.60(m,0.5H),4.11-4.18(m,1H),3.77-3.92(m,2H),3.56-3. 72(m,2H),2.90-3.51(m,11H),2.44-2.64(m,2H),2.15-2.28(m,1H),1.82-2.08(m,6H),1.43-1.54(m,3H),1.12-1.26(m,10H).

[1246] Example 61: (R)-5-Fluoro-N,N-Diisopropyl-2-((4-(3-((7-(methanesulfonyl)-2-azaspiro) [3.5]Nonane-2-yl)methyl)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)benzamide

[1247]

[1248] Referring to the method in Example 36, intermediate 1 was replaced with intermediate 26, and intermediate 29 was replaced with intermediate 49, to obtain (R)-5-fluoro-N,N-diisopropyl-2-((4-(3-((7-(methanesulfonyl)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)benzamide. MS m / z [LC-MS]: 617.33 [M+1]. 1 H NMR (400MHz, CDCl3): δ = 8.39 (s, 0.5H), 8.38 (s, 0.5H), 7.79 (s, 1H), 6.91-6.98 (m, 2H), 6.66 (d d,J=9.6Hz,4.4Hz,0.5H),6.59(dd,J=8.8Hz,4.4Hz,0.5H),4.10(d,J=7.6Hz,1H),3.76-3.90( m,2H),3.60-3.74(m,1.5H),3.41-3.54(m,1.5H),3.12-3.40(m,2.5H),2.82-3.05(m,6.5H),2 .38-2.52(m,2H),2.11-2.4(m,1H),1.82-2.06(m,6H),1.43-1.56(m,10H),1.12-1.16(m,6H).

[1249] Example 62: (R)-N-ethyl-2-((4-(3-((7-(methanesulfonyl)-2-azaspiro[3.5]nonane-2-yl) Methylpyrrolidone-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

[1250]

[1251] Referring to the method in Example 36, intermediate 48 was used instead of intermediate 29 to obtain (R)-N-ethyl-2-((4-(3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide. MS m / z [LC-MS]: 603.32 [M+1]. 1H NMR (400MHz, CDCl3): δ=8.39-8.40(m,1H),7.79-7.81(m,1H),6.94-7.02(m,2H),6. 57-6.68(m,1H),4.08-4.15(m,1H),3.78-3.92(m,2H),3.59-3.72(m,1.5H),3.40-3 .53(m,1.5H),3.12-3.38(m,4H),2.83-3.01(m,7H),2.38-2.50(m,2H),2.10-2.23( m,1H),1.94-2.05(m,1H),1.85-1.93(m,4H),1.42-1.53(m,3H),1.06-1.26(m,10H).

[1252] Example 63: (R)-2-((4-(3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyridine (Pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1253]

[1254] Referring to the method in Example 36, intermediate 1 was replaced with intermediate 26 and intermediate 29 was replaced with intermediate 47 to obtain (R)-2-((4-(3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide. MS m / z [LC-MS]: 617.33 [M+1]. 1 H NMR (400MHz, CDCl3): δ = 8.39 (s, 0.5H), 8.38 (s, 0.5H), 7.79 (s, 1H), 6.90-6.98 (m, 2H), 6.66 (dd, J = 10.4Hz, 4.4Hz, 0.5H), 6. 60(dd,J=9.2Hz,4.4Hz,0.5H),3.98(d,J=7.6Hz,1H),3.76-3.90(m,2H),3.58-3.74(m,1.5H),3.41-3.54(m,1.5H),3.30-3.4 0(m,0.5H),3.13-3.28(m,1.5H),2.84-3.04(m,6H),2.38-2.50(m,2H),2.10-2.23(m,1H),1.95-2.05(m,1H),1.81-1.94(m,4 H),1.56-1.66(m,1H),1.53(d,J=6.8Hz,3H),1.41-1.51(m,5H),1.35(t,J=7.2Hz,3H),1.20-1.31(m,2H),1.11-1.16(m,6H).

[1255] Example 64: (S)-5-Fluoro-N,N-Diisopropyl-2-((4-(3-((7-(trifluoromethanesulfonyl)-2-azaspiro) [3.5]Nonane-2-yl)methyl)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)benzamide

[1256]

[1257] Referring to the method in Example 36, intermediate 1 was replaced with intermediate 26 and intermediate 29 was replaced with intermediate 50 to obtain (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((7-(trifluoromethanesulfonyl)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)benzamide. MS m / z [LC-MS]: 671.30 [M+1]. 1 H NMR (400MHz, CDCl3): δ = 8.43 (s, 0.5H), 8.42 (s, 0.5H), 7.84 (s, 0.5H), 7.83 (s,0.5H),6.91-7.04(m,2H),6.68-6.74(m,0.5H),6.52-6.58(m,0.5H),3. 93-4.10(m,1H),3.64-3.89(m,3H),3.36-3.62(m,4H),2.96-3.34(m,3H),2 .63-2.83(m,1H),2.26-2.55(m,2H),1.90-2.18(m,5H),1.10-1.63(m,18H).

[1258] Example 65: 2-((4-((3S)-3-((6-(ethanesulfonamido)-3-azabicyclo[3.1.0]hexane-3-yl)methyl 1-(1-)pyrrolidine-5-)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1259]

[1260] Referring to the method in Example 36, intermediate 1 was replaced with intermediate 26, and intermediate 29 was replaced with intermediate 51, to obtain 2-((4-((3S)-3-((6-(ethanesulfonamido)-3-azabicyclo[3.1.0]hexane-3-yl)methyl)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide. MS m / z [LC-MS]: 589.30 [M+1]. 1H NMR (400MHz, CDCl3): δ = 8.41 (s, 0.5H), 8.40 (s, 0.5H), 7.81 (s, 1H), 6.92-6.99 (m, 2H), 6.45-6.68 (m ,0.5H),6.55-6.64(m,0.5H),4.41-4.58(m,1H),3.76-3.87(m,2H),3.58-3.75(m,2H),3.43-3.55(m ,2H),3.28-3.42(m,1H),2.98-3.23(m,4H),2.68-2.88(m,1H),2.22-2.46(m,4H),1.93-2.09(m,1H) ,1.56-1.68(m,3H),1.51-1.54(m,3H),1.45-1.48(m,3H),1.38(t,J=7.2Hz,3H),1.11-1.18(m,6H).

[1261] Example 66: (S)-2-((4-(3-((7-((N,N-dimethylaminosulfonyl)amino)-2-azaspiro[3.5]nonane- 2-yl)methyl)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1262]

[1263] Referring to the method in Example 36, intermediate 1 was replaced with intermediate 26 and intermediate 29 was replaced with intermediate 52 to obtain (S)-2-((4-(3-((7-((N,N-dimethylaminosulfonyl)amino)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide. MS m / z [LC-MS]: 646.36 [M+1]. 1 HNMR (400MHz, CDCl3): δ = 8.40 (s, 0.5H), 8.39 (s, 0.5H), 7.81 (s, 1H), 6.91-6.99 (m, 2 H),6.65-6.69(m,0.5H),6.57-6.60(m,0.5H),3.76-3.90(m,3H),3.56-3.74(m,1.5H) ,3.40-3.54(m,1.5H),2.88-3.20(m,6H),2.77(s,6H),2.40-2.56(m,2H),2.13-2.28 (m,1H),1.96-2.07(m,1H),1.82-1.95(m,5H),1.42-1.64(m,10H),1.12-1.17(m,6H).

[1264] Example 67: (S)-2-((4-(3-((7-(cyclopropylsulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl 1-(1-)pyrrolidine-5-)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1265]

[1266] Referring to the method in Example 36, intermediate 1 was replaced with intermediate 26 and intermediate 29 was replaced with intermediate 53 to obtain (S)-2-((4-(3-((7-(cyclopropylsulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide. MS m / z [LC-MS]: 643.34 [M+1]. 1 H NMR (400MHz, CDCl3): δ = 8.41 (s, 0.5H), 8.40 (s, 0.5H), 7.82 (s, 1H), 6.91-7.00 (m, 2H) ,6.66-6.71(m,0.5H),6.54-6.69(m,0.5H),4.12(d,J=7.2Hz,1H),3.75-3.96(m,2H), 3.56-3.74(m,2H),2.92-3.54(m,7H),2.46-2.78(m,2H),2.36-2.43(m,1H),2.15-2.3 4(m,1H),1.86-2.12(m,5H),1.44-1.78(m,11H),1.10-1.18(m,8H),0.95-1.01(m,2H).

[1267] Example 68: (S)-2-((4-(3-((7-(ethanesulfonyl)-2,7-diazaspiro[3.5]nonane-2-yl)methyl) Pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1268]

[1269] Referring to the method in Example 36, intermediate 1 was replaced with intermediate 26 and intermediate 29 was replaced with intermediate 54 to obtain (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((7-(propylsulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)benzamide. MS m / z [LC-MS]: 645.36 [M+1]. 1H NMR (400MHz, CDCl3): δ = 8.40 (s, 0.5H), 8.39 (s, 0.5H), 7.80 (s, 1H), 6.91-6.99 (m, 2H), 6.65 -6.68(m,0.5H),6.57-6.60(m,0.5H),4.01-4.08(m,1H),3.75-3.90(m,2H),3.55-3.73(m,1 .5H),3.31-3.54(m,2H),3.13-3.28(m,1.5H),2.88-3.12(m,6H),2.45-2.58(m,2H),2.14-2 .28(m,1H),1.78-2.08(m,9H),1.42-1.64(m,9H),1.10-1.17(m,6H),1.04(t,J=7.6Hz,3H).

[1270] Example 69: (S)-2-((4-(3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-yl) Pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1271]

[1272] Referring to the method in Example 36, intermediate 1 was replaced with intermediate 26, and intermediate 29 was replaced with intermediate 55, to obtain (S)-2-((4-(3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide. MS m / z [LC-MS]: 605.33 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ = 8.29 (s, 1H), 7.70-7.78 (m, 1H), 6.91-7.22 (m, 3H), 6.77 -6.90(m,1H),3.30-4.04(m,6H),3.06-3.25(m,2H),2.68-3.01(m,6H),2.33-2.49( m,1H),2.12-2.28(m,1H),1.71-2.10(m,3H),1.49-1.70(m,3H),1.42(d,J=6.8Hz,3 H),1.22-1.37(m,5H),1.15(t,J=7.6Hz,3H),1.06-1.08(m,3H),0.99-1.03(m,3H).

[1273] Example 70: (S)-2-((4-(3-((7-(cyclopropylsulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl 1-(1-)pyrrolidine-5-)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1274]

[1275] Referring to the method in Example 36, intermediate 1 was replaced with intermediate 26 and intermediate 29 was replaced with intermediate 56 to obtain (S)-2-((4-(3-((7-(ethanesulfonyl)-2,7-diazaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide. MS m / z [LC-MS]: 617.33 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=8.29(s,1H),7.79(s,1H),7.13-7.22(m,2H),6.80-6.90(m,1H),3.36-4.02(m,7H),2.72-3.18(m,9H),2.06-2.4 2(m,2H),1.50-2.02(m,7H),1.42(d,J=7.2Hz,3H),1.32(d,J=6.0Hz,3H),1.16(t,J=7.6Hz,3H),1.07(d,J=7.2Hz,3H),0.98-1.03(m,3H).

[1276] Example 71: (S)-5-Fluoro-N,N-Diisopropyl-2-((4-(3-((7-Sulfanamido-2,7-diazaspiro) [3.5]Nonane-2-yl)methyl)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)benzamide

[1277]

[1278] Referring to the method in Example 36, intermediate 1 was replaced with intermediate 26 and intermediate 29 was replaced with intermediate 57 to obtain (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((7-sulfonamido-2,7-diazaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)benzamide. MS m / z [LC-MS]: 604.31 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=8.27(s,1H),7.76(s,1H),7.13-7.22(m,2H),6.81-6.88(m ,1H),6.68(s,2H),3.35-3.83(m,6H),3.12-3.18(m,1H),2.72-3.08(m,7H),2.30-2. 61(m,1H),2.08-2.26(m,1H),1.86-2.01(m,1H),1.64-1.80(m,4H),1.48-1.61(m,2H ),1.41(d,J=6.8Hz,3H),1.30-1.33(m,3H),1.06(d,J=7.2Hz,3H),0.99-1.02(m,3H).

[1279] Example 72: (S)-2-((4-(3-((2-(ethanesulfonamido)-7-azaspiro[3.5]nonane-7-yl)methyl)pyridine (Pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1280]

[1281] Referring to the method in Example 36, intermediate 26 was used instead of intermediate 1, and intermediate 58 was used instead of intermediate 29 to obtain (S)-2-((4-(3-((2-(ethanesulfonamido)-7-azaspiro[3.5]nonane-7-yl)methyl)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide. MS m / z [LC-MS]: 631.34 [M+1]. 1 H NMR (400MHz, CDCl3): δ = 8.40 (s, 0.5H), 8.39 (s, 0.5H), 7.80 (s, 1H), 6.90-6.9 8(m,2H),6.58-6.68(m,1H),4.43(d,J=7.6Hz,1H),3.57-3.92(m,5H),3.33-3 .53(m,2H),2.97(q,J=7.6Hz,2H),2.14-2.47(m,10H),1.94-2.07(m,1H),1.7 2-1.90(m,1H),1.45-1.69(m,11H),1.34(t,J=7.6Hz,3H),1.11-1.16(m,6H).

[1282] Example 73: (S)-2-((4-(3-((9-(ethanesulfonamido)-3-azaspiro[5.5]undecane-3-yl)methyl) Pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1283]

[1284] Referring to the method in Example 36, intermediate 1 was replaced with intermediate 26, and intermediate 29 was replaced with intermediate 59, to obtain (S)-2-((4-(3-((9-(ethanesulfonamido)-3-azaspiro[5.5]undecane-3-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide. MS m / z [LC-MS]: 659.38 [M+1]. 1H NMR (400MHz, CDCl3): δ = 8.40 (s, 0.5H), 8.39 (s, 0.5H), 7.80 (s, 1H), 6.90-6.98 (m, 2H) ,6.59-6.68(m,1H),4.04(d,J=7.2Hz,1H),3.60-3.90(m,3.5H),3.33-3.53(m,2H),3.2 0-3.30(m,1.5H),3.02(q,J=7.2Hz,2H),2.25-2.43(m,7H),1.95-2.07(m,1H),1.76-1. 85(m,2H),1.57-1.70(m,3H),1.44-1.56(m,8H),1.31-1.42(m,7H),1.06-1.22(m,8H).

[1285] Example 74: 2-((4-((S)-3-(((S)-1-(ethanesulfonamide)-8-azaspiro[4.5]decane-8-yl)methyl 1-(1-)pyrrolidine-5-)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1286]

[1287] Referring to the method in Example 36, intermediate 1 was replaced with intermediate 26 and intermediate 29 was replaced with intermediate 60 to obtain 2-((4-((S)-3-(((S)-1-(ethanesulfonamido)-8-azaspiro[4.5]decane-8-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide. MS m / z [LC-MS]: 645.36 [M+1]. 1 H NMR (400MHz, CD3OD): δ = 8.26 (s, 0.5H), 8.25 (s, 0.5H), 7.78 (s, 0.5H), 7.77 (s, 0.5H),7.09-7.16(m,2H),6.84-6.9(m,1H),3.52-4.01(m,5H),3.31-3.48(m,1H ),3.22-3.26(m,1H),3.01(q,J=7.6Hz,2H),2.71-2.83(m,2H),2.34-2.52(m,3H ),2.00-2.20(m,4H),14.2-18.8(m,13H),1.24-1.42(m,6H),1.13-1.18(m,6H).

[1288] Example 75: N-Ethyl-2-((4-((S)-3-(((S)-1-(ethanesulfonamido)-8-azaspiro[4.5]decane- 8-yl)methyl)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

[1289]

[1290] Referring to the method in Example 36, intermediate 29 was replaced with intermediate 60 to obtain N-ethyl-2-((4-((S)-3-(((S)-1-(ethanesulfonamido)-8-azaspiro[4.5]decane-8-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide. MS m / z [LC-MS]: 631.34 [M+1]. 1 H NMR (400MHz, CDCl3): δ=8.37-8.39(m,1H),7.79(s,1H),6.93-7.02(m,2H),6.58-6.67(m,1H),4.28-4.51(m,1H),3.60-3.92(m,3H),3.42-3.53 (m,1H),3.17-3.40(m,3H),2.94-3.08(m,2H),2.61-2.73(m,2H),2.20- 2.42(m,3H),1.92-2.13(m,4H),1.44-1.80(m,8H),1.05-1.36(m,14H).

[1291] Example 76: 2-((4-((3S)-3-((3-(ethanesulfonamide)-1-oxa-8-azaspiro[4.5]decane-8- 5-(methyl)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1292]

[1293] Referring to the method in Example 36, intermediate 1 was replaced with intermediate 26, and intermediate 29 was replaced with intermediate 61, to obtain 2-((4-((3S)-3-((3-(ethanesulfonamido)-1-oxa-8-azaspiro[4.5]decane-8-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide. MS m / z [LC-MS]: 647.34 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ = 8.28 (s, 1H), 7.76 (s, 1H), 7.30 (s, 1H), 7.13-7.22 (m, 2H),6.79-6.88(m,1H),3.26-3.96(m,9H),3.13-3.23(m,1H),2.99(q,J=7.2Hz, 2H),2.12-2.62(m,5H),1.76-2.10(m,3H),1.38-1.71(m,8H),1.30-1.33(m,3H) ,1.20-1.25(m,1H),1.15(t,J=7.2Hz,3H),1.06-1.08(m,3H),1.00-1.02(m,3H).

[1294] Example 77: (S)-N-ethyl-2-((4-(3-((9-(ethanesulfonamido)-3-azaspiro[5.5]undecane-3- 1-yl)methyl)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

[1295]

[1296] Referring to the method in Example 36, intermediate 29 was replaced with intermediate 59 to obtain (S)-N-ethyl-2-((4-(3-((9-(ethanesulfonamido)-3-azaspiro[5.5]undecane-3-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide. MS m / z [LC-MS]: 645.36 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ = 8.30 (s, 1H), 7.80 (s, 1H), 7.15-7.28 (m, 2H), 6.96 (d, J = 6.4Hz, 1H), 6.76-6.88 (m, 1H), 3 .49-3.82(m,3H),3.09-3.45(m,3H),2.85-3.08(m,4H),2.10-2.64(m,4H),1.75-2.08(m,2H),0.94-1.68(m,27H).

[1297] Example 78: 2-((4-((3S)-3-((6-(ethanesulfonamide methyl)-3-azabicyclo[3.1.0]hexane-3- 5-(methyl)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1298]

[1299] Referring to the method in Example 36, intermediate 1 was replaced with intermediate 26, and intermediate 29 was replaced with intermediate 62, to obtain 2-((4-((3S)-3-((6-(ethanesulfonamidomethyl)-3-azabicyclo[3.1.0]hexane-3-yl)methyl)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide. MS m / z [LC-MS]: 603.31 [M+1]. 1H NMR (400MHz, CDCl3): δ=8.40(s,1H),7.76(s,1H),6.92-7.01(m,2H),6.60-6.67(m,1H),4.14-4.86(m, 1H),3.76-3.91(m,2H),3.60-3.74(m,1.5H),3.44-3.55(m,1.5H),3.33-3.40(m,0.5H),3.20-3.26(m, 0.5H),2.83-3.09(m,5H),2.18-2.50(m,4H),1.93-2.05(m,1H),1.55-1.65(m,1H),1.52-1.55(m,3H), 1.47(d,J=7.2Hz,3H), 1.36(t,J=7.6Hz,3H), 1.21-1.32(m,3H), 1.11-1.18(m,6H), 0.82-0.88(m,2H).

[1300] Example 79: (S)-5-Fluoro-2-((4-(3-((7-(((2-hydroxy-2-methylpropyl)amino)-2-azaspiro) [3.5]Nonane-2-yl)methyl)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide

[1301]

[1302] Referring to the method in Example 36, intermediate 1 was replaced with intermediate 26 and intermediate 29 was replaced with intermediate 63 to obtain (S)-5-fluoro-2-((4-(3-((7-(((2-hydroxy-2-methylpropyl)amino)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide. MS m / z [LC-MS]: 611.41 [M+1]. 1 HNMR (400MHz, CDCl3): δ = 8.39 (s, 0.5H), 8.38 (s, 0.5H), 7.80 (s, 1H), 6.91-6.99 (m, 2H), 6.65-6.6 9(m,0.5H),6.58-6.62(m,0.5H),3.61-3.89(m,3.5H),3.29-3.52(m,2.5H),3.15-3.20(m,1H),2. 85-3.00(m,4H),2.30-2.52(m,5H),2.10-2.24(m,1H),1.95-2.06(m,1H),1.83-1.93(m,2H),1.73 -1.82(m,2H),1.53(d,J=6.8Hz,3H),1.47(d,J=6.8Hz,3H),1.33-1.43(m,2H),0.98-1.16(m,14H).

[1303] Example 80:(S)-5-Fluoro-N,N-Diisopropyl-2-((4-(3-((7-(aminosulfonamido)-2-azaspiro) [3.5]Nonane-2-yl)methyl)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)benzamide

[1304]

[1305] Referring to the method in Example 36, intermediate 1 was replaced with intermediate 26 and intermediate 29 was replaced with intermediate 64 to obtain (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((7-(aminosulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)benzamide. MS m / z [LC-MS]: 618.32 [M+1]. 1 H NMR (400MHz, CDCl3): δ = 8.41 (s, 0.5H), 8.40 (s, 0.5H), 7.82 (s, 1H), 6.90-7.00 (m, 2H), 6. 65-6.70(m,0.5H),6.53-6.59(m,0.5H),4.08-4.16(m,1H),3.75-3.95(m,2H),3.55-3.75 (m,2H),2.90-3.55(m,7H),2.50-2.70(m,1H),2.36-2.42(m,2H),2.17-2.36(m,1H),1.82 -2.16(m,5H),1.43-1.55(m,8H),1.35-1.45(m,2H),1.05-1.22(m,6H),0.90-1.02(m,2H).

[1306] Example 81: (S)-5-Fluoro-N,N-Diisopropyl-2-((4-(3-((7-(isopropylsulfonamido)-2-azaspiro) [3.5]Nonane-2-yl)methyl)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)benzamide

[1307]

[1308] Referring to the method in Example 36, intermediate 1 was replaced with intermediate 26 and intermediate 29 was replaced with intermediate 65 to obtain (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((7-(isopropylsulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)benzamide. MS m / z [LC-MS]: 645.36 [M+1]. 1H NMR (400MHz, CDCl3): δ = 8.40 (s, 1H), 7.80 (s, 1H), 6.88-6.98 (m, 2H), 6.64-6.68 (m, 0.5H) ,6.56-6.60(m,0.5H),4.00-4.08(m,1H),3.75-3.96(m,2H),3.56-3.75(m,2H),3.30-3.56 (m,2H),3.10-3.28(m,2H),2.90-3.08(m,6H),2.45-2.55(m,2H),2.13-2.27(m,2H),1.95 -2.07(m,2H),1.78-1.95(m,7H),1.42-1.55(m,8H),1.00-1.19(m,6H),1.00-1.08(m,2H).

[1309] Example 82: (S)-2-((5-(3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyridine (1-yl)-1,2,4-triazine-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1310]

[1311] Step 1: (S)-N-(2-((1-(3,6-dichloro-1,2,4-triazin-5-yl)pyrrolidine-3-yl)methyl)-2-hexaspiro[3,5]nonane-7-yl)ethanesulfonamide

[1312] Intermediate 56 (315 mg) and diisopropylethylamine (516 mg) were added to tetrahydrofuran (10 mL), cooled to 0°C in an ice bath, and 3,5,6-trichloro-1,2,4-triazine (185 mg) was added. The mixture was slowly heated to room temperature and stirred for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain (S)-N-(2-((1-(3,6-dichloro-1,2,4-triazin-5-yl)pyrrolidine-3-yl)methyl)-2-hexaspiro[3,5]nonane-7-yl)ethanesulfonamide (480 mg), which was used directly in the next step. MS m / z [LC-MS]: 463.15 [M+1].

[1313] Step 2: (S)-2-((3-chloro-5-(3-((7-(ethanesulfonamide)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1314] Add (S)-N-(2-((1-(3,6-dichloro-1,2,4-triazin-5-yl)pyrrolidine-3-yl)methyl)-2-hexaspiro[3.5]nonane-7-yl)ethanesulfonamide (240 mg), 5-fluoro-2-hydroxy-N,N-diisopropylbenzamide (180 mg) and potassium carbonate (210 mg) to 1,4-dioxane (10 mL) and reflux for 12 hours. Cool to room temperature, filter, concentrate the filtrate under reduced pressure, and separate by silica gel column chromatography (dichloromethane / methanol, 20:1) to obtain (S)-2-((3-chloro-5-(3-((7-(ethanesulfonamide)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide (205 mg). MS m / z [LC-MS]: 666.30 [M+1].

[1315] Step 3: (S)-2-((5-(3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1316] (S)-2-((3-chloro-5-(3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide (200 mg) and 10% palladium on carbon (40 mg) were added to methanol (20 mL). The air in the reactor was replaced with hydrogen gas at a hydrogen pressure of 3... The reaction was carried out at 60°C for 10 hours under atmospheric pressure. After filtration, the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (dichloromethane / methanol, 20:1) to obtain (S)-2-((5-(3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide (140 mg). MS m / z [LC-MS]: 632.34 [M+1]. 1H NMR (400MHz, DMSO-d6): δ = 11.0 (brs, 1H), 8.48 (s, 1H), 7.22-7.42 (m, 2H), 6.97 (d ,J=7.2Hz,1H),4.08-4.24(m,1H),3.60-3.95(m,4H),3.33-3.60(m,5H),3.15-3.3 0(m,2H),2.90-3.08(m,3H),2.00-2.20(m,2H),1.82-1.98(m,2H),1.58-1.78(m, 2H),1.38-1.58(m,2H),1.30-1.40(m,2H),1.08-1.28(m,13H),1.00-1.08(m,3H).

[1317] Example 83: 2-((4-((S)-3-((7-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]) (heptane)-2-sulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5- Fluoro-N,N-diisopropylbenzamide

[1318]

[1319] Step 1: (1S,4S)-5-(N-(2-(((S)-1-(5-(2-(diisopropylaminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)-2-azaspiro[3.5]nonane-7-yl)aminosulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[1320] Intermediate 66 (107 mg) and diisopropylethylamine (78 mg) were added to dichloromethane (5 mL), cooled to 0 °C in an ice bath, and (1S,4S)-5-(chlorosulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (71 mg) were added. The mixture was slowly heated to room temperature and stirred for 2 hours, then refluxed for 12 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (dichloromethane / methanol, 15:1) to obtain the target compound (72 mg). MS m / z [LC-MS]: 799.44 [M+1].

[1321] Step 2: 2-((4-((S)-3-((7-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-sulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride

[1322] (1S,4S)-5-(N-(2-(((S)-1-(5-(2-(diisopropylaminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)-2-azaspiro[3.5]nonane-7-yl)aminosulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (70 mg) was added to a 4 mol / L dioxane chloride solution (5 mL), stirred at room temperature for 2 hours, then ether (30 mL) was added, stirred for 1 hour, filtered, the filter cake was washed with ether, and dried to obtain the target compound (55 mg). MS m / z [LC-MS]: 699.38 [M+1].

[1323] Step 3: 2-((4-((S)-3-((7-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptane)-2-sulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1324] 2-((4-((S)-3-((7-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-sulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride (55 mg) and diisopropylethylamine (63 mg) were added to dichloromethane (5 mL), cooled to 0 °C in an ice bath, acryloyl chloride (7 μL) was added, the mixture was slowly heated to room temperature and stirred for 2 hours, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (dichloromethane / methanol, 15:1) to obtain the target compound (28 mg). MS m / z [LC-MS]: 753.39 [M+1]. 1H NMR (400MHz, CD3OD): δ = 8.33 (s, 0.4H), 8.32 (s, 0.6H), 7.91 (s, 0.4H), 7.88 (s, 0.6H), 7.08-7.24 (m, 2H), 6.86-6.91(m,0.6H),6.76-6.71(m,0.4H),6.71(dd,J=16.8Hz,10.4Hz,0.6H),6.47(dd,J=1 6.8Hz, 10.4Hz, 0.4H), 6.29 (d, J=16.8Hz, 1H), 5.77 (dd, J=10.4Hz, 1.6Hz, 1H), 4.39 (d, J=6.8 Hz,1H),3.60-3.96(m,7H),3.34-3.58(m,3H),3.09-3.32(m,3H),2.72-3.08(m,4H),2.58-2 .70(m,1H),1.80-2.36(m,6H),1.50-1.78(m,10H),1.47(t,J=7.2Hz,3H),1.15-1.38(m,6H).

[1325] Example 84: (S)-2-((4-(3-((7-(ethanesulfonamide methyl)-2-azaspiro[3.5]nonane-2-yl)methyl 1-(1-)pyrrolidine-5-)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1326]

[1327] Following the method described in Example 36, intermediate 1 was replaced with intermediate 26, and intermediate 29 was replaced with intermediate 67 to obtain the target compound. MS m / z [LC-MS]: 645.36 [M+1]. 1 H NMR (400MHz, CDCl3): δ=8.35-8.42(m,1H),7.79(s,1H),6.90-6.99(m,2H),6.64-6.68(m,0.5H),6 .58-6.61(m,0.5H),4.34-4.44(m,1H),3.57-3.90(m,4.5H),3.29-3.54(m,2.5H),3.13-3.21(m,0 .5H),2.84-3.05(m,7.5H),2.38-2.52(m,2.5H),2.09-2.30(m,1.5H),1.83-2.07(m,4H),1.57-1. 72(m,4H),1.52(d,J=6.4Hz,3H),1.46(d,J=7.2Hz,3H),1.33(t,J=7.2Hz,3H),1.09-1.15(m,6H).

[1328] Example 85: (S)-2-((4-(3-((7-acrylamido-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrole Alkyl-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamideCompared with Example 86: (S)-2-((4-(3-((7- (N-Acryloylacrylamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidone-1-yl)pyrimidin-5-yl)oxy 5-Fluoro-N,N-Diisopropylbenzamide

[1329]

[1330] Intermediate 66 (107 mg) and diisopropylethylamine (78 mg) were added to dichloromethane (5 mL), cooled to 0 °C in an ice bath, and acryloyl chloride (22 mg) was added dropwise. The mixture was slowly heated to room temperature and stirred for 4 hours. The mixture was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (dichloromethane / methanol, 15:1) to give (S)-2-((4-(3-((7-acrylamido-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide (40 mg). MS m / z [LC-MS]: 593.36 [M+1]. 1 H NMR (400MHz, CDCl3): δ = 8.47 (s, 0.6H), 8.44 (s, 0.4H), 7.93 (s, 1H), 6.86-7.06 (m, 2H), 6.67-6.76 (m, 0.4H), 6.36-6.54 (m, 2H), 6.24-6.30 (m ,0.6H),5.62-5.78(m,1H),4.58-4.66(m,0.4H),3.22-4.38(m,9.6H), 2.96-3.21(m,1H),2.66-2.92(m,2H),2.30-2.58(m,2H),2.03-2.20(m, 2H),1.81-1.96(m,3H),1.36-1.80(m,11H),1.11-1.32(m,6H).

[1331] Simultaneously, (S)-2-((4-(3-((7-(N-acryloylacrylamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide (16 mg) was obtained. MS m / z [LC-MS]: 647.37 [M+1]. 1H NMR (400MHz, CDCl3): δ=8.41(s,1H),7.85(s,1H),6.91-6.99(m,2H),6.42-6.68(m,3H),6.24-6.38(m,2H),5.60-5.72(m,2H),4.54-4.58(m,0.6 H),3.63-4.02(m,5.4H),3.08-3.52(m,7H),2.62-2.78(m,0.6H),2.24-2 .50(m,1.4H),1.95-2.11(m,2H),1.42-1.91(m,13H),1.04-1.20(m,6H).

[1332] Example 87: (S)-2-((4-(3-((7-cyanoamino-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrole Alkyl-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide Compared with Example 88: (S)-2-((4-(3-((7- Dicyanoamino-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N- Diisopropylbenzamide

[1333]

[1334] Following the method in Example 85, bromonitrile was used instead of acryloyl chloride to obtain (S)-2-((4-(3-((7-cyanoamino-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide. MS m / z [LC-MS]: 564.35 [M+1]. 1 H NMR (400MHz, CDCl3): δ=8.40-8.59(m,1H),7.84-8.10(m,1H),6.94-7.09(m,2H),6.72-6.76 (m,0.4H),6.48-6.53(m,0.6H),4.18-4.30(m,0.6H),3.77-3.92(m,2H),3.54-3.75(m,2.4H) ,2.95-3.52(m,6H),2.64-2.90(m,2H),2.42-2.52(m,1H),1.86-2.18(m,5H),1.64-1.84(m, 5H), 1.54-1.59 (m, 4.5H), 1.47 (d, J = 6.4Hz, 1.5H), 1.21-1.28 (m, 3H), 1.16 (d, J = 6.4Hz, 3H).

[1335] (S)-2-((4-(3-((7-dicyanoamino-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide was also obtained. MS m / z [LC-MS]: 589.34 [M+1].1 HNMR (400MHz, CDCl3): δ = 8.44 (s, 0.5H), 8.42 (s, 0.5H), 7.89 (s, 1H), 6.92-7.02 (m,2H),6.69-6.72(m,0.5H),6.56-6.60(m,0.5H),3.73-4.06(m,4H),3.42-3.58 (m,2H),3.15-3.29(m,1H),2.78-3.08(m,5H),2.52-2.63(m,1H),2.03-2.24(m, 4H),1.56-1.74(m,7H),1.50-1.53(m,3H),1.43-1.46(m,3H),1.09-1.16(m,6H).

[1336] Example 89: 2-((4-(7-(3-(4-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptane alkyl)-2-sulfonyl)phenyl)prop-2-yn-1-yl)-2,7-azaspiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)-N-ethyl 5-Fluoro-N-isopropylbenzamide

[1337]

[1338] Step 1: (1S,4S)-5-((4-(3-(2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-yl)prop-1-yn-1-yl)phenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[1339] Under nitrogen protection, intermediates 68 (233 mg), 69 (250 mg), cuprous iodide (10 mg), and bis(triphenylphosphine)palladium dichloride (35 mg) were added to a 1:1 mixture of tetrahydrofuran and triethylamine (10 mL). The mixture was heated to 80 °C and stirred for 10 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (dichloromethane / methanol, 20:1) to obtain the target compound. MS m / z [LC-MS]: 802.38 [M+1].

[1340] Step 2: 2-((4-(7-(3-(4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)sulfonyl)phenyl)prop-2-yn-1-yl)-2,7-azaspiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide hydrochloride

[1341] Referring to step 2 of Example 83, (1S,4S)-5-((4-(3-(2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-yl)prop-1-yn-1-yl)phenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid The target compound was obtained by substituting tert-butyl ester for (1S,4S)-5-(N-(2-(((S)-1-(5-(2-(diisopropylaminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)-2-azaspiro[3.5]nonane-7-yl)aminosulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 702.33 [M+1].

[1342] Step 3: (S)-2-((4-(3-((7-((1-acryloylpiperidin-4-yl)sulfonyl)-2,7-diazaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1343] Referring to step 3 of Example 83, the target compound was obtained by replacing 2-((4-(7-(3-(4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)sulfonyl)phenyl)prop-2-yn-1-yl)-2,7-azaspiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide hydrochloride with 2-((4-((S)-3-((7-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-sulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride. MS m / z[LC-MS]:756.33[M+1]. 1H NMR (400MHz, CDCl3): δ = 8.35 (s, 1H), 7.71-7.80 (m, 3H), 7.55 (d, J = 8.4Hz, 2H), 6.96-7.02 (m, 2H), 6.71-6.78 (m,1H),6.31-6.37(m,1.3H),6.11-6.18(m,0.7H),5.66-5.70(m,1H),4.86-4.90(m,0.7H),4.50-4.55(m,1.3 H),3.76-4.06(m,5H),3.57-3.64(m,1H),3.41-3.54(m,4H),3.12-3.39(m,3H),2.40-2.70(m,4H),1.80-1.8 8(m,4H),1.74-1.79(m,0.3H),1.66-1.68(m,0.7H),1.28-1.44(m,1H),1.20-1.25(m,3H),1.03-1.13(m,6H).

[1344] Example 90: (S)-2-((4-(3-((7-((1-Acryloylpiperidin-4-yl)sulfonyl)-2,7-diazaspiro [3.5]Nonane-2-yl)methyl)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1345]

[1346] Step 1: (S)-4-((2-((1-(5-(2-(diisopropylaminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-7-yl)sulfonyl)piperidine-1-carboxylic acid tert-butyl ester

[1347] Following the method in step 1 of Example 83, intermediate 66 was replaced with intermediate 70, and tert-butyl 4-(chlorosulfonyl)piperidine-1-carboxylate was replaced with (1S,4S)-5-(chlorosulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate to obtain the target compound. MS m / z [LC-MS]: 772.43 [M+1].

[1348] Step 2: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((7-(piperidin-4-sulfonyl)-2,7-diazaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

[1349] Following the method in step 2 of Example 83, the target compound was obtained by replacing (1S,4S)-5-(N-(2-(((S)-1-(5-((((S)-1-(5-((2-((diisopropylaminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-7-yl)aminosulfonyl)piperidine-1-carboxylic acid tert-butyl ester with (S)-4-((2-(((S)-1-(5-(2-(diisopropylaminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)-2-diazaspiro[3.5]nonane-7-yl)aminosulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 672.37 [M+1].

[1350] Step 3: (S)-2-((4-(3-((7-((1-acryloylpiperidin-4-yl)sulfonyl)-2,7-diazaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1351] Following the method in step 3 of Example 83, the target compound was obtained by replacing 2-((4-(3-((7-(piperidin-4-sulfonyl)-2,7-diazaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride. MS m / z [LC-MS]: 726.38 [M+1]. 1H NMR (400MHz, CDCl3): δ = 8.42 (s, 0.5H), 8.41 (s, 0.5H), 7.85 (s, 1H), 6.91-7.03 (m, 2H), 6.65-6.6 9(m,0.5H),6.51-6.58(m,1.5H),6.25(dd,J=16.8Hz,1.6Hz,1H),5.69(dd,J=10.8Hz,1.6Hz,1H), 4.68-4.80(m,1H),4.04-4.15(m,1H),3.22-3.93(m,13H),2.40-3.20(m,6H),2.24-2.38(m,1H),1 .78-2.16(m,8H),1.60-1.74(m,2H),1.52(d,J=6.8Hz,3H),1.45-1.48(m,3H),1.12-1.20(m,6H).

[1352] Example 91: (S)-2-((4-(3-((7-((4-acryloylpiperazin-1-yl)sulfonyl)-2,7-diazaspiro [3.5]Nonane-2-yl)methyl)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1353]

[1354] Step 1: (S)-4-((2-((1-(5-(2-(diisopropylaminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-7-yl)sulfonyl)piperazine-1-carboxylic acid tert-butyl ester

[1355] Following the method in step 1 of Example 83, intermediate 66 was replaced with intermediate 70, and (1S,4S)-5-(chlorosulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester was replaced with 4-(chlorosulfonyl)piperazine-1-carboxylic acid tert-butyl ester to obtain the target compound. MS m / z [LC-MS]: 773.42 [M+1].

[1356] Step 2: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((7-(piperazin-1-sulfonyl)-2,7-diazaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

[1357] Following the method in step 2 of Example 83, the target compound was obtained by replacing (1S,4S)-5-(N-(2-(((S)-1-(5-((((S)-1-(5-((((((diisopropylaminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-7-yl)sulfonyl)piperazine-1-carboxylic acid tert-butyl ester with (S)-4-((2-((((S)-1-(5-(2-(diisopropylaminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)-2-diazaspiro[3.5]nonane-7-yl)aminosulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 673.37 [M+1].

[1358] Step 3: (S)-2-((4-(3-((7-((4-acryloylpiperazin-1-yl)sulfonyl)-2,7-diazaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1359] Following the method in step 3 of Example 83, the target compound was obtained by replacing 2-((4-(3-((7-(piperazin-1-sulfonyl)-2,7-diazaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride. MS m / z [LC-MS]: 727.38 [M+1]. 1 H NMR (400MHz, CDCl3): δ=8.40(s,1H),7.82(s,1H),6.88-7.00(m,2H),6.65-6.68( m,0.5H),6.49-6.58(m,1.5H),6.30(dd,J=16.8Hz,1.2Hz,1H),5.73(d,J=11.2Hz ,1H),3.02-3.94(m,23H),2.46-2.70(m,2H),2.16-2.38(m,1H),1.97-2.10(m,1H ),1.74-1.89(m,4H),1.49-1.53(m,3H),1.45(d,J=6.8Hz,3H),1.11-1.17(m,6H).

[1360] Example 92: (S)-5-Fluoro-N,N-Diisopropyl-2-((4-(3-((9-((2,2,2-trifluoroethyl)amino)-3- Azaspiro[5.5]undecane-3-yl)methyl)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)benzamide

[1361]

[1362] Intermediate 75 (113 mg), 2,2,2-trifluoroethylamine (30 mg), and acetic acid (12 mg) were added to 1,2-dichloroethane (10 mL) and stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (128 mg) was added, and the mixture was stirred overnight at room temperature. The reaction was quenched with saturated sodium bicarbonate solution, filtered, and the filtrate was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (dichloromethane / methanol, 12:1) to obtain the target compound (52 mg). MS m / z [LC-MS]: 649.38 [M+1]. 1 H NMR (400MHz, CDCl3): δ = 8.40 (s, 1H), 7.81 (s, 1H), 6.90-6.99 (m, 2H), 6.64-6.69 (m, 0.5H), 6.57-6.62 (m, 0.5H), 3.58-3.94 (m, 4.5H),3.34-3.53(m,2.5H),3.13-3.25(m,3H),2.20-2.56(m,10H),1.93-2.10(m,2H),1.43-1.73(m,15H),1.10-1.17(m,6H).

[1363] Example 93: (S)-2-((4-(3-((8-(ethanesulfonamido)-2-azaspiro[4.5]decane-2-yl)methyl)pyridine (Pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1364]

[1365] Following the method described in Example 36, intermediate 1 was replaced with intermediate 26, and intermediate 29 was replaced with intermediate 77 to obtain the target compound. MS m / z [LC-MS]: 645.36 [M+1]. 1 H NMR (400MHz, CDCl3): δ=8.40(s,1H),7.80(s,1H),6.90-7.01(m,2H),6.58-6.71(m,1H),3.59-4.26(m,4H),3.34-3.53(m,2.5H),3.18-3.31(m ,1.5H),2.98-3.05(m,2H),2.18-2.60(m,6H),1.96-2.10(m,1H),1.80- 1.94(m,2H),1.44-1.71(m,12H),1.28-1.42(m,6H),1.06-1.17(m,7H).

[1366] Example 94: 5-Fluoro-N,N-Diisopropyl-2-((4-((S)-3-((9-(((R)-1,1,1-trifluoropropyl-2-yl) (amino)-3-azaspiro[5.5]undecane-3-yl)methyl)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)benzamide

[1367]

[1368] Following the method described in Example 92, the target compound was obtained by replacing 2,2,2-trifluoroethylamine with (R)-1,1,1-trifluoroprop-2-amine. MS m / z [LC-MS]: 663.40 [M+1]. 1 H NMR (400MHz, CDCl3): δ = 8.40 (s, 0.5H), 8.39 (s, 0.5H), 7.80 (s, 1H), 6.90 -6.98(m,2H),6.65-6.68(m,0.5H),6.57-6.62(m,0.5H),3.60-3.92(m,4H ),3.32-3.54(m,2.5H),3.16-3.27(m,1.5H),2.52-2.61(m,1H),2.22-2.4 5(m,6.5H),1.96-2.09(m,1.5H),1.42-1.71(m,14H),1.10-1.38(m,13H).

[1369] Example 95: (S)-2-((3-chloro-5-(3-((9-(ethanesulfonamido)-3-azaspiro[5.5]undecane-3-yl) Methylpyrrolidone-1-yl)-1,2,4-triazine-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1370]

[1371] Step 1: (S)-N-(3-((1-(3,6-dichloro-1,2,4-triazin-5-yl)pyrrolidine-3-yl)methyl)-3-azaspiro[5.5]undecane-9-yl)ethanesulfonamide

[1372] Following the method in step 1 of Example 82, intermediate 56 was replaced with intermediate 78 to obtain the target compound. MS m / z [LC-MS]: 491.18 [M+1].

[1373] Step 2: (S)-2-((3-chloro-5-(3-((9-(ethanesulfonamido)-3-azaspiro[5.5]undecane-3-yl)methyl)pyrrolidine-1-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1374] Following the method in step 2 of Example 82, the target compound was obtained by replacing (S)-N-(2-((1-(3,6-dichloro-1,2,4-triazin-5-yl)pyrrolidine-3-yl)methyl)-3-azaspiro[5.5]undecane-9-yl)ethanesulfonamide with (S)-N-(2-((1-(3,6-dichloro-1,2,4-triazin-5-yl)pyrrolidine-3-yl)methyl)-2-azaspiro[3.5]nonane-7-yl)ethanesulfonamide. MS m / z [LC-MS]: 694.33 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.37-7.44(m,1H),7.24-7.36(m,2H),6.92-7.00(m,1H),3.16-4.36(m,5 H),2.86-3.08(m,4H),2.16-2.42(m,4H),1.90-2.11(m,2H),1.00-1.72(m,27H),0.64-0.75(m,3H).

[1375] Example 96: (S)-2-((5-(3-((9-(ethanesulfonamido)-3-azaspiro[5.5]undecane-3-yl)methyl) Pyrrolidine-1-yl)-1,2,4-triazine-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1376]

[1377] Following the method in step 3 of Example 82, the target compound was obtained by replacing (S)-2-((3-chloro-5-(3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide with that of Example 95. MS m / z [LC-MS]: 660.37 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ = 8.46 (s, 1H), 7.36-7.42 (m, 1H), 7.24-7.34 (m, 2H), 6.94-7.00 (m, 1H), 3.15-4.3 8(m,5H),2.90-3.08(m,4H),2.34-2.82(m,4H),1.97-2.15(m,2H),0.96-1.73(m,27H),0.54-0.80(m,3H).

[1378] Example 97: 2-((4-((S)-3-((7-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]) Heptane-2-yl)sulfonyl)-2,7-diazaspiro[3.5]nonane-2-yl)methyl)pyrrolidone-1-yl)pyrimidin-5-yl)oxy 5-Fluoro-N,N-Diisopropylbenzamide

[1379]

[1380] Step 1: (1S,4S)-5-((2-(((S)-1-(5-(2-(diisopropylaminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-7-yl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[1381] Following the method in step 1 of Example 83, intermediate 66 was replaced with intermediate 70 to obtain the target compound. MS m / z [LC-MS]: 785.42 [M+1].

[1382] Step 2: 2-((4-((S)-3-((7-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)sulfonyl)-2,7-diazaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride

[1383] Referring to step 2 of Example 83, (1S,4S)-5-((2-(((S)-1-(5-(2-(diisopropylaminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-7-yl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert- The target compound was obtained by substituting butyl ester for (1S,4S)-5-(N-(2-(((S)-1-(5-(2-(diisopropylaminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)-2-azaspiro[3.5]nonane-7-yl)aminosulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 685.37 [M+1].

[1384] Step 3: 2-((4-((S)-3-((7-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)sulfonyl)-2,7-diazaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1385] Referring to step 3 of Example 83, the target compound was obtained by replacing 2-((4-((S)-3-((7-((((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)sulfonyl)-2,7-diazaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride with 2-((4-((S)-3-((7-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-sulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride. MS m / z[LC-MS]:739.38[M+1]. 1 H NMR (400MHz, CDCl3): δ = 8.40 (s, 0.5H), 8.39 (s, 0.5H), 7.81 (s, 1H), 6.89-6.99 (m, 2H), 6.6 4-6.69(m,0.5H),6.51-6.59(m,0.5H),6.37-6.42(m,1H),6.23-6.29(m,1H),5.69-5.73(m, 1H),4.97(s,0.7H),4.61(s,0.3H),4.41(s,0.7H),4.38(s,0.3H),3.40-3.94(m,8H),2.86 -3.36(m,10H),2.16-2.72(m,3H),1.71-2.12(m,6H),1.44-1.63(m,8H),1.11-1.16(m,6H).

[1386] Example 98: 2-((4-((S)-3-((9-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]) Heptane-2-yl)sulfonyl)-3,9-diazaspiro[5.5]undecane-3-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy 5-Fluoro-N,N-Diisopropylbenzamide

[1387]

[1388] Step 1: (1S,4S)-5-((9-(((S)-1-(5-(2-(diisopropylaminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)-3,9-diazaspiro[5.5]undecane-3-yl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[1389] Following the method in step 1 of Example 83, intermediate 66 was replaced with intermediate 79 to obtain the target compound. MS m / z [LC-MS]: 813.45 [M+1].

[1390] Step 2: 2-((4-((S)-3-((9-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)sulfonyl)-3,9-diazaspiro[5.5]undecane-3-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride

[1391] Referring to step 2 of Example 83, (1S,4S)-5-((9-(((S)-1-(5-(2-(diisopropylaminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)-3,9-diazaspiro[5.5]undecane-3-yl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert- The target compound was obtained by substituting butyl ester for (1S,4S)-5-(N-(2-(((S)-1-(5-(2-(diisopropylaminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)-2-azaspiro[3.5]nonane-7-yl)aminosulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 713.40 [M+1].

[1392] Step 3: 2-((4-((S)-3-((9-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)sulfonyl)-3,9-diazaspiro[5.5]undecane-3-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1393] Referring to step 3 of Example 83, the target compound was obtained by replacing 2-((4-((S)-3-((9-((((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)sulfonyl)-3,9-diazaspiro[5.5]undecane-3-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride with 2-((4-((S)-3-((7-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-sulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride. MS m / z[LC-MS]:767.41[M+1]. 1H NMR (400MHz, CDCl3): δ = 8.40 (s, 0.5H), 8.39 (s, 0.5H), 7.80 (s, 1H), 6.89-6.98 (m, 2H), 6.63-6. 67(m,0.5H),6.54-6.61(m,0.5H),6.38-6.42(m,1H),6.23-6.30(m,1H),5.69-5.73(m,1H),4.97 (s,0.7H),4.61(s,0.3H),4.42(s,0.7H),4.39(s,0.3H),3.59-3.94(m,4.5H),3.45-3.53(m,2. 5H),3.36(d,J=9.2Hz,1H),3.31(dd,J=9.2Hz,2.0Hz,1H),3.12-3.22(m,5H),2.22-2.55(m,7H), 1.81-2.10(m,5H),1.44-1.68(m,13H),1.11-1.16(m,6H).

[1394] Example 99: 5-Fluoro-N,N-Diisopropyl-2-((4-((S)-3-((9-(((S)-1,1,1-trifluoropropyl-2-yl) (amino)-3-azaspiro[5.5]undecane-3-yl)methyl)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)benzamide

[1395]

[1396] Following the method described in Example 92, the target compound was obtained by replacing 2,2,2-trifluoroethylamine with (S)-1,1,1-trifluoropropane-2-amine. MS m / z [LC-MS]: 663.40 [M+1]. 1 H NMR (400MHz, CDCl3): δ = 8.40 (s, 0.5H), 8.39 (s, 0.5H), 7.80 (s, 1H), 6.91-6.98 (m ,2H),6.64-6.69(m,0.5H),6.58-6.62(m,0.5H),3.58-3.90(m,3.5H),3.34-3.53( m,2H),3.18-3.26(m,1.5H),2.52-2.61(m,1H),2.24-2.44(m,7H),1.96-2.08(m, 1H),1.57-1.71(m,6H),1.43-1.56(m,9H),1.30-1.37(m,2H),1.01-1.23(m,11H).

[1397] Example 100: (S)-2-((4-(3-((7-((1-Acryloylpiperidine)-4-sulfonamido)-2-azaspiro [3.5]Nonane-2-yl)methyl)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1398]

[1399] Step 1: (S)-4-(N-(2-((1-(5-(2-(diisopropylaminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)-2-azaspiro[3.5]nonane-7-yl)aminosulfonyl)piperidine-1-carboxylic acid tert-butyl ester

[1400] Following the method in step 1 of Example 83, the target compound was obtained by replacing (1S,4S)-5-(chlorosulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester with 4-(chlorosulfonyl)piperidine-1-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 786.44 [M+1].

[1401] Step 2: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((7-(piperidin-4-sulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

[1402] Following the method in step 2 of Example 83, the target compound was obtained by replacing (1S,4S)-5-(N-(2-(((S)-1-(5-((((S)-1-(5-(((((((diisopropylaminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)-2-azaspiro[3.5]nonane-7-yl)aminosulfonyl)piperidine-1-carboxylic acid tert-butyl ester with (S)-4-(N-(2-(((S)-1-(5-(2-(diisopropylaminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)-2-azaspiro[3.5]nonane-7-yl)aminosulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester. MS m / z [LC-MS]: 686.39 [M+1].

[1403] Step 3: (S)-2-((4-(3-((7-((1-acryloylpiperidine)-4-sulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1404] Following the method in step 3 of Example 83, the target compound was obtained by replacing 2-((4-(3-((7-(piperidin-4-sulfonamido)-2-azaspiro[3.5]nonane-2-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride. MS m / z [LC-MS]: 740.40 [M+1]. 1 H NMR (400MHz, CDCl3): δ = 8.48 (s, 0.5H), 8.46 (s, 0.5H),7.94-8.00(m,1H),6.94-7.08(m,2H),6.71-6.74(m,0.5H),6.47- 6.60(m,1.5H),6.23-6.30(m,1H),5.66-5.72(m,1H),4.73-4.84(m,1H), 4.06-4.31(m,1.5H),3.32-3.94(m,10H),3.04-3.28(m,3.5H),2.64-2.8 2(m,2.5H),1.94-2.24(m,6.5H),1.42-1.84(m,15H),1.15-1.28(m,6H).

[1405] Example 101: (S)-2-((4-(3-((9-(ethanesulfonamide methyl)-3-azaspiro[5.5]undecane-3-yl) Methylpyrrolidone-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1406]

[1407] Following the method described in Example 36, intermediate 1 was replaced with intermediate 26, and intermediate 29 was replaced with intermediate 80 to obtain the target compound. MS m / z [LC-MS]: 673.39 [M+1]. 1H NMR (400MHz, CDCl3): δ = 8.41 (s, 0.5H), 8.40 (s, 0.5H), 7.82 (s, 1H), 6.90-6.99 (m, 2H),6.64-6.69(m,0.5H),6.53-6.61(m,0.5H),4.14-4.26(m,1H),3.58-3.99(m,3. 5H),3.36-3.55(m,2H),3.13-3.26(m,0.5H),2.94-3.05(m,4H),2.20-2.60(m,6H) ,1.75-2.16(m,3H),1.40-1.74(m,15H),1.35(t,J=7.2Hz,3H),1.04-1.18(m,10H).

[1408] Example 102: (S)-N-ethyl-2-((4-(3-((9-(ethanesulfonamide methyl)-3-azaspiro[5.5] eleven Alkyl-3-yl)methyl)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

[1409]

[1410] Following the method described in Example 36, intermediate 29 was replaced with intermediate 80 to obtain the target compound. MS m / z [LC-MS]: 659.38 [M+1]. 1 H NMR (400MHz, CDCl3): δ = 8.40 (s, 1H), 7.81 (s, 1H), 6.92-7.02 (m, 2H), 6.63-6.69 (m, 0.5H), 6.54-6.61 (m, 0.5H), 4.16-4.23 (m,1H),3.58-3.90(m,3H),3.15-3.55(m,8H),2.88-3.04(m,4H),2.15-2.50(m,7H),1.92-2.08(m,2H),0.98-1.72(m,21H).

[1411] Example 103: (S)-3-((1-(5-(2-(diisopropylaminoformyl)-4-fluorophenoxy)pyrimidin-4-yl) pyrrolidine-3-yl)methyl)-N-(ethanesulfonyl)-3-azaspiro[5.5]undecane-9-carboxamide

[1412]

[1413] Following the method described in Example 36, intermediate 1 was replaced with intermediate 26, and intermediate 29 was replaced with intermediate 81 to obtain the target compound. MS m / z [LC-MS]: 687.37 [M+1]. 1H NMR (400MHz, CDCl3): δ = 8.40 (s, 0.5H),8.39(s,0.5H),7.81(s,1H),6.91-7.00(m,2H),6.65-6.70(m,0. 5H),6.56-6.61(m,0.5H),4.04-4.84(brs,1H),3.58-3.97(m,4H),3.28 -3.56(m,4.5H),3.16-2.24(m,0.5H),2.32-2.64(m,7.5H),1.96-2.25( m, 2.5H), 1.38-1.78 (m, 15H), 1.33 (t, J = 7.2Hz, 3H), 1.02-1.17 (m, 8H).

[1414] Example 104: (S)-3-((1-(5-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)pyrimidine-4- (3-yl)pyrrolidine-3-yl)methyl)-N-(ethanesulfonyl)-3-azaspiro[5.5]undecane-9-carboxamide

[1415]

[1416] Following the method described in Example 36, intermediate 81 was used instead of intermediate 29 to obtain the target compound. MS m / z [LC-MS]: 673.35 [M+1]. 1 H NMR (400MHz, CDCl3): δ = 8.44 (s, 0.5H), 8.42 (s, 0.5H), 7.87 (s, 1H), 6.94 -7.05(m,2H),6.68-6.71(m,0.5H),6.50-6.55(m,0.5H),4.03-4.12(m,0. 5H),3.63-3.92(m,2.5H),3.30-3.62(m,5.5H),2.86-3.28(m,5.5H),2.55 -2.85(m,3H),2.12-2.38(m,3H),1.48-1.95(m,10H),1.08-1.36(m,14H).

[1417] Example 105: (S)-2-((4-(3-((9-((4-acryloylpiperazin-1-yl)sulfonyl)-3,9-diazaspiro [5.5] Undecane-3-yl)methyl)pyrrolidone-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1418]

[1419] Step 1: (S)-4-((9-((1-(5-(2-(diisopropylaminoformyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-3-yl)methyl)-3,9-diazaspiro[5.5]undecane-3-yl)sulfonyl)piperazine-1-carboxylic acid tert-butyl ester

[1420] Following the method in step 1 of Example 83, intermediate 66 was replaced with intermediate 79, and (1S,4S)-5-(chlorosulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester was replaced with 4-(chlorosulfonyl)piperazine-1-carboxylic acid tert-butyl ester to obtain the target compound. MS m / z [LC-MS]: 801.45 [M+1].

[1421] Step 2: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-(piperazin-1-ylsulfonyl)-3,9-diazaspiro[5.5]undecane-3-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

[1422] Following the method in step 2 of Example 83, the target compound was obtained by replacing (1S,4S)-5-(N-(2-((S)-1-(5-( ...

[1423] Step 3: (S)-2-((4-(3-((9-((4-acryloylpiperazin-1-yl)sulfonyl)-3,9-diazaspiro[5.5]undecane-3-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

[1424] Following the method in step 3 of Example 83, the target compound was obtained by replacing 2-((4-(3-((9-(piperazin-1-ylsulfonyl)-3,9-diazaspiro[5.5]undecane-3-yl)methyl)pyrrolidine-1-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride. MS m / z [LC-MS]: 755.41 [M+1]. 1H NMR (400MHz, CDCl3): δ = 8.40 (s, 0.5H), 8.39 (s, 0.5H), 7.81 (s, 1H), 6.88-6.99 (m, 2H),6.63-6.67(m,0.5H),6.48-6.57(m,1.5H),6.29(dd,J=16.8Hz,1.6Hz,1H),5. 72(dd,J=10.4Hz,1.6Hz,1H),3.54-3.86(m,7...

Claims

1. The following compounds or their pharmaceutically acceptable salts: ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； 。

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