WO2022253309A1

WO2022253309A1 - Substituted heterocyclic compounds and application thereof

Info

Publication number: WO2022253309A1
Application number: PCT/CN2022/096814
Authority: WO
Inventors: 袁保昆; 陈坤成; 白云; 许新合; 刘志华; 陈曦; 任仁; 雷永珂; 段小伟; 刘希杰; 李红娟; 孙颖慧
Original assignee: 首药控股(北京)股份有限公司
Priority date: 2021-06-03
Filing date: 2022-06-02
Publication date: 2022-12-08
Also published as: CN117412964A

Abstract

The present application relates to a class of substituted heterocyclic compounds that are represented by formula (III) and that have cell proliferation inhibitory activity, a preparation method therefor, and a use thereof. The use comprises a use of the compounds represented by formula (III) in the preparation of a drug for the treatment of MLL-related diseases. In the preparation process, the compounds of the present invention are obtained by means of a series of reactions such as substitution, cyclization, and deprotection.

Description

Substituted Heterocyclic Compounds and Their Applications

cross reference

This application requires the Chinese patent application No. 202110617682.0 filed on June 3, 2021 with the title of "Substituted Heterocyclic Compounds as Menin-MLL Inhibitors", and the patent titled "Substituted Heterocyclic Compounds as Menin-MLL Inhibitors" Chinese Patent Application No. 202111066260.5 for Cyclic Compounds as Menin-MLL Inhibitors, Chinese Patent Application No. 202111607724.9 with the patent title "Substituted Heterocyclic Compounds as Menin-MLL Inhibitors", filed on December 24, 2021 The Chinese patent application No. 202210110663.3 filed on February 7, 2022 with the title "Substituted Heterocyclic Compounds as Menin-MLL Inhibitors" and the patent titled "Substituted Heterocyclic Compounds as Menin-MLL Inhibitors" on April 2, 2022 - The priority of Chinese patent application No. 202210340962.6 of "MLL Inhibitor", the entire disclosure content of which is incorporated herein by reference in its entirety.

technical field

The present invention generally relates to novel substituted heterocyclic compounds having Menin-MLL interaction inhibitory activity, methods for their preparation, and pharmaceutical compositions thereof, as well as to such compounds and pharmaceutical compositions thereof, which benefit from the inhibition of Menin-MLL interaction diseases, such as the treatment of acute leukemia.

Background technique

Acute leukemias are usually caused by acquired mutations in hematopoietic progenitor cells. In these leukemia disorders, chromosomal abnormalities are often a discrete mutational signature. Many chromosomal abnormalities are due to specific translocations leading to the formation of fusion genes that become drivers of tumorigenesis.

Acute leukemia in both adults and children can be caused by a rearrangement of the MLL gene located on chromosome 11q23, which produces a chimeric gene that encodes an oncogenic fusion protein consisting of the N-terminus of MLL with more than 80 It is fused to the C-terminus of one of the known fusion partners (Meyer et al., 2018). MLL fusion proteins bind to DNA/chromatin and induce leukemic transformation of hematopoietic stem and progenitor cells by deregulating transcription of fusion protein target genes. Depending on the progenitor cell of origin, MLLr can manifest as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), or a minority of mixed-phenotype acute leukemia (MPAL). In addition, MLL translocations can also be observed in ~33% of treatment-associated acute leukemias, usually following treatment with topoisomerase II inhibitors (Winters 2017).

MLL gene rearrangements occur in 5-10% of acute leukemias and are more prevalent especially in infants (up to 70% of cases) (Krivtsov 2007). The incidence of MLLr-ALL has a peak in the first 2 years, declines in childhood and adolescence, and then increases steadily with age. A similar pattern was observed in patients with MLLr AML, which was observed in nine other cases except for a postnatal peak in infants with ALL (Meyer 2018). The MLLr leukemia subtype is characterized by aggressiveness, resistance to treatment, and high frequency of early relapses even after an initial complete remission (Armstrong 2002; Krivtsov 2007; Pieters 2007; Muntean 2012; Sanjuan Pla, 2015 year). MLLr in childhood ALL is a strong predictor of poor outcome (Inaba 2013; Zhang 2019). In the Interfant-06 study, children with MLLr ALL had a 6-year event-free survival (EFS) rate of 36.4% (Pieters 2019). In a large cohort of pediatric AML patients with various MLL rearrangements, 5-year EFS and overall survival (OS) were worse (38% EFS and 58% OS) (Guest 2016) (Zwaan 2015). Due to the high-risk classification of MLLr leukemia, clinical chemotherapy regimens are aggressive, with significant short-term toxicity and serious long-term health effects in surviving patients. Pediatric MLLr acute leukemia is a disease with a poor prognosis, and new therapeutic approaches are urgently needed to improve prognosis.

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

Recent studies have shown that nucleophosmin 1 (NPM1c) cells also depend on the interaction of Menin with wtMLL to maintain this leukemogenesis and that these cells are sensitive to the blockade of Menin-MLL binding (Uckelmann 2020). MLLr and NPM1c are targeted in the same manner because the MLL fusion protein and wt-MLL share an N-terminal domain. Therefore, NPM1c acute myeloid leukemia is also a focus of the adult acute leukemia clinical development program.

Inhibitors of the Menin-MLL interaction demonstrated activity in a line of cells containing MLLr fusions, disrupting the interaction between Menin and the MLL1 fusion protein required for leukemogenesis activity, thereby affecting the expression of key oncogenes and leading to growth arrest and inhibition of cell proliferation. Such inhibitors have shown strong single-agent activity in a variety of leukemia xenograft models, and have good survival benefits after oral administration in non-clinical models (Cierpicki 2014; Bojin 2015). Taken together, these data suggest that pharmacological inhibition of the Menin-MLL interaction is a potential targeted strategy for the treatment of MLLr acute leukemia.

At present, no Menin-MLL inhibitor has been approved for marketing, and three inhibitors have recently entered the clinical research stage. Syndax's inhibitor SNDX-5613 first entered phase I/II clinical research (NCT04065399) on August 22, 2019, targeting acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) with MLL rearrangement or NPM1 mutation , mixed lineage acute leukemia (MLAL), mixed phenotype acute leukemia (MPAL), and unknown lineage acute leukemia (ALAL). Immediately after, Kura's inhibitor KO-539 started phase I/II clinical research (NCT04067336) on August 26, 2019, targeting advanced malignant tumors, AML, mixed lineage leukemia (MLL), MLAL, MPAL, ALAL. Recently, Janssen started the clinical phase I study of JNJ-75276617 (NCT04065399) on March 21, 2021, targeting acute leukemia, AML, and ALL. The molecular structures of the first two inhibitors have been disclosed, but the structure of the latter has not. Bayer, Agios, University of Michigan, University of Pennsylvania, Sumitomo, etc. also have patent arrangements.

Inhibition of the interaction between Menin and MLL fusion proteins by small molecules has proven to be a potential therapeutic strategy for the treatment of MLL-r leukemia, and has proven clinical translational value. More effective and selective small molecule inhibitors are crucial for in vivo research. We use computer-aided drug design as a means to discover compounds with novel structures, and achieve what we want with stronger potency and better drugs through structural modification. medicinal purpose.

Contents of the invention

The present invention provides a compound represented by formula (III) or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof,

in,

Y ₃ is NR ₆ or

X is

L is a bond, -(CO)-, or -CH ₂ -,

V is N or CH,

U is N or CR ₁₆ ,

Ring A is a 3-12 membered carbocyclic ring or a 3-12 membered heterocyclic ring,

Ring B is a benzene ring or a 5-6 membered heteroaromatic ring,

The C ring is a 3-12 member nitrogen-containing heterocycle,

Y ₁ is -O-, -S-, -NR ₁₃ -, or -CR ₁₁ R ₁₂ -,

Y ₂ is a bond, -O-, -S-, or -NR ₁₃ -,

R ₆ is -CN, C _1-6 alkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -(CO)-CH=CH ₂ ,

or

The alkyl, aryl and heteroaryl groups can be optionally substituted by halogen, CF ₃ , C _1-6 alkyl, -NR ₁₃ R ₁₄ or -OR ₁ ,

R ₇ is hydrogen, -OR ₁₃ , -NR ₁₃ R ₁₄ , C _1-6 alkyl, or C _3-8 cycloalkyl, and the C _1-6 alkyl or C _3-8 cycloalkyl can be optionally replaced by halogen,

Z is -(CO)-NR ₁₃ R ₁₄ or -(CO)-OR ₁₃ ,

R ₁ is hydrogen, halogen, CN, NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, CF ₃ , -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) ₂ R ₁₅ , -S(O) ₂ NR ₁₃ R ₁₄ , -S(O) ₂ OR ₁₃ , -OS(O) ₂ R ₁₅ , -NR ₁₃ -S(O) ₂ R ₁₅ ,

or

R ₂ are each independently hydrogen, halogen, CN, NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl , CF ₃ , -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) ₂ R ₁₅ , -S(O) ₂ NR ₁₃ R ₁₄ , -S(O) ₂ OR ₁₃ , -OS (O) ₂ R ₁₅ , -NR ₁₃ -S(O) ₂ R ₁₅ ,

or

_R3 is halogen,

R ₄ is hydrogen, halogen, CN, NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, CF ₃ , -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) ₂ R ₁₅ , -S(O) ₂ NR ₁₃ R ₁₄ , -S(O) ₂ OR ₁₃ , -OS(O) ₂ R ₁₅ , -NR ₁₃ -S(O) ₂ R ₁₅ ,

or

R ₅ are each independently hydrogen, halogen, CN, NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl , CF ₃ , -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) ₂ R ₁₅ , -S(O) ₂ NR ₁₃ R ₁₄ , -S(O) ₂ OR ₁₃ , -OS (O) ₂ R ₁₅ , -NR ₁₃ -S(O) ₂ R ₁₅ ,

or

R ₁₁ and R ₁₂ are each independently selected from H, halogen, CN, OH, C _1-6 alkyl, C _1-6 alkyl-O-, C _3-8 cycloalkyl, amino, C _1-6 alkane Baseamino or C _2-8 dialkylamino; said C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 alkylamino or C _2-8 dialkylamino can optionally be halogen substitution,

R ₁₅ are each independently selected from H, 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, the C _1-6 alkyl, C _3-8 cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered hetero Aryl, C _2-6 alkenyl or C _2-6 alkynyl 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 is substituted,

R ₄₁ is H or C _1-6 alkyl, said alkyl may be optionally substituted by halogen, -CN, -NR ₁₃ R ₁₄ or -OR ₁₃ ,

R ₄₂ and R ₄₃ are each independently selected from H and halogen,

R ₁₃ and R ₁₄ are each independently selected from hydrogen, C _1-6 alkyl and C _3-8 cycloalkyl, said C _1-6 alkyl or C _3-8 cycloalkyl may be optionally substituted by halogen ,

R ¹⁶ is selected from H, halogen, CN, OH, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, amino, C _1-6 alkylamino or C _2-8 di Alkylamino; the C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, C _1-6 alkylamino or C _2-8 dialkylamino can optionally be halogen substitution,

R ₃₀ and R ₃₁ are each independently selected from hydrogen, C _1-6 alkyl and C _3-8 cycloalkyl,

R ₄₀ is selected from hydrogen, -CN, -(CO)-CH═CH ₂ , C _1-6 alkyl and C _3-8 cycloalkyl, the C _1-6 alkyl or C _3-8 cycloalkyl optionally substituted by halogen,

m is each independently 0, 1, or 2,

n is each independently 0, 1, 2, or 3,

p is each independently 0 or 1.

In some embodiments, _Y3 is

In some embodiments, ring C is a 3-6 membered nitrogen-containing heterocycle.

In some embodiments, the C ring is

In some embodiments, L is a bond.

In some embodiments, V is N.

In some embodiments, p is 1.

In some embodiments, each m is independently 0 or 1.

In some embodiments, each n is independently 0 or 1.

In some embodiments, Z is -(CO)-NR ₁₃ R ₁₄ .

In some embodiments, Y ₂ is a bond or -NR ₁₃ -.

In some embodiments, Y ₁ is -NR ₁₃ -.

In some embodiments, U is N.

In some embodiments, R ₆ is

In some embodiments, Z is -(CO)-NR ₁₃ R ₁₄ .

In some embodiments, R ₁ is hydrogen, halogen, CN, NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-6 alkenyl, or C _{2 -6} alkynyl.

In some embodiments, each R ₂ is independently hydrogen, halogen, CN, NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, CF ₃ , -NR ₁₃ R ₁₄ , or -OR ₁₃ .

In some embodiments, R ₃ is fluoro.

In some embodiments, R ₄ is hydrogen, halogen, CN, NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-6 alkenyl, C _{2- 6} alkynyl, CF ₃ , -NR ₁₃ R ₁₄ , or -OR ₁₃ .

In some embodiments, each R ₅ is independently hydrogen, halogen, CN, NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, CF ₃ , -NR ₁₃ R ₁₄ , or -OR ₁₃ .

In some embodiments, R ₁₁ and R ₁₂ are hydrogen.

In some embodiments, R ₁₃ and R ₁₄ are each independently selected from hydrogen and C _1-6 alkyl, preferably hydrogen and C _1-3 alkyl;

In some embodiments, R ₁₅ is selected from C _1-6 alkyl and C _3-8 cycloalkyl, preferably C _1-6 alkyl.

In some embodiments, R ₄₂ and R ₄₃ are H.

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,

in,

Y ₃ is NR ₆ or

X is

L is a bond, -(CO)-, or -CH ₂ -,

V is N or CH,

U is N or CR ₁₆ ,

Ring B is a benzene ring or a 5-6 membered heteroaromatic ring,

The C ring is a 3-12 member nitrogen-containing heterocycle,

Y ₁ is -O-, -S-, -NR ₁₃ -, or -CR ₁₁ R ₁₂ -,

Y ₂ is a bond, -O-, -S-, or -NR ₁₃ -,

R ₆ is -CN, C _1-6 alkyl, 5-12 membered heteroaryl, -(CO)-CH=CH ₂ ,

or

The alkyl group can be optionally substituted by halogen,

Z is -(CO)-NR ₁₃ R ₁₄ or -(CO)-OR ₁₃ ,

or

_R3 is halogen,

or

R ₁₅ are each independently selected from H, C _1-6 alkyl, C _3-8 cycloalkyl, 3-12 membered heterocycloalkyl, C _2-6 alkenyl and C _2-6 alkynyl, the C _1-6 alkyl, C _3-8 cycloalkyl, 3-12 membered heterocycloalkyl, C _2-6 alkenyl or C _2-6 alkynyl can be optionally replaced by halogen, -(CO)-R ₄₁ , or -(CO)-CH=CHR ₄₁ substituted,

R ₄₁ is H or C _1-6 alkyl, the alkyl may be optionally substituted by -NR ₁₃ R ₁₄ or -OR ₁₃ ,

m is each independently 0, 1, or 2,

n is each independently 0, 1, 2, or 3,

p is each independently 0 or 1.

In some embodiments, _Y3 is

In some embodiments, ring C is a 3-6 membered nitrogen-containing heterocycle.

In some embodiments, L is a bond.

In some embodiments, V is N.

In some embodiments, p is 1.

In some embodiments, each m is independently 0 or 1.

In some embodiments, each n is independently 0 or 1.

In some embodiments, Z is -(CO)-NR ₁₃ R ₁₄ .

In some embodiments, Y ₂ is a bond or -NR ₁₃ -.

In some embodiments, Y ₁ is -NR ₁₃ -.

In some embodiments, U is N.

In some embodiments, R ₆ is

In some embodiments, Z is -(CO)-NR ₁₃ R ₁₄ .

In some embodiments, R ₃ is fluoro.

In some embodiments, R ₁₁ and R ₁₂ are hydrogen.

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,

in,

X is

L is a bond or -CH ₂ -,

V is N or CH,

U is N or CR ₁₆ ,

Ring B is a benzene ring or a 5-6 membered heteroaromatic ring,

The C ring is a 3-12 member nitrogen-containing heterocycle,

Y ₁ is -O-, -S-, -NR ₁₃ -, or -CR ₁₁ R ₁₂ -,

Y ₂ is a bond, -O-, -S-, or -NR ₁₃ -,

R ₆ is C _1-6 alkyl,

or

The alkyl group can be optionally substituted by halogen,

Z is -(CO)-NR ₁₃ R ₁₄ or -(CO)-OR ₁₃ ,

or

_R3 is halogen,

or

R ₁₅ are each independently selected from H, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-6 alkenyl and C _2-6 alkynyl, the C _1-6 alkyl, C _{3- 8} cycloalkyl, C _2-6 alkenyl or C _2-6 alkynyl may be optionally substituted by halogen,

m is each independently 0, 1, or 2,

n is each independently 0, 1, 2, or 3,

p is each independently 0 or 1.

In some embodiments, L is a bond.

In some embodiments, V is N.

In some embodiments, p is 1.

In some embodiments, each m is independently 0 or 1.

In some embodiments, each n is independently 0 or 1.

In some embodiments, Z is -(CO)-NR ₁₃ R ₁₄ .

In some embodiments, Y ₂ is a bond or -NR ₁₃ -.

In some embodiments, Y ₁ is -NR ₁₃ -.

In some embodiments, U is N.

In some embodiments, R ₆ is

In some embodiments, Z is -(CO)-NR ₁₃ R ₁₄ .

In some embodiments, R ₃ is fluoro.

In some embodiments, R ₁₁ and R ₁₂ are hydrogen.

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,

in,

X is

U is N or CR ₁₆ ,

Ring B is a benzene ring or a 5-6 membered heteroaromatic ring,

The C ring is a 3-12 member nitrogen-containing heterocycle,

Y ₁ is -O-, -S-, -NR ₁₃ -, or -CR ₁₁ R ₁₂ -,

Y ₂ is a bond, -O-, -S-, or -NR ₁₃ -,

_R6 is

or

Z is -(CO)-NR ₁₃ R ₁₄ or -(CO)-OR ₁₃ ,

or

_R3 is halogen,

or

R ₁₅ is selected from H, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-6 alkenyl and C _2-6 alkynyl, the C _1-6 alkyl, C _3-8 cycloalkane Base, C _2-6 alkenyl or C _2-6 alkynyl may be optionally substituted by halogen,

m is each independently 0, 1, or 2,

n is each independently 0, 1, 2, or 3,

p is each independently 0 or 1.

In some embodiments, p is 1.

In some embodiments, each m is independently 0 or 1.

In some embodiments, each n is independently 0 or 1.

In some embodiments, Z is -(CO)-NR ₁₃ R ₁₄ .

In some embodiments, Y ₂ is a bond or -NR ₁₃ -.

In some embodiments, Y ₁ is -NR ₁₃ -.

In some embodiments, U is N.

In some embodiments, R ₆ is

In some embodiments, Z is -(CO)-NR ₁₃ R ₁₄ .

In some embodiments, R ₃ is fluoro.

In some embodiments, R ₁₁ and R ₁₂ are hydrogen.

in,

X is

U is N or CR ₁₆ ,

Ring B is a benzene ring or a 5-6 membered heteroaromatic ring,

The C ring is a 3-8 membered nitrogen-containing heterocycle,

Y ₁ is -O-, -S-, -NR ₁₃ -, or -CR ₁₁ R ₁₂ -,

Y ₂ is -O-, -S-, or -NR ₁₃ -,

_R6 is

or

Z is -(CO)-NR ₁₃ R ₁₄ or -(CO)-OR ₁₃ ,

or

R ₂ is hydrogen, halogen, CN, NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, CF ₃ , -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) ₂ R ₁₅ , -S(O) ₂ NR ₁₃ R ₁₄ , -S(O) ₂ OR ₁₃ , -OS(O) ₂ R ₁₅ , -NR ₁₃ -S(O) ₂ R ₁₅ ,

or

_R3 is halogen,

or

R ₅ is hydrogen, halogen, CN, NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, CF ₃ , -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) ₂ R ₁₅ , -S(O) ₂ NR ₁₃ R ₁₄ , -S(O) ₂ OR ₁₃ , -OS(O) ₂ R ₁₅ , -NR ₁₃ -S(O) ₂ R ₁₅ ,

or

m is each independently 0, 1, or 2,

n is each independently 0, 1, 2, or 3,

p is each independently 0 or 1.

In some embodiments, p is 1.

In some embodiments, each m is independently 0 or 1.

In some embodiments, each n is independently 0 or 1.

In some embodiments, Z is -(CO)-NR ₁₃ R ₁₄ .

In some embodiments, Y ₂ is -NR ₁₃ -.

In some embodiments, Y ₁ is -NR ₁₃ -.

In some embodiments, U is N.

In some embodiments, R ₆ is

In some embodiments, Z is -(CO)-NR ₁₃ R ₁₄ .

In some embodiments, R ₂ is hydrogen, halogen, CN, NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-6 alkenyl, C _{2- 6} alkynyl, CF ₃ , -NR ₁₃ R ₁₄ , or -OR ₁₃ .

In some embodiments, R ₃ is fluoro.

In some embodiments, R ₅ is hydrogen, halogen, CN, NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-6 alkenyl, C _{2- 6} alkynyl, CF ₃ , -NR ₁₃ R ₁₄ , or -OR ₁₃ .

In some embodiments, R ₁₁ and R ₁₂ are hydrogen.

In another aspect, the present invention provides the following compound or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof,

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 a pharmaceutically acceptable Carrier.

In another aspect, the present invention provides a method for treating a disease associated with MLL activity, comprising administering to a subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, polymorph, tautovariant Constructs, metabolites or prodrugs, or the 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 myelogenous leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma (including B-cell lymphoid cancer), 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, chorioepithelial tumor, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, urothelial cancer, kidney cancer, renal cell carcinoma, prostate cancer, testicular tumor, testicular cancer Germ cell tumor, ovarian germ cell tumor, Wilms tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue sarcoma, or skin cancer.

A compound of the invention, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof, or a pharmaceutical composition of the invention, for use in combination with at least one different pharmaceutical agent , wherein the different agents are selected from antitumor alkylating agents, antitumor antibiotics, plant-derived antitumor drugs, antitumor platinum coordination compounds, antitumor camptothecin derivatives, antitumor tyrosine kinase inhibitors , anti-tumor serine/threonine kinase inhibitors, anti-tumor phospholipid kinase inhibitors, anti-tumor monoclonal antibodies, interferons, biological response modifiers, hormone preparations, angiogenesis inhibitors, immune checkpoint inhibitors, epigenetic At least one agent of biologically related molecular inhibitors, protein post-translational modification inhibitors, proteasome inhibitors and other anti-tumor drugs.

In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention for use in the preparation of 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 mutation Acute leukemia, MOZ acute leukemia, NUP98 acute leukemia and CALM acute leukemia), chronic lymphocytic leukemia, chronic myelogenous leukemia, myelodysplastic syndrome, 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, chorioepithelial tumor, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, urothelial cancer, 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.

Detailed description of the invention

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 present invention may be better understood by reference to the following summary.

It should be understood that the protection scope of each aspect of the present invention is determined by the claims, and the methods and structures within the scope of these claims and their equivalent methods and structures are all within the scope covered by the claims.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited in their entirety herein are hereby incorporated by reference in their entirety unless otherwise indicated.

It is to be understood that both the foregoing brief description and the following detailed description are exemplary and explanatory and are not restrictive of any of the inventive subject matter. The use of the singular includes the plural unless specifically stated otherwise. The use of "or", "or" means "and/or" unless otherwise stated. Furthermore, the use of the term "comprises" as well as other forms, such as "comprises", "comprises" and "comprises" is not limiting.

certain chemical terms

The terms "optional,""optional," or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes that said event or circumstance occurs and that it does not. For example, "optionally substituted alkyl" means "unsubstituted alkyl" or "substituted alkyl". And, optionally substituted groups can be unsubstituted (eg: -CH ₂ CH ₃ ), fully substituted (eg: -CF ₂ CF ₃ ), monosubstituted (eg: -CH ₂ CH ₂ F) or _Any hierarchy between monosubstitution and full substitution (for example: _-CH2CHF2 , _-CF2CH3 , -CFHCHF2 _, _etc. ). It will be appreciated by those skilled in the art that for any group containing one or more substituents, no sterically impossible and/or synthetically impossible substitution or substitution pattern is introduced.

Unless otherwise stated, conventional methods within the skill 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 specific definitions are set forth, the relevant terms, as well as the laboratory procedures and techniques herein, in analytical chemistry, synthetic organic chemistry, and pharmaceutical and medicinal chemistry are those known in the art. Standard techniques can be used in chemical syntheses, chemical analyses, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, reactions and purifications can be carried out using the manufacturer's instructions for the kit, or by methods known in the art or as described herein. The techniques and methods described above can generally be performed according to conventional methods well known in the art as described in various general and more specific documents that are cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable moieties and compounds.

When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH ₂ O- is equivalent to -OCH ₂ -.

The terms "group" and "chemical group" as used herein refer to a specific part or functional group of a molecule. Chemical groups are often thought of as chemical entities embedded or attached to a molecule.

Some of the chemical groups named here may use an abbreviated notation to indicate the total number of carbon atoms. For example, C ₁ -C ₆ alkyl describes an alkyl group, as defined below, having a total of 1 to 6 carbon atoms. The total number of carbon atoms indicated by the abbreviation does not include the carbon atoms on the possible substituents.

The term "halogen", "halo" or "halide" refers to bromine, chlorine, fluorine or iodine.

As used herein, the terms "aromatic", "aromatic ring", "aromatic", "aromatic", and "aromatic ring" refer to a planar ring or ring moiety having 4n+2 A delocalized electron conjugate system of electrons, where n is an integer. Aromatic rings may be formed by 5, 6, 7, 8, 9 or more atoms. The aromatic compound may be optionally substituted and may be monocyclic or polycyclic with fused rings. The term aromatic includes all carbocyclic rings (eg benzene rings) and rings containing one or more heteroatoms (eg pyridine).

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

The terms "fused" or "fused ring", as used herein, alone or in combination, refer to a cyclic structure in which two or more rings share one or more bonds.

The terms "spiro" or "spirocycle" as used herein, alone or in combination, refer to a ring structure in which two or more rings share one or more atoms.

The term "alkyl" as used herein alone or as part of another component (e.g. monoalkylamino) refers to an optionally substituted linear or optionally substituted branched monovalent saturated hydrocarbon having 1-12 carbon atoms, preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms, are connected to other parts of the molecule through 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.

The term "alkenyl" as used herein, alone or in combination, refers to an optionally substituted straight chain or optionally substituted branched monovalent hydrocarbon radical having one or more C=C double bonds and having from 2 to about 10 carbons atoms, more preferably 2 to about 6 carbon atoms. The double bond in these groups can be in either the cis or trans configuration and should be understood to encompass both isomers. Examples include, but are not limited to vinyl (CH=CH ₂ ), 1-propenyl (CH ₂ CH=CH ₂ ), isopropenyl (C(CH ₃ )=CH ₂ ), butenyl, and 1,3-but dienyl etc. When the alkenyl defined herein appears in a numerical range, for example, "C ₂ -C ₆ alkenyl" or "C ₂ - ₆ alkenyl" means that it can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms Atoms or alkenyl groups composed of 6 carbon atoms, the alkenyl group herein also covers the case where the numerical range is not specified.

The term "alkynyl" as used herein, alone or in combination, refers to an optionally substituted linear 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, 1,3-butadiynyl, and the like. When the alkynyl group defined herein appears in a numerical range, for example, "C ₂ -C ₆ alkynyl" or "C ₂ - ₆ alkynyl" means that it can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms atom or an alkynyl group composed of 6 carbon atoms, the alkynyl group herein also covers the situation where the numerical range is not specified.

The term "aryl" refers to an all-carbon monocyclic or fused ring having a fully conjugated pi-electron system, having 6-14 carbon atoms, preferably 6-12 carbon atoms, most preferably 6 carbon atoms . Aryl 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, hydroxy, sulfonyl , sulfinyl, phosphoryl and heteroalicyclic. Non-limiting examples of unsubstituted aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.

The terms "heteroaryl", "heteroaromatic ring" refer to a single or condensed ring of 5-12 ring atoms, having 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, containing 1, 2, 3 or 4 ring atoms selected from N, O, S, the rest of the ring atoms are C, and have 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 hetero Alicyclic. Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, iso Quinolinyl, tetrazolyl, triazinyl.

The term "cycloalkyl" as used herein alone or in combination refers to a stable monovalent non-aromatic monocyclic or polycyclic hydrocarbon radical containing only carbon and hydrogen atoms, which may include fused, spiro or bridged ring systems, including 3-15 ring-forming carbon atoms, preferably 3-10 ring-forming carbon atoms, more preferably 3-8 ring-forming carbon atoms, can be saturated or unsaturated, connected to other parts of the molecule through a single bond. Non-limiting examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

The terms "heterocyclyl", "heterocycloalkyl" and "heterocycle" as used herein alone or as part of another composition refer to a stable 3-18 membered monovalent non-aromatic ring comprising 2-12 carbon atoms, 1 -6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise specified, a heterocyclyl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may contain fused, spiro or bridged ring systems, and the nitrogen, carbon or sulfur on the heterocyclyl can be optionally The nitrogen atom can be optionally quaternized, and the heterocyclic group can be partially or fully saturated. A heterocyclyl group can be attached to the rest of the molecule by a single bond through a ring carbon atom or a heteroatom. A heterocyclyl group containing fused rings may contain one or more aromatic or heteroaryl rings, as long as the non-aromatic ring atoms are attached to the rest of the molecule. For the purposes of this application, the heterocyclic group is preferably a stable 4-11 membered monovalent non-aromatic monocyclic or bicyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable A 4-8 membered monovalent non-aromatic monocyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclyl include azepanyl, azetidinyl, decahydroisoquinolinyl, dihydrofuryl, indolinyl, dioxolyl, 1,1 -dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, Piperazinyl, piperidinyl, 4-piperidinonyl, pyranyl, pyrazolidinyl, pyrrolidinyl, quinazinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl and the like.

The term "carbocycle" refers to a structure covalently closed by carbon, which may be saturated or partially unsaturated. Carbocyclic rings may be formed by 3, 4, 5, 6, 7, 8, 9 or more atoms. The difference between the terms carbocycle and heterocycle is that the ring skeleton of the heterocycle contains at least one atom different from carbon. The "carbocycle" herein may be monocyclic or polycyclic, and polycyclic carbocycles include spiro rings, fused rings and bridged rings. Carbocycles can be optionally substituted. A "carbocycle" herein preferably contains from about 5 to about 20 or 5 to 10 or 5-8 or 5-6 skeletal ring atoms.

As used herein, the term "polymorph" or "polymorphism (phenomenon)" means that the compounds of the present invention have multiple crystal lattice forms. Some compounds of the present invention may have more than one crystal form, and the present invention covers all polymorphic forms or mixtures thereof.

Intermediate compounds of the compounds of the present invention and polymorphs thereof are also within the scope of the present invention.

Unless otherwise specified, olefinic double bonds contained in the compounds of the present invention include both E and Z isomers.

Compounds of the present invention include compounds having one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of that element. For example, a reference to hydrogen includes within its scope1H, ^2H (D) ^and3H ( ^T ). Similarly, references to carbon and oxygen include within their scope12C, ^13C , ^and14C ^and16O ^and18O , respectively ^.

It is understood that compounds of the present invention may contain asymmetric centers. These asymmetric centers can independently be in the R or S configuration. It will be apparent to those skilled in the art that some of the compounds of the present invention may also exhibit cis-trans isomerism. It is to 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 may be isolated from their mixtures by implementation or adaptation of known methods, such as chromatographic techniques and recrystallization techniques, or they may be prepared separately from appropriate isomers of their intermediates.

The term "pharmaceutically acceptable salt" as used herein includes both salts and bases.

"Pharmaceutically acceptable salt addition" refers to those salts that retain the biological potency and properties of the free base of the compound, are not biologically or otherwise undesirable, and are combined with inorganic acids such as, but not limited to, hydrochloric acid, hydrogen Bromic 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, Salts of capric acid, caproic acid, carbonic acid, cinnamic acid, citric acid, etc. "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acid of the compound and are not biologically or otherwise undesirable. These salts are prepared by reacting the free acid with an inorganic or organic base. Salts formed by reacting with inorganic bases 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, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and manganese salts.

Salt-forming organic bases include, but are not limited to, primary, secondary, tertiary, cyclic amines, and the like, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine , dicyclohexylamine, ethylenediamine, purine, piperazine, piperidine, choline and caffeine, etc. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

Crystallization often results in solvates of compounds of the invention. The term "solvate" as used herein refers to a combination of one or more molecules of a compound of the present invention and one or more molecules of a solvent.

The solvent may be water, in which case the solvate is a hydrate. In addition, organic solvents are also possible. Accordingly, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, trihydrates, tetrahydrates, etc., and the corresponding solvated forms. The compounds of the present invention may be true solvates, but in other cases, the compounds of the present invention may only incidentally retain water or a mixture of water and some other solvent. The compounds of the present invention can be reacted in a solvent or precipitated or crystallized in a solvent. Solvates of the compounds of the present invention are also included within the scope of the present invention.

The term "pharmaceutical composition" as used herein refers to a preparation of a compound of the present invention in admixture with a vehicle generally accepted in the art for delivering a biologically active compound to a mammal, such as a human. This medium contains all pharmaceutically acceptable carriers.

The term "acceptable" as used herein in relation to a formulation, composition or ingredient means that there is no persistent adverse effect on the general health of the subject being treated.

The term "pharmaceutically acceptable" as used herein refers to 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 nontoxic, i.e., the substance can be administered to an individual without causing adverse biological effects. React or interact in an undesirable manner with any component contained in the composition.

"Pharmaceutically acceptable carriers" include but are not limited to adjuvants, carriers, excipients, auxiliary agents, deodorants, diluents, preservatives, Dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersing agents, suspending agents, stabilizing agents, isotonic agents, solvents, or emulsifying agents.

The term "subject", "patient", "subject" or "individual" as used herein refers to an individual suffering from a disease, disorder or condition, etc., including mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (such as chimpanzees and other apes and monkeys); livestock such as cattle, horses, sheep, goats, pigs; domesticated animals , such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the related methods and compositions provided herein, the mammal is a human.

The term "treatment" as used herein refers to the treatment of relevant diseases or conditions in mammals, especially humans, including

(i) preventing the development of a disease or condition in mammals, particularly mammals that have been previously exposed to a disease or condition but have not been diagnosed with the disease or condition;

(ii) inhibiting a disease or condition, i.e. controlling its development;

(iii) ameliorating a disease or condition, i.e. causing regression of the disease or condition;

(iv) Relief of symptoms caused by a disease or disorder.

As used herein, the terms "disease" and "disorder" can be used interchangeably or with different meanings, as some specific diseases or conditions do not have a known causative agent (so the cause of the disease is unknown), so they cannot yet be recognized as Diseases can only be seen as unwanted conditions or syndromes with more or less specific symptoms that have been confirmed by clinical researchers.

The term "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" as used herein refers to at least one agent or compound which, when administered, is sufficient to relieve to some extent one or more symptoms of the disease or condition being treated amount. The result may be a reduction and/or alleviation of a sign, symptom or cause, or any other desired change in a biological system. For example, a therapeutically "effective amount" is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant disease-modifying effect. Effective amounts suitable for any individual case can be determined using techniques such as dose escalation assays.

As used herein, the terms "administering", "administering", "administering" and the like refer to methods capable of delivering a compound or composition to the desired site of biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration and rectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

Preparation of compounds of the present invention

The purpose of the following specific examples is to enable those skilled in the art to understand and implement the present invention more clearly. They should not be considered as limiting the scope of the invention, but only illustrative and typical of the invention. It will be appreciated by those skilled in the art that there are other synthetic routes to the compounds of the present invention and the following non-limiting examples are provided.

All operations involving easily oxidized or hydrolyzed raw materials were carried out under nitrogen protection. Unless otherwise stated, the raw materials used in the present invention are directly purchased from the market and directly used without further purification.

For column chromatography, silica gel (200-300 mesh) produced by Qingdao Chemical Co., Ltd. was used. Thin layer chromatography adopts the prefabricated plate (silica gel 60 PF ₂₅₄ , 0.25 mm) produced by E.Merck Company. Chiral compound separation and enantiomeric excess value (ee) determination using Agilent LC 1200 series (column: CHIRALPAK AD-H,

mm, 5 microns, 30°C). Nuclear magnetic resonance chromatography (NMR) was determined using a Varian VNMRS-400 nuclear magnetic resonance instrument; liquid mass spectrometry (LC/MS) was measured using FINNIGAN Thermo LCQ Advantage MAX, Agilent LC 1200 series (column: Waters Symmetry C18,

mm, 5 μm, 35°C), using ESI (+) ion mode.

Experimental part

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

2-((4-chloropyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide was synthesized according to the method of the same intermediate in Example 253 of patent WO2017214367.

Intermediate 2: (trans-4-(methylsulfonamido)cyclohexyl)methyl 4-methylbenzenesulfonate

(Trans-4-(methylsulfonamido)cyclohexyl)methyl 4-methylbenzenesulfonate was synthesized according to the same method as intermediate 50 in patent WO2017214367.

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

(Trans-4-(Ethylsulfonamido)cyclohexyl)methyl 4-methylbenzenesulfonate was synthesized according to the method of intermediate 50 in patent WO2017214367.

Intermediate 4: N-(trans-4-formylcyclohexyl)methanesulfonamide

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

Intermediate 5: 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N- Isopropyl benzamide

2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzene Formamide was synthesized according to the method of the same intermediate in Example 253 in patent WO2017214367.

Intermediate 6: N-Ethyl-5-fluoro-N-isopropyl-2-((4-((piperidin-4-ylmethyl)amino)pyrimidin-5-yl)oxy)benzoyl amine

Step 1: 4-(((5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)piperidine-1- tert-butyl carboxylate

Add Intermediate 1 (675mg), tert-butyl 4-aminomethylpiperidine-1-carboxylate (642mg) and diisopropylethylamine (774mg) into isopropanol (10mL), stir at 80°C Reacted for 18 hours, after cooling down to room temperature, concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether/ethyl acetate, 1:2) to obtain 4-(((5-(2-(ethyl (isopropyl) amine) (formyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester (880 mg). MS m/z [LC-MS]: 516.30 [M+1].

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

4-(((5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)piperidine-1-carboxylic acid Tert-butyl ester (880 mg) was added to 4N methanolic hydrogen chloride solution (10 mL), stirred at room temperature for 2 hours, concentrated under reduced pressure, adjusted to pH=11-12 with 10% sodium hydroxide solution, and dichloromethane/isopropanol ( 4:1) mixed solvent extraction, the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give N-ethyl-5-fluoro-N-isopropyl-2-((4-((piperidine-4- (methyl)amino)pyrimidin-5-yl)oxy)benzamide (645 mg). MS m/z [LC-MS]: 416.25 [M+1].

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

Step 1: (1R,5S,6s)-6-(((5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)amino) Methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester

Referring to the method of step 1 in intermediate 6, replace 4- Aminomethylpiperidine-1-carboxylate tert-butyl ester to get (1R,5S,6s)-6-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluoro phenoxy)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].

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

Referring to the method of step 2 in intermediate 6, use (1R,5S,6s)-6-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy) Pyrimidin-4-yl)amino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester instead of 4-(((5-(2-(ethyl(isopropyl )carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester to get 2-((4-((((1R,5S ,6r)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)amino)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropyl benzamide. MS m/z [LC-MS]: 414.23 [M+1].

Intermediate 8: 2-((4-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)amino)pyrimidin-5-yl)oxy)-N -Ethyl -5-fluoro-N-isopropylbenzamide

Step 1: (1R,5S,6s)-6-((5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)- tert-butyl 3-azabicyclo[3.1.0]hexane-3-carboxylate

Referring to the method of step 1 in intermediate 6, replace 4-aminomethylpiperene with (1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl Pyridine-1-carboxylic acid tert-butyl ester to get (1R,5S,6s)-6-((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine -4-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester. MS m/z [LC-MS]: 500.27 [M+1].

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

Referring to the method of step 2 in intermediate 6, use (1R,5S,6s)-6-((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine -4-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester instead of 4-(((5-(2-(ethyl(isopropyl)aminomethyl) Acyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)piperidine-1-carboxylate tert-butyl ester to get 2-((4-(((1R,5S,6s)-3 -Azabicyclo[3.1.0]hexan-6-yl)amino)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide. MS m/z [LC-MS]: 400.22 [M+1].

Intermediate 9: 2-((4-(3-(Aminomethyl)azetidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-iso Propyl benzamide

Step 1: ((1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)azetidin-3-yl) Methyl) tert-butyl carbamate

Referring to the method of step 1 in intermediate 6, replace tert-butyl 4-aminomethylpiperidine-1-carboxylate with (azetidin-3-ylmethyl) tert-butyl carbamate to obtain ((1 -(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)azetidin-3-yl)methyl)carbamate butyl ester. MS m/z [LC-MS]: 488.27 [M+1].

Step 2: 2-((4-(3-(Aminomethyl)azetidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropyl phenylbenzamide

Referring to the method of step 2 in intermediate 6, use ((1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)azepine Cyclobutan-3-yl)methyl)carbamate tert-butyl ester instead of 4-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine- 4-base) amino) methyl) piperidine-1-carboxylic acid tert-butyl ester, get 2-((4-(3-(aminomethyl) azetidin-1-yl) pyrimidin-5-yl )oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide. MS m/z [LC-MS]: 388.22 [M+1].

Intermediate 10: 2-((4-(4-aminopiperidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

Step 1: tert-butyl (1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)piperidin-4-yl)carbamate ester

With reference to the method of step 1 in intermediate 6, replace tert-butyl 4-aminomethylpiperidine-1-carboxylate with piperidin-4-ylcarbamic acid tert-butyl ester to obtain (1-(5-(2-( tert-butyl ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)piperidin-4-yl)carbamate. MS m/z [LC-MS]: 502.29 [M+1].

Step 2: 2-((4-(4-Aminopiperidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

Referring to the method of step 2 in intermediate 6, use (1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)piperidine- 4-yl) tert-butyl carbamate instead of 4-(((5-(2-(ethyl(isopropyl) carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl Base) piperidine-1-carboxylate tert-butyl ester to get 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].

Intermediate 11: (R)-2-((4-(3-aminopyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzene Formamide _

Step 1: (R)-(1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl) tert-butyl carbamate

With reference to the method of step 1 in intermediate 6, replace tert-butyl 4-aminomethylpiperidine-1-carboxylate with (R)-pyrrolidin-3-ylcarbamic acid tert-butyl ester to obtain (R)-(1 -(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl)carbamate tert-butyl ester. MS m/z [LC-MS]: 488.27 [M+1].

Step 2: (R)-2-((4-(3-Aminopyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzyl Amide

Referring to the method of step 2 in intermediate 6, use (R)-(1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl )pyrrolidin-3-yl)carbamate tert-butyl ester instead of 4-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl )amino)methyl)piperidine-1-carboxylic acid tert-butyl ester, to get (R)-2-((4-(3-aminopyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N -Ethyl-5-fluoro-N-isopropylbenzamide. MS m/z [LC-MS]: 388.22 [M+1].

Intermediate 12: N-Ethyl-5-fluoro-2-((4-(3-(hydroxymethyl)azetidin-1-yl)pyrimidin-5-yl)oxy)-N-iso Propyl benzamide

Referring to the method of step 1 in intermediate 6, substituting azetidin-3-ylmethanol for tert-butyl 4-aminomethylpiperidine-1-carboxylate, N-ethyl-5-fluoro-2- ((4-(3-(Hydroxymethyl)azetidin-1-yl)pyrimidin-5-yl)oxy)-N-isopropylbenzamide. MS m/z [LC-MS]: 389.20 [M+1].

Intermediate 13: N-Ethyl-5-fluoro-2-((4-(((4-fluoropiperidin-4-yl)methyl)amino)pyrimidin-5-yl)oxy)-N-iso Propyl benzamide

Step 1: 4-(((5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)-4-fluoropiper tert-butyl pyridine-1-carboxylate

With reference to the method of step 1 in intermediate 6, replace tert-butyl 4-aminomethylpiperidine-1-carboxylate with 4-aminomethyl-4-fluoropiperidine-1-carboxylic acid tert-butyl ester to obtain (4 -(((5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidine-1- Tert-Butyl Carboxylate.MS m/z[LC-MS]:534.29[M+1].

Step 2: N-Ethyl-5-fluoro-2-((4-(((4-fluoropiperidin-4-yl)methyl)amino)pyrimidin-5-yl)oxy)-N-isopropyl phenylbenzamide

Referring to the method of step 2 in intermediate 6, use 4-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)amino) Methyl)-4-fluoropiperidine-1-carboxylate tert-butyl ester instead of 4-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine -4-yl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester, to get 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].

Intermediate 14: (R)-2-((4-(3-aminopyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzene Formamide _

Step 1: (S)-((1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl ) methyl) tert-butyl carbamate

With reference to the method of step 1 in intermediate 6, replace tert-butyl 4-aminomethylpiperidine-1-carboxylate with (R)-pyrrolidin-3-ylmethylcarbamate tert-butyl ester to obtain (S)- ((1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)carbamate butyl ester. MS m/z [LC-MS]: 502.29 [M+1].

Referring to the method of step 2 in intermediate 6, use (S)-((1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine-4- Base)pyrrolidin-3-yl)methyl)carbamate tert-butyl ester instead of 4-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine -4-yl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester to get (S)-2-((4-(3-aminomethylpyrrolidin-1-yl)pyrimidin-5-yl )oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide. MS m/z [LC-MS]: 402.23 [M+1].

Intermediate 15: 2-((4-(4-(Aminomethyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzene Formamide _

Step 1: ((1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)piperidin-4-yl)methyl) tert-butyl carbamate

With reference to the method of step 1 in intermediate 6, replace tert-butyl 4-aminomethylpiperidine-1-carboxylate with 4-aminomethyl-4-fluoropiperidine-1-carboxylic acid tert-butyl ester to obtain (( tert-Butyl 1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)piperidin-4-yl)methyl)carbamate . MS m/z [LC-MS]: 516.30 [M+1].

Step 2: 2-((4-(4-(Aminomethyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzyl Amide

Referring to the method of step 2 in intermediate 6, use ((1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)piperidine -4-yl)methyl)carbamate tert-butyl ester instead of 4-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl ) amino) methyl) piperidine-1-carboxylate tert-butyl ester, to get 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].

Intermediate 16: 2-((4-(3-(Aminomethyl)-3-fluoroazetidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro -N-Isopropylbenzamide

Step 1: ((1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-fluoroazetidine- 3-yl)methyl)carbamate tert-butyl ester

Referring to the method of step 1 in intermediate 6, replace tert-butyl 4-aminomethylpiperidine-1-carboxylate with ((3-fluoroazetidin-3-yl)methyl)tert-butyl carbamate , to give ((1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-fluoroazetidine-3 -yl) methyl) tert-butyl carbamate. MS m/z [LC-MS]: 506.26 [M+1].

Step 2: 2-((4-(3-(Aminomethyl)-3-fluoroazetidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro- N-isopropylbenzamide

Referring to the method of step 2 in intermediate 6, use ((1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3 -Fluoroazetidin-3-yl)methyl)carbamate tert-butyl ester instead of 4-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy Base) pyrimidin-4-yl) amino) methyl) piperidine-1-carboxylic acid tert-butyl ester, get 2-((4-(3-(aminomethyl)-3-fluoroazetidine-1 -yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide. MS m/z [LC-MS]: 406.21 [M+1].

Intermediate 17: (R)-2-((4-(3-(Aminomethyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N- Isopropyl benzamide

Step 1: (R)-((1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl ) methyl) tert-butyl carbamate

With reference to the method of step 1 in intermediate 6, replace tert-butyl 4-aminomethylpiperidine-1-carboxylate with (S)-(pyrrolidin-3-ylmethyl)carbamate tert-butyl ester to obtain (R )-((1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)amino tert-butyl formate. MS m/z [LC-MS]: 502.29 [M+1].

Step 2: (R)-2-((4-(3-(Aminomethyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-iso Propyl benzamide

Referring to the method of step 2 in intermediate 6, use (R)-((1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine-4- Base)pyrrolidin-3-yl)methyl)carbamate tert-butyl ester instead of 4-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine -4-yl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester to get (R)-2-((4-(3-(aminomethyl)pyrrolidin-1-yl)pyrimidine-5 -yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide. MS m/z [LC-MS]: 402.23 [M+1].

Intermediate 18: 2-((4-(6-Amino-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro -N- Isopropylbenzamide

Step 1: (3-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-azabicyclo[3.1.0] Hexan-6-yl) tert-butyl carbamate

Referring to the method of step 1 in intermediate 6, replace tert-butyl 4-aminomethylpiperidine-1-carboxylate with (3-azabicyclo[3.1.0]hexane-6-yl)carbamate tert-butyl , to get (3-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexyl alk-6-yl) tert-butyl carbamate. MS m/z [LC-MS]: 500.27 [M+1].

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

Referring to the method of step 2 in intermediate 6, use (3-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3- Azabicyclo[3.1.0]hexan-6-yl)carbamate tert-butyl ester instead of 4-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy Base) pyrimidin-4-yl) amino) methyl) piperidine-1-carboxylic acid tert-butyl ester, get 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].

Intermediate 19: 2-((4-(3-Aminoazetidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N- isopropylbenzyl Amide

Step 1: (1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)azetidin-3-yl)amino tert-butyl formate

With reference to the method of step 1 in intermediate 6, replace tert-butyl 4-aminomethylpiperidine-1-carboxylate with azetidin-3-ylcarbamate tert-butyl to obtain (1-(5-( tert-butyl 2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)azetidin-3-yl)carbamate. MS m/z [LC-MS]: 474.25 [M+1].

Step 2: 2-((4-(3-Aminoazetidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

Referring to the method of step 2 in intermediate 6, use (1-(5-(2-(ethyl(isopropyl) carbamoyl)-4-fluorophenoxy) pyrimidin-4-yl) azacyclic Butan-3-yl)carbamate tert-butyl ester instead of 4-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl) Amino) methyl) piperidine-1-carboxylic acid tert-butyl ester to get 2-((4-(3-aminoazetidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl Base-5-fluoro-N-isopropylbenzamide. MS m/z [LC-MS]: 374.20 [M+1].

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

Step 1: 2-(((5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)morpholine-4- tert-butyl carboxylate

With reference to the method of step 1 in intermediate 6, replace tert-butyl 4-aminomethylpiperidine-1-carboxylate with 2-(aminomethyl)morpholine-4-carboxylic acid tert-butyl ester to obtain ((1- (5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)piperidin-4-yl)methyl)carbamate tert-butyl ester 2- (((5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester . MS m/z [LC-MS]: 518.28 [M+1].

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

Referring to the method of step 2 in intermediate 6, use 2-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)amino) Methyl)morpholine-4-carboxylate tert-butyl ester instead of 4-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl ) amino) methyl) piperidine-1-carboxylic acid tert-butyl ester, get N-ethyl-5-fluoro-N-isopropyl-2-((4-((morpholin-2-ylmethyl) amino)pyrimidin-5-yl)oxy)benzamide. MS m/z [LC-MS]: 418.23 [M+1].

Intermediate 21: (S)-2-((4-(3-Aminopyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzene Formamide _

Step 1: (S)-(1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl) tert-butyl carbamate

With reference to the method of step 1 in intermediate 6, replace tert-butyl 4-aminomethylpiperidine-1-carboxylate with (S)-pyrrolidin-3-ylcarbamic acid tert-butyl ester to obtain (S)-(1 -(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl)carbamate tert-butyl ester. MS m/z [LC-MS]: 488.27 [M+1].

Step 2: (S)-2-((4-(3-Aminopyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzyl Amide

Referring to the method of step 2 in intermediate 6, use (S)-(1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl )pyrrolidin-3-yl)carbamate tert-butyl ester instead of 4-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl )amino)methyl)piperidine-1-carboxylic acid tert-butyl ester, to get (S)-2-((4-(3-aminopyrrolidin-1-yl)pyrimidin-5-yl)oxyl)-N -Ethyl-5-fluoro-N-isopropylbenzamide. MS m/z [LC-MS]: 388.22 [M+1].

Intermediate 22: 2-((4-(3-(Aminomethyl)-3-methylazetidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5- Fluoro -N-isopropylbenzamide

Step 1: ((1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-methylazetidine -3-yl)methyl)carbamate tert-butyl ester

Referring to the method of step 1 in intermediate 6, replace tert-butyl 4-aminomethylpiperidine-1-carboxylate with ((3-methylazetidin-3-yl)methyl)tert-butyl carbamate ester to give ((1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-methylazetidine -3-yl)methyl)carbamate tert-butyl ester. MS m/z [LC-MS]: 502.29 [M+1].

Step 2: 2-((4-(3-(Aminomethyl)-3-methylazetidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro -N-Isopropylbenzamide

Referring to the method of step 2 in intermediate 6, use ((1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3 -Methylazetidin-3-yl)methyl)carbamate tert-butyl ester instead of 4-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorobenzene Oxygen) pyrimidin-4-yl) amino) methyl) piperidine-1-carboxylic acid tert-butyl ester, get 2-((4-(3-(aminomethyl)-3-methylazetidine -1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide. MS m/z [LC-MS]: 402.23 [M+1].

Intermediate 23: 2-((4-(4-Aminomethyl)-4-hydroxypiperidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-iso Propyl benzamide

Step 1: ((1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-4-hydroxypiperidin-4-yl ) methyl) tert-butyl carbamate

With reference to the method of step 1 in intermediate 6, replace tert-butyl 4-aminomethylpiperidine-1-carboxylate with ((4-hydroxypiperidin-4-yl) methyl) tert-butyl carbamate to obtain ( (1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-4-hydroxypiperidin-4-yl)methyl) tert-butyl carbamate. MS m/z [LC-MS]: 532.30 [M+1].

Step 2: 2-((4-(4-Aminomethyl)-4-hydroxypiperidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropyl phenylbenzamide

Referring to the method of step 2 in intermediate 6, use ((1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-4 -Hydroxypiperidin-4-yl)methyl)carbamate tert-butyl ester instead of 4-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine -4-yl)amino)methyl)piperidine-1-carboxylate tert-butyl ester to give 2-((4-(4-aminomethyl)-4-hydroxypiperidin-1-yl)pyrimidine-5- base)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide. MS m/z [LC-MS]: 432.24 [M+1].

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

Step 1: ((3-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-azabicyclo[3.1.0 ]Hexan-6-yl)methyl)carbamate tert-butyl ester

Referring to the method of step 1 in intermediate 6, replace 4-aminomethylpiperidine-1-carboxylate with ((3-azabicyclo[3.1.0]hexane-6-yl)methyl)carbamate tert-butyl ester Acid tert-butyl ester, get ((3-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-azabicyclo[ 3.1.0] Hexan-6-yl)methyl)carbamate tert-butyl ester. MS m/z [LC-MS]: 514.29 [M+1].

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

Referring to the method of step 2 in intermediate 6, use ((3-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3 -Azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate tert-butyl ester instead of 4-(((5-(2-(ethyl(isopropyl)carbamoyl)-4 -Fluorophenoxy)pyrimidin-4-yl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester to give 2-((4-(6-(aminomethyl)-3-azabicyclo[ 3.1.0] Hexan-3-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide. MS m/z [LC-MS]: 414.23 [M+1].

Intermediate 25: N-(trans-4-formylcyclohexyl)ethanesulfonamide

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

Intermediate 26: 2-((4-Chloropyridin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

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

Intermediate 27: (S)-N-ethyl-5-fluoro-N-isopropyl-2-((4-((pyrrolidin-3-ylmethyl)amino)pyrimidin-5-yl)oxy ) benzamide

Step 1: (R)-3-(((5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)pyrrole tert-butyl alkane-1-carboxylate

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

Step 2: (S)-N-Ethyl-5-fluoro-N-isopropyl-2-((4-((pyrrolidin-3-ylmethyl)amino)pyrimidin-5-yl)oxy) benzamide

Referring to the method of step 2 in intermediate 6, use (R)-3-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine-4- base)amino)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester as raw material to obtain the target compound. MS m/z [LC-MS]: 402.23 [M+1].

Intermediate 28: (R)-N-ethyl-5-fluoro-N-isopropyl-2-((4-((pyrrolidin-3-ylmethyl)amino)pyrimidin-5-yl)oxy ) benzamide

Step 1: (S)-3-(((5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)pyrrole tert-butyl alkane-1-carboxylate

Referring to the method of step 1 in 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].

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

Referring to the method of step 2 in intermediate 6, use (S)-3-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine-4- base)amino)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester as raw material to obtain the target compound. MS m/z [LC-MS]: 402.23 [M+1].

Intermediate 29: N-((1r,4r)-4-((((3-hydroxypyrrolidin-3-yl)methyl)amino)methyl)cyclohexyl)methanesulfonamide

Step 1: tert-butyl 3-(aminomethyl)-3-hydroxypyrrolidine-1-carboxylate

Add tert-butyl 1-oxa-5-azaspiro[2.4]heptane-5-carboxylate (1.0 g) and concentrated ammonia water (25%, 10 mL) into the sealed tube, heat to 70°C and stir for 4 hours, Cool to room temperature and concentrate under reduced pressure to obtain the target compound (1.05 g), which is directly used in the next step. MS m/z [LC-MS]: 217.16 [M+1].

Step 2: tert-Butyl 3-Hydroxy-3-(((((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)amino)methyl)pyrrolidine-1-carboxylate

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

Step 3: N-((1r,4r)-4-((((3-hydroxypyrrolidin-3-yl)methyl)amino)methyl)cyclohexyl)methanesulfonamide

3-Hydroxy-3-(((((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)amino)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.35g) Add it into 4mol/L hydrogen chloride methanol solution (20mL), stir at room temperature for 2 hours, concentrate under reduced pressure, adjust to pH=11~12 with 10% sodium hydroxide solution, and dichloromethane/isopropanol (4:1) Mixed solvents were extracted, the extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (900mg). MS m/z [LC-MS]: 306.19 [M+1].

Intermediate 30: (S)-2-((4-(3-(Aminomethyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N- Cumamide _

Step 1: (S)-((1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)piperidin-3-yl ) methyl) tert-butyl carbamate

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

Step 2: (S)-2-((4-(3-(Aminomethyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-iso Propyl benzamide

Referring to the method of step 2 in intermediate 6, use (S)-((1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine-4- base) piperidin-3-yl) methyl) tert-butyl carbamate as raw material to obtain the target compound. MS m/z [LC-MS]: 416.25 [M+1].

Intermediate 31: N-(4-fluoro-4-formylcyclohexyl)methanesulfonamide

Step 1: 4-Amino-1-fluorocyclohexane-1-carbaldehyde hydrochloride

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

Step 2: N-(4-fluoro-4-formylcyclohexyl)methanesulfonamide

Add 4-amino-1-fluorocyclohexane-1-carbaldehyde hydrochloride (350mg) and diisopropylethylamine (780mg) into dichloromethane (20mL), cool to 0°C, and add formaldehyde dropwise Sulfonyl chloride (225mg), stirred for 1 hour, the reaction solution was washed successively with 1mol/L dilute hydrochloric acid, saturated aqueous sodium bicarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (400mg) .

Intermediate 32: (R)-2-((4-(3-(Aminomethyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N- Cumamide _

Step 1: (R)-((1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)piperidin-3-yl ) methyl) tert-butyl carbamate

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

Step 2: (R)-2-((4-(3-(Aminomethyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-iso Propyl benzamide

Referring to the method of step 2 in intermediate 6, use (R)-((1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine-4- base) piperidin-3-yl) methyl) tert-butyl carbamate as raw material to obtain the target compound. MS m/z [LC-MS]: 416.25 [M+1].

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

Step 1: (R)-((1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-methylpyrrole tert-butyl (alk-3-yl)methyl)carbamate

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

Step 2: (R)-2-((4-(3-(Aminomethyl)-3-methylpyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5- Fluoro-N-isopropylbenzamide

Referring to the method of step 2 in intermediate 6, use (R)-((1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine-4- Base)-3-methylpyrrolidin-3-yl)methyl)carbamate tert-butyl ester as raw material to obtain the target compound. MS m/z [LC-MS]: 416.25 [M+1].

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

Step 1: (S)-((1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-methylpyrrole tert-butyl (alk-3-yl)methyl)carbamate

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

Step 2: (S)-2-((4-(3-(Aminomethyl)-3-methylpyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5- Fluoro-N-isopropylbenzamide

Referring to the method of step 2 in intermediate 6, use (S)-((1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine-4- Base)-3-methylpyrrolidin-3-yl)methyl)carbamate tert-butyl ester as raw material to obtain the target compound. MS m/z [LC-MS]: 416.25 [M+1].

Intermediate 35: N-(2-(Pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)ethanesulfonamide hydrochloride

Step 1: tert-butyl 3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylate

tert-Butyl 3-formylpyrrolidine-1-carboxylate (500 mg), N-(2-azaspiro[3.5]nonan-7-yl)ethanesulfonamide (464 mg) and glacial acetic acid (20 mg) were added 1,2-dichloroethane (10 mL), stirred at room temperature for 1 hour, then added sodium triacetoxyborohydride (1.27 g), stirred at room temperature overnight, added saturated aqueous sodium bicarbonate to quench the reaction, Filtration, the filtrate was extracted with dichloromethane, the extract was dried over anhydrous sodium sulfate, 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 (490 mg). MS m/z [LC-MS]: 416.26 [M+1].

Step 2: N-(2-(pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)ethanesulfonamide hydrochloride

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

Intermediate 36: 2-((4-(3-(Aminomethyl)-3-ethylazetidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5- Fluoro-N- isopropylbenzamide

Step 1: ((3-Ethyl-1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)azetidine -3-yl)methyl)carbamate tert-butyl ester

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

Step 2: 2-((4-(3-(Aminomethyl)-3-ethylazetidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro -N-Isopropylbenzamide

Referring to the method of step 2 in intermediate 6, use ((3-ethyl-1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine-4 -yl) azetidin-3-yl) methyl) tert-butyl carbamate as starting material to obtain the target compound. MS m/z [LC-MS]: 416.25 [M+1].

Intermediate 37: 2-((4-((3R,4S)-3-(aminomethyl)-4-fluoropyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl- 5-Fluoro -N-isopropylbenzamide

Step 1: (((3R,4S)-1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-4-fluoro tert- butyl pyrrolidin-3-yl)methyl)carbamate

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

Step 2: 2-((4-((3R,4S)-3-(aminomethyl)-4-fluoropyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5 -Fluoro-N-isopropylbenzamide

Referring to the method of step 2 in intermediate 6, using (((3R,4S)-1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine- 4-yl)-4-fluoropyrrolidin-3-yl)methyl)carbamate tert-butyl ester as starting material to obtain the target compound. MS m/z [LC-MS]: 420.22 [M+1].

Intermediate 38: 2-((4-((3S,4S)-3-(aminomethyl)-4-fluoropyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl- 5-Fluoro -N-isopropylbenzamide

Step 1: (((3S,4S)-1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-4-fluoro tert- butyl pyrrolidin-3-yl)methyl)carbamate

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

Step 2: 2-((4-((3S,4S)-3-(aminomethyl)-4-fluoropyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5 -Fluoro-N-isopropylbenzamide

Referring to the method of step 2 in intermediate 6, use (((3S,4S)-1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine- 4-yl)-4-fluoropyrrolidin-3-yl)methyl)carbamate tert-butyl ester as starting material to obtain the target compound. MS m/z [LC-MS]: 420.22 [M+1].

Intermediate 39: (S)-2-((4-(2-(Aminomethyl)morpholinyl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropyl Benzamide _

Step 1: (S)-((4-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)morpholinyl-2- base) methyl) tert-butyl carbamate

Referring to the method of step 1 in intermediate 6, the target compound was obtained by using tert-butyl (S)-(piperidin-3-ylmethyl)carbamate as a starting material. MS m/z [LC-MS]: 518.28 [M+1].

Step 2: (S)-2-((4-(2-(Aminomethyl)morpholinyl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzene Formamide

Referring to the method of step 2 in intermediate 6, use (S)-((4-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine-4- base) morpholinyl-2-yl) methyl) tert-butyl carbamate as raw material to obtain the target compound. MS m/z [LC-MS]: 418.23 [M+1].

Intermediate 40: (S)-2-((4-(3-aminomethylpyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzene Formamide

Step 1: (S)-((1-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl)methyl ) tert-butyl carbamate

Referring to the method of step 1 in intermediate 6, using intermediate 26 and tert-butyl (R)-pyrrolidin-3-ylmethylcarbamate as starting materials, the title compound was obtained. MS m/z [LC-MS]: 516.30 [M+1].

Step 2: (S)-2-((4-(3-Aminomethylpyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzyl Amide

Referring to the method of step 2 in intermediate 6, use (S)-((1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrole Alk-3-yl)methyl)carbamate tert-butyl ester as starting material to obtain the target compound. MS m/z [LC-MS]: 416.25 [M+1].

Intermediate 41: 2-((4-(3-(aminomethyl)-3-methylazetidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N -Diisopropylbenzamide _

Step 1: ((1-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-methylazetidine-3- base) methyl) tert-butyl carbamate

Referring to the method of step 1 in intermediate 6, using intermediate 26 and tert-butyl ((3-methylazetidin-3-yl)methyl)carbamate as starting materials, the title compound was obtained. MS m/z [LC-MS]: 516.30 [M+1].

Step 2: 2-((4-(3-(Aminomethyl)-3-methylazetidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N- Diisopropylbenzamide

Referring to the method of step 2 in intermediate 6, use ((1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-methyl Azetidin-3-yl) methyl) carbamate tert-butyl ester as starting material to obtain the target compound. MS m/z [LC-MS]: 416.25 [M+1].

Intermediate 42: N-(2-(azetidin-3-ylmethyl)-2-azaspiro[3.3]heptan-6-yl)ethanesulfonamide hydrochloride

Step 1: tert-butyl 3-((6-(ethanesulfonamido)-2-azaspiro[3.3]heptan-2-yl)methyl)azetidine-1-carboxylate

Referring to the method of step 1 in intermediate 35, using tert-butyl 3-formylazetidine-1-carboxylate and N-(2-azaspiro[3.3]heptane-6-yl)ethanesulfonamide The target compound is obtained as a starting material. MS m/z [LC-MS]: 374.21 [M+1].

Step 2: N-(2-(azetidin-3-ylmethyl)-2-azaspiro[3.3]heptan-6-yl)ethanesulfonamide hydrochloride

Referring to the method of step 2 in intermediate 35, using 3-((6-(ethanesulfonamido)-2-azaspiro[3.3]heptane-2-yl)methyl)azetidine-1- The target compound was obtained from tert-butyl carboxylate. MS m/z [LC-MS]: 274.16 [M+1].

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

Step 1: (R)-tert-butyl 3-((6-(ethanesulfonamido)-2-azaspiro[3.3]heptan-2-yl)methyl)pyrrolidine-1-carboxylate

Referring to the method of step 1 in intermediate 35, using tert-butyl (S)-3-formylpyrrolidine-1-carboxylate and N-(2-azaspiro[3.3]heptane-6-yl)ethanesulfonate Amides are used as starting materials to obtain the target compounds. MS m/z [LC-MS]: 388.23 [M+1].

Step 2: (S)-N-(2-(pyrrolidin-3-yl)methyl)-2-azaspiro[3.3]heptan-6-yl)ethanesulfonamide hydrochloride

Referring to the method of step 2 in intermediate 35, use (R)-3-((6-(ethanesulfonamido)-2-azaspiro[3.3]heptane-2-yl)methyl)pyrrolidin-1 - tert-butyl carboxylate as starting material to obtain the target compound. MS m/z [LC-MS]: 288.18 [M+1].

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

Step 1: (S)-tert-butyl 3-((6-(ethanesulfonamido)-2-azaspiro[3.3]heptan-2-yl)methyl)pyrrolidine-1-carboxylate

Referring to the method of step 1 in intermediate 35, using tert-butyl (R)-3-formylpyrrolidine-1-carboxylate and N-(2-azaspiro[3.3]heptane-6-yl)ethanesulfonate Amides are used as starting materials to obtain the target compounds. MS m/z [LC-MS]: 388.23 [M+1].

Step 2: (R)-N-(2-(pyrrolidin-3-yl)methyl)-2-azaspiro[3.3]heptan-6-yl)ethanesulfonamide hydrochloride

Referring to the method of step 2 in intermediate 35, use (S)-3-((6-(ethanesulfonamido)-2-azaspiro[3.3]heptan-2-yl)methyl)pyrrolidin-1 - tert-butyl carboxylate as starting material to obtain the target compound. MS m/z [LC-MS]: 288.18 [M+1].

Intermediate 45: N-(2-(azetidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)ethanesulfonamide hydrochloride

Step 1: tert-butyl 3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)azetidine-1-carboxylate

Referring to the method of step 1 in intermediate 35, the target compound was obtained from tert-butyl 3-formylazetidine-1-carboxylate. MS m/z [LC-MS]: 402.24 [M+1].

Step 2: N-(2-(azetidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)ethanesulfonamide hydrochloride

Referring to the method of step 2 in intermediate 35, using 3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)azetidine-1- The target compound was obtained from tert-butyl carboxylate. MS m/z [LC-MS]: 302.19 [M+1].

Intermediate 46: (R)-N-(2-(Pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)ethanesulfonamide hydrochloride

Step 1: (S)-tert-butyl 3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylate

Referring to the method of step 1 in 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].

Step 2: (R)-N-(2-(pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)ethanesulfonamide hydrochloride

Referring to the method of step 2 in intermediate 35, use (S)-3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1 - tert-butyl carboxylate as starting material to obtain the target compound. MS m/z [LC-MS]: 316.21 [M+1].

Intermediate 47: (S)-N-(2-(Pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)ethanesulfonamide hydrochloride

Step 1: (R)-tert-butyl 3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylate

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

Step 2: (S)-N-(2-(pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)ethanesulfonamide hydrochloride

Referring to the method of step 2 in intermediate 35, use (R)-3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1 - tert-butyl carboxylate as starting material to obtain the target compound. MS m/z [LC-MS]: 316.21 [M+1].

Intermediate 48: (R)-N-(2-(Pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)methanesulfonamide hydrochloride

Step 1: (S)-tert-butyl 3-((7-(methylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylate

Referring to the method of step 1 in 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].

Step 2: (R)-N-(2-(pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)methanesulfonamide hydrochloride

Referring to the method of step 2 in intermediate 35, using (S)-3-((7-(methylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1 - tert-butyl carboxylate as starting material to obtain the target compound. MS m/z [LC-MS]: 302.19 [M+1].

Intermediate 49: (S)-N-(2-(Pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)methanesulfonamide hydrochloride

Step 1: (R)-tert-butyl 3-((7-(methylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylate

Referring to the method of step 1 in intermediate 35, replace tert-butyl 3-formylpyrrolidine-1-carboxylate with (S)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester, and use N-(2-nitro Heterospiro[3.5]nonan-7-yl)methanesulfonamide replaces N-(2-azaspiro[3.5]nonan-7-yl)ethanesulfonamide to obtain (R)-3-((7-( Methanesulfonylamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m/z [LC-MS]: 402.24 [M+1].

Step 2: (S)-N-(2-(pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)methanesulfonamide hydrochloride

Referring to the method of step 2 in intermediate 35, use (R)-3-((7-(methylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1 - tert-butyl formate replaces 3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-formate tert-butyl to give (S )-N-(2-(pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)methanesulfonamide hydrochloride. MS m/z [LC-MS]: 302.19 [M+1].

Intermediate 50: (R)-1,1,1-Trifluoro-N-(2-(pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)methanesulfonate Amide hydrochloride

Step 1: (S)-tert-butyl 3-((7-(trifluoromethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylate

Referring to the method of step 1 in intermediate 35, replace tert-butyl 3-formylpyrrolidine-1-carboxylate with (R)-tert-butyl 3-formylpyrrolidine-1-carboxylate, 1,1,1-tri Fluoro-N-(2-azaspiro[3.5]nonan-7-yl)methanesulfonamide replaces N-(2-azaspiro[3.5]nonan-7-yl)ethanesulfonamide to obtain (S) - tert-butyl 3-((7-(trifluoromethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylate. MS m/z [LC-MS]: 456.21 [M+1].

Step 2: (R)-1,1,1-Trifluoro-N-(2-(pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)methanesulfonamide Hydrochloride

Referring to the method of step 2 in intermediate 35, using (S)-3-((7-(trifluoromethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine -1- tert-butyl carboxylate instead of 3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester, to obtain (R)-1,1,1-Trifluoro-N-(2-(pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)methanesulfonamide hydrochloride . MS m/z [LC-MS]: 356.16 [M+1].

Intermediate 51: N-(3-(((R)-pyrrolidin-3-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-yl)ethanesulfonamide hydrochloride

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

Referring to the method of step 1 in intermediate 35, replace tert-butyl 3-formylpyrrolidine-1-carboxylate with (R)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester, N-(3-aza Bicyclo[3.1.0]hexane-6-yl)ethanesulfonamide replaces N-(2-azaspiro[3.5]nonan-7-yl)ethanesulfonamide to obtain (3S)-3-((6- (Ethylsulfonamido)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m/z [LC-MS]: 374.21 [M+1].

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

Referring to the method of step 2 in intermediate 35, use (3S)-3-((6-(ethanesulfonamido)-3-azabicyclo[3.1.0]hexane-3-yl)methyl)pyrrolidine -1- tert-butyl carboxylate instead of 3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester, to obtain N-(3-(((R)-pyrrolidin-3-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-yl)ethanesulfonamide hydrochloride. MS m/z [LC-MS]: 274.16 [M+1].

Intermediate 52: N-(2-(((R)-pyrrolidin-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)-N',N'-dimethyl Sulfonylurea hydrochloride

Step 1: tert-butyl 7-((N,N-dimethylaminosulfonyl)amino)-2-azaspiro[3.5]nonane-2-carboxylate

Add tert-butyl 7-amino-2-azaspiro[3.5]nonane-2-carboxylate (480mg) into pyridine (10mL), add dimethylaminosulfonyl chloride (340mg) dropwise under ice-cooling, and the addition is complete Then heated to 60°C and stirred for 2 hours. Concentrate under reduced pressure to remove the solvent, add ethyl acetate to the residue, wash with 1mol/L dilute hydrochloric acid, water, saturated brine successively, dry over anhydrous sodium sulfate, filter, after the filtrate is concentrated under reduced pressure, use silica gel column chromatography (petroleum ether/acetic acid ethyl ester, 3:1) to give tert-butyl 7-((N,N-dimethylaminosulfonyl)amino)-2-azaspiro[3.5]nonane-2-carboxylate (550mg). MS m/z [LC-MS]: 348.20 [M+1].

Step 2: N-(2-azaspiro[3.5]nonan-7-yl)-N’,N’-dimethylsulfonylurea hydrochloride

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

Step 3: (S)-3-((7-((N,N-Dimethylaminosulfonyl)amino)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine- tert-Butyl 1-formate

Add (R)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester (385mg), N-(2-azaspiro[3.5]nonan-7-yl)-N',N'-dimethyl Add sulfonylurea hydrochloride (400mg) and sodium acetate (115mg) into 1,2-dichloroethane (10mL), stir at room temperature for 1 hour, then add sodium triacetoxyborohydride (0.91g), Stir overnight at room temperature, add saturated aqueous sodium bicarbonate solution to quench the reaction, filter, the filtrate is extracted with dichloromethane, the extracts are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure and then purified by silica gel column chromatography (dichloromethane /methanol, 20:1) separation to give (S)-3-((7-((N,N-dimethylaminosulfonyl)amino)-2-azaspiro[3.5]nonan-2-yl )Methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (420mg). MS m/z [LC-MS]: 431.27 [M+1].

Step 4: N-(2-(((R)-pyrrolidin-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)-N',N'-dimethyl Sulfonylurea hydrochloride

(S)-3-((7-((N,N-Dimethylaminosulfonyl)amino)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1- Add tert-butyl formate (420 mg) into 4 mol/L hydrogen chloride dioxane solution (10 mL), stir at room temperature for 2 hours, add diethyl ether (40 mL), stir for 1 hour, filter, rinse the filter cake with diethyl ether, and dry to obtain N -(2-(((R)-pyrrolidin-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)-N',N'-dimethylsulfonylurea salt salt (320mg). MS m/z [LC-MS]: 331.22 [M+1].

Intermediate 53: (R)-N-(2-(Pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)cyclopropylsulfonamide hydrochloride

Step 1: (S)-tert-butyl 3-((7-(cyclopropylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylate

Referring to the method of step 1 in intermediate 35, replace tert-butyl 3-formylpyrrolidine-1-carboxylate with (R)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester, N-(2-aza Spiro[3.5]nonan-7-yl)cyclopropylsulfonamide replaces N-(2-azaspiro[3.5]nonan-7-yl)ethanesulfonamide to obtain (S)-3-((7- (Cyclopropylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m/z [LC-MS]: 428.26 [M+1].

Step 2: (R)-N-(2-(pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)cyclopropylsulfonamide hydrochloride

Referring to the method of step 2 in intermediate 35, using (S)-3-((7-(cyclopropylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine -1- tert-butyl carboxylate instead of 3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester, to obtain (R)-N-(2-(pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)cyclopropylsulfonamide hydrochloride. MS m/z [LC-MS]: 328.21 [M+1].

Intermediate 54: (R)-N-(2-(Pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)propane-1-sulfonamide hydrochloride

Step 1: (S)-tert-butyl 3-((7-(propylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylate

Referring to the method of step 1 in intermediate 35, replace tert-butyl 3-formylpyrrolidine-1-carboxylate with (R)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester, N-(2-aza Spiro[3.5]nonan-7-yl)propane-1-sulfonamide replaces N-(2-azaspiro[3.5]nonan-7-yl)ethanesulfonamide to obtain (S)-3-((7 -(Propylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m/z [LC-MS]: 430.27 [M+1].

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

Referring to the method of step 2 in intermediate 35, using (S)-3-((7-(propylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine- 1-formic acid tert-butyl ester replaces 3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain ( R)-N-(2-(pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)propane-1-sulfonamide hydrochloride. MS m/z [LC-MS]: 330.22 [M+1].

Intermediate 55: (R)-N-((1-(pyrrolidin-3-ylmethyl)piperidin-4-yl)methyl)ethanesulfonamide hydrochloride

Step 1: tert-butyl 4-(ethanesulfonamidomethyl)piperidine-1-carboxylate

Add tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (500mg) and diisopropylethylamine (300mg) into 1,2-dichloroethane (10mL), add dropwise under ice-cooling Ethylsulfonyl chloride (360 mg), after the dropwise addition, was stirred at room temperature for 2 hours. Add saturated aqueous sodium bicarbonate solution to quench the reaction, separate the liquids to remove the water phase, wash the organic phase with 1mol/L dilute hydrochloric acid, water, and saturated brine successively, dry over anhydrous sodium sulfate, filter, and use silica gel column chromatography after the filtrate is concentrated under reduced pressure ( Petroleum ether/ethyl acetate, 3:1) separation to obtain tert-butyl 4-(ethanesulfonamidomethyl)piperidine-1-carboxylate (610mg). MS m/z [LC-MS]: 307.17 [M+1].

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

Add tert-butyl 4-(ethanesulfonamidomethyl)piperidine-1-carboxylate (600 mg) into 4 mol/L hydrogen chloride dioxane solution (10 mL), stir at room temperature for 2 hours, add diethyl ether (40 mL), Stir for 1 hour, filter, rinse the filter cake with ether, and dry to give N-(piperidin-4-ylmethyl)ethanesulfonamide hydrochloride (450 mg), which is directly used in the next step. MS m/z [LC-MS]: 207.12 [M+1].

Step 3: (S)-tert-butyl 3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate

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

Step 4: (R)-N-((1-(pyrrolidin-3-ylmethyl)piperidin-4-yl)methyl)ethanesulfonamide hydrochloride

Add (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (570mg) to 4mol/L hydrogen chloride dioxane Ring solution (10mL), stirred at room temperature for 2 hours, added diethyl ether (40mL), stirred for 2 hours, filtered, the filter cake was rinsed with diethyl ether, dried to obtain (R)-N-((1-(pyrrolidin-3-yl Methyl)piperidin-4-yl)methyl)ethanesulfonamide hydrochloride (480 mg) was used directly in the next step. MS m/z [LC-MS]: 290.19 [M+1].

Intermediate 56: (R)-7-(Ethylsulfonyl)-2-(pyrrolidin-3-ylmethyl)-2,7-diazaspiro[3.5]nonane hydrochloride

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

Referring to the method of step 1 in intermediate 55, substituting tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate for tert-butyl 4-(aminomethyl)piperidine-1-carboxylate to give tert-butyl 7-(ethylsulfonyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate. MS m/z [LC-MS]: 319.17 [M+1].

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

Referring to the method of step 2 in intermediate 55, replace 4-(ethanesulfonylamidomethyl) with tert-butyl 7-(ethylsulfonyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate Piperidine-1-carboxylic acid tert-butyl ester, in 7-(ethylsulfonyl)-2,7-diazaspiro[3.5]nonane hydrochloride. MS m/z [LC-MS]: 219.12 [M+1].

Step 3: (S)-tert-butyl 3-((7-(ethylsulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylate

Referring to the method of step 3 in intermediate 55, replace N-(piperidin-4-ylmethyl)ethanesulfonate with 7-(ethylsulfonyl)-2,7-diazaspiro[3.5]nonane hydrochloride Amide hydrochloride, (S)-3-((7-(ethylsulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylic acid tert butyl ester. MS m/z [LC-MS]: 402.24 [M+1].

Step 4: (R)-7-(Ethylsulfonyl)-2-(pyrrolidin-3-ylmethyl)-2,7-diazaspiro[3.5]nonane hydrochloride

Referring to the method of step 4 in intermediate 55, using (S)-3-((7-(ethylsulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidine -1- tert-butyl carboxylate instead of (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain (R) -7-(Ethylsulfonyl)-2-(pyrrolidin-3-ylmethyl)-2,7-diazaspiro[3.5]nonane hydrochloride. MS m/z [LC-MS]: 302.19 [M+1].

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

Step 1: tert-butyl 7-aminosulfonyl-2,7-diazaspiro[3.5]nonane-2-carboxylate

Referring to the method of step 1 in intermediate 55, replace tert-butyl 4-(aminomethyl)piperidine-1-carboxylate with tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate, and use Aminosulfonyl chloride replaces ethylsulfonyl chloride to obtain tert-butyl 7-aminosulfonyl-2,7-diazaspiro[3.5]nonane-2-carboxylate. MS m/z [LC-MS]: 306.15 [M+1].

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

Referring to the method of step 2 in intermediate 55, replace 4-(ethanesulfonamidomethyl)piperidine with tert-butyl 7-aminosulfonyl-2,7-diazaspiro[3.5]nonane-2-carboxylate -1-tert-butyl formate, in 2,7-diazaspiro[3.5]nonane-7-sulfonamide hydrochloride. MS m/z [LC-MS]: 206.10 [M+1].

Step 3: (S)-tert-butyl 3-((7-aminosulfonyl-2,7-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylate

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

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

Referring to the method of step 4 in intermediate 55, use (S)-3-((7-aminosulfonyl-2,7-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1- Tert-butyl formate replaces (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate tert-butyl to obtain (R)-2- (Pyrrolidin-3-ylmethyl)-2,7-diazaspiro[3.5]nonane-7-sulfonamide hydrochloride. MS m/z [LC-MS]: 289.17 [M+1].

Intermediate 58: (R)-N-(7-(Pyrrolidin-3-ylmethyl)-7-azaspiro[3.5]nonan-2-yl)ethanesulfonamide hydrochloride

Step 1: tert-butyl 2-(ethanesulfonamido)-7-azaspiro[3.5]nonane-7-carboxylate

Referring to the method of step 1 in intermediate 55, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate was replaced with tert-butyl 2-amino-7-azaspiro[3.5]nonane-7-carboxylate, tert-butyl 2-(ethanesulfonamido)-7-azaspiro[3.5]nonane-7-carboxylate was obtained. MS m/z [LC-MS]: 333.18 [M+1].

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

Referring to the method of step 2 in intermediate 55, replace 4-(ethanesulfonamidomethyl)piperidine with 2-(ethanesulfonamido)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester -1-tert-butyl carboxylate to obtain N-(7-azaspiro[3.5]nonan-2-yl)ethanesulfonamide hydrochloride. MS m/z [LC-MS]: 233.13 [M+1].

Step 3: (S)-tert-butyl 3-((2-(ethanesulfonamido)-7-azaspiro[3.5]nonan-7-yl)methyl)pyrrolidine-1-carboxylate

Referring to the method of step 3 in intermediate 55, replace N-(piperidin-4-ylmethyl)ethanesulfonate with N-(7-azaspiro[3.5]nonan-2-yl)ethanesulfonamide hydrochloride Amide hydrochloride to get (S)-3-((2-(ethanesulfonamido)-7-azaspiro[3.5]nonan-7-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester . MS m/z [LC-MS]: 416.26 [M+1].

Step 4: (R)-N-(7-(pyrrolidin-3-ylmethyl)-7-azaspiro[3.5]nonan-2-yl)ethanesulfonamide hydrochloride

Referring to the method of step 4 in intermediate 55, using (S)-3-((2-(ethanesulfonamido)-7-azaspiro[3.5]nonan-7-yl)methyl)pyrrolidin-1 - tert-butyl formate instead of (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate tert-butyl to give (R)-N -(7-(Pyrrolidin-3-ylmethyl)-7-azaspiro[3.5]nonan-2-yl)ethanesulfonamide hydrochloride. MS m/z [LC-MS]: 316.21 [M+1].

Intermediate 59: (R)-N-(3-(Pyrrolidin-3-ylmethyl)-3-azaspiro[5.5]undec-9-yl)ethanesulfonamide hydrochloride

Step 1: tert-butyl 9-(ethanesulfonamido)-3-azaspiro[5.5]undecane-3-carboxylate

Referring to the method of step 1 in intermediate 55, replace tert-butyl 4-(aminomethyl)piperidine-1-carboxylate with 9-amino-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester , in tert-butyl 9-(ethanesulfonamido)-3-azaspiro[5.5]undecane-3-carboxylate. MS m/z [LC-MS]: 361.22 [M+1].

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

Referring to the method of step 2 in intermediate 55, replace 4-(ethanesulfonamidomethyl)piperene with 9-(ethanesulfonamido)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester Pyridine-1-carboxylic acid tert-butyl ester to obtain N-(3-azaspiro[5.5]undecyl-9-yl)ethanesulfonamide hydrochloride. MS m/z [LC-MS]: 261.16 [M+1].

Step 3: (S)-tert-butyl 3-((9-(ethanesulfonamido)-3-azaspiro[5.5]undec-3-yl)methyl)pyrrolidine-1-carboxylate

Referring to the method of step 3 in intermediate 55, replace N-(piperidin-4-ylmethyl)ethane with N-(3-azaspiro[5.5]undec-9-yl)ethanesulfonamide hydrochloride Sulfonamide hydrochloride, get (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].

Step 4: (R)-N-(3-(pyrrolidin-3-ylmethyl)-3-azaspiro[5.5]undec-9-yl)ethanesulfonamide hydrochloride

Referring to the method of step 4 in intermediate 55, using (S)-3-((9-(ethanesulfonamido)-3-azaspiro[5.5]undecyl-3-yl)methyl)pyrrolidine- 1-formic acid tert-butyl ester replaces (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain (R)- N-(3-(pyrrolidin-3-ylmethyl)-3-azaspiro[5.5]undec-9-yl)ethanesulfonamide hydrochloride. MS m/z [LC-MS]: 344.24 [M+1].

Intermediate 60: N-((S)-8-(((R)-pyrrolidin-3-yl)methyl)-8-azaspiro[4.5]decane-1-yl)ethanesulfonamide hydrochloride Salt

Step 1: (S)-tert-butyl 1-(ethanesulfonamido)-8-azaspiro[4.5]decane-8-carboxylate

Referring to the method of step 1 in intermediate 55, replace 4-(aminomethyl)piperidine-1-carboxylic acid with (S)-1-amino-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester Tert-butyl ester to get (S)-1-(ethanesulfonamido)-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester. MS m/z [LC-MS]: 347.20 [M+1].

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

Referring to the method of step 2 in intermediate 55, replace 4-(ethanesulfonamidomethanol with (S)-1-(ethanesulfonamido)-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl Base) tert-butyl 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].

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

Referring to the method of step 3 in intermediate 55, replace N-(piperidin-4-ylmethyl) with (S)-N-(8-azaspiro[4.5]decane-1-yl)ethanesulfonamide hydrochloride Base) ethanesulfonamide hydrochloride, get (S)-3-(((S)-1-(ethanesulfonamido)-8-azaspiro[4.5]decane-8-yl)methyl)pyrrole tert-butyl alkane-1-carboxylate. MS m/z [LC-MS]: 430.27 [M+1].

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

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

Intermediate 61: N-(8-(((R)-pyrrolidin-3-yl)methyl)-1-oxa-8-azaspiro[4.5]decane-3-yl)ethanesulfonamide salt salt

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

Referring to step 1 in intermediate 55, replace 4-(aminomethyl)piperidine-1- with 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate Formate tert-butyl ester to get 3-(ethanesulfonamido)-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester. MS m/z [LC-MS]: 349.18 [M+1].

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

Referring to the method of step 2 in intermediate 55, replace 4-(ethanesulfonylamino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl Methyl)piperidine-1-carboxylic acid tert-butyl ester to obtain N-(1-oxa-8-azaspiro[4.5]decane-3-yl)ethanesulfonamide hydrochloride. MS m/z [LC-MS]: 249.13 [M+1].

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

Referring to the method of step 3 in intermediate 55, replace N-(piperidin-4-yl) with N-(1-oxa-8-azaspiro[4.5]decane-3-yl)ethanesulfonamide hydrochloride Methyl)ethanesulfonamide hydrochloride, to get (3S)-3-((3-(ethanesulfonamido)-1-oxa-8-azaspiro[4.5]decane-8-yl)methyl ) tert-butyl pyrrolidine-1-carboxylate. MS m/z [LC-MS]: 432.25 [M+1].

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

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

Intermediate 62: N-((3-(((R)-pyrrolidin-3-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)ethanesulfonamide Hydrochloride

Step 1: tert-butyl 6-(ethanesulfonamidomethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

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

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

Referring to the method of step 2 in intermediate 55, tert-butyl 6-(ethanesulfonamidomethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate was used instead of 4-(ethanesulfonamidomethyl Base) piperidine-1-carboxylic acid tert-butyl ester to obtain N-((3-azabicyclo[3.1.0]hexane-6-yl)methyl)ethanesulfonamide hydrochloride. MS m/z [LC-MS]: 205.10 [M+1].

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

Referring to the method of step 3 in intermediate 55, replace N-((3-azabicyclo[3.1.0]hexane-6-yl)methyl)ethanesulfonamide hydrochloride with N-(piperidine-4- (3S)-3-((6-(ethanesulfonamidomethyl)-3-azabicyclo[3.1.0]hexane-3-yl)methyl ) tert-butyl pyrrolidine-1-carboxylate. MS m/z [LC-MS]: 388.23 [M+1].

Step 4: N-((3-(((R)-pyrrolidin-3-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)ethanesulfonamide salt salt

Referring to the method of step 4 in intermediate 55, use (3S)-3-((6-(ethanesulfonamidomethyl)-3-azabicyclo[3.1.0]hexane-3-yl)methyl) Pyrrolidine-1-carboxylic acid tert-butyl ester replaces (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain N -((3-(((R)-Pyrrolidin-3-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)ethanesulfonamide hydrochloride. MS m/z [LC-MS]: 288.17 [M+1].

Intermediate 63: (R)-2-Methyl-1-((2-(pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)amino)propan-2 -alcohol hydrochloride

Step 1: tert-butyl 7-((2-hydroxy-2-methylpropyl)amino)-2-azaspiro[3.5]nonane-2-carboxylate

7-Oxo-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (480 mg), 1-amino-2-methylpropan-2-ol (260 mg) and acetic acid (24 mg) were added in 1 , 2-dichloroethane (10mL), stirred at room temperature for 1 hour, then added sodium triacetoxyborohydride (1.27g), stirred at room temperature overnight, added saturated aqueous sodium bicarbonate to quench the reaction, filtered , 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, 15:1) to obtain 7-((2-hydroxyl - tert-butyl 2-methylpropyl)amino)-2-azaspiro[3.5]nonane-2-carboxylate (420 mg). MS m/z [LC-MS]: 313.25 [M+1].

Step 2: 1-((2-azaspiro[3.5]nonan-7-yl)amino)-2-methylpropan-2-ol hydrochloride

Referring to the method of step 2 in intermediate 55, replace 4-( Ethylsulfonylamidomethyl)piperidine-1-carboxylate tert-butyl ester to get 1-((2-azaspiro[3.5]nonan-7-yl)amino)-2-methylpropan-2-alcohol salt salt. MS m/z [LC-MS]: 213.10 [M+1].

Step 3: (S)-3-((7-((2-Hydroxy-2-methylpropyl)amino)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine- tert-Butyl 1-formate

Referring to the method of step 3 in intermediate 55, use 1-((2-azaspiro[3.5]nonan-7-yl)amino)-2-methylpropan-2-ol hydrochloride instead of N-(piper Pyridine-4-ylmethyl)ethanesulfonamide hydrochloride, to get (S)-3-((7-((2-hydroxy-2-methylpropyl)amino)-2-azaspiro[3.5] Nonan-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS m/z [LC-MS]: 396.32 [M+1].

Step 4: (R)-2-Methyl-1-((2-(pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)amino)propan-2- Alcohol hydrochloride

Referring to the method of step 4 in intermediate 55, use (S)-3-((7-((2-hydroxy-2-methylpropyl)amino)-2-azaspiro[3.5]nonane-2- Base)methyl)pyrrolidine-1-carboxylate tert-butyl instead of (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate tert Butyl ester to get (R)-2-methyl-1-((2-(pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)amino)propan-2 -alcohol hydrochloride. MS m/z [LC-MS]: 296.27 [M+1].

Intermediate 64: N-(2-(((R)-pyrrolidin-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)sulfonylurea hydrochloride

Step 1: tert-Butyl 7-((aminosulfonyl)amino)-2-azaspiro[3.5]nonane-2-carboxylate

Referring to the method of step 1 in intermediate 52, using aminosulfonyl chloride instead of dimethylaminosulfonyl chloride, 7-((aminosulfonyl)amino)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester. MS m/z [LC-MS]: 320.16 [M+1].

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

Referring to the method of step 2 in intermediate 52, replace 7-((N,N-dimethyl Aminosulfonyl)amino)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester, N-(2-azaspiro[3.5]nonane-7-yl)sulfonylurea hydrochloride Salt. MS m/z [LC-MS]: 220.11 [M+1].

Step 3: (S)-tert-butyl 3-((7-((aminosulfonyl)amino)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylate

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

Step 4: N-(2-(((R)-pyrrolidin-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)sulfonylurea hydrochloride

Referring to the method of step 4 in intermediate 52, using (S)-3-((7-((aminosulfonyl)amino)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine -1-tert-butyl carboxylate instead of (S)-3-((7-((N,N-dimethylaminosulfonyl)amino)-2-azaspiro[3.5]nonan-2-yl)methyl Base) pyrrolidine-1-carboxylic acid tert-butyl ester, N-(2-(((R)-pyrrolidin-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl) Sulfonylurea hydrochloride. MS m/z [LC-MS]: 303.19 [M+1].

Intermediate 65: (R)-N-(2-(Pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)propane-2-sulfonamide hydrochloride

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

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

Referring to the method of step 2 in intermediate 55, replace 4-(ethanesulfonamidomethyl) with 7-(isopropylsulfonamido)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester Piperidine-1-carboxylic acid tert-butyl ester to obtain N-(2-azaspiro[3.5]nonan-7-yl)propane-2-sulfonamide hydrochloride. MS m/z [LC-MS]: 247.15 [M+1].

Step 3: (S)-tert-butyl 3-((7-(isopropylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylate

Referring to the method of step 3 in intermediate 55, replace N-(piperidin-4-ylmethyl with N-(2-azaspiro[3.5]nonan-7-yl)propane-2-sulfonamide hydrochloride ) ethanesulfonamide hydrochloride, to get (S)-3-((7-(isopropylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1 - tert-butyl formate. MS m/z [LC-MS]: 430.27 [M+1].

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

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

Intermediate 66: (S)-2-((4-(3-((7-Amino-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidine- 5-yl) oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: tert-butyl 7-(((benzyloxy)carbonyl)amino)-2-azaspiro[3.5]nonane-2-carboxylate

Referring to the method of step 1 in intermediate 55, replace tert-butyl 4-(aminomethyl)piperidine-1-carboxylate with tert-butyl 7-amino-2-azaspiro[3.5]nonane-2-carboxylate ester, and benzyl chloroformate was substituted for ethylsulfonyl chloride to give the title compound. MS m/z [LC-MS]: 375.23 [M+1].

Step 2: Benzyl (2-azaspiro[3.5]nonan-7-yl)carbamate hydrochloride

Referring to the method of step 2 in intermediate 55, 7-(((benzyloxy)carbonyl)amino)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl methyl)piperidine-1-carboxylate tert-butyl to give the title compound. MS m/z [LC-MS]: 275.18 [M+1].

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

Following the procedure of step 3 in Intermediate 55, substituting benzyl (2-azaspiro[3.5]nonan-7-yl)carbamate hydrochloride for N-(piperidin-4-ylmethyl)ethanesulfonamide hydrochloride to obtain the target compound. MS m/z [LC-MS]: 458.30 [M+1].

Step 4: Benzyl (R)-(2-(pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)carbamate hydrochloride

Referring to the method of step 4 in intermediate 55, using (S)-3-((7-((((benzyloxy)carbonyl)amino)-2-azaspiro[3.5]nonan-2-yl)methyl )pyrrolidine-1-carboxylate tert-butyl instead of (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate tert-butyl , to obtain the target compound. MS m/z [LC-MS]: 358.25 [M+1].

Step 5: (S)-(2-((1-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl )methyl)-2-azaspiro[3.5]nonan-7-yl)benzyl carbamate

Referring to the method in Example 36, intermediate 26 was used instead of intermediate 1, and (R)-(2-(pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl ) benzyl carbamate hydrochloride instead of intermediate 29 to obtain the target compound. MS m/z [LC-MS]: 673.39 [M+1].

Step 6: (S)-2-((4-(3-((7-Amino-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidine-5 -yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Put (S)-(2-((1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl)methyl Base)-2-azaspiro[3.5]nonan-7-yl)benzyl carbamate (700mg) and 10% palladium carbon (70mg) were added in methanol (20mL), and the air in the reactor was replaced with hydrogen, and Stir at room temperature under 3 atmospheres of hydrogen for 4 hours, filter, and concentrate the filtrate under reduced pressure to obtain the target compound (550 mg), which is directly used in the next step. MS m/z [LC-MS]: 539.35 [M+1].

Intermediate 67: (R)-N-((2-(Pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)methyl)ethanesulfonamide hydrochloride

Step 1: tert-butyl 7-(ethanesulfonamidomethyl)-2-azaspiro[3.5]nonane-2-carboxylate

Referring to the method of step 1 in intermediate 55, replace 4-(aminomethyl)piperidine-1- with 7-(aminomethyl)-2-azaspiro[3.5]nonane-2-carboxylate tert-butyl carboxylate to obtain the target compound. MS m/z [LC-MS]: 333.18 [M+1].

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

Referring to the method of step 2 in intermediate 55, replace 4-(ethanesulfonamidomethyl) with tert-butyl 7-(ethanesulfonamidomethyl)-2-azaspiro[3.5]nonane-2-carboxylate ) tert-butyl piperidine-1-carboxylate to obtain the title compound. MS m/z [LC-MS]: 233.13 [M+1].

Step 3: (S)-tert-butyl 3-((7-(ethanesulfonamidomethyl)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylate

Referring to the method of step 3 in intermediate 55, N-((2-azaspiro[3.5]nonan-7-yl)methyl)ethanesulfonamide hydrochloride was used instead of N-(piperidin-4-ylmethyl base) ethanesulfonamide hydrochloride to obtain the target compound. MS m/z [LC-MS]: 416.26 [M+1].

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

Referring to the method of step 4 in intermediate 55, using (S)-3-((7-(ethanesulfonamidomethyl)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine -1-carboxylic acid tert-butyl ester instead of (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]: 316.21 [M+1].

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

Add intermediate 5 (428mg) into dry tetrahydrofuran (20mL), add sodium hydride (48mg) under ice-cooling, stir for 0.5 hours, add propargyl bromide (131mg) dropwise, slowly rise to room temperature after the dropwise addition, and stir for 2 Hour. Concentrate under reduced pressure to remove the solvent, add ethyl acetate (30 mL) to the residue, wash with water and saturated brine successively, dry over anhydrous sodium sulfate, filter, the filtrate is concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography (dichloromethane/methanol, 15:1) to obtain the title compound (410 mg). MS m/z [LC-MS]: 466.26 [M+1].

Intermediate 69: tert-butyl (1S,4S)-5-((4-bromophenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

Add (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl ester (396mg) into pyridine (10mL), add 4-bromobenzenesulfonyl chloride under ice-cooling (613 mg), and stirred at room temperature for 2 hours after the addition. Concentrate under reduced pressure to remove the solvent, add ethyl acetate (30 mL) to the residue, wash with 1 mol/L dilute hydrochloric acid, water, and saturated brine successively, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is chromatographed on a silica gel column. (Petroleum ether/ethyl acetate, 3:1) was separated to obtain the title compound (790 mg). MS m/z [LC-MS]: 417.05 [M+1].

Intermediate 70: (S)-2-((4-(3-((2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidine-5 -yl)oxy )-5-fluoro-N,N-diisopropylbenzamide

Step 1: tert-Butyl 7-((Benzyloxy)carbonyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

Referring to the method of step 1 in intermediate 55, replace tert-butyl 4-(aminomethyl)piperidine-1-carboxylate with 2,7-diazaspiro[3.5]nonane-2-carboxylate tert-butyl , substituting benzyl chloroformate for ethylsulfonyl chloride gave the title compound. MS m/z [LC-MS]: 361.21 [M+1].

Step 2: Benzyl 2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride

Referring to step 2 in intermediate 55, replace 4-(ethanesulfonamide with 7-((benzyloxy)carbonyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate methyl)piperidine-1-carboxylate tert-butyl to give the title compound. MS m/z [LC-MS]: 261.16 [M+1].

Step 3: (S)-Benzyl 2-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

Referring to the method of step 3 in intermediate 55, replace N-(piperidin-4-ylmethyl)ethanesulfonamide with 2,7-diazaspiro[3.5]nonane-7-carboxylate benzyl ester hydrochloride hydrochloride to obtain the target compound. MS m/z [LC-MS]: 444.28 [M+1].

Step 4: Benzyl (R)-(2-(pyrrolidin-3-ylmethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride

Referring to the method of step 4 in intermediate 55, use (S)-2-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonane Benzyl alkane-7-carboxylate instead of tert-butyl (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate affords the target compound. MS m/z [LC-MS]: 344.23 [M+1].

Step 5: (S)-(2-((1-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl )methyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate benzyl ester

Referring to the method in Example 36, intermediate 26 was used instead of intermediate 1, and (R)-(2-(pyrrolidin-3-ylmethyl)-2,7-diazaspiro[3.5]nonane- Benzyl 7-carboxylate hydrochloride was used instead of intermediate 29 to obtain the target compound. MS m/z[LC-MS]: 659.37[M+1].

Step 6: (S)-2-((4-(3-((2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidine-5- base)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 6 in intermediate 66, use (S)-(2-((1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine-4- Base)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate benzyl ester instead of (S)-(2-((1-(5-(2 -(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl ) benzyl carbamate to obtain the target compound. MS m/z[LC-MS]: 525.33[M+1].

Intermediate 71: tert -butyl 2-(chlorosulfonyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

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

Intermediate 72: tert-Butyl 5-(chlorosulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

Referring to the method in Intermediate 71, tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate was used instead of 2,7-diazaspiro[3.5]nonane-7-carboxylate acid tert-butyl ester to obtain the target compound. MS m/z [LC-MS]: 311.09 [M+1].

Intermediate 73: tert -butyl 7-(chlorosulfonyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

Referring to the method in Intermediate 71, replace tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate with tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate butyl ester to obtain the target compound. MS m/z [LC-MS]: 325.10 [M+1].

Intermediate 74: tert -butyl 7-(chlorosulfonyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

Referring to the method in Intermediate 71, tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate was replaced with tert-butyl 1,4-diazepane-1-carboxylate, to obtain the target compound. MS m/z [LC-MS]: 299.09 [M+1].

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

Step 1: (S)-tert-butyl 3-((9-oxo-3-azaspiro[5.5]undecane-3-)methyl)pyrrolidine-1-carboxylate

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

Step 2: (R)-3-(Pyrrolidin-3-ylmethyl)-3-azaspiro[5.5]undecan-9-one hydrochloride

Referring to the method of step 4 in intermediate 55, using (S)-3-((9-oxo-3-azaspiro[5.5]undec-3-yl)methyl)pyrrolidine-1-carboxylic acid Substitution of (S)-tert-butyl 3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate with tert-butyl ester afforded the title compound. MS m/z [LC-MS]: 251.21 [M+1].

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

Referring to the method in Example 36, intermediate 26 was used instead of intermediate 1, and (R)-3-(pyrrolidin-3-ylmethyl)-3-azaspiro[5.5]undecane-9-one was used The hydrochloride salt replaces intermediate 29 to give the title compound. MS m/z [LC-MS]: 566.35 [M+1].

Intermediate 76: (S)-2-((4-(3-((9-Amino-3-azaspiro[5.5]undec-3-yl)methyl)pyrrolidin-1-yl)pyrimidine -5- yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method in Example 92, ammonium acetate was used instead of 2,2,2-trifluoroethylamine to obtain the title compound. MS m/z [LC-MS]: 567.38 [M+1].

Intermediate 77: (R)-N-(2-(Pyrrolidin-3-ylmethyl)-2-azaspiro[4.5]decane-8-yl)ethanesulfonamide hydrochloride

Step 1: tert-butyl 8-(ethanesulfonamido)-2-azaspiro[4.5]decane-2-carboxylate

Referring to the method of step 1 in intermediate 55, replace tert-butyl 4-(aminomethyl)piperidine-1-carboxylate with 8-amino-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester ester to obtain the target compound. MS m/z [LC-MS]: 347.20 [M+1].

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

Referring to the method of step 2 in intermediate 55, replace 4-(ethanesulfonamidomethyl)piperene with 8-(ethanesulfonamido)-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester Pyridine-1-carboxylic acid tert-butyl ester to obtain the target compound. MS m/z [LC-MS]: 247.15 [M+1].

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

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

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

Referring to the method of step 4 in intermediate 55, use (S)-3-((8-(ethanesulfonamido)-2-azaspiro[4.5]decane-2-yl)methyl)pyrrolidin-1 - tert-butyl carboxylate instead of (S)-tert-butyl 3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate gave the title compound. MS m/z [LC-MS]: 330.22 [M+1].

Intermediate 78: (R)-N-(3-(Pyrrolidin-3-ylmethyl)-3-azaspiro[5.5]undec-9-yl)ethanesulfonamide hydrochloride

Step 1: tert-butyl 9-(ethanesulfonamido)-3-azaspiro[5.5]undecane-3-carboxylate

Referring to the method of step 1 in intermediate 55, replace 4-(aminomethyl)piperidine-1-carboxylate tert-butyl with 9-amino-3-azaspiro[5.5]undecane-3-carboxylate butyl ester to obtain the target compound. MS m/z [LC-MS]: 361.22 [M+1].

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

Referring to the method of step 2 in intermediate 55, replace 4-(ethanesulfonamidomethyl) with 9-(ethanesulfonamido)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester tert-butyl piperidine-1-carboxylate to give the title compound. MS m/z [LC-MS]: 261.17 [M+1].

Referring to the method of step 3 in intermediate 55, replace N-(piperidin-4-ylmethyl)ethane with N-(3-azaspiro[5.5]undec-9-yl)ethanesulfonamide hydrochloride Sulfonamide hydrochloride, to obtain the target compound. MS m/z [LC-MS]: 444.29 [M+1].

Referring to the method of step 4 in intermediate 55, using (S)-3-((9-(ethanesulfonamido)-3-azaspiro[5.5]undecyl-3-yl)methyl)pyrrolidine- tert-butyl 1-carboxylate instead of (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate tert-butyl yields the title compound . MS m/z [LC-MS]: 344.24 [M+1].

Intermediate 79: (S)-2-((4-(3-((3,9-diazaspiro[5.5]undec-3-yl)methyl)pyrrolidin-1-yl)pyrimidine- 5-yl) oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: 3-Benzyl 9-(tert-butyl) 3,9-diazaspiro[5.5]undecane-3,9-dicarboxylate

Referring to the method of step 1 in intermediate 55, replace tert-butyl 4-(aminomethyl)piperidine-1-carboxylate with 3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester ester, and benzyl chloroformate was substituted for ethylsulfonyl chloride to give the title compound. MS m/z [LC-MS]: 389.25 [M+1].

Step 2: Benzyl 3,9-diazaspiro[5.5]undecane-3-carboxylate hydrochloride

Referring to the method of step 2 in intermediate 55, replace 4-(ethyl Sulfonamidomethyl) piperidine-1-carboxylic acid tert-butyl ester to obtain the target compound. MS m/z [LC-MS]: 289.19 [M+1].

Step 3: Benzyl (S)-9-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate ester

Referring to the method of step 3 in intermediate 55, replace N-(piperidin-4-ylmethyl)ethanesulfonate with 3,9-diazaspiro[5.5]undecane-3-carboxylic acid benzyl ester hydrochloride Amide hydrochloride, to obtain the target compound. MS m/z [LC-MS]: 472.32 [M+1].

Step 4: Benzyl (R)-9-(pyrrolidin-3-ylmethyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate hydrochloride

Referring to the method of step 4 in intermediate 55, use (S)-9-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methyl)-3,9-diazaspiro[5.5]deca Benzyl monoalkane-3-carboxylate instead of tert-butyl (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate gives target compound. MS m/z [LC-MS]: 372.27 [M+1].

Step 5: (S)-9-((1-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl) Benzyl methyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

Referring to the method in Example 36, intermediate 26 was used instead of intermediate 1, and (R)-9-(pyrrolidin-3-ylmethyl)-3,9-diazaspiro[5.5]undecane- 3-Carboxylic acid benzyl ester hydrochloride instead of intermediate 29 affords the title compound. MS m/z [LC-MS]: 687.41 [M+1].

Step 6: (S)-2-((4-(3-((3,9-diazaspiro[5.5]undec-3-yl)methyl)pyrrolidin-1-yl)pyrimidine-5 -yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 6 in intermediate 66, use (S)-9-((1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl )pyrrolidin-3-yl)methyl)-3,9-diazaspiro[5.5]benzyl undecane-3-carboxylate instead of (S)-(2-((1-(5-(2 -(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl ) benzyl carbamate to obtain the target compound. MS m/z [LC-MS]: 553.37 [M+1].

Intermediate 80: (R)-N-((3-(Pyrrolidin-3-ylmethyl)-3-azaspiro[5.5]undec-9-yl)methyl)ethanesulfonamide hydrochloride

Step 1: tert-butyl 9-(ethanesulfonamidomethyl)-3-azaspiro[5.5]undecane-3-carboxylate

Referring to the method of step 1 in intermediate 55, replace 4-(aminomethyl)piperidine-1 with 9-(aminomethyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester - tert-butyl carboxylate to give the target compound. MS m/z [LC-MS]: 375.23 [M+1].

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

Referring to the method of step 2 in intermediate 55, replace 4-(ethanesulfonamidomethyl) with 9-(ethanesulfonamidomethyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester Base) tert-butyl piperidine-1-carboxylate to obtain the title compound. MS m/z [LC-MS]: 275.18 [M+1].

Step 3: (S)-tert-butyl 3-((9-(ethanesulfonamidomethyl)-3-azaspiro[5.5]undec-3-yl)methyl)pyrrolidine-1-carboxylate ester

Referring to the method of step 3 in intermediate 55, use N-((3-azaspiro[5.5]undec-9-yl)methyl)ethanesulfonamide hydrochloride to obtain the target compound. MS m/z [LC-MS]: 458.31 [M+1].

Step 4: (R)-N-((3-(Pyrrolidin-3-ylmethyl)-3-azaspiro[5.5]undec-9-yl)methyl)ethanesulfonamide hydrochloride

Referring to the method of step 4 in intermediate 55, using (S)-3-((9-(ethanesulfonamidomethyl)-3-azaspiro[5.5]undecane-3-yl)methyl)pyrrole Substituting tert-butyl alkane-1-carboxylate for (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate tert-butyl gives target compound. MS m/z [LC-MS]: 358.25 [M+1].

Intermediate 81: (R)-N-(Ethylsulfonyl)-3-(pyrrolidin-3-ylmethyl)-3-azaspiro[5.5]undecane-9-carboxamide hydrochloride

Step 1: tert-butyl 9-(chloroformyl)-3-azaspiro[5.5]undecane-3-carboxylate

Dissolve 3-(tert-butoxycarbonyl)-3-azaspiro[5.5]undecane-9-carboxylic acid (1.50 g) and 1 drop of N,N-dimethylformamide in dichloromethane (15 mL) , dropwise added oxalyl chloride (1.27g) under cooling in an ice bath, after the addition was slowly raised to room temperature and stirred for 2 hours, concentrated under reduced pressure to remove the solvent and oxalyl chloride to obtain the target compound (1.60g), which was directly used in the next step.

Step 2: tert-Butyl 9-((ethylsulfonyl)carbamoyl)-3-azaspiro[5.5]undecane-3-carboxylate

tert-butyl 9-(chloroformyl)-3-azaspiro[5.5]undecane-3-carboxylate (790 mg), ethanesulfonamide (545 mg), triethylamine (758 mg) and 4-dimethyl Aminopyridine (61 mg) was added to dichloromethane (15 mL), stirred at room temperature for 6 hours, the reaction solution was washed 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 title compound (580 mg). MS m/z [LC-MS]: 389.21 [M+1].

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

Referring to the method of step 2 in intermediate 55, replace 4-(ethanesulfonamidomethyl) with 9-(ethanesulfonamidomethyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester Base) tert-butyl piperidine-1-carboxylate to obtain the title compound. MS m/z [LC-MS]: 289.16 [M+1].

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

Referring to the method of step 3 in intermediate 55, N-(ethylsulfonyl)-3-azaspiro[5.5]undecane-9-carboxamide hydrochloride was used to obtain the target compound. MS m/z [LC-MS]: 472.29 [M+1].

Step 5: (R)-N-(Ethylsulfonyl)-3-(pyrrolidin-3-ylmethyl)-3-azaspiro[5.5]undecane-9-carboxamide hydrochloride

Referring to the method of step 4 in intermediate 55, using (S)-3-((9-((ethylsulfonyl)carbamoyl)-3-azaspiro[5.5]undecane-3-yl)methyl )pyrrolidine-1-carboxylate tert-butyl instead of (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate tert-butyl , to obtain the target compound. MS m/z [LC-MS]: 372.23 [M+1].

Intermediate 82: 2-((4-(7-((4-aminocyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy base)-5-fluoro-N,N-diisopropylbenzamide hydrochloride

2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide Synthesized according to the method of the same intermediate in Example 6A in patent WO2017214367.

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

Referring to the method of step 1 in intermediate 63, use 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro- N,N-Diisopropylbenzamide in place of 1-amino-2-methylpropan-2-ol and tert-butyl (4-formylcyclohexyl)carbamate in place of 7-oxo-2-aza Spiro[3.5]nonane-2-carboxylate tert-butyl to obtain the target compound. MS m/z [LC-MS]: 653.42 [M+1].

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

Referring to the method of step 2 in intermediate 55, with (4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2, Substituting tert-butyl 7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)carbamate for tert-butyl 4-(ethanesulfonamidomethyl)piperidine-1-carboxylate to give target compound. MS m/z [LC-MS]: 553.37 [M+1].

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

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

Referring to the method of step 1 in intermediate 63, replace 1-amino-2-methylpropan-2-ol with intermediate 5, and replace 7-oxo-2 with tert-butyl 4-formylpiperidine-1-carboxylate - tert-butyl azaspiro[3.5]nonane-2-carboxylate to give the title compound. MS m/z [LC-MS]: 625.39 [M+1].

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

Referring to the method of step 2 in intermediate 55, using 4-((2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)- 2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester instead of 4-(ethanesulfonamidomethyl)piperidine-1-carboxylic acid tert-butyl ester to obtain the target compound. MS m/z [LC-MS]: 525.34 [M+1].

Intermediate 84: tert -butyl 6-(chlorosulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

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

Intermediate 85: tert -butyl 3-(chlorosulfonyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

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

Intermediate 86: (S)-4-(Chlorosulfonyl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

Referring to the method in Intermediate 71, the title compound was obtained from (S)-3-methylpiperazine-1-carboxylic acid tert-butyl ester. MS m/z [LC-MS]: 299.08 [M+1].

Intermediate 87: (S)-4-(Chlorosulfonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester

Referring to the method in Intermediate 71, the title compound was obtained from (S)-2-methylpiperazine-1-carboxylic acid tert-butyl ester. MS m/z [LC-MS]: 299.08 [M+1].

Intermediate 88: (3aR,6aS)-5-(Chlorosulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester

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

Intermediate 89: (S)-2-((5-(3-((2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)-1, 2,4-Triazin-6- yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: (S)-2-((1-(3,6-dichloro-1,2,4-triazin-5-yl)pyrrolidin-3-yl)methyl)-2,7-di Benzyl azaspiro[3.5]nonane-7-carboxylate

Referring to the method of Step 1 in Example 82, the target compound was obtained by using the product of Step 4 in Intermediate 70 as a starting material. MS m/z [LC-MS]: 491.17 [M+1].

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

Referring to the method of step 2 in Example 82, use (S)-2-((1-(3,6-dichloro-1,2,4-triazin-5-yl)pyrrolidin-3-yl)methyl base)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid benzyl ester as raw material to obtain the target compound. MS m/z [LC-MS]: 694.33 [M+1].

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

Referring to the method of step 3 in Example 82, use (S)-2-((1-(3-chloro-6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)- 1,2,4-Triazin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid benzyl ester as starting material to obtain the target compound. MS m/z [LC-MS]: 526.33 [M+1].

Intermediate 90: (R)-1-(pyrrolidin-3-ylmethyl)-3'-(trifluoromethyl)-5',6'-dihydro-8'H-spiro[piperidine-4 ,7'-[1,2,4] triazolo[4,3-a]pyridine]hydrochloride

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

Add tert-butyl 8-oxo-3,9-diazaspiro[5.5]undecane-3-carboxylate (268mg) and Lawson’s reagent (424mg) into toluene (10mL), stir overnight at 100°C, After filtration and concentration under reduced pressure, it was 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].

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

Add tert-butyl 8-thio-3,9-diazaspiro[5.5]undecane-3-carboxylate (250mg), trifluoroacetylhydrazide (460mg), mercury acetate (630mg), tetrahydrofuran (10mL) In a sealed tube, stirred at 80°C for two days, 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].

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

Referring to the method of step 2 in intermediate 55, use 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 as raw material to obtain the target compound. MS m/z [LC-MS]: 261.13 [M+1].

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-carboxylate tert-butyl

Referring to the method of step 3 in intermediate 55, use 3'-(trifluoromethyl)-5',6'-dihydro-8'H-spiro[piperidine-4,7'-[1,2,4 ]Triazolo[4,3-a]pyridine]hydrochloride as raw material to obtain the target compound. MS m/z [LC-MS]: 444.26 [M+1].

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

Referring to the method of step 4 in intermediate 55, use (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 as raw material to obtain the target compound. MS m/z [LC-MS]: 344.21 [M+1].

Intermediate 91: tert -butyl 9-(chlorosulfonyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

Referring to the method in Intermediate 71, the target compound was obtained from tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate. MS m/z [LC-MS]: 353.13 [M+1].

Intermediate 92 : Benzyl (R)-(3-(pyrrolidin-3-ylmethyl)-3-azaspiro[5.5]undec-9-yl)carbamate hydrochloride

Step 1: tert-Butyl 9-(((Benzyloxy)carbonyl)amino)-3-azaspiro[5.5]undecane-3-carboxylate

Referring to the method of step 1 in 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].

Step 2: Benzyl (3-azaspiro[5.5]undec-9-yl)carbamate hydrochloride

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

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

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

Step 4: Benzyl (R)-(3-(pyrrolidin-3-ylmethyl)-3-azaspiro[5.5]undec-9-yl)carbamate hydrochloride

Referring to the method of step 4 in intermediate 55, use (S)-3-((9-((((benzyloxy)carbonyl)amino)-3-azaspiro[5.5]undecyl-3-yl)methanol Base) pyrrolidine-1-carboxylic acid tert-butyl ester as raw material to obtain the target compound. MS m/z [LC-MS]: 386.28 [M+1].

Intermediate 93: (S)-2-((5-(3-((9-Amino-3-azaspiro[5.5]undec-3-yl)methyl)pyrrolidin-1-yl)- 1,2,4- Triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: (S)-(3-((1-(3,6-Dichloro-1,2,4-triazin-5-yl)pyrrolidin-3-yl)methyl)-3-aza Benzyl spiro[5.5]undec-9-yl)carbamate

Referring to the method in Step 1 in Example 82, the title compound was obtained using Intermediate 92 as a starting material. MS m/z [LC-MS]: 533.22 [M+1].

Step 2: (S)-(3-((1-(3-chloro-6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)-1,2,4-tri Azin-5-yl)pyrrolidin-3-yl)methyl)-3-azaspiro[5.5]undec-9-yl)carbamate benzyl ester

Referring to the method of step 2 in Example 82, use (S)-(3-((1-(3,6-dichloro-1,2,4-triazin-5-yl)pyrrolidin-3-yl) Methyl)-3-azaspiro[5.5]undec-9-yl)benzyl carbamate was used as starting material to obtain the target compound. MS m/z [LC-MS]: 736.38 [M+1].

Step 3: (S)-2-((5-(3-((9-Amino-3-azaspiro[5.5]undec-3-yl)methyl)pyrrolidin-1-yl)-1 ,2,4-Triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 82, use (S)-(3-((1-(3-chloro-6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy) -1,2,4-triazin-5-yl)pyrrolidin-3-yl)methyl)-3-azaspiro[5.5]undecan-9-yl)benzyl carbamate as raw material to obtain the target compound . MS m/z [LC-MS]: 568.38 [M+1].

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

Step 1: 4-((2-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5] Nonan-7-yl)methyl)piperidine-1-carboxylate tert-butyl

Referring to the method of step 1 in intermediate 63, use 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro- N,N-Diisopropylbenzamide and tert-butyl 4-formylpiperidine-1-carboxylate were used as starting materials to obtain the target compound. MS m/z [LC-MS]: 639.40 [M+1].

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

Referring to the method of step 2 in intermediate 55, use 4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7 -Diazaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester as raw material to obtain the target compound. MS m/z [LC-MS]: 539.35 [M+1].

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

Referring to the method in Intermediate 71, the title compound was obtained from tert-butyl piperidin-4-ylcarbamate. MS m/z [LC-MS]: 299.08 [M+1].

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

Referring to the method in Intermediate 71, the title compound was obtained from tert-butyl (R)-piperidin-3-ylcarbamate. MS m/z [LC-MS]: 299.08 [M+1].

Intermediate 97: (S)-2-((4-(3-((9-Amino-3-azaspiro[5.5]undec-3-yl)methyl)pyrrolidin-1-yl)pyrimidine -5- yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

Step 1: (S)-(3-((1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine- 3-yl)methyl)-3-azaspiro[5.5]undec-9-yl)benzyl carbamate

Referring to the method in Example 36, the title compound was obtained using Intermediate 92 as a starting material. MS m/z [LC-MS]: 687.40 [M+1].

Step 2: (S)-2-((4-(3-((9-Amino-3-azaspiro[5.5]undec-3-yl)methyl)pyrrolidin-1-yl)pyrimidine- 5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

Referring to the method of step 6 in intermediate 66, using (S)-(3-((1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine -4-yl)pyrrolidin-3-yl)methyl)-3-azaspiro[5.5]undec-9-yl)benzyl carbamate as starting material to obtain the target compound. MS m/z [LC-MS]: 553.37 [M+1].

Intermediate 98: tert-butyl (1-(chlorosulfonyl)azetidin-3-yl)carbamate

Referring to the method in Intermediate 71, the title compound was obtained from tert-butyl azetidin-3-ylcarbamate. MS m/z [LC-MS]: 271.05 [M+1].

Intermediate 99: tert-butyl (R)-(1-(chlorosulfonyl)pyrrolidin-3-yl)carbamate

Referring to the method in Intermediate 71, the title compound was obtained using (R)-tert-butylpyrrolidin-3-ylcarbamate as starting material. MS m/z [LC-MS]: 285.07 [M+1].

Intermediate 100: Benzyl 4-((2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carboxylate hydrochloride

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

Referring to the method of step 1 in intermediate 35, using benzyl 4-formylpiperidine-1-carboxylate and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate as raw materials to obtain the target compound . MS m/z [LC-MS]: 458.30 [M+1].

Step 2: Benzyl 4-((2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carboxylate hydrochloride

Referring to the method of step 2 in intermediate 35, using 7-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane -2-Tert-butyl carboxylate was used as starting material to obtain the target compound. MS m/z [LC-MS]: 358.25 [M+1].

Intermediate 101: 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

Step 1: 4-((2-(3,6-Dichloro-1,2,4-triazin-5-yl)pyrrolidin-3-yl)-2,7-diazaspiro[3.5]nonane Benzyl-7-yl)methyl)piperidine-1-carboxylate

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

Step 2: 4-((2-(3-chloro-6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl )-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carboxylic acid benzyl ester

Referring to the method of step 2 in Example 82, use 4-((2-(3,6-dichloro-1,2,4-triazin-5-yl)pyrrolidin-3-yl)-2,7- The target compound was obtained from benzyl diazaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carboxylate. MS m/z [LC-MS]: 708.34 [M+1].

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

Referring to the method of step 3 in Example 82, with 4-((2-(3-chloro-6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)-1,2, 4-Triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carboxylic acid benzyl ester was used as starting material to obtain the target compound. MS m/z [LC-MS]: 540.35 [M+1].

Intermediate 102: (S)-5-fluoro-N,N-diisopropyl-2-((4-(7-(pyrrolidin-3-ylmethyl)-2,7-diazaspiro[ 3.5] Nonan -2-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

Step 1: (R)-3-((2-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazepine Spiro[3.5]nonan-7-yl)methyl)pyrrolidine-1-carboxylate tert-butyl

Referring to the method of step 1 in intermediate 63, use 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro- N,N-Diisopropylbenzamide and (S)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester were used as raw materials to obtain the target compound. MS m/z [LC-MS]: 625.39 [M+1].

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

Referring to the method of step 2 in intermediate 55, use (R)-3-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl) -2,7-diazaspiro[3.5]nonan-7-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester was used as starting material to obtain the target compound. MS m/z [LC-MS]: 525.34 [M+1].

Intermediate 103: (R)-5-fluoro-N,N-diisopropyl-2-((4-(7-(pyrrolidin-3-ylmethyl)-2,7-diazaspiro[ 3.5] Nonan -2-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

Step 1: (S)-3-((2-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazepine Spiro[3.5]nonan-7-yl)methyl)pyrrolidine-1-carboxylate tert-butyl

Referring to the method of step 1 in intermediate 63, use 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro- N,N-Diisopropylbenzamide was used as starting material to obtain the target compound. MS m/z [LC-MS]: 625.39 [M+1].

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

Referring to the method of step 2 in intermediate 55, using (S)-3-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl) -2,7-diazaspiro[3.5]nonan-7-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester was used as starting material to obtain the target compound. MS m/z [LC-MS]: 525.34 [M+1].

Intermediate 104: tert -butyl 4-((4-(bromomethyl)phenyl)sulfonyl)-1,4-diazepane-1-carboxylate

Referring to the method in Intermediate 71, using tert-butyl 1,4-diazepane-1-carboxylate and 4-(bromomethyl)benzenesulfonyl chloride as starting materials, the title compound was obtained. MS m/z [LC-MS]: 433.08 [M+1].

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

Referring to the method in Intermediate 71, using tert-butyl (R)-piperidin-3-ylcarbamate and 4-(bromomethyl)benzenesulfonyl chloride as starting materials, the title compound was obtained. MS m/z [LC-MS]: 433.08 [M+1].

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

Referring to the method in Intermediate 71, using tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate and 4-(bromomethyl)benzenesulfonyl chloride as raw materials to obtain the target compound. MS m/z [LC-MS]: 431.06 [M+1].

Intermediate 107: tert-butyl (1R,5R)-3-(chlorosulfonyl)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate

Referring to the method in Intermediate 71, the title compound was obtained from tert-butyl (1S,5R)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate as starting material. MS m/z [LC-MS]: 297.07 [M+1].

Intermediate 108: 5-fluoro-N,N-diisopropyl-2-((4-(7-((1,2,3,6-tetrahydropyridin-4-yl)methyl)-2, 7-diazaspiro [3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

Step 1: tert-butyl 4-(((methylsulfonyl)oxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylate

Add tert-butyl 4-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylate (426 mg), diisopropylethylamine (774 mg) into dichloromethane (10 mL), After cooling to -5°C in an ice-salt bath, a solution of trifluoromethanesulfonic anhydride (620 mg) in dichloromethane (5 mL) was slowly added dropwise. After the dropwise addition was completed, it was stirred at -5°C to 0°C for 1 hour, and the reaction solution was washed with 0.5mol/L dilute hydrochloric acid, saturated sodium bicarbonate solution and saturated brine successively, concentrated under reduced pressure, and subjected to silica gel column chromatography (petroleum ether/ethyl acetate). , 4:1) to obtain the title compound (495mg). MS m/z [LC-MS]: 292.12 [M+1].

Step 2: 4-((2-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5] Nonan-7-yl)methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

tert-butyl 4-(((methylsulfonyl)oxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylate (437 mg), 2-((4-(2,7- Diazaspiro[3.5]nonan-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 title compound (763 mg). MS m/z [LC-MS]: 637.39 [M+1].

Step 3: 5-fluoro-N,N-diisopropyl-2-((4-(7-((1,2,3,6-tetrahydropyridin-4-yl)methyl)-2,7 -Diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

Referring to the method of step 2 in intermediate 55, use 4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7 -Diazaspiro[3.5]nonan-7-yl)methyl)-3,6-dihydropyridine-1(2H)-tert-butyl carboxylate as starting material to obtain the target compound. MS m/z [LC-MS]: 537.34 [M+1].

Intermediate 109: (R)-5-fluoro-N,N-diisopropyl-2-((4-(7-(pyrrolidin-3-ylmethyl)-2,7-diazaspiro[ 3.5] Nonan -2-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

Step 1: 4-((2-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5] Nonan-7-yl)methyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester

Referring to the method of step 1 in intermediate 63, 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro- N,N-Diisopropylbenzamide and tert-butyl 4-fluoro-4-formylpiperidine-1-carboxylate were used as raw materials to obtain the target compound. MS m/z [LC-MS]: 657.39 [M+1].

Step 2: 5-fluoro-2-((4-(7-((4-fluoropiperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl) Pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide hydrochloride

Referring to the method of step 2 in intermediate 55, 4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7 - Diazaspiro[3.5]nonan-7-yl)methyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester as starting material to obtain the target compound. MS m/z [LC-MS]: 557.34 [M+1].

Intermediate 110: 2-((5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro -N,N- Diisopropylbenzamide

Step 1: Benzyl 2-(3,6-dichloro-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

Referring to the method in step 1 in Example 82, using benzyl 2,7-diazaspiro[3.5]nonane-7-carboxylate as raw material, the title compound was obtained. MS m/z [LC-MS]: 408.10 [M+1].

Step 2: 2-(3-Chloro-6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2, Benzyl 7-diazaspiro[3.5]nonane-7-carboxylate

Referring to the method of step 2 in Example 82, 2-(3,6-dichloro-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7 - Benzyl carboxylate as starting material to obtain the target compound. MS m/z [LC-MS]: 611.25 [M+1].

Step 3: 2-((5-(2,7-Diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro- N,N-Diisopropylbenzamide

Referring to the method of step 3 in Example 82, 2-(3-chloro-6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)-1,2,4-triazine -5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid benzyl ester as raw material to obtain the target compound. MS m/z [LC-MS]: 443.26 [M+1].

Intermediate 111: (R)-5-fluoro-N,N-diisopropyl-2-((5-(7-(pyrrolidin-3-ylmethyl)-2,7-diazaspiro[ 3.5] Nonan -2-yl)-1,2,4-triazin-6-yl)oxy)benzamide hydrochloride

Step 1: (S)-3-((2-(6-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl )-2,7-diazaspiro[3.5]nonan-7-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

Referring to the method of step 1 in intermediate 63, using intermediate 110 and (R)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester as starting materials, the title compound was obtained. MS m/z [LC-MS]: 626.38 [M+1].

Step 2: (R)-5-fluoro-N,N-diisopropyl-2-((5-(7-(pyrrolidin-3-ylmethyl)-2,7-diazaspiro[3.5 ]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide hydrochloride

Referring to the method of step 2 in intermediate 55, with (S)-3-((2-(6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)-1,2, 4-Triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester was used as starting material to obtain the target compound. MS m/z [LC-MS]: 526.33 [M+1].

Intermediate 112: (S)-5-fluoro-N,N-diisopropyl-2-((5-(7-(pyrrolidin-3-ylmethyl)-2,7-diazaspiro[ 3.5] Nonan -2-yl)-1,2,4-triazin-6-yl)oxy)benzamide hydrochloride

Step 1: (R)-3-((2-(6-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl )-2,7-diazaspiro[3.5]nonan-7-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

Referring to the method of step 1 in intermediate 63, using intermediate 110 and (S)-tert-butyl 3-formylpyrrolidine-1-carboxylate as starting materials, the title compound was obtained. MS m/z [LC-MS]: 626.38 [M+1].

Step 2: (S)-5-fluoro-N,N-diisopropyl-2-((5-(7-(pyrrolidin-3-ylmethyl)-2,7-diazaspiro[3.5 ]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide hydrochloride

Referring to the method of step 2 in intermediate 55, with (R)-3-((2-(6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)-1,2, 4-Triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester was used as starting material to obtain the target compound. MS m/z [LC-MS]: 526.33 [M+1].

Intermediate 113: tert-butyl (1S,5S)-3-(chlorosulfonyl)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate

Referring to the method in Intermediate 71, the title compound was obtained from tert-butyl (1R,5S)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate as starting material. MS m/z [LC-MS]: 297.07 [M+1].

Intermediate 114: (S)-5-fluoro-N,N-diisopropyl-2-((4-(7-(pyrrolidin-3-ylmethyl)-2,7-diazaspiro[ 3.5] Nonan -2-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

Referring to the method of step 1 in intermediate 63, 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro- N,N-diisopropylbenzamide and (S)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester were used as raw materials to obtain the target compound. MS m/z [LC-MS]: 625.39 [M+1].

Referring to the method of step 2 in intermediate 55, (R)-3-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl) -2,7-diazaspiro[3.5]nonan-7-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester as raw material to obtain the target compound. MS m/z [LC-MS]: 525.34 [M+1].

Intermediate 115: 5-fluoro-N,N-diisopropyl-2-((5-(7-((1,2,3,6-tetrahydropyridin-4-yl)methyl)-2, 7-diazaspiro [3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide hydrochloride

Step 1: 4-((2-(6-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2, 7-diazaspiro[3.5]nonan-7-yl)methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

Referring to the method of step 1 in intermediate 108, using intermediate 110 and tert-butyl 4-(((methylsulfonyl)oxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylate as raw materials to obtain the target compound. MS m/z [LC-MS]: 638.38 [M+1].

Step 2: 5-fluoro-N,N-diisopropyl-2-((5-(7-((1,2,3,6-tetrahydropyridin-4-yl)methyl)-2,7 -Diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide hydrochloride

Referring to the method of step 2 in intermediate 55, 4-((2-(6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)-1,2,4-triazine -5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester as starting material to obtain target compound. MS m/z [LC-MS]: 538.33 [M+1].

Intermediate 116: 5-fluoro-2-((4-(7-((4-fluoropiperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl )-1,2,4- triazin-6-yl)oxy)benzamide hydrochloride

Step 1: 4-((2-(6-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2, tert-Butyl 7-diazaspiro[3.5]nonan-7-yl)methyl)-4-fluoropiperidine-1-carboxylate

Referring to the method in step 1 in intermediate 63, using intermediate 110 and tert-butyl 4-fluoro-4-formylpiperidine-1-carboxylate as starting materials, the title compound was obtained. MS m/z [LC-MS]: 658.39 [M+1].

Step 2: 5-fluoro-2-((4-(7-((4-fluoropiperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl) -1,2,4-Triazin-6-yl)oxy)benzamide hydrochloride

Referring to the method of step 2 in intermediate 55, 4-((2-(6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)-1,2,4-triazine -5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester as raw material to obtain the target compound. MS m/z [LC-MS]: 558.34 [M+1].

Intermediate 117: (S)-2-((5-(3-((7-Amino-2-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)- 1,2,4- Triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

Step 1: (S)-(2-((1-(3,6-Dichloro-1,2,4-triazin-5-yl)pyrrolidin-3-yl)methyl)-2-diazepine Benzyl heterospiro[3.5]nonan-7-yl)carbamate

Referring to the method of step 1 in Example 82, (R)-(2-(pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)carbamate benzyl hydrochloride salt and 3,5,6-trichloro-1,2,4-triazine as raw materials to obtain the target compound. MS m/z [LC-MS]: 505.19 [M+1].

Step 2: (S)-(2-((1-(3-chloro-6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2, Benzyl 4-triazin-5-yl)pyrrolidin-3-yl)methyl)-2-diazaspiro[3.5]nonan-7-yl)carbamate

Referring to the method of step 2 in Example 82, (S)-(2-((1-(3,6-dichloro-1,2,4-triazin-5-yl)pyrrolidin-3-yl) Starting from methyl)-2-diazaspiro[3.5]nonan-7-yl)benzyl carbamate and N-ethyl-5-fluoro-2-hydroxy-N-isopropylbenzamide, the target compound. MS m/z [LC-MS]: 694.33 [M+1].

Step 3: (S)-2-((5-(3-((7-Amino-2-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)-1 ,2,4-Triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

Referring to the method of step 3 in Example 82, (S)-(2-((1-(3-chloro-6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorobenzene Oxy)-1,2,4-triazin-5-yl)pyrrolidin-3-yl)methyl)-2-diazaspiro[3.5]nonan-7-yl)benzyl carbamate as raw material , to obtain the target compound. MS m/z [LC-MS]: 526.33 [M+1].

Example 1: N-ethyl-5-fluoro-N-isopropyl-2-((4-(7-((trans-4-((2-methoxy-3,4-dioxocyclo But-1-en-1- yl)amino)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide

Step 1: ((trans-4-((2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7 -Diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)carbamate tert-butyl

Add intermediate 5 (214 mg), tert-butyl 4-formylcyclohexylcarbamate (136 mg) and tetraethyl titanate (138 mg) into 1,2-dichloroethane (10 mL), and stir at room temperature for 1 hour, then added sodium triacetoxyborohydride (212 mg), stirred at room temperature overnight, added saturated sodium bicarbonate solution to quench the reaction, filtered, the filtrate was extracted with dichloromethane, combined organic phases, dried over anhydrous sodium sulfate, Filtration, 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) aminomethyl) Acyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)carbamate (190 mg). MS m/z [LC-MS]: 639.41 [M+1].

Step 2: 2-((4-(7-((trans-4-aminocyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl) Oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

((trans-4-((2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-di Azaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)carbamate tert-butyl ester (190mg) was added to 4N hydrogen chloride methanol solution (5mL), stirred at room temperature for 2 hours, concentrated under reduced pressure and then used 10% The sodium hydroxide solution was adjusted to pH=11~12, extracted with a mixed solvent of dichloromethane/isopropanol (4:1), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 2-((4-( 7-((trans-4-aminocyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5 -Fluoro-N-isopropylbenzamide (140 mg). MS m/z [LC-MS]: 539.35 [M+1].

Step 3: N-ethyl-5-fluoro-N-isopropyl-2-((4-(7-((trans-4-((2-methoxy-3,4-dioxocyclidine -1-en-1-yl)amino)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide

2-((4-(7-((trans-4-aminocyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy )-N-ethyl-5-fluoro-N-isopropylbenzamide (54mg), 3,4-dimethoxycyclobut-3-ene-1,2-dione (28mg) and diiso Propylethylamine (26mg) was added to ethanol (2mL), stirred at 80°C for 6 hours, poured into water (20mL), extracted with ethyl acetate (3×10mL), and the organic phase was washed with water and saturated brine successively. Dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and use silica gel column chromatography (dichloromethane/methanol, 15:1) to separate 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-di Azaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide (30 mg). MS m/z [LC-MS]: 649.35 [M+1]. ¹ H NMR (400MHz, DMSO-d ₆ ): 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).

Example 2: N-ethyl-5-fluoro-N-isopropyl-2-((4-(7-((trans-4-((2-methylamino-3,4-dioxocyclo But-1-en-1- yl)amino)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method of step 3 in Example 1, replace 3,4-dimethoxycyclobutane-3 with 3-methoxy-4-(methylamino)cyclobut-3-ene-1,2-dione -ene-1,2-dione, sealed tube reaction 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-d ₆ ): 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,2H),1.40-2.08(m,10H),1.11-1.31(m,6H),1.04-1.07(m,5H),0.94- 1.01(m,5H).

Example 3: 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)amino)pyrimidin-5-yl)oxy)benzamide

Step 1: tert-butyl 4-((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)piperidine-1-carboxylate ester

Intermediate 1 (675 mg), tert-butyl 4-aminopiperidine-1-carboxylate (600 mg) and diisopropylethylamine (774 mg) were added to isopropanol (10 mL), and the reaction was stirred at 80°C for 18 Hours, after cooling down to room temperature, concentrate under reduced pressure and use silica gel column chromatography (petroleum ether/ethyl acetate, 1:2) to separate 4-((5-(2-(ethyl (isopropyl) carbamoyl) -tert-butyl 4-fluorophenoxy)pyrimidin-4-yl)amino)piperidine-1-carboxylate (900 mg). MS m/z [LC-MS]: 502.29 [M+1].

Step 2: N-Ethyl-5-fluoro-N-isopropyl-2-((4-(piperidin-4-ylamino)pyrimidin-5-yl)oxy)benzamide

4-((5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)piperidine-1-carboxylic acid tert-butyl ester ( 900 mg) was added to 4N methanolic hydrogen chloride solution (10 mL), stirred at room temperature for 2 hours, concentrated under reduced pressure, adjusted to pH=11-12 with 10% sodium hydroxide solution, and dichloromethane/isopropanol (4:1) Mixed solvent extraction, the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain N-ethyl-5-fluoro-N-isopropyl-2-((4-(piperidin-4-ylamino)pyrimidine- 5-yl)oxy)benzamide (650 mg). MS m/z [LC-MS]: 402.23 [M+1].

Step 3: (trans-4-((4-((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)piperidine -1-yl) methyl) cyclohexyl) tert-butyl carbamate

N-ethyl-5-fluoro-N-isopropyl-2-((4-(piperidin-4-ylamino)pyrimidin-5-yl)oxy)benzamide (201 mg), 4-form Add tert-butyl acylcyclohexylcarbamate (136mg) and tetraethyl titanate (138mg) into 1,2-dichloroethane (10mL), stir at room temperature for 1 hour, then add sodium triacetoxyborohydride (212 mg), stirred overnight at room temperature, added saturated sodium bicarbonate solution to quench the reaction, filtered, the filtrate was extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography ( Dichloromethane/methanol, 20:1) isolated (trans-4-((4-((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine -4-yl)amino)piperidin-1-yl)methyl)cyclohexyl)tert-butyl carbamate (160 mg). MS m/z [LC-MS]: 613.39 [M+1].

Step 4: 2-((4-((1-((trans-4-aminocyclohexyl)methyl)piperidin-4-yl)amino)pyrimidin-5-yl)oxy)-N-ethyl- 5-Fluoro-N-isopropylbenzamide

Put (trans-4-((4-((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)piperidine-1 - Base) methyl) cyclohexyl) tert-butyl carbamate (160 mg) was added to 4N hydrogen chloride methanol solution (5 mL), stirred at room temperature for 2 hours, concentrated under reduced pressure and adjusted to pH = 11 ~ 1 with 10% sodium hydroxide solution 12, extracted with a mixed solvent of dichloromethane/isopropanol (4:1), dried the organic phase with anhydrous sodium sulfate, filtered, and concentrated the filtrate to obtain 2-((4-((1-((trans-4-amino Cyclohexyl)methyl)piperidin-4-yl)amino)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (120 mg). MS m/z [LC-MS]: 513.34 [M+1].

Step 5: N-ethyl-5-fluoro-N-isopropyl-2-((4-((1-((trans-4-((2-methoxy-3,4-dioxocyclo But-1-en-1-yl)amino)cyclohexyl)methyl)piperidin-4-yl)amino)pyrimidin-5-yl)oxy)benzamide

2-((4-((1-((trans-4-aminocyclohexyl)methyl)piperidin-4-yl)amino)pyrimidin-5-yl)oxy)-N-ethyl-5- Fluoro-N-isopropylbenzamide (52mg), 3,4-dimethoxycyclobut-3-ene-1,2-dione (28mg) and diisopropylethylamine (26mg) were added In ethanol (2mL), stirred at 80°C for 6 hours, poured into water (20mL), extracted with ethyl acetate (3×10mL), the organic phase was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, filtered, and the filtrate Concentrate under reduced pressure, and use silica gel column chromatography (dichloromethane/methanol, 15:1) to separate 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). MS m/z [LC-MS]: 623.34 [M+1]. ¹ H NMR (400MHz, DMSO-d ₆ ): 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).

Example 4: N-ethyl-5-fluoro-N-isopropyl-2-((4-((1-((trans-4-(methylsulfonamido)cyclohexyl)methyl)piperidine- 4- yl)amino)pyrimidin-5-yl)oxy)benzamide

The intermediate N-ethyl-5-fluoro-N-isopropyl-2-((4-(piperidin-4-ylamino)pyrimidin-5-yl)oxy)benzamide (40 mg), carbonic acid Potassium (40mg) and potassium iodide (7mg) were added to a solution of intermediate 2 (43mg) in N,N-dimethylformamide (2mL), stirred at 80°C for 4 hours, poured into water (20mL), and washed with acetic acid Ethyl ester (3×10mL) was extracted, the organic phase was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by silica gel column chromatography (dichloromethane/methanol, 15:1) to obtain N -Ethyl-5-fluoro-N-isopropyl-2-((4-((1-((trans-4-(methylsulfonamido)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, CD ₃ OD): 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).

Example 5: N-ethyl-2-((4-(((1-((trans-4-(ethylsulfonamido)cyclohexyl)methyl)piperidin-4-yl)methyl)amino ) pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

Referring to the method in Example 4, use intermediate 6 instead of N-ethyl-5-fluoro-N-isopropyl-2-((4-(piperidin-4-ylamino)pyrimidin-5-yl)oxy Base) benzamide, use intermediate 3 instead of intermediate 2 to give 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, CDCl ₃ ):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).

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

Step 1: (trans-4-((4-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl Base) piperidin-1-yl) methyl) cyclohexyl) tert-butyl carbamate

With reference to the method of step 1 in Example 1, intermediate 6 is used instead of intermediate 5 to obtain (trans-4-((4-(((5-(2-(ethyl (isopropyl) carbamoyl) -4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)methyl)cyclohexyl)carbamate tert-butyl ester. MS m/z [LC-MS]: 627.41 [M+1].

Step 2: 2-((4-(((1-((trans-4-aminocyclohexyl)methyl)piperidin-4-yl)methyl)amino)pyrimidin-5-yl)oxy)-N -Ethyl-5-fluoro-N-isopropylbenzamide

With reference to the method of step 2 in Example 1, use (trans-4-((4-(((5-(2-(ethyl (isopropyl) carbamoyl)-4-fluorophenoxy) pyrimidine -4-yl)amino)methyl)piperidin-1-yl)methyl)cyclohexyl)carbamate tert-butyl ester instead of ((trans-4-((2-(5-(2-(ethyl(iso Propyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)carbamate tert Butyl ester, get 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].

Step 3: 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

With reference to the method of step 3 in Example 1, use 2-((4-(((1-((trans-4-aminocyclohexyl)methyl)piperidin-4-yl)methyl)amino)pyrimidine-5 -yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide instead of 2-((4-(7-((trans-4-aminocyclohexyl)methyl)-2, 7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide, N-ethyl- 5-fluoro-N-isopropyl-2-((4-(((1-((trans-4-((2-methoxy-3,4-dioxocyclobut-1-ene-1 -yl)amino)cyclohexyl)methyl)piperidin-4-yl)methyl)amino)pyrimidin-5-yl)oxy)benzamide. MS m/z [LC-MS]: 637.35 [M+1]. ¹ H NMR (400MHz, DMSO-d ₆ ): δ=8.78(d, J=7.6Hz, 0.6H), 8.57(d, J=7.6Hz, 0.4H), 8.24(s, 1H), 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),1.93-1.99(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).

Example 7: N-ethyl-5-fluoro-N-isopropyl-2-((4-((((1R,5S,6S)-3-((trans-4-(methylsulfonamido) Cyclohexyl)methyl )-3-azabicyclo[3.1.0]hexane-6-yl)methyl)amino)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 4, use intermediate 7 instead of N-ethyl-5-fluoro-N-isopropyl-2-((4-(piperidin-4-ylamino)pyrimidin-5-yl)oxy base) benzamide to give N-ethyl-5-fluoro-N-isopropyl-2-((4-((((1R,5S,6S)-3-((trans-4-(methylsulfonate Amino)cyclohexyl)methyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)amino)pyrimidin-5-yl)oxy)benzamide. MS m/z [LC-MS]: 603.32 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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,2H),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).

Example 8: N-ethyl-5-fluoro-N-isopropyl-2-((4-(((1R,5S,6S)-3-((trans-4-(methylsulfonamido)cyclo Hexyl)methyl )-3-azabicyclo[3.1.0]hexan-6-yl)amino)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 4, use intermediate 8 instead of N-ethyl-5-fluoro-N-isopropyl-2-((4-(piperidin-4-ylamino)pyrimidin-5-yl)oxy base) benzamide to give N-ethyl-5-fluoro-N-isopropyl-2-((4-(((1R,5S,6S)-3-((trans-4-(methanesulfonamide base)cyclohexyl)methyl)-3-azabicyclo[3.1.0]hexan-6-yl)amino)pyrimidin-5-yl)oxy)benzamide. MS m/z [LC-MS]: 589.30 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 9: N-ethyl-5-fluoro-N-isopropyl-2-((4-(3-((((trans-4-(methylsulfonamido)cyclohexyl)methyl)amino) Methyl )azetidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Add Intermediate 9 (97 mg), Intermediate 4 (66 mg) and tetraethyl titanate (70 mg) into 1,2-dichloroethane (5 mL), stir at room temperature for 1 hour, and then add triacetoxy Sodium borohydride (106mg), stirred overnight at room temperature, quenched the reaction by adding saturated sodium bicarbonate solution, filtered, the filtrate was extracted with dichloromethane, combined organic phases, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and washed with silica gel Column chromatography (dichloromethane/methanol, 15:1) separation, N-ethyl-5-fluoro-N-isopropyl-2-((4-(3-((((trans-4-(methyl Sulfonamido)cyclohexyl)methyl)amino)methyl)azetidin-1-yl)pyrimidin-5-yl)oxy)benzamide (55 mg). MS m/z [LC-MS]: 577.30 [M+1]. ¹ H NMR (400MHz, DMSO-d ₆ ): 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).

Example 10: N-ethyl-5-fluoro-N-isopropyl-2-((4-(3-(((((trans-4-(methylsulfonamido)cyclohexyl)methyl)amino) Methyl)azetidin-1-yl)pyrimidin-5-yl)oxy)benzamide

With reference to the method in Example 9, use N-ethyl-5-fluoro-N-isopropyl-2-((4-(3-((((trans-4-(methylsulfonamido)cyclohexyl) Methyl)amino)methyl)azetidin-1-yl)pyrimidin-5-yl)oxy)benzamide in place of intermediate 9 to give N-ethyl-5-fluoro-N-isopropyl -2-((4-(3-((methyl((trans-4-(methylsulfonamido)cyclohexyl)methyl)amino)methyl)azetidin-1-yl)pyrimidine-5 -yl)oxy)benzamide. MS m/z [LC-MS]: 591.32 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 11: N-ethyl-5-fluoro-N-isopropyl-2-((4-(4-(((trans-4-(methylsulfonamido)cyclohexyl)methyl)amino) piper Pyridin-1-yl)pyrimidin-5-yl)oxy)benzamide

With reference to the method in Example 9, Intermediate 9 was replaced by Intermediate 10 to obtain N-ethyl-5-fluoro-N-isopropyl-2-((4-(4-(((trans-4-( Methanesulfonylamido)cyclohexyl)methyl)amino)piperidin-1-yl)pyrimidin-5-yl)oxy)benzamide. MS m/z [LC-MS]: 591.32 [M+1].

Example 12: N-ethyl-5-fluoro-N-isopropyl-2-((4-((R)-3-(((trans-4-(methylsulfonamido)cyclohexyl)methyl )amino )pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

With reference to the method in Example 9, Intermediate 9 was replaced by Intermediate 11 to obtain N-ethyl-5-fluoro-N-isopropyl-2-((4-((R)-3-((((trans -4-(methylsulfonamido)cyclohexyl)methyl)amino)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide. MS m/z [LC-MS]: 577.30 [M+1]. ¹ H NMR (400MHz, CD ₃ OD): 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).

Example 13: N-ethyl-5-fluoro-N-isopropyl-2-((4-(3-(((trans-4-(methylsulfonamido)cyclohexyl)methoxy)methyl ) azetidin-1-yl) pyrimidin-5-yl) oxy) benzamide

Referring to the method in Example 4, use intermediate 12 instead of N-ethyl-5-fluoro-N-isopropyl-2-((4-(piperidin-4-ylamino)pyrimidin-5-yl)oxy Base) benzamide, N-ethyl-5-fluoro-N-isopropyl-2-((4-(3-(((trans-4-(methylsulfonamido)cyclohexyl)methoxy )methyl)azetidin-1-yl)pyrimidin-5-yl)oxy)benzamide. MS m/z [LC-MS]: 578.28 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 14: N-ethyl-5-fluoro-2-((4-(((4-fluoro-1-((trans-4-(methylsulfonamido)cyclohexyl)methyl)piperidine-4 -yl) methyl)amino)pyrimidin-5-yl)oxy)-N-isopropylbenzamide

Referring to the method in Example 4, use intermediate 13 instead of N-ethyl-5-fluoro-N-isopropyl-2-((4-(piperidin-4-ylamino)pyrimidin-5-yl)oxy base) benzamide to give N-ethyl-5-fluoro-2-((4-(((4-fluoro-1-((trans-4-(methylsulfonamido)cyclohexyl)methyl)piper Pyridin-4-yl)methyl)amino)pyrimidin-5-yl)oxy)-N-isopropylbenzamide. MS m/z [LC-MS]: 623.32 [M+1]. ¹ H NMR (400MHz, DMSO-d ₆ ): 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).

Example 15: N-ethyl-5-fluoro-N-isopropyl-2-((4-((S)-3-((((cis-4-(methylsulfonamido)cyclohexyl)methyl) base)amino )methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Example 16: N-ethyl-5-fluoro-N-isopropyl-2-((4-((S)-3-((((trans-4-(methylsulfonamido)cyclohexyl)methyl) base)amino )methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 9, intermediate 14 was used instead of intermediate 9, and the product was separated by thin-layer silica gel chromatography to obtain a relatively less polar product as N-ethyl-5-fluoro-N-isopropyl-2 -((4-((S)-3-((((cis-4-(methylsulfonamido)cyclohexyl)methyl)amino)methyl)pyrrolidin-1-yl)pyrimidin-5-yl) Oxy) benzamide. MS m/z [LC-MS]: 591.32 [M+1]. ¹ H NMR (400MHz, DMSO-d ₆ ): 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),3.10-3.46(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).

Obtaining the larger product of relative polarity simultaneously is N-ethyl-5-fluoro-N-isopropyl-2-((4-((S)-3-((((trans-4-(methanesulfonamide base)cyclohexyl)methyl)amino)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide. MS m/z [LC-MS]: 591.32 [M+1]. ¹ H NMR (400MHz, DMSO-d ₆ ): 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), 2.53-2.62(m,1H), 2.01-2.11(m,1H), 1.54-1.94(m,6H), 0.93-1.21(m,15H).

Example 17: N-Ethyl-5-fluoro-N-isopropyl-2-((4-(4-(((((trans-4-(methylsulfonamido)cyclohexyl)methyl)amino) Methyl)piperidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Example 18: N-ethyl-5-fluoro-N-isopropyl-2-((4-(4-((((cis-4-(methylsulfonamido)cyclohexyl)methyl)amino) Methyl)piperidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 9, intermediate 15 was used instead of intermediate 9, and the product was separated by thin-layer silica gel chromatography to obtain a relatively polar product which was N-ethyl-5-fluoro-N-isopropyl-2 -((4-(4-((((trans-4-(methylsulfonamido)cyclohexyl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-5-yl)oxy)benzene Formamide. MS m/z [LC-MS]: 605.33 [M+1]. ¹ H NMR (400MHz, DMSO-d ₆ ): δ=8.40(s,1H),7.90(s,1H),7.25-7.30(m,1H),7.16-7.21(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,3H),1.56-1.65(m,2H),1.44-1.54(m,4H),1.30-1.42(m,2H),0.96- 1.29(m,11H).

Obtain relatively less polar product simultaneously and be N-ethyl-5-fluoro-N-isopropyl-2-((4-(4-((((cis-4-(methylsulfonamido)cyclohexyl) )methyl)amino)methyl)piperidin-1-yl)pyrimidin-5-yl)oxy)benzamide. MS m/z [LC-MS]: 591.32 [M+1]. ¹ H NMR (400MHz, DMSO-d ₆ ): 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).

Example 19: N-ethyl-5-fluoro-2-((4-(3-fluoro-3-((((trans-4-(methylsulfonamido)cyclohexyl)methyl)amino)methyl ) azetidin-1-yl)pyrimidin-5-yl)oxy)-N-isopropylbenzamide

With reference to the method in Example 9, Intermediate 9 was replaced by Intermediate 16 to obtain N-ethyl-5-fluoro-2-((4-(3-fluoro-3-((((trans-4-(methyl Sulfonamido)cyclohexyl)methyl)amino)methyl)azetidin-1-yl)pyrimidin-5-yl)oxy)-N-isopropylbenzamide. MS m/z [LC-MS]: 595.29 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 20: N-ethyl-5-fluoro-N-isopropyl-2-((4-((R)-3-((((trans-4-(methylsulfonamido)cyclohexyl)methyl base)amino )methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

With reference to the method in Example 9, Intermediate 9 was replaced by Intermediate 17 to obtain N-ethyl-5-fluoro-N-isopropyl-2-((4-((R)-3-(((( trans-4-(methylsulfonamido)cyclohexyl)methyl)amino)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide. MS m/z [LC-MS]: 591.32 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 21: N-ethyl-5-fluoro-N-isopropyl-2-((4-(6-(((trans-4-(methylsulfonamido)cyclohexyl)methyl)amino)- 3- Azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)oxy)benzamide

Example 22: N-ethyl-5-fluoro-N-isopropyl-2-((4-(6-(((cis-4-(methylsulfonamido)cyclohexyl)methyl)amino)- 3- Azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 9, intermediate 18 was used instead of intermediate 9, and the product was separated by thin-layer silica gel chromatography to obtain a relatively polar product that was N-ethyl-5-fluoro-N-isopropyl-2 -((4-(6-(((trans-4-(methylsulfonamido)cyclohexyl)methyl)amino)-3-azabicyclo[3.1.0]hexane-3-yl)pyrimidine-5 -yl)oxy)benzamide. MS m/z [LC-MS]: 589.30 [M+1]. ¹ H NMR (400MHz, CDCl ₃ : 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), 2.68-2.79(m,2H), 1.94-2.35(m,8H), 1.60-1.84(m,2H), 0.98-1.36(m,11H).

At the same time, the relatively less polar product is N-ethyl-5-fluoro-N-isopropyl-2-((4-(6-(((cis-4-(methylsulfonamido)cyclohexyl) Methyl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)oxy)benzamide. MS m/z [LC-MS]: 589.30 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.40(s,1H),7.85(s,1H),6.98-7.05(m,2H),6.63-6.72(m,1H),5.90-6.01(br, 1H),4.03-4.16(m,2H),3.81-3.88(m,1H),3.54-3.72(m,3H),3.39-3.49(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).

Example 23: N-Ethyl-5-fluoro-N-isopropyl-2-((4-(3-((((trans-4-(methylsulfonamido)cyclohexyl)methyl)amino) nitrogen Heterobutan-1-yl)pyrimidin-5-yl)oxy)benzamide

With reference to the method in Example 9, Intermediate 9 was replaced by Intermediate 19 to obtain N-ethyl-5-fluoro-N-isopropyl-2-((4-(3-(((trans-4-( Methanesulfonylamido)cyclohexyl)methyl)amino)azetidin-1-yl)pyrimidin-5-yl)oxy)benzamide. MS m/z [LC-MS]: 563.28 [M+1].

Example 24: N-Ethyl-5-fluoro-N-isopropyl-2-((4-(((4-((trans-4-(methylsulfonamido)cyclohexyl)methyl)morpholine -2- yl)methyl)amino)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 4, use intermediate 20 instead of N-ethyl-5-fluoro-N-isopropyl-2-((4-(piperidin-4-ylamino)pyrimidin-5-yl)oxy base) benzamide to give N-ethyl-5-fluoro-N-isopropyl-2-((4-(((4-((trans-4-(methylsulfonamido)cyclohexyl)methyl) )morpholin-2-yl)methyl)amino)pyrimidin-5-yl)oxy)benzamide. MS m/z [LC-MS]: 607.31 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 25: N-ethyl-5-fluoro-N-isopropyl-2-((4-((S)-3-(((cis-4-(methylsulfonamido)cyclohexyl)methyl )amino ) pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Example 26: N-Ethyl-5-fluoro-N-isopropyl-2-((4-((S)-3-(((trans-4-(methylsulfonamido)cyclohexyl)methyl )amino ) pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 9, intermediate 21 was used instead of intermediate 9, and the product was separated by thin-layer silica gel chromatography to obtain a relatively less polar product as N-ethyl-5-fluoro-N-isopropyl-2 -((4-((S)-3-(((cis-4-(methylsulfonamido)cyclohexyl)methyl)amino)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzene Formamide. MS m/z [LC-MS]: 577.30 [M+1]. ¹ HNMR (400MHz, DMSO-d ₆ ): 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).

Obtaining the larger product of relative polarity simultaneously is N-ethyl-5-fluoro-N-isopropyl-2-((4-((S)-3-(((trans-4-(methylsulfonamide) )cyclohexyl)methyl)amino)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide. MS m/z [LC-MS]: 577.30 [M+1]. ¹ H NMR (400MHz, DMSO-d ₆ ): 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), 1.96-2.28 (m, 2H), 1.74-1.93 (m, 4H), 1.47-1.62 (m, 2H), 0.90-1.30 (m, 13H).

Example 27: N-Ethyl-5-fluoro-2-((4-(3-((((1-hydroxy-4-(methylsulfonamido)cyclohexyl)methyl)amino)methyl) nitrogen Heterobutan-1-yl)pyrimidin-5-yl)oxy)-N-isopropylbenzamide

Intermediate 9 (97 mg), N-(1-oxaspiro[2.5]octane-6-yl)methanesulfonamide (63 mg) and tetrahydrofuran (1 mL) were added into a sealed tube, and the reaction was stirred at 90°C for 6 hours. After cooling down to room temperature, it 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-(methylsulfonamido)cyclohexyl)methyl)amino)methyl)azetidin-1-yl)pyrimidin-5-yl)oxy)-N-isopropylbenzamide ( 85mg). MS m/z [LC-MS]: 593.29 [M+1]. ¹ H NMR (400MHz, CD ₃ OD): 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).

Example 28: N-ethyl-5-fluoro-N-isopropyl-2-((4-(3-methyl-3-((((trans-4-(methylsulfonamido)cyclohexyl) Methyl) amino)methyl)azetidin-1-yl)pyrimidin-5-yl)oxy)benzamide

With reference to the method in Example 9, Intermediate 9 was replaced by Intermediate 22 to obtain N-ethyl-5-fluoro-N-isopropyl-2-((4-(3-methyl-3-((( (trans-4-(methylsulfonamido)cyclohexyl)methyl)amino)methyl)azetidin-1-yl)pyrimidin-5-yl)oxy)benzamide. MS m/z [LC-MS]: 591.32 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 29: N-ethyl-5-fluoro-2-((4-(4-hydroxy-4-((((trans-4-(methylsulfonamido)cyclohexyl)methyl)amino)methyl ) piperidin-1-yl)pyrimidin-5-yl)oxy)-N-isopropylbenzamide

With reference to the method in Example 9, intermediate 23 was used instead of intermediate 9 to obtain N-ethyl-5-fluoro-2-((4-(4-hydroxyl-4-((((trans-4-(methyl Sulfonamido)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-d ₆ ): 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).

Example 30: N-Ethyl-5-fluoro-N-isopropyl-2-((4-(6-((((trans-4-(methylsulfonamido)cyclohexyl)methyl)amino) Methyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)oxy)benzamide

With reference 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- (methylsulfonylamido)cyclohexyl)methyl)amino)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)oxy)benzamide. MS m/z [LC-MS]: 603.32 [M+1].

Example 31: N-Ethyl-5-fluoro-N-isopropyl-2-((4-(3-((((trans-4-(ethanesulfonamido)cyclohexyl)methyl)amino) Methyl)azetidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 9, intermediate 25 was used instead of intermediate 4 to obtain N-ethyl-5-fluoro-N-isopropyl-2-((4-(3-((((trans-4- (Ethylsulfonamido)cyclohexyl)methyl)amino)methyl)azetidin-1-yl)pyrimidin-5-yl)oxy)benzamide. MS m/z [LC-MS]: 591.32 [M+1]. ¹ H NMR (400MHz, CD ₃ OD): 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),1.98-2.06(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).

Example 32: N-Ethyl-5-fluoro-N-isopropyl-2-((4-((R)-3-(((trans-4-(methylsulfonamido)cyclohexyl)methyl )amino )pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

With reference to the method in Example 9, intermediate 22 was used to replace intermediate 9, and intermediate 25 was used to replace intermediate 4 to obtain N-ethyl-2-((4-(3-((((trans-4-( Ethylsulfonamido)cyclohexyl)methyl)amino)methyl)-3-methylazetidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl benzamide. MS m/z [LC-MS]: 605.33 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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),3.68-4.08(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).

Example 33: N-Ethyl-2-((4-((S)-3-((((trans-4-(ethanesulfonamido)cyclohexyl)methyl)amino)methyl) pyrrolidine- 1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

With reference to the method in Example 9, Intermediate 9 was replaced by Intermediate 14, Intermediate 4 was replaced by Intermediate 25, to obtain N-ethyl-2-((4-((S)-3-(((((trans -4-(Ethylsulfonamido)cyclohexyl)methyl)amino)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide. MS m/z [LC-MS]: 605.33 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 34: N-Ethyl-5-fluoro-N-isopropyl-2-((4-((((R)-1-(((1r,4R)-4-(methylsulfonamido) Cyclohexyl)methyl )pyrrolidin-3-yl)methyl)amino)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 9, the target compound was obtained using intermediate 27 as a starting material. MS m/z [LC-MS]: 591.32 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 35: N-Ethyl-5-fluoro-N-isopropyl-2-((4-((((S)-1-(((1r,4S)-4-(methylsulfonamido) Cyclohexyl)methyl) pyrrolidin-3-yl)methyl)amino)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 9, the target compound was obtained using intermediate 28 as a starting material. MS m/z [LC-MS]: 591.32 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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) .

Example 36: N-Ethyl-5-fluoro-2-((4-(3-hydroxy-3-(((((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl) Amino) methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N-isopropylbenzamide

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, cooled to room temperature, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (dichloromethane/methanol, 20:1) to obtain the title compound (84 mg). MS m/z [LC-MS]: 607.31 [M+1].

Example 37: N-Ethyl-5-fluoro-N-isopropyl-2-((4-((S)-3-(((((1r,4S)-4-(methylsulfonamido) Cyclohexyl)methyl) amino)methyl)piperidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 9, the target compound was obtained by using intermediate 30 as a raw material. MS m/z [LC-MS]: 605.33 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 38: N-Ethyl-5-fluoro-2-((4-(3-((((1-fluoro-4-(methylsulfonamido)cyclohexyl)methyl)amino)methyl)nitrogen Heterobutan -1-yl)pyrimidin-5-yl)oxy)-N-isopropylbenzamide

Referring to the method in Example 9, the target compound was obtained by using intermediate 31 as a starting material. MS m/z [LC-MS]: 595.29 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 39: N-Ethyl-5-fluoro-N-isopropyl-2-((4-((R)-3-(((((1r,4R)-4-(methylsulfonamido) Cyclohexyl)methyl )amino)methyl)piperidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 9, the target compound was obtained using intermediate 32 as a starting material. MS m/z [LC-MS]: 605.33 [M+1]. ¹ H NMR (400MHz, DMSO-d ₆ ):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).

Example 40: N-Ethyl-2-((4-((R)-3-(((((1r,4R)-4-(ethanesulfonamido)cyclohexyl)methyl)amino)methyl )-3- methylpyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

Referring to the method in Example 9, using Intermediate 33 and Intermediate 25 as raw materials, the target compound was obtained. MS m/z [LC-MS]: 619.35 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 41: N-Ethyl-2-((4-((S)-3-(((((1r,4S)-4-(ethanesulfonamido)cyclohexyl)methyl)amino)methyl )-3- methylpyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

Referring to the method in Example 9, using Intermediate 34 and Intermediate 25 as raw materials, the target compound was obtained. MS m/z [LC-MS]: 619.35 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 42: N-ethyl-2-((4-(3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine- 1- yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

Referring to the method in Example 36, the title compound was obtained using Intermediate 35 as a starting material. MS m/z [LC-MS]: 617.33 [M+1]. ¹ H NMR (400MHz, DMSO-d ₆ ): 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).

Example 43: N-ethyl-2-((4-(3-ethyl-3-(((((1r,4r)-4-(ethanesulfonamido)cyclohexyl)methyl)amino)methyl Base) azetidin-1-yl) pyrimidin-5-yl) oxy)-5-fluoro-N-isopropylbenzoyl

Referring to the method in Example 9, using Intermediate 36 and Intermediate 25 as raw materials, the target compound was obtained. MS m/z [LC-MS]: 619.35 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 44: N-Ethyl-2-((4-((3R,4S)-3-(((((1r,4R)-4-(ethylsulfonamido)cyclohexyl)methyl)amino) Methyl )-4-fluoropyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

Referring to the method in Example 9, using Intermediate 37 and Intermediate 25 as raw materials, the target compound was obtained. MS m/z [LC-MS]: 623.32 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 45: N-ethyl-2-((4-((3S,4S)-3-(((((1r,4S)-4-(ethylsulfonamido)cyclohexyl)methyl)amino) Methyl )-4-fluoropyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

Referring to the method in Example 9, using Intermediate 38 and Intermediate 25 as raw materials, the target compound was obtained. MS m/z [LC-MS]: 623.32 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 46: N-Ethyl-2-((4-((S)-2-(((((1r,4S)-4-(ethanesulfonamido)cyclohexyl)methyl)amino)methyl ) morpholinyl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

Referring to the method in Example 9, using Intermediate 39 and Intermediate 25 as raw materials, the target compound was obtained. MS m/z [LC-MS]: 621.33 [M+1]. ¹ H NMR (400MHz, DMSO-d ₆ ): 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).

Example 47: 2-((4-((S)-3-(((((1r,4S)-4-(ethanesulfonamido)cyclohexyl)methyl)amino)methyl)pyrrolidine-1 -yl )pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method in Example 9, using intermediate 40 and intermediate 25 as raw materials, the target compound was obtained. MS m/z [LC-MS]: 619.35 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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),2.44-2.68(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).

Example 48: 2-((4-(3-(((((1r,4r)-4-(ethanesulfonamido)cyclohexyl)methyl)amino)methyl)-3-methylazaheterocycle Butan-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method in Example 9, using Intermediate 41 and Intermediate 25 as raw materials, the target compound was obtained. MS m/z [LC-MS]: 619.35 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.25(s,1H),7.76(s,1H),6.92-7.01(m,2H),6.66-6.73(m,1H),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).

Example 49: N-Ethyl-2-((4-(3-((6-(ethanesulfonamido)-2-azaspiro[3.3]heptan-2-yl)methyl)azacyclo Butane -1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

Referring to the method in Example 36, the title compound was obtained using intermediate 42 as a starting material. MS m/z [LC-MS]: 575.28 [M+1]. ¹ H NMR (400MHz, CD ₃ OD): 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).

Example 50: (R)-N-ethyl-2-((4-(3-((6-(ethanesulfonamido)-2-azaspiro[3.3]heptan-2-yl)methyl ) pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

Referring to the method in Example 36, the title compound was obtained using intermediate 43 as a starting material. MS m/z [LC-MS]: 589.30 [M+1]. ¹ H NMR (400MHz, CD ₃ OD): 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).

Example 51: (S)-N-ethyl-2-((4-(3-((6-(ethanesulfonamido)-2-azaspiro[3.3]heptan-2-yl)methyl )pyrrolidin -1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

Referring to the method in Example 36, the title compound was obtained using intermediate 44 as a starting material. MS m/z [LC-MS]: 589.30 [M+1]. ¹ H NMR (400MHz, CD ₃ OD): 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),2.82-3.01(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).

Example 52: N-Ethyl-2-((4-(3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)azaheterocycle Butane -1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

Referring to the method in Example 36, the target compound was obtained using intermediate 45 as a starting material. MS m/z [LC-MS]: 603.32 [M+1]. ¹ H NMR (400MHz, DMSO-d ₆ ): 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).

Example 53: (S)-N-ethyl-2-((4-(3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl )pyrrolidin -1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

Referring to the method in Example 36, the target compound was obtained using intermediate 46 as a starting material. MS m/z [LC-MS]: 617.33 [M+1]. ¹ H NMR (400MHz, DMSO-d ₆ ): 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).

Example 54: (R)-N-ethyl-2-((4-(3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl ) pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

Referring to the method in Example 36, the target compound was obtained using intermediate 47 as a starting material. MS m/z [LC-MS]: 617.33 [M+1]. ¹ H NMR (400MHz, DMSO-d ₆ ): 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).

Example 55: 2-((4-(3-((7-(Ethsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)azetidine-1- Base) pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method in Example 36, using Intermediate 26 and Intermediate 45 as starting materials, the target compound was obtained. MS m/z [LC-MS]: 617.33 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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),3.42-3.50(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).

Example 56: (S)-2-((4-(3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1 -yl) pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method in Example 36, using Intermediate 26 and Intermediate 46 as starting materials, the target compound was obtained. MS m/z [LC-MS]: 631.35 [M+1]. ¹ H NMR (400MHz, DMSO-d ₆ ): δ=8.28(s,1H),7.78(s,1H),7.13-7.20(m,2H),6.94(d,J=7.6Hz,1H),6.80 -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).

Example 57: (S)-2-((4-(3-((7-(methylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1 -yl) pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method in Example 36, using Intermediate 26 and Intermediate 48 as starting materials, the title compound was obtained. MS m/z [LC-MS]: 617.33 [M+1]. ¹ H NMR (400MHz, DMSO-d ₆ ): 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).

Example 58: 2-((4-((S)-3-(((((1r,4S)-4-(methylsulfonamido)cyclohexyl)methyl)amino)methyl)pyrrolidine-1 -yl )pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method in Example 9, the target compound was obtained by using intermediate 40 as a raw material. MS m/z [LC-MS]: 605.33 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 59: 2-((4-(3-(((((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)amino)methyl)-3-methylazaheterocycle Butan-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method in Example 9, the target compound was obtained by using intermediate 41 as a starting material. MS m/z [LC-MS]: 605.33 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.33(s,1H),7.79(s,1H),6.91-7.00(m,2H),6.63-6.69(m,1H),5.44-5.69(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),1.51-1.63(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).

Example 60: (S)-N-Ethyl-5-fluoro-N-isopropyl-2-((4-(3-((7-(methylsulfonamido)-2-azaspiro[3.5 ]nonan-2- yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 36, intermediate 48 was used instead of intermediate 29 to obtain (S)-N-ethyl-5-fluoro-N-isopropyl-2-((4-(3-((7- (Methanesulfonylamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide. MS m/z [LC-MS]: 603.31 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 61: (R)-5-Fluoro-N,N-diisopropyl-2-((4-(3-((7-(methylsulfonamido)-2-azaspiro[3.5]nonane Alk-2-yl) methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 36, Intermediate 1 was replaced by Intermediate 26, Intermediate 29 was replaced by Intermediate 49, to obtain (R)-5-fluoro-N,N-diisopropyl-2-((4- (3-((7-(methylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzyl amides. MS m/z [LC-MS]: 617.33 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.39(s,0.5H),8.38(s,0.5H),7.79(s,1H),6.91-6.98(m,2H),6.66(dd,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).

Example 62: (R)-N-Ethyl-2-((4-(3-((7-(methylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl ) pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

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-nitrogen heterospiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide. MS m/z [LC-MS]: 603.32 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 63: (R)-2-((4-(3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1 -yl) pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method in Example 36, Intermediate 1 was replaced by Intermediate 26, Intermediate 29 was replaced by Intermediate 47, to obtain (R)-2-((4-(3-((7-(ethanesulfonamido) -2-Azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzyl amides. MS m/z [LC-MS]: 617.33 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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),3.30-3.40(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,4H),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).

Example 64: (S)-5-Fluoro-N,N-diisopropyl-2-((4-(3-((7-(trifluoromethanesulfonamido)-2-azaspiro[3.5 ]nonan -2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 36, Intermediate 1 was replaced by Intermediate 26, Intermediate 29 was replaced by Intermediate 50, to obtain (S)-5-fluoro-N,N-diisopropyl-2-((4- (3-((7-(trifluoromethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy) benzamide. MS m/z [LC-MS]: 671.30 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 65: 2-((4-((3S)-3-((6-(ethanesulfonamido)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)pyrrolidine -1- yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

With reference to the method in Example 36, Intermediate 1 was replaced by Intermediate 26, Intermediate 29 was replaced by Intermediate 51, to obtain 2-((4-((3S)-3-((6-(ethanesulfonamido) -3-Azabicyclo[3.1.0]hexan-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropyl benzamide. MS m/z [LC-MS]: 589.30 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

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

Referring to the method in Example 36, Intermediate 1 was replaced by Intermediate 26, Intermediate 29 was replaced by Intermediate 52, to obtain (S)-2-((4-(3-((7-((N,N- Dimethylaminosulfonyl)amino)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro- N,N-Diisopropylbenzamide. MS m/z [LC-MS]: 646.36 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.40(s,0.5H),8.39(s,0.5H),7.81(s,1H),6.91-6.99(m,2H),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).

Example 67: (S)-2-((4-(3-((7-(cyclopropylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine -1- yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

With reference to the method in Example 36, Intermediate 1 was replaced by Intermediate 26, Intermediate 29 was replaced by Intermediate 53, to obtain (S)-2-((4-(3-((7-(cyclopropylsulfonamide Base)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropyl benzamide. MS m/z [LC-MS]: 643.34 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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),2.15-2.34(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).

Example 68: (S)-2-((4-(3-((7-(ethylsulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidine -1-yl) pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method in Example 36, Intermediate 1 was replaced by Intermediate 26, Intermediate 29 was replaced by Intermediate 54, to obtain (S)-5-fluoro-N,N-diisopropyl-2-((4- (3-((7-(Propylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzene Formamide. MS m/z [LC-MS]: 645.36 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 69: (S)-2-((4-(3-((4-(Esulphonamidomethyl)piperidin-1-yl)methyl)pyrrolidin-1-yl)pyrimidine-5- base) oxy)-5-fluoro-N,N-diisopropylbenzamide

With reference to the method in Example 36, intermediate 26 was used to replace intermediate 1, and intermediate 55 was used to replace intermediate 29 to obtain (S)-2-((4-(3-((4-(ethanesulfonamidomethyl yl)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-d ₆ ): 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,3H),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).

Example 70: (S)-2-((4-(3-((7-(cyclopropylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine -1- yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method in Example 36, Intermediate 1 was replaced by Intermediate 26, Intermediate 29 was replaced by Intermediate 56, to obtain (S)-2-((4-(3-((7-(ethylsulfonyl)- 2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropyl benzamide. MS m/z [LC-MS]: 617.33 [M+1]. ¹ H NMR (400MHz, DMSO-d ₆ ): 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),2.06-2.42(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).

Example 71: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((7-sulfonamido-2,7-diazaspiro[3.5]nonane Alk-2-yl) methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 36, Intermediate 1 was replaced by Intermediate 26, Intermediate 29 was replaced by Intermediate 57, to obtain (S)-5-fluoro-N,N-diisopropyl-2-((4- (3-((7-sulfonamido-2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzyl amides. MS m/z [LC-MS]: 604.31 [M+1]. ¹ H NMR (400MHz, DMSO-d ₆ ): 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).

Example 72: (S)-2-((4-(3-((2-(ethanesulfonamido)-7-azaspiro[3.5]nonan-7-yl)methyl)pyrrolidine-1 -yl) pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

With reference to the method in Example 36, Intermediate 1 was replaced by Intermediate 26, Intermediate 29 was replaced by Intermediate 58, to obtain (S)-2-((4-(3-((2-(ethanesulfonamido) -7-Azaspiro[3.5]nonan-7-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzyl amides. MS m/z [LC-MS]: 631.34 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.40(s,0.5H),8.39(s,0.5H),7.80(s,1H),6.90-6.98(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),1.72-1.90(m,1H),1.45-1.69(m,11H),1.34(t,J＝7.6Hz,3H),1.11-1.16(m,6H ).

Example 73: (S)-2-((4-(3-((9-(ethanesulfonamido)-3-azaspiro[5.5]undec-3-yl)methyl)pyrrolidine- 1- yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

With reference to the method in Example 36, Intermediate 1 was replaced by Intermediate 26, Intermediate 29 was replaced by Intermediate 59, to obtain (S)-2-((4-(3-((9-(ethanesulfonamido) -3-Azaspiro[5.5]undecyl-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzene Formamide. MS m/z [LC-MS]: 659.38 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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), 3.20-3.30(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).

Example 74: 2-((4-((S)-3-(((S)-1-(ethanesulfonamido)-8-azaspiro[4.5]decane-8-yl)methyl) Pyrrolidin-1- yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

With reference to the method in Example 36, Intermediate 1 was replaced by Intermediate 26, Intermediate 29 was replaced by Intermediate 60, to obtain 2-((4-((S)-3-(((S)-1-(B Sulfonamido)-8-azaspiro[4.5]decane-8-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diiso Propyl benzamide. MS m/z [LC-MS]: 645.36 [M+1]. ¹ H NMR (400MHz, CD ₃ OD): 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).

Example 75: N-Ethyl-2-((4-((S)-3-(((S)-1-(ethanesulfonamido)-8-azaspiro[4.5]decane-8- base)methyl)pyrrolidin -1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

Referring to the method in Example 36, intermediate 60 was used instead of intermediate 29 to obtain N-ethyl-2-((4-((S)-3-(((S)-1-(ethanesulfonamido) -8-azaspiro[4.5]decane-8-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide. MS m/z [LC-MS]: 631.34 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 76: 2-((4-((3S)-3-((3-(ethanesulfonamido)-1-oxa-8-azaspiro[4.5]decane-8-yl)methyl ) pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

With reference to the method in Example 36, Intermediate 1 was replaced by Intermediate 26, Intermediate 29 was replaced by Intermediate 61, to obtain 2-((4-((3S)-3-((3-(Ethylsulfonyl) -1-Oxa-8-azaspiro[4.5]decane-8-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-di Cumamide. MS m/z [LC-MS]: 647.34 [M+1]. ¹ H NMR (400MHz, DMSO-d ₆ ): 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).

Example 77: (S)-N-ethyl-2-((4-(3-((9-(ethanesulfonamido)-3-azaspiro[5.5]undec-3-yl)methyl Base) pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

Referring to the method in Example 36, intermediate 59 was used instead of intermediate 29 to obtain (S)-N-ethyl-2-((4-(3-((9-(ethanesulfonamido)-3-nitrogen heterospiro[5.5]undec-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide. MS m/z [LC-MS]: 645.36 [M+1]. ¹ H NMR (400MHz, DMSO-d ₆ ): 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).

Example 78: 2-((4-((3S)-3-((6-(ethanesulfonamidomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl) Pyrrolidin -1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method in Example 36, Intermediate 1 was replaced by Intermediate 26, Intermediate 29 was replaced by Intermediate 62, to obtain 2-((4-((3S)-3-((6-(ethanesulfonamidomethyl Base)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diiso Propyl benzamide. MS m/z [LC-MS]: 603.31 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 79: (S)-5-fluoro-2-((4-(3-((7-((2-hydroxy-2-methylpropyl)amino)-2-azaspiro[3.5]nonane Alk-2-yl) methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide

Referring to the method in Example 36, Intermediate 1 was replaced by Intermediate 26, Intermediate 29 was replaced by Intermediate 63, to obtain (S)-5-fluoro-2-((4-(3-((7-(( 2-Hydroxy-2-methylpropyl)amino)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N , N-Diisopropylbenzamide. MS m/z [LC-MS]: 611.41 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.39(s,0.5H),8.38(s,0.5H),7.80(s,1H),6.91-6.99(m,2H),6.65-6.69(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).

Example 80: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((7-(aminosulfonamido)-2-azaspiro[3.5]nonane Alk-2- yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 36, Intermediate 1 was replaced by Intermediate 26, Intermediate 29 was replaced by Intermediate 64, to obtain (S)-5-fluoro-N,N-diisopropyl-2-((4- (3-((7-(aminosulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzyl amides. MS m/z [LC-MS]: 618.32 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 81: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((7-(isopropylsulfonamido)-2-azaspiro[3.5 ]nonan -2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 36, Intermediate 1 was replaced by Intermediate 26, Intermediate 29 was replaced by Intermediate 65, to obtain (S)-5-fluoro-N,N-diisopropyl-2-((4- (3-((7-(isopropylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy) benzamide. MS m/z [LC-MS]: 645.36 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 82: (S)-2-((5-(3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1 -yl )-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: (S)-N-(2-((1-(3,6-dichloro-1,2,4-triazin-5-yl)pyrrolidin-3-yl)methyl)-2- Heterospiro[3.5]nonan-7-yl)ethanesulfonamide

Add intermediate 56 (315mg) and diisopropylethylamine (516mg) into tetrahydrofuran (10mL), cool in an ice bath to 0°C, add 3,5,6-trichloro-1,2,4-triazine (185 mg), slowly warmed up to room temperature and then stirred for 1 hour. Filtration, and the filtrate was concentrated under reduced pressure to obtain (S)-N-(2-((1-(3,6-dichloro-1,2,4-triazin-5-yl)pyrrolidin-3-yl)methyl )-2-heterospiro[3.5]nonan-7-yl)ethanesulfonamide (480 mg) was used directly in the next step. MS m/z [LC-MS]: 463.15 [M+1].

Step 2: (S)-2-((3-Chloro-5-(3-((7-(ethanesulfonamide)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine -1-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Put (S)-N-(2-((1-(3,6-dichloro-1,2,4-triazin-5-yl)pyrrolidin-3-yl)methyl)-2-heterospiro [3.5] Nonan-7-yl)ethanesulfonamide (240mg), 5-fluoro-2-hydroxy-N,N-diisopropylbenzamide (180mg) and potassium carbonate (210mg) were added to 1,4- Dioxane (10 mL) was refluxed for 12 hours. Cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (dichloromethane/methanol, 20:1) to obtain (S)-2-((3-chloro-5-(3-((7- (Ethylsulfonamide)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-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].

Step 3: (S)-2-((5-(3-((7-(Ethylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1- Base)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Put (S)-2-((3-chloro-5-(3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-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 (20mL), replace the air in the reactor with hydrogen, react at 60°C for 10 hours at a hydrogen pressure of 3 atmospheres, filter, and concentrate the filtrate under reduced pressure with silica gel column chromatography (dichloromethane/methanol, 20:1 ) separation to obtain (S)-2-((5-(3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-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]. ¹ H NMR (400MHz, DMSO-d ₆ ):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),3.15-3.30(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).

Example 83: 2-((4-((S)-3-((7-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptane) -2-sulfonamido )-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N -Diisopropylbenzamide _

Step 1: (1S,4S)-5-(N-(2-(((S)-1-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine -4-yl)pyrrolidin-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)aminosulfonyl)-2,5-diazabicyclo[2.2.1] tert-butyl heptane-2-carboxylate

Add intermediate 66 (107mg) and diisopropylethylamine (78mg) into dichloromethane (5mL), cool in an ice bath to 0°C, add (1S,4S)-5-(chlorosulfonyl)-2 , 5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (71mg), slowly rose to room temperature, stirred for 2 hours, and refluxed for 12 hours. Cool to room temperature, filter, and concentrate the filtrate under reduced pressure. The residue is 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].

Step 2: 2-((4-((S)-3-((7-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-sulfonamido)- 2-Azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide Hydrochloride

(1S,4S)-5-(N-(2-(((S)-1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine-4 -yl)pyrrolidin-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)aminosulfonyl)-2,5-diazabicyclo[2.2.1]heptane - tert-butyl 2-carboxylate (70 mg) was added to 4 mol/L hydrogen chloride dioxane solution (5 mL), stirred at room temperature for 2 hours, added diethyl ether (30 mL), stirred for 1 hour, filtered, and the filter cake was rinsed with diethyl ether, After drying, the title compound (55 mg) was obtained. MS m/z [LC-MS]: 699.38 [M+1].

Step 3: 2-((4-((S)-3-((7-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptane))- 2-sulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N- Diisopropylbenzamide

2-((4-((S)-3-((7-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-sulfonamido)-2- Azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride Salt (55 mg) and diisopropylethylamine (63 mg) were added to dichloromethane (5 mL), cooled in an ice bath to 0 ° C, added acryloyl chloride (7 μ L), slowly warmed to room temperature and stirred for 2 hours, filtered, and the filtrate It was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (dichloromethane/methanol, 15:1) to obtain the title compound (28 mg). MS m/z [LC-MS]: 753.39 [M+1]. ¹ H NMR (400MHz, CD ₃ OD): 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＝16.8Hz,10.4 Hz,0.4H),6.29(d,J=16.8Hz,1H),5.77(dd,J=10.4Hz,1.6Hz,1H),4.39(d,J=6.8Hz,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).

Example 84: (S)-2-((4-(3-((7-(ethanesulfonamidomethyl)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine -1- yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method in Example 36, Intermediate 1 was replaced by Intermediate 26, Intermediate 29 was replaced by Intermediate 67, to obtain the target compound. MS m/z [LC-MS]: 645.36 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 85: (S)-2-((4-(3-((7-acrylamido-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl) Pyrimidin -5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide and Example 86: (S)-2-((4-(3-((7-(N -acryloylacrylamido )-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N, N-Diisopropyl benzamide

Add intermediate 66 (107mg) and diisopropylethylamine (78mg) into dichloromethane (5mL), cool in an ice bath to 0°C, add acryloyl chloride (22mg) dropwise, slowly warm to room temperature and stir for 4 hours , washed with water and saturated brine successively, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (dichloromethane/methanol, 15:1) to obtain (S)-2-((4 -(3-((7-acrylamido-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-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, CDCl ₃ ): 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).

At the same time, (S)-2-((4-(3-((7-(N-acryloylacrylamide)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine- 1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide (16 mg). MS m/z [LC-MS]: 647.37 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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,0.6H),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).

Example 87: (S)-2-((4-(3-((7-cyanoamino-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl) Pyrimidin -5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide and Example 88: (S)-2-((4-(3-((7-dicyano Amino-2- azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzene Formamide

Referring to the method in Example 85, nitrile bromide was used instead of acryloyl chloride to obtain (S)-2-((4-(3-((7-cyanoamino-2-azaspiro[3.5]nonane-2 -yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide. MS m/z [LC-MS]: 564.35 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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＝6.4 Hz, 1.5H), 1.21-1.28 (m, 3H), 1.16 (d, J=6.4Hz, 3H).

At the same time, (S)-2-((4-(3-((7-dicyanoamino-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidine -5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide. MS m/z [LC-MS]: 589.34 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 89: 2-((4-(7-(3-(4-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptane))-2 -sulfonyl) phenyl)prop-2-yn-1-yl)-2,7-azaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl- 5-Fluoro-N - isopropylbenzamide

Step 1: (1S,4S)-5-((4-(3-(2-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine-4 -yl)-2,7-diazaspiro[3.5]nonan-7-yl)prop-1-yn-1-yl)phenyl)sulfonyl)-2,5-diazabicyclo[2.2. 1] tert-butyl heptane-2-carboxylate

Under nitrogen protection, intermediate 68 (233 mg), intermediate 69 (250 mg), cuprous iodide (10 mg) and bistriphenylphosphine palladium dichloride (35 mg) were added to a 1:1 mixture of tetrahydrofuran and triethylamine In a solvent (10 mL), heated to 80°C and stirred for 10 hours, cooled to room temperature, concentrated under reduced pressure, and 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].

Step 2: 2-((4-(7-(3-(4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)sulfonyl)benzene Base) prop-2-yn-1-yl)-2,7-azaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N -Cumenyl benzamide hydrochloride

Referring to the method of step 2 in Example 83, use (1S,4S)-5-((4-(3-(2-(5-(2-(ethyl(isopropyl)carbamoyl)-4- Fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)prop-1-yn-1-yl)phenyl)sulfonyl)-2,5 - tert-butyl diazabicyclo[2.2.1]heptane-2-carboxylate instead of (1S,4S)-5-(N-(2-(((S)-1-(5-(2-( Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)amine tert-butyl sulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate to obtain the target compound. MS m/z [LC-MS]: 702.33 [M+1].

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

Referring to the method of step 3 in Example 83, use 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]nonan-2-yl)pyrimidin-5-yl)oxy)-N- Ethyl-5-fluoro-N-isopropylbenzamide hydrochloride instead of 2-((4-((S)-3-((7-((1S,4S)-2,5-diazepine Bicyclo[2.2.1]heptane-2-sulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy) -5-fluoro-N,N-diisopropylbenzamide hydrochloride to obtain the target compound. MS m/z [LC-MS]: 756.33 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ):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,1.3H),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 ),1.80-1.88(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).

Example 90: (S)-2-((4-(3-((7-((1-acryloylpiperidin-4-yl)sulfonyl)-2,7-diazaspiro[3.5]nonyl Alk-2- yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: (S)-4-((2-((1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine- 3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)piperidine-1-carboxylate tert-butyl ester

Referring to the method of step 1 in Example 83, intermediate 66 was replaced by intermediate 70, and (1S,4S)-5-(chlorosulfonyl) was replaced by tert-butyl 4-(chlorosulfonyl)piperidine-1-carboxylate )-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester to obtain the target compound. MS m/z [LC-MS]: 772.43 [M+1].

Step 2: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((7-(piperidine-4-sulfonyl)-2,7-diazepine Spiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

Referring to the method of step 2 in Example 83, use (S)-4-((2-((1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine -4-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)piperidine-1-carboxylic acid tert-butyl ester instead of (1S ,4S)-5-(N-(2-(((S)-1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl) Pyrrolidin-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)aminosulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2- tert-butyl carboxylate to obtain the target compound. MS m/z [LC-MS]: 672.37 [M+1].

Referring to the method of step 3 in Example 83, use (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((7-(piperidine-4-sulfonyl) -2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride instead of 2-((4 -((S)-3-((7-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-sulfonamido)-2-azaspiro[3.5] Nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride to give the title compound. MS m/z [LC-MS]: 726.38 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.42(s,0.5H),8.41(s,0.5H),7.85(s,1H),6.91-7.03(m,2H),6.65-6.69(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).

Example 91: (S)-2-((4-(3-((7-((4-acryloylpiperazin-1-yl)sulfonyl)-2,7-diazaspiro[3.5]nonyl Alk-2- yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

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

Referring to the method of step 1 in Example 83, intermediate 66 was replaced by intermediate 70, and (1S,4S)-5-(chlorosulfonyl) was replaced by tert-butyl 4-(chlorosulfonyl)piperazine-1-carboxylate )-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester to obtain the target compound. MS m/z [LC-MS]: 773.42 [M+1].

Step 2: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((7-(piperazine-1-sulfonyl)-2,7-diazepine Spiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

Referring to the method of step 2 in Example 83, use (S)-4-((2-((1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine -4-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)piperazine-1-carboxylic acid tert-butyl ester instead of (1S ,4S)-5-(N-(2-(((S)-1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl) Pyrrolidin-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)aminosulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2- tert-butyl carboxylate to obtain the target compound. MS m/z [LC-MS]: 673.37 [M+1].

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

Referring to the method of step 3 in Example 83, use (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((7-(piperazine-1-sulfonyl) -2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride instead of 2-((4 -((S)-3-((7-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-sulfonamido)-2-azaspiro[3.5] Nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride to give the title compound. MS m/z [LC-MS]: 727.38 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 92: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-((2,2,2-trifluoroethyl)amino)- 3-Azaspiro[5.5] undec-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Add intermediate 75 (113mg), 2,2,2-trifluoroethylamine (30mg) and acetic acid (12mg) into 1,2-dichloroethane (10mL), stir at room temperature for 1 hour, then add Sodium triacetoxyborohydride (128 mg), stirred overnight at room temperature, quenched the reaction by adding saturated sodium bicarbonate solution, filtered, extracted the filtrate with dichloromethane, dried the extract with anhydrous sodium sulfate, filtered, and decompressed the filtrate After concentration, the residue was separated by silica gel column chromatography (dichloromethane/methanol, 12:1) to obtain the title compound (52 mg). MS m/z [LC-MS]: 649.38 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 93: (S)-2-((4-(3-((8-(Ethylsulfonamido)-2-azaspiro[4.5]decane-2-yl)methyl)pyrrolidin-1 -yl) pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method in Example 36, Intermediate 1 was replaced by Intermediate 26, Intermediate 29 was replaced by Intermediate 77, to obtain the target compound. MS m/z [LC-MS]: 645.36 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 94 : 5-fluoro-N,N-diisopropyl-2-((4-((S)-3-((9-(((R)-1,1,1-trifluoropropane- 2-yl)amino)-3- azaspiro[5.5]undec-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 92, substituting (R)-1,1,1-trifluoropropan-2-amine for 2,2,2-trifluoroethylamine, the title compound was obtained. MS m/z [LC-MS]: 663.40 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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 ), 2.22-2.45 (m, 6.5H), 1.96-2.09 (m, 1.5H), 1.42-1.71 (m, 14H), 1.10-1.38 (m, 13H).

Example 95: (S)-2-((3-Chloro-5-(3-((9-(ethanesulfonamido)-3-azaspiro[5.5]undec-3-yl)methyl) )pyrrolidin -1-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: (S)-N-(3-((1-(3,6-dichloro-1,2,4-triazin-5-yl)pyrrolidin-3-yl)methyl)-3- Azaspiro[5.5]undec-9-yl)ethanesulfonamide

Referring to the method of Step 1 in Example 82, using Intermediate 78 instead of Intermediate 56, the title compound was obtained. MS m/z [LC-MS]: 491.18 [M+1].

Step 2: (S)-2-((3-Chloro-5-(3-((9-(ethanesulfonamido)-3-azaspiro[5.5]undec-3-yl)methyl) Pyrrolidin-1-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 2 in Example 82, use (S)-N-(3-((1-(3,6-dichloro-1,2,4-triazin-5-yl)pyrrolidin-3- Base)methyl)-3-azaspiro[5.5]undec-9-yl)ethanesulfonamide instead of (S)-N-(2-((1-(3,6-dichloro-1,2 ,4-triazin-5-yl)pyrrolidin-3-yl)methyl)-2-heterospiro[3.5]nonan-7-yl)ethanesulfonamide to obtain the target compound. MS m/z [LC-MS]: 694.33 [M+1]. ¹ H NMR (400MHz, DMSO-d ₆ ): δ=7.37-7.44(m,1H),7.24-7.36(m,2H),6.92-7.00(m,1H),3.16-4.36(m,5H), 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).

Example 96: (S)-2-((5-(3-((9-(ethanesulfonamido)-3-azaspiro[5.5]undec-3-yl)methyl)pyrrolidine- 1- yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 82, use Example 95 instead of (S)-2-((3-chloro-5-(3-((7-(ethanesulfonamido)-2-azaspiro[3.5 ]nonan-2-yl)methyl)pyrrolidin-1-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzyl amides to obtain the target compound. MS m/z [LC-MS]: 660.37 [M+1]. ¹ H NMR (400MHz, DMSO-d ₆ ): 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- 4.38(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 ).

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]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro -N,N- Diisopropylbenzamide

Step 1: (1S,4S)-5-((2-(((S)-1-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine-4 -yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane tert-butyl alkane-2-carboxylate

Referring to the method of Step 1 in Example 83, using Intermediate 70 instead of Intermediate 66, the title compound was obtained. MS m/z [LC-MS]: 785.42 [M+1].

Step 2: 2-((4-((S)-3-((7-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)sulfonyl )-2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diiso Propylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, use (1S,4S)-5-((2-(((S)-1-(5-(2-(diisopropylcarbamoyl)-4- Fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)-2,5-diaza Heterobicyclo[2.2.1]heptane-2-carboxylate tert-butyl instead of (1S,4S)-5-(N-(2-(((S)-1-(5-(2-(diisopropyl Carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)aminosulfonyl )-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester to obtain the target compound. MS m/z [LC-MS]: 685.37 [M+1].

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]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N ,N-Diisopropylbenzamide

Referring to the method of step 3 in Example 83, use 2-((4-((S)-3-((7-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane Alkyl-2-yl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5- Fluoro-N,N-diisopropylbenzamide hydrochloride instead of 2-((4-((S)-3-((7-((1S,4S)-2,5-diazabicyclo[ 2.2.1] Heptane-2-sulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5 -Fluoro-N,N-diisopropylbenzamide hydrochloride to obtain the title compound. MS m/z [LC-MS]: 739.38 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.40(s,0.5H),8.39(s,0.5H),7.81(s,1H),6.89-6.99(m,2H),6.64-6.69(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).

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]undecyl-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5- Fluoro-N,N- diisopropylbenzamide

Step 1: (1S,4S)-5-((9-(((S)-1-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine-4 -yl)pyrrolidin-3-yl)methyl)-3,9-diazaspiro[5.5]undecyl-3-yl)sulfonyl)-2,5-diazabicyclo[2.2.1] tert-butyl heptane-2-carboxylate

Referring to the method of Step 1 in Example 83, using Intermediate 79 instead of Intermediate 66, the title compound was obtained. MS m/z [LC-MS]: 813.45 [M+1].

Step 2: 2-((4-((S)-3-((9-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)sulfonyl )-3,9-diazaspiro[5.5]undec-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-di Cumyl benzamide hydrochloride

Referring to the method of step 2 in Example 83, use (1S,4S)-5-((9-(((S)-1-(5-(2-(diisopropylcarbamoyl)-4- Fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-3,9-diazaspiro[5.5]undec-3-yl)sulfonyl)-2,5-di Azabicyclo[2.2.1]heptane-2-carboxylate tert-butyl instead of (1S,4S)-5-(N-(2-(((S)-1-(5-(2-(diiso Propylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)sulfamate Acyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester to obtain the target compound. MS m/z [LC-MS]: 713.40 [M+1].

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]undec-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro- N,N-Diisopropylbenzamide

Referring to the method of step 3 in Example 83, use 2-((4-((S)-3-((9-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane Alkyl-2-yl)sulfonyl)-3,9-diazaspiro[5.5]undecyl-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5 -Fluoro-N,N-diisopropylbenzamide hydrochloride instead of 2-((4-((S)-3-((7-((1S,4S)-2,5-diazabicyclo [2.2.1] Heptane-2-sulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)- 5-fluoro-N,N-diisopropylbenzamide hydrochloride to obtain the target compound. MS m/z [LC-MS]: 767.41 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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＝9.2 Hz,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).

Example 99: 5-fluoro-N,N-diisopropyl-2-((4-((S)-3-((9-(((S)-1,1,1-trifluoropropane- 2-yl)amino)-3- azaspiro[5.5]undec-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 92, substituting (S)-1,1,1-trifluoropropan-2-amine for 2,2,2-trifluoroethylamine, the title compound was obtained. MS m/z [LC-MS]: 663.40 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 100: (S)-2-((4-(3-((7-((1-acryloylpiperidine)-4-sulfonamido)-2-azaspiro[3.5]nonane-2 -yl) methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: (S)-4-(N-(2-((1-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrole Alk-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)aminosulfonyl)piperidine-1-carboxylate tert-butyl

Referring to the method of step 1 in Example 83, replace (1S,4S)-5-(chlorosulfonyl)-2,5-diazepine with tert-butyl 4-(chlorosulfonyl)piperidine-1-carboxylate Bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester to obtain the target compound. MS m/z [LC-MS]: 786.44 [M+1].

Step 2: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((7-(piperidine-4-sulfonamido)-2-azaspiro[ 3.5] Nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

Referring to the method of step 2 in Example 83, use (S)-4-(N-(2-((1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy )pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)aminosulfonyl)piperidine-1-carboxylic acid tert-butyl ester instead of ( 1S,4S)-5-(N-(2-(((S)-1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl )pyrrolidin-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)aminosulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2 - tert-butyl carboxylate to give the target compound. MS m/z [LC-MS]: 686.39 [M+1].

Step 3: (S)-2-((4-(3-((7-((1-acryloylpiperidine)-4-sulfonamido)-2-azaspiro[3.5]nonane-2- Base)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, use (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((7-(piperidine-4-sulfonamide )-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride instead of 2-((4-( (S)-3-((7-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-sulfonamido)-2-azaspiro[3.5]nonane -2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride to give the title compound. MS m/z [LC-MS]: 740.40 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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,1.5 H),3.32-3.94(m,10H),3.04-3.28(m,3.5H),2.64-2.82(m,2.5H),1.94-2.24(m,6.5H),1.42-1.84(m,15H) ,1.15-1.28(m,6H).

Example 101: (S)-2-((4-(3-((9-(ethanesulfonamidomethyl)-3-azaspiro[5.5]undec-3-yl)methyl)pyrrole Alk-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method in Example 36, intermediate 26 was used instead of intermediate 1, and intermediate 80 was used instead of intermediate 29 to obtain the target compound. MS m/z [LC-MS]: 673.39 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 102: (S)-N-ethyl-2-((4-(3-((9-(ethanesulfonamidomethyl)-3-azaspiro[5.5]undec-3-yl )methyl )pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

Referring to the method in Example 36, using Intermediate 80 instead of Intermediate 29, the title compound was obtained. MS m/z [LC-MS]: 659.38 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 103: (S)-3-((1-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3- yl )methyl)-N-(ethylsulfonyl)-3-azaspiro[5.5]undecane-9-carboxamide

Referring to the method in Example 36, intermediate 26 was used instead of intermediate 1, and intermediate 81 was used instead of intermediate 29 to obtain the target compound. MS m/z [LC-MS]: 687.37 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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 ).

Example 104: (S)-3-((1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl) pyrrolidine- 3-yl)methyl)-N-(ethylsulfonyl)-3-azaspiro[5.5]undecane-9-carboxamide

Referring to the method in Example 36, using Intermediate 81 instead of Intermediate 29, the title compound was obtained. MS m/z [LC-MS]: 673.35 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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).

Example 105: (S)-2-((4-(3-((9-((4-acryloylpiperazin-1-yl)sulfonyl)-3,9-diazaspiro[5.5]dec One alkyl -3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: (S)-4-((9-((1-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine- 3-yl)methyl)-3,9-diazaspiro[5.5]undec-3-yl)sulfonyl)piperazine-1-carboxylic acid tert-butyl ester

Referring to the method of step 1 in Example 83, intermediate 66 was replaced by intermediate 79, and (1S,4S)-5-(chlorosulfonyl) was replaced by tert-butyl 4-(chlorosulfonyl)piperazine-1-carboxylate )-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester to obtain the target compound. MS m/z [LC-MS]: 801.45 [M+1].

Step 2: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-(piperazin-1-ylsulfonyl)-3,9-diazepine Heterospiro[5.5]undec-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

Referring to the method of step 2 in Example 83, use (S)-4-((9-((1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine -4-yl)pyrrolidin-3-yl)methyl)-3,9-diazaspiro[5.5]undec-3-yl)sulfonyl)piperazine-1-carboxylic acid tert-butyl ester instead of ( 1S,4S)-5-(N-(2-(((S)-1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl )pyrrolidin-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)aminosulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2 - tert-butyl carboxylate to give the target compound. MS m/z [LC-MS]: 701.40 [M+1].

Step 3: (S)-2-((4-(3-((9-((4-acryloylpiperazin-1-yl)sulfonyl)-3,9-diazaspiro[5.5]undeca Alk-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, use (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-(piperazin-1-ylsulfonyl )-3,9-diazaspiro[5.5]undec-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride instead of 2-( (4-((S)-3-((7-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-sulfonamido)-2-azaspiro[ 3.5] Nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride to give the target compound. MS m/z [LC-MS]: 755.41 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): 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, 7H),3.41-3.53(m,2H),3.12-3.27(m,9H),2.22-2.84(m,7H),1.90-2.18(m,2H),1.42-1.73(m,14H),1.10- 1.17(m,6H).

Example 106: (S)-2-((4-(3-((9-((4-acryloyl-1,4-diazepan-1-yl)sulfonyl)-3,9 -diazaspiro [5.5]undec-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzyl Amide

Step 1: (S)-4-((9-((1-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine- 3-yl)methyl)-3,9-diazaspiro[5.5]undec-3-yl)sulfonyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester

Referring to the method of step 1 in Example 83, intermediate 79 was used to replace intermediate 66, and intermediate 74 was used to replace (1S,4S)-5-(chlorosulfonyl)-2,5-diazabicyclo[2.2.1 ] Heptane-2-carboxylic acid tert-butyl ester to obtain the target compound. MS m/z [LC-MS]: 815.47 [M+1].

Step 2: (S)-2-((4-(3-((9-((1,4-diazepan-1-yl)sulfonyl)-3,9-diazaspiro[ 5.5] Undecyl-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, use (S)-4-((9-((1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine -4-yl)pyrrolidin-3-yl)methyl)-3,9-diazaspiro[5.5]undecane-3-yl)sulfonyl)-1,4-diazepane- tert-butyl 1-carboxylate instead of (1S,4S)-5-(N-(2-(((S)-1-(5-(2-(diisopropylcarbamoyl)-4-fluoro Phenoxy)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)aminosulfonyl)-2,5-diazabicyclo [2.2.1] Heptane-2-carboxylic acid tert-butyl ester to obtain the target compound. MS m/z [LC-MS]: 715.42 [M+1].

Referring to the method of step 3 in Example 83, use (S)-2-((4-(3-((9-((1,4-diazepan-1-yl)sulfonyl)-3 ,9-diazaspiro[5.5]undec-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropyl Benzamide hydrochloride instead of 2-((4-((S)-3-((7-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-sulfo Amino)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropyl phenylbenzamide hydrochloride to obtain the target compound. MS m/z [LC-MS]: 769.42 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.40(s,0.5H),8.39(s,0.5H),7.80(s,1H),6.90-6.97(m,2H),6.64-6.67(m, 0.5H),6.48-6.59(m,1.5H),6.30-6.40(m,1H),5.68-5.73(m,1H),3.61-3.92(m,7.5H),3.32-3.52(m,6.5H ), 3.04-3.14 (m, 4H), 2.17-2.56 (m, 8H), 1.89-2.10 (m, 4H), 1.42-1.72 (m, 13H), 1.11-1.16 (m, 6H).

Example 107: (S)-2-((4-(3-((7-((7-acryloyl-2,7-diazaspiro[3.5]nonan-2-yl)sulfonyl)- 2,7- diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropyl benzamide

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

Referring to the method of step 1 in Example 83, intermediate 70 was used instead of intermediate 66, and intermediate 71 was used instead of (1S,4S)-5-(chlorosulfonyl)-2,5-diazabicyclo[2.2.1 ] Heptane-2-carboxylic acid tert-butyl ester to obtain the target compound. MS m/z [LC-MS]: 813.45 [M+1].

Step 2: (S)-2-((4-(3-((7-((2,7-diazaspiro[3.5]nonan-2-yl)sulfonyl)-2,7-diaze Heterospiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, use (S)-2-((2-((1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine -4-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)-2,7-diazaspiro[3.5]nonan tert-butyl alkane-7-carboxylate instead of (1S,4S)-5-(N-(2-(((S)-1-(5-(2-(diisopropylcarbamoyl)-4 -fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)aminosulfonyl)-2,5-diazepine Heterobicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester to obtain the target compound. MS m/z [LC-MS]: 713.40 [M+1].

Step 3: (S)-2-((4-(3-((7-((7-acryloyl-2,7-diazaspiro[3.5]nonan-2-yl)sulfonyl)-2 ,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzene Formamide

Referring to the method of step 3 in Example 83, use (S)-2-((4-(3-((7-((2,7-diazaspiro[3.5]nonan-2-yl)sulfonyl) )-2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diiso Propylbenzamide hydrochloride instead of 2-((4-((S)-3-((7-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2 -sulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-di Cumyl benzamide hydrochloride to obtain the target compound. MS m/z [LC-MS]: 767.41 [M+1].

Example 108: 2-((4-((3S)-3-((7-((5-acryloylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl) sulfonyl )-2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diiso Propyl benzamide

Step 1: 5-((2-(((S)-1-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine- 3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert Butyl ester

Referring to the method of step 1 in Example 83, intermediate 70 was used instead of intermediate 66, and intermediate 72 was used instead of (1S,4S)-5-(chlorosulfonyl)-2,5-diazabicyclo[2.2.1 ] Heptane-2-carboxylic acid tert-butyl ester to obtain the target compound. MS m/z [LC-MS]: 799.43 [M+1].

Step 2: 5-fluoro-2-((4-((3S)-3-((7-((hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)- 2,7-Diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide salt salt

Referring to the method of step 2 in Example 83, use 5-((2-(((S)-1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine -4-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)hexahydropyrrolo[3,4-c]pyrrole- 2(1H)-tert-butyl carboxylate instead of (1S,4S)-5-(N-(2-(((S)-1-(5-(2-(diisopropylcarbamoyl)- 4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)aminosulfonyl)-2,5-di Azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester to obtain the target compound. MS m/z [LC-MS]: 699.38 [M+1].

Step 3: 2-((4-((3S)-3-((7-((5-acryloylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)- 2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropyl benzamide

Referring to the method of step 3 in Example 83, use 5-fluoro-2-((4-((3S)-3-((7-((hexahydropyrrolo[3,4-c]pyrrole-2(1H )-yl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N,N- Diisopropylbenzamide hydrochloride instead of 2-((4-((S)-3-((7-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane -2-sulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N -diisopropylbenzamide hydrochloride to obtain the target compound. MS m/z [LC-MS]: 753.39 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.45(s,0.5H),8.43(s,0.5H),7.87(s,1H),6.90-7.05(m,2H),6.69-6.74(m, 0.5H),6.45-6.52(m,0.5H),6.37-6.41(m,2H),5.69-5.73(m,1H),3.74-3.85(m,5H),3.42-3.58(m,8H), 2.90-3.28(m,11H),2.10-2.28(m,2H),1.54-2.03(m,7H),1.49-1.52(m,3H),1.46(d,J＝6.8Hz,3H),1.11- 1.22(m,6H).

Example 109: (S)-2-((4-(3-((7-((2-acryloyl-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)- 2,7- diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropyl benzamide

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

Referring to the method of step 1 in Example 83, intermediate 70 was used instead of intermediate 66, and intermediate 73 was used instead of (1S,4S)-5-(chlorosulfonyl)-2,5-diazabicyclo[2.2.1 ] Heptane-2-carboxylic acid tert-butyl ester to obtain the target compound. MS m/z [LC-MS]: 813.45 [M+1].

Step 2: (S)-2-((4-(3-((7-((2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)-2,7-diaza Heterospiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, use (S)-7-((2-((1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine -4-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)-2,7-diazaspiro[3.5]nonan tert-butyl alkane-2-carboxylate instead of (1S,4S)-5-(N-(2-(((S)-1-(5-(2-(diisopropylcarbamoyl)-4 -fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)aminosulfonyl)-2,5-diazepine Heterobicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester to obtain the target compound. MS m/z [LC-MS]: 713.40 [M+1].

Step 3: (S)-2-((4-(3-((7-((2-acryloyl-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)-2 ,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzene Formamide

Referring to the method of step 3 in Example 83, use (S)-2-((4-(3-((7-((2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl) )-2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diiso Propylbenzamide hydrochloride instead of 2-((4-((S)-3-((7-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2 -sulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-di Cumyl benzamide hydrochloride to obtain the target compound. MS m/z [LC-MS]: 767.41 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.42-8.50(m,1H),7.82-7.94(m,1H),6.90-7.06(m,2H),6.71-6.74(m,0.5H),6.43 -6.49(m,0.5H),6.39(dd,J=17.2Hz,1.6Hz,1H),6.17(dd,J=17.2Hz,10.4Hz,1H),5.68(dd,J=10.4Hz,1.6Hz ,1H),3.93-4.29(m,2H),3.91(s,2H),3.76-3.85(m,4H),2.88-3.74(m,14H),2.53-2.66(m,1H),1.78-2.24 (m,8H), 1.45-1.66(m,10H), 1.11-1.15(m,6H).

Example 110: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-(pyrimidin-2-ylamino)-3-azaspiro[5.5 ]undecyl -3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 92, substituting 2-aminopyrimidine for 2,2,2-trifluoroethylamine, the title compound was obtained. MS m/z [LC-MS]: 645.40 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.39(s,0.5H),8.38(s,0.5H),8.23(d,J=4.8Hz,2H),7.79(s,1H),6.89-6.97 (m,2H),6.64-6.68(m,0.5H),6.58-6.61(m,0.5H),6.46(t,J＝4.8Hz,1H),5.07(d,J＝8.4Hz,1H), 3.58-3.90(m,4.5H),3.33-3.52(m,2H),3.20-3.25(m,0.5H),2.22-2.50(m,7H),1.94-2.08(m,1H),1.78-1.90 (m, 2H), 1.43-1.70 (m, 11H), 1.18-1.42 (m, 6H), 1.10-1.16 (m, 6H).

Example 111: (S)-2-((4-(3-((9-((4-acrylamidophenyl)sulfonyl)-3,9-diazaspiro[5.5]undecane- 3- yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-((4-nitrophenyl)sulfonyl)-3,9- Diazaspiro[5.5]undec-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method of step 1 in Example 83, intermediate 66 was replaced by intermediate 79, and (1S,4S)-5-(chlorosulfonyl)-2,5-diazabicyclo was replaced by 4-nitrobenzenesulfonyl chloride [2.2.1] Heptane-2-carboxylic acid tert-butyl ester to obtain the target compound. MS m/z [LC-MS]: 738.35 [M+1].

Step 2: (S)-2-((4-(3-((9-((4-aminophenyl)sulfonyl)-3,9-diazaspiro[5.5]undec-3-yl )methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 82, use (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-((4-nitrophenyl) Sulfonyl)-3,9-diazaspiro[5.5]undec-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide instead of (S)- 2-((3-chloro-5-(3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)- 1,2,4-Triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide to give the title compound. MS m/z [LC-MS]: 708.37 [M+1].

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

Referring to the method of step 3 in Example 83, use (S)-2-((4-(3-((9-((4-aminophenyl)sulfonyl)-3,9-diazaspiro[5.5 ]undecyl-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide instead of 2-((4 -((S)-3-((7-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-sulfonamido)-2-azaspiro[3.5] Nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride to give the title compound. MS m/z [LC-MS]: 762.38 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.46(s,0.5H), 8.44(s,0.5H), 7.83-7.91(m,3H), 7.65-7.70(m,2H), 6.90-7.01( m,1.5H),6.75-6.82(m,0.5H),6.64-6.68(m,0.5H),6.34-6.50(m,2.5H),5.79-5.84(m,1H),3.97-4.27(m ,1H),3.72-3.84(m,2H),3.41-3.67(m,4H),2.56-3.14(m,12H),2.10-2.26(m,1H),1.38-1.74(m,14H),1.12 -1.19(m,6H).

Example 112: 2-((4-(7-((4-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptane)-2-sulfo Amino) cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5- Fluoro-N,N- diisopropylbenzamide

Step 1: (1S,4S)-5-(N-(4-((2-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl )-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)aminosulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxy tert-butyl acid

Referring to the method of step 1 in Example 83, intermediate 66 was replaced by intermediate 82 to obtain the target compound. MS m/z [LC-MS]: 813.45 [M+1].

Step 2: 2-((4-(7-((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)sulfonamido)cyclohexyl) Methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, use (1S,4S)-5-(N-(4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorobenzene Oxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)aminosulfonyl)-2,5-diazabicyclo[2.2. 1] tert-butyl heptane-2-carboxylate instead of (1S,4S)-5-(N-(2-(((S)-1-(5-(2-(diisopropylcarbamoyl )-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)aminosulfonyl)-2,5 - tert-butyl diazabicyclo[2.2.1]heptane-2-carboxylate to obtain the target compound. MS m/z [LC-MS]: 713.40 [M+1].

Step 3: 2-((4-(7-((4-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptane))-2-sulfonamide Base)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro -N,N-Diisopropylbenzamide

Referring to the method of step 3 in Example 83, use 2-((4-(7-((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl )sulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diiso Propylbenzamide hydrochloride instead of 2-((4-((S)-3-((7-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2 -sulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-di Cumyl benzamide hydrochloride to obtain the target compound. MS m/z [LC-MS]: 767.41 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.35(s,1H),7.75(s,1H),6.95-7.00(m,2H),6.74-6.78(m,1H),6.38-6.43(m, 1H),6.24-6.30(m,1H),5.70-5.74(m,1H),4.99(s,0.7H),4.62(s,0.3H),4.45(s,0.7H),4.43(s,0.3 H),3.66-4.05(m,7H),3.24-3.52(m,4H),3.08-3.19(m,1H),2.16-2.38(m,4H),1.68-2.10(m,14H),1.52( d, J = 6.8Hz, 3H), 1.47 (d, J = 7.2Hz, 3H), 1.07-1.24 (m, 9H).

Example 113: (S)-5-Fluoro-N,N-diisopropyl-2-((4-(3-((7-((4-propionylpiperazin-1-yl)sulfonyl) -2,7- diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in step 3 in Example 91, using propionyl chloride instead of acryloyl chloride, the title compound was obtained. MS m/z [LC-MS]: 729.39 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.42(s,0.5H),8.41(s,0.5H),7.84(s,1H),6.88-7.02(m,2H),6.67-6.70(m, 0.5H),6.45-6.52(m,0.5H),3.28-4.02(m,12H),2.42-3.25(m,12H),2.32(q,J＝7.2Hz,2H),1.73-2.20(m, 5H), 1.42-1.62(m, 8H), 1.08-1.25(m, 9H).

Example 114: 2-((4-(7-((1-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptan-2-yl) Sulfonyl ) piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro -N - Isopropylbenzamide

Step 1: (1S,4S)-5-((4-((2-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine-4- Base)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane -2-Tert-butyl carboxylate

Referring to the method of Step 1 in Example 83, using Intermediate 83 instead of Intermediate 66, the title compound was obtained. MS m/z [LC-MS]: 785.42 [M+1].

Step 2: 2-((4-(7-((1-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)sulfonyl)piperidine- 4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropyl Benzamide hydrochloride

Referring to the method of step 2 in Example 83, use (1S,4S)-5-((4-((2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluoro Phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)-2,5-diaza Bicyclo[2.2.1]heptane-2-carboxylate tert-butyl instead of (1S,4S)-5-(N-(2-(((S)-1-(5-(2-(diisopropyl Carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)aminosulfonyl) -2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester to obtain the target compound. MS m/z [LC-MS]: 685.37 [M+1].

Step 3: 2-((4-(7-((1-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)sulfo Acyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro- N-isopropylbenzamide

Referring to the method of step 3 in Example 83, use 2-((4-(7-((1-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2- Base)sulfonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5 -Fluoro-N-isopropylbenzamide hydrochloride instead of 2-((4-((S)-3-((7-((1S,4S)-2,5-diazabicyclo[2.2. 1] Heptane-2-sulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro -N,N-diisopropylbenzamide hydrochloride to obtain the target compound. MS m/z [LC-MS]: 739.38 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.33(s,1H),7.73(s,1H),6.94-6.98(m,2H),6.72-6.76(m,1H),6.37-6.42(m, 1.3H),6.22-6.29(m,0.7H),5.69-5.72(m,1H),4.96(s,0.7H),4.60(s,0.3H),4.41(s,0.7H),4.38(s ,0.3H),3.62-4.02(m,9H),3.41-3.52(m,3H),3.19-3.52(m,2H),2.64-2.72(m,2H),2.16-2.40(m,4H), 2.04-2.15(m,2H),1.86-2.02(m,2H),1.64-1.83(m,7H),1.51(d,J=6.4Hz,3H),1.45(d,J=6.8Hz,3H) , 1.10 (d, J=6.8Hz, 3H), 1.06 (d, J=7.2Hz, 3H).

Example 115: (S,E)-5-fluoro-N,N-diisopropyl-2-((4-(3-((7-((4-(4-methoxybutan-2- Enyl)piperazin-1- yl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy ) benzamide

Referring to the method in step 3 in Example 91, substituting (E)-4-methoxybut-2-enoyl chloride for acryloyl chloride, the title compound was obtained. MS m/z [LC-MS]: 771.40 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.39-8.50(m,1H),7.82-7.96(m,1H),6.86-7.05(m,3H),6.70-6.73(m,0.5H),6.44 -6.52(m,1.5H),3.96-4.13(m,3H),3.43-3.86(m,12H),3.39(s,3H),3.02-3.30(m,9H),2.50-3.00(m,2H ), 1.76-2.30 (m, 6H), 1.44-1.65 (m, 7H), 1.11-1.21 (m, 6H).

Example 116: (S,E)-2-((4-(3-((7-((4-(4-(Dimethylamino)but-2-enoyl)piperazin-1-yl) Sulfonyl)-2,7- diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N- Diisopropylbenzamide

Referring to the method in step 3 in Example 91, substituting (E)-4-(dimethylamino)but-2-enoyl chloride for acryloyl chloride, the title compound was obtained. MS m/z [LC-MS]: 784.43 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.40(s,0.5H),8.39(s,0.5H),7.81(s,1H),6.90-6.99(m,2H),6.80-6.88(m, 1H),6.65-6.68(m,0.5H),6.48-6.56(m,1.5H),3.55-3.96(m,8H),3.33-3.52(m,2H),3.06-3.30(m,14H), 2.53-2.81(m,2H),2.24-2.42(m,7H),2.01-2.11(m,1H),1.76-1.91(m,4H),1.42-1.62(m,7H),1.08-1.17(m ,6H).

Example 117: (S)-2-((4-(3-((9-((4-acryloylpiperazine)-1-sulfonamido)-3-azaspiro[5.5]undecane- 3- yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: (S)-4-(N-(3-((1-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrole Alk-3-yl)methyl)-3-azaspiro[5.5]undec-9-yl)sulfonamido)piperazine-1-carboxylic acid tert-butyl ester

Referring to the method of step 1 in Example 83, intermediate 66 was replaced by intermediate 76, and (1S,4S)-5-(chlorosulfonyl) was replaced by tert-butyl 4-(chlorosulfonyl)piperazine-1-carboxylate )-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester to obtain the target compound. MS m/z [LC-MS]: 815.47 [M+1].

Step 2: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-(piperazine-1-sulfonamido)-3-azaspiro[ 5.5] Undecyl-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

Referring to the method of step 2 in Example 83, use (S)-4-(N-(3-((1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy )pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-3-azaspiro[5.5]undec-9-yl)sulfonamido)piperazine-1-carboxylic acid tert-butyl ester instead of ( 1S,4S)-5-(N-(2-(((S)-1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl )pyrrolidin-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)aminosulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2 - tert-butyl carboxylate to give the target compound. MS m/z [LC-MS]: 715.42 [M+1].

Step 3: (S)-2-((4-(3-((9-((4-acryloylpiperazine)-1-sulfonamido)-3-azaspiro[5.5]undecane-3 -yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, use (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-(piperazine-1-sulfonamide )-3-azaspiro[5.5]undec-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride instead of 2-((4- ((S)-3-((7-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-sulfonyl)-2-azaspiro[3.5]nonanyl Alk-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride to give the title compound. MS m/z [LC-MS]: 769.42 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.40(s,0.5H),8.39(s,0.5H),7.80(s,1H),6.90-6.97(m,2H),6.63-6.68(m, 0.5H), 6.58-6.61(m, 0.5H), 6.53(dd, J＝16.8Hz, 10.8Hz, 1H), 6.30(dd, J＝16.8Hz, 1.6Hz, 1H), 5.73(dd, J＝ 10.8Hz, 2.0Hz, 1H), 4.20(d, J=7.6Hz, 1H), 3.56-3.90(m, 7H), 3.34-3.53(m, 2.5H), 3.10-3.26(m, 5.5H), 2.22-2.44(m,7H),1.94-2.07(m,1H),1.75-1.86(m,3H),1.56-1.66(m,4H),1.52(d,J＝7.2Hz,3H),1.43- 1.49 (m, 5H), 1.26-1.37 (m, 4H), 1.11-1.14 (m, 6H).

Example 118: (S)-2-((4-(3-((7-((4-acryloyl-1,4-diazepan-1-yl)sulfonyl)-2,7 -diazaspiro [3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

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

Referring to the method of step 1 in Example 83, intermediate 70 was used instead of intermediate 66, and intermediate 74 was used instead of (1S,4S)-5-(chlorosulfonyl)-2,5-diazabicyclo[2.2.1 ] Heptane-2-carboxylic acid tert-butyl ester to obtain the target compound. MS m/z [LC-MS]: 787.44 [M+1].

Step 2: (S)-2-((4-(3-((7-((1,4-diazepan-1-yl)sulfonyl)-2,7-diazaspiro[ 3.5] Nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy))-5-fluoro-N,N-diisopropylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, use (S)-4-((2-((1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine -4-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)-1,4-diazepane-1 - tert-butyl carboxylate instead of (1S,4S)-5-(N-(2-(((S)-1-(5-(2-(diisopropylcarbamoyl)-4-fluorobenzene Oxy)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)aminosulfonyl)-2,5-diazabicyclo[ 2.2.1] tert-butyl heptane-2-carboxylate to obtain the target compound. MS m/z [LC-MS]: 687.38 [M+1].

Step 3: (S)-2-((4-(3-((7-((4-acryloyl-1,4-diazepan-1-yl)sulfonyl)-2,7- Diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, use (S)-2-((4-(3-((7-((1,4-diazepan-1-yl)sulfonyl)-2 ,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy))-5-fluoro-N,N-diisopropyl Benzamide hydrochloride instead of 2-((4-((S)-3-((7-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-sulfo Amino)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropyl phenylbenzamide hydrochloride to obtain the target compound. MS m/z [LC-MS]: 741.39 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.38-8.39 (m, 1H), 7.80 (s, 1H), 6.90-6.97 (m, 2H), 6.48-6.68 (m, 2H), 6.31-6.41 ( m,1H),5.68-5.74(m,1H),3.60-3.89(m,7.5H),3.31-3.52(m,6.5H),3.02-3.08(m,4H),2.90-3.00(m,4H ),2.36-2.50(m,2H),2.08-2.23(m,1H),1.88-2.04(m,3H),1.71-1.87(m,5H),1.52(d,J＝6.8Hz,3H), 1.46 (d, J=6.8Hz, 3H), 1.11-1.16 (m, 6H).

Example 119: 2-((4-(7-((1-(6-acrylamidinylpyridin-3-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5 ] nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

Step 1: N-Ethyl-5-fluoro-N-isopropyl-2-((4-(7-((1-(6-nitropyridin-3-yl)piperidin-4-yl)methanol base)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method of step 1 in Example 83, intermediate 66 was replaced by intermediate 83, and (1S,4S)-5-(chlorosulfonyl)-2,5-diazepine was replaced by 5-fluoro-2-nitropyridine Heterobicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester to obtain the target compound. MS m/z [LC-MS]: 647.35 [M+1].

Step 2: 2-((4-(7-((1-(6-aminopyridin-3-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane -2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

Referring to the method of step 3 in Example 82, N-ethyl-5-fluoro-N-isopropyl-2-((4-(7-((1-(6-nitropyridin-3-yl) Piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide instead of (S)-2-(( 3-chloro-5-(3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)-1,2, 4-Triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide to give the title compound. MS m/z [LC-MS]: 617.37 [M+1].

Step 3: 2-((4-(7-((1-(6-acrylamidopyridin-3-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5] Nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

Referring to the method of step 3 in Example 83, use 2-((4-(7-((1-(6-aminopyridin-3-yl)piperidin-4-yl)methyl)-2,7-bis Azaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide instead of 2-((4-((S )-3-((7-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-sulfonyl)-2-azaspiro[3.5]nonane-2 -yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride to give the title compound. MS m/z [LC-MS]: 671.38 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.40(s,1H),8.32(s,1H),8.13(d,J=8.8Hz,1H),7.83(s,1H),7.54(s,1H ),6.96-7.04(m,2H),6.85-6.90(m,1H),6.65-6.74(m,1H),6.40(d,J=16.8Hz,1H),6.27(dd,J=16.8Hz, 10.0Hz, 1H), 5.73(d, J=10.0Hz, 1H), 3.76-4.16(m, 2H), 3.15-3.50(m, 6H), 2.89-3.02(m, 3H), 1.60-2.38(m , 15H), 1.39 (t, J=7.2Hz, 3H), 1.14 (d, J=6.8, 6H).

Example 120: (S,E)-2-((4-(3-((7-((4-(4-(Dimethylamino)but-2-enoyl)-1,4-diazenoyl) Hepan-1-yl) sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy) -5-fluoro-N,N- diisopropylbenzamide

Referring to the method in Step 3 in Example 91, the title compound was obtained using (E)-4-(dimethylamino)but-2-enoyl chloride and the product in Step 2 in Example 118 as starting materials. MS m/z [LC-MS]: 798.45 [M+1]. ¹ H NMR (400MHz, CD ₃ OD): δ=8.31-8.33(m,1H),7.84-7.88(m,1H),7.11-7.18(m,2H),6.66-6.90(m,3H), 3.81 -4.10(m,6H),3.60-3.78(m,7H),3.37-3.58(m,5H),3.07-3.30(m,6H),2.70(s,3H),2.67(s,3H),2.40 -2.54(m,1H),1.81-2.20(m,8H),1.55-1.72(m,2H),1.53-1.55(m,3H),1.44-1.47(m,3H),1.18(d,J= 6.4Hz, 4.5H), 1.14 (d, J = 6.4Hz, 1.5H).

Example 121: (S)-2-((4-(3-((9-((1-acryloylpiperidine)-4-sulfonamido)-3-azaspiro[5.5]undecane- 3- yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: (S)-4-(N-(3-((1-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrole Alk-3-yl)methyl)-3-azaspiro[5.5]undec-9-yl)sulfonamido)piperidine-1-carboxylic acid tert-butyl ester

Referring to the method in step 1 in Example 83, the title compound was obtained by using intermediate 76 and tert-butyl 4-(chlorosulfonyl)piperidine-1-carboxylate as starting materials. MS m/z [LC-MS]: 814.47 [M+1].

Step 2: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-(piperidine-4-sulfonamido)-3-azaspiro[ 5.5] Undecyl-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

Referring to the method of step 2 in Example 83, use (S)-4-(N-(3-((1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy )pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-3-azaspiro[5.5]undec-9-yl)sulfonamido)piperidine-1-carboxylic acid tert-butyl ester is obtained as raw material target compound. MS m/z [LC-MS]: 714.42 [M+1].

Step 3: (S)-2-((4-(3-((9-((1-acryloylpiperidine)-4-sulfonamido)-3-azaspiro[5.5]undecane-3 -yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, use (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-(piperidine-4-sulfonamide )-3-azaspiro[5.5]undecyl-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride as raw material to obtain the target compound. MS m/z [LC-MS]: 768.43 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.39(s,0.5H),8.38(s,0.5H),7.79(s,1H),6.90-6.96(m,2H),6.64-6.67(m, 0.5H), 6.51-6.61(m, 1.5H), 6.66(dd, J＝16.8Hz, 1.6Hz, 1H), 5.70(dd, J＝10.8Hz, 1.6Hz, 1H), 4.71-4.82(m, 1H), 4.22(d, J＝8.0Hz, 1H), 4.06-4.16(m, 1H), 3.58-3.89(m, 4H), 3.17-3.52(m, 4H), 2.98-3.14(m, 2H) ,2.60-2.72(m,1H),2.23-2.42(m,7H),2.10-2.22(m,2H),1.94-2.06(m,1H),1.57-1.84(m,8H),1.52(d, J=6.8Hz, 3H), 1.46(d, J=6.8Hz, 3H), 1.30-144(m, 6H), 1.11-1.16(m, 6H).

Example 122: (S)-2-((4-(3-((7-((4-(but-2-ynoyl)piperazin-1-yl)sulfonyl)-2,7-diazepine Heterospiro[3.5]nonan -2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method in step 3 in Example 91, the title compound was obtained using but-2-ynoyl chloride as a starting material. MS m/z [LC-MS]: 739.38 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.41-8.43(m,1H),7.85(s,1H), 6.90-7.02(m,2H),6.68-6.71(m,0.5H),6.46-6.52 (m,0.5H),3.32-4.04(m,13H),3.04-3.28(m,9H),2.76-2.90(m,1H),2.46-2.66(m,1H),2.09-2.21(m,1H ),1.80-2.06(m,7H),1.50-1.68(m,2H),1.48-1.50(m,3H),1.44(d,J＝6.8Hz,3H),1.18(d,J＝6.8Hz, 1.5H), 1.10-1.13 (m, 4.5H).

Example 123: (S)-2-((4-(3-((7-((4-acryloylpiperazine)-1-sulfonamido)-2-azaspiro[3.5]nonane-2 -yl) methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: (S)-4-(N-(2-((1-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrole Alk-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)sulfonamido)piperazine-1-carboxylic acid tert-butyl ester

Referring to the method in Step 1 in Example 83, the title compound was obtained using tert-butyl 4-(chlorosulfonyl)piperazine-1-carboxylate as a starting material. MS m/z [LC-MS]: 787.43 [M+1].

Step 2: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((7-(piperazine-1-sulfonamido)-2-azaspiro[ 3.5] Nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

Referring to the method of step 2 in Example 83, use (S)-4-(N-(2-((1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy )pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)sulfonamido)piperazine-1-carboxylic acid tert-butyl ester as raw material to obtain target compound. MS m/z [LC-MS]: 687.38 [M+1].

Step 3: (S)-2-((4-(3-((7-((4-acryloylpiperazine)-1-sulfonamido)-2-azaspiro[3.5]nonane-2- Base)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, use (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((7-(piperazine-1-sulfonamide )-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride as raw material to obtain the target compound. MS m/z [LC-MS]: 741.39 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.45(s,0.5H),8.44(s,0.5H),7.94(s,0.5),7.92(s,0.5H),6.93-7.19(m,2H ),6.69-6.72(m,0.5H),6.54-6.57(m,0.5H),6.49-6.53(m,1H),6.26-6.32(m,1H),5.70-5.74(m,1H),4.05 -4.22(brs,0.5H),3.36-3.90(m,11.5H),3.16-3.34(m,6H),2.65-3.08(m,4H),2.42-2.50(m,1H),1.92-2.14( m, 3H), 1.42-1.84 (m, 13H), 1.19 (d, J=6.8Hz, 1.5H), 1.14 (d, J=6.8Hz, 4.5H).

Example 124: (S)-2-((4-(3-((7-((6-acryloyl-2,6-diazaspiro[3.3]heptan-2-yl)sulfonyl)- 2,7- diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropyl benzamide

Step 1: (S)-6-((2-((1-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine- 3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

Referring to the method of step 1 in Example 83, the title compound was obtained by using intermediates 70 and 84 as starting materials. MS m/z [LC-MS]: 785.42 [M+1].

Step 2: (S)-2-((4-(3-((7-((2,6-diazaspiro[3.3]heptan-2-yl)sulfonyl)-2,7-diaze Heterospiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, use (S)-6-((2-((1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine -4-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane The target compound can be obtained from tert-butyl alkane-2-carboxylate. MS m/z [LC-MS]: 685.37 [M+1].

Step 3: (S)-2-((4-(3-((7-((6-acryloyl-2,6-diazaspiro[3.3]heptan-2-yl)sulfonyl)-2 ,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzene Formamide

Referring to the method of step 3 in Example 83, use (S)-2-((4-(3-((7-((2,6-diazaspiro[3.3]heptane-2-yl)sulfonyl) )-2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diiso Propylbenzamide hydrochloride was used as starting material to obtain the target compound. MS m/z [LC-MS]: 739.38 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.40(s,0.5H),8.39(s,0.5H),7.80(s,1H),6.91-6.97(m,2H),6.64-6.67(m, 0.5H), 6.57-6.61(m, 0.5H), 6.33(dd, J＝17.2Hz, 1.6Hz, 1H), 6.12(dd, J＝17.2Hz, 10.4Hz, 1H), 5.68(dd, J＝ 10.4Hz,1.6Hz,1H),4.30(s,2H),4.17(s,2H),3.95-4.00(m,4H),3.77-3.88(m,2H),3.62-3.74(m,2H), 3.42-3.52(m,1.5H),3.30-3.40(m,0.5H),3.12-3.14(m,4H),2.93-3.02(m,4H),2.38-2.50(m,2H),2.08-2.22 (m,1H),1.94-2.06(m,2H),1.72-1.79(m,4H),1.53(d,J=6.8Hz,3H),1.46(d,J=6.8Hz,3H),1.11- 1.16(m,6H).

Example 125: (S)-2-((4-(3-((7-((4-cyanopiperidin-1-yl)sulfonyl)-2,7-diazaspiro[3.5]nononyl Alk-2-yl) methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method in step 1 in Example 83, the title compound was obtained by using intermediate 70 and 4-cyanopiperidine-1-sulfonyl chloride as starting materials. MS m/z [LC-MS]: 697.37 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.45(s,0.5H),8.43(s,0.5H),7.86(s,1H),6.91-7.06(m,2H),6.68-6.75(m, 0.5H),6.43-6.56(m,0.5H),3.90-4.36(m,2H),3.74-3.86(m,2H),3.33-3.70(m,6H),2.89-3.31(m,6H), 2.78-2.88 (m, 1H), 2.41-2.70 (m, 1H), 1.76-2.24 (m, 9H), 1.46-1.76 (m, 10H), 1.10-1.17 (m, 6H).

Example 126: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-(thiazol-2-ylamino)-3-azaspiro[5.5 ]undecyl -3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 92, the title compound was obtained using 2-aminothiazole as a starting material. MS m/z [LC-MS]: 650.37 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.42(s,0.5H),8.41(s,0.5H),7.83(s,1H),7.08(d,J=2.8Hz,1H),6.91-7.00 (m,2H),6.65-6.69(m,0.5H),6.53-6.60(m,0.5H),6.46(d,J=3.6Hz,1H),5.08-5.34(brs,1H),3.58-4.04 (m,4H),3.10-3.56(m,3H),3.12-3.25(m,1H),2.26-2.86(m,6H),1.88-2.22(m,5H),1.56-1.76(m,5H) , 1.51-1.54 (m, 3H), 1.46 (d, J=6.8Hz, 3H), 1.34-1.44 (m, 2H), 1.21-1.33 (m, 2H), 1.11-1.18 (m, 6H).

Example 127: 2-((4-((3S)-3-((7-((8-acryloyl-3,8-diazabicyclo[3.2.1]octane-3-yl)sulfonyl Base)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-di Cumamide _

Step 1: 3-((2-(((S)-1-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine- 3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert Butyl ester

Referring to the method of step 1 in Example 83, the title compound was obtained by using intermediates 70 and 85 as starting materials. MS m/z [LC-MS]: 799.43 [M+1].

Step 2: 2-((4-((3S)-3-((7-((3,8-diazabicyclo[3.2.1]octane-3-yl)sulfonyl)-2,7- Diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide salt salt

Referring to the method of step 2 in Example 83, use 3-((2-(((S)-1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine -4-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)-3,8-diazabicyclo[3.2.1 ] Octane-8-carboxylic acid tert-butyl ester as raw material to obtain the target compound. MS m/z [LC-MS]: 699.38 [M+1].

Step 3: 2-((4-((3S)-3-((7-((8-acryloyl-3,8-diazabicyclo[3.2.1]octane-3-yl)sulfonyl) -2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropyl phenylbenzamide

Referring to the method of step 3 in Example 83, use 2-((4-((3S)-3-((7-((3,8-diazabicyclo[3.2.1]octane-3-yl) Sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N- Diisopropylbenzamide hydrochloride was used as the starting material to obtain the target compound. MS m/z [LC-MS]: 753.39 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.40(s,0.5H),8.39(s,0.5H),7.80(s,1H),6.90-6.98(m,2H),6.64-6.67(m, 0.5H),6.57-6.60(m,0.5H),6.37-6.48(m,2H),5.73-5.76(m,1H),4.77-4.82(m,1H),4.30-4.36(m,1H), 3.75-3.90(m,2H),3.60-3.72(m,1.5H),3.26-3.55(m,5H),3.06-3.20(m,5.5H),2.88-3.02(m,4H),2.36-2.53 (m,2H),2.09-2.22(m,1H),1.82-2.06(m,6H),1.71-1.80(m,4H),1.52(d,J＝6.8Hz,3H),1.46(d,J =7.2Hz, 3H), 1.15(d, J=6.8Hz, 1.5H), 1.12(d, J=6.8Hz, 4.5H).

Example 128: 2-((4-((S)-3-((7-(((S)-4-acryloyl-2-methylpiperazin-1-yl)sulfonyl)-2,7 -diazaspiro [3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: (S)-4-((2-(((S)-1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl )pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

Referring to the method of step 1 in Example 83, the title compound was obtained by using intermediates 70 and 86 as starting materials. MS m/z [LC-MS]: 787.43 [M+1].

Step 2: 5-fluoro-N,N-diisopropyl-2-((4-((S)-3-((7-(((S)-2-methylpiperazin-1-yl) Sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

Referring to the method of step 2 in Example 83, use (S)-4-((2-(((S)-1-(5-(2-(diisopropylcarbamoyl)-4-fluorobenzene Oxy)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)-3-methylpiperazine-1 - tert-butyl formate is the starting material to obtain the target compound. MS m/z [LC-MS]: 687.38 [M+1].

Step 3: 2-((4-((S)-3-((7-(((S)-4-acryloyl-2-methylpiperazin-1-yl)sulfonyl)-2,7- Diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, use 5-fluoro-N,N-diisopropyl-2-((4-((S)-3-((7-(((S)-2-methyl Basepiperazin-1-yl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzene Formamide hydrochloride was used as starting material to obtain the target compound. MS m/z [LC-MS]: 741.39 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.40(s,0.5H),8.39(s,0.5H),7.80(s,1H),6.90-6.96(m,2H),6.64-6.67(m, 0.5H), 6.43-6.60(m, 1.5H), 6.32(dd, J=16.8Hz, 1.6Hz, 1H), 5.73(d, J=10.8Hz, 1H), 4.61(d, J=12.0Hz, 0.5H), 4.42(d, J＝12.0Hz, 0.5H), 3.95-4.04(m, 1H), 3.60-3.92(m, 4H), 2.88-3.56(m, 14H), 2.72-2.84(m, 1H), 2.36-2.52(m, 2H), 2.08-2.24(m, 1H), 1.90-2.06(m, 2H), 1.70-1.82(m, 4H), 1.52(d, J＝6.4Hz, 3H) ,1.46(d,J=7.2Hz,3H),1.21(d,J=7.2Hz,3H),1.15(d,J=6.8Hz,1.5H),1.12(d,J=6.4HZ,4.5H) .

Example 129: 2-((4-((S)-3-((7-(((S)-4-acryloyl-3-methylpiperazin-1-yl)sulfonyl)-2,7 -diazaspiro [3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: (S)-4-((2-(((S)-1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl )pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester

Referring to the method of step 1 in Example 83, the title compound was obtained by using intermediates 70 and 87 as starting materials. MS m/z [LC-MS]: 787.43 [M+1].

Step 2: 5-fluoro-N,N-diisopropyl-2-((4-((S)-3-((7-(((S)-3-methylpiperazin-1-yl) Sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

Referring to the method of step 2 in Example 83, use (S)-4-((2-(((S)-1-(5-(2-(diisopropylcarbamoyl)-4-fluorobenzene Oxy)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)-2-methylpiperazine-1 - tert-butyl formate is the starting material to obtain the target compound. MS m/z [LC-MS]: 687.38 [M+1].

Step 3: 2-((4-((S)-3-((7-(((S)-4-acryloyl-3-methylpiperazin-1-yl)sulfonyl)-2,7- Diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, use 5-fluoro-N,N-diisopropyl-2-((4-((S)-3-((7-(((S)-3-methyl Basepiperazin-1-yl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzene Formamide hydrochloride was used as starting material to obtain the target compound. MS m/z [LC-MS]: 741.39 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.40(s,0.5H),8.39(s,0.5H),7.80(s,1H),6.90-6.96(m,2H),6.64-6.67(m, 0.5H), 6.57-6.60(m, 0.5H), 6.51(dd, J＝16.8Hz, 10.4Hz, 1H), 6.29(dd, J＝16.8Hz, 1.6Hz, 1H), 5.71(dd, J＝ 10.4Hz,1.6Hz,1H),4.10-4.68(m,1H),3.74-3.90(m,2.5H),3.58-3.72(m,2.5H),3.30-3.53(m,4H),3.08-3.22 (m,5H),2.86-3.05(m,5H),2.77(td,J=12.0Hz,3.2Hz,1H),2.35-2.52(m,2H),2.08-2.22(m,1H),1.90- 2.06(m,2H),1.70-1.83(m,4H),1.52(d,J=6.8Hz,3H),1.46(d,J=7.2Hz,3H),1.30(d,J=6.4Hz,3H ), 1.15 (, dJ = 6.8Hz, 1.5H), 1.12 (d, J = 6.4Hz, 4.5H).

Example 130: (S)-2-((4-(3-((7-((4-acrylamidophenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane-2 -yl) methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: (S)-2-((4-(3-((7-((4-aminophenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl) Methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method in step 1 in Example 83, the title compound was obtained using intermediate 70 and 4-aminobenzenesulfonyl chloride as starting materials. MS m/z [LC-MS]: 680.34 [M+1].

Step 2: (S)-2-((4-(3-((7-((4-acrylamidophenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane-2- Base)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, (S)-2-((4-(3-((7-((4-aminophenyl)sulfonyl)-2,7-diazaspiro[3.5 ]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide as starting material to obtain the target compound. MS m/z [LC-MS]: 734.35 [M+1]. ¹ H NMR (400MHz, CD ₃ OD): δ=8.24(s, 1H), 7.88(d, J=8.8Hz, 2H), 7.78(s, 0.5H), 7.77(s, 0.5H), 7.71( d,J＝8.8Hz,2H),7.07-7.13(m,1H),6.94-7.03(m,1H),6.78-6.86(m,1H),6.37-6.47(m,2H),5.81(dd, J＝8.8Hz, 3.6Hz, 1H), 3.68-3.94(m, 3H), 3.44-3.66(m, 2.5H), 3.13-3.18(m, 0.5H), 2.86-3.03(m, 8H), 2.47 -2.57(m,2H),2.13-2.24(m,1H),1.94-2.06(m,2H),1.75-1.84(m,4H),1.50(d,J＝6.8Hz,3H),1.40-1.42 (m,3H), 1.09-1.15(m,6H).

Example 131: (S)-5-Fluoro-N,N-diisopropyl-2-((4-(3-((7-((7-(2,2,2-trifluoroacetyl) -2,7-diazaspiro [3.5]nonan-2-yl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl )pyrimidin-5-yl)oxy) benzamide

Referring to the method in step 3 in Example 107, the title compound was obtained using trifluoroacetyl chloride as a starting material. MS m/z [LC-MS]: 809.38 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.41(s,0.5H),8.40(s,0.5H),7.82(s,1H),6.91-6.99(m,2H),6.65-6.68(m, 0.5H),6.56-6.60(m,0.5H),4.08(s,2H),3.74-3.94(m,4H),3.56-3.73(m,2H),3.32-3.55(m,3H),2.88- 3.26(m,11H),2.37-2.64(m,2H),2.12-2.32(m,1H),1.96-2.10(m,2H),1.70-1.92(m,8H),1.52(d,J＝6.4 Hz, 3H), 1.46 (d, J = 7.2Hz, 3H), 1.16 (d, J = 6.4Hz, 1.5H), 1.12 (d, J = 6.4Hz, 4.5H).

Example 132: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-(pyrimidin-4-ylamino)-3-azaspiro[5.5 ]undecyl -3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 92, the title compound was obtained using 4-aminopyrimidine as a starting material. MS m/z [LC-MS]: 645.40 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.51(s, 1H), 8.41(s, 0.5H), 8.40(s, 0.5H), 8.12(d, J=5.2Hz, 1H), 7.82(s ,1H),6.91-6.98(m,2H),6.65-6.69(m,0.5H),6.53-6.60(m,0.5H),6.27(d,J＝6.0Hz,1H),4.80-5.08(m ,2H),3.34-4.02(m,7H),3.13-3.24(m,1H),2.22-2.80(m,7H),1.96-2.17(m,2H),1.82-1.92(m,3H),1.54 -1.76 (m, 6H), 1.51-1.53 (m, 3H), 1.46 (d, J=7.2Hz, 3H), 1.32-1.39 (m, 1H), 1.11-1.17 (m, 6H).

Example 133: 2-((4-((S)-3-((7-(((3aR,6aS)-5-acryloylhexahydropyrrolo[3,4-c]pyrrole-2(1H) -yl) sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N ,N- Diisopropylbenzamide

Step 1: (3aR,6aS)-5-((2-(((S)-1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine-4 -yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2( 1H)-tert-butyl formate

Referring to the method of step 1 in Example 83, the title compound was obtained by using intermediates 70 and 88 as starting materials. MS m/z [LC-MS]: 799.43 [M+1].

Step 2: 5-fluoro-2-((4-((S)-3-((7-(((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)- Base)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N,N-diiso Propylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, use (3aR,6aS)-5-((2-(((S)-1-(5-(2-(diisopropylcarbamoyl)-4- Fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)hexahydropyrrolo[3, 4-c] tert-butyl pyrrole-2(1H)-carboxylate as starting material to obtain the target compound. MS m/z [LC-MS]: 699.38 [M+1].

Step 3: 2-((4-((S)-3-((7-(((3aR,6aS)-5-acryloylhexahydropyrrolo[3,4-c]pyrrole-2(1H)- Base)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N, N-Diisopropylbenzamide

Referring to the method of step 3 in Example 83, use 5-fluoro-2-((4-((S)-3-((7-(((3aR,6aS)-hexahydropyrrolo[3,4-c ]pyrrole-2(1H)-yl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy )-N,N-diisopropylbenzamide hydrochloride as raw material to obtain the target compound. MS m/z [LC-MS]: 753.39 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.40(s,0.5H),8.39(s,0.5H),7.81(s,1H),6.91-6.96(m,2H),6.65-6.68(m, 0.5H),6.57-6.60(m,0.5H),6.35-6.44(m,2H),5.68-5.71(m,1H),3.74-3.90(m,4H),3.59-3.73(m,2H), 3.41-3.57(m,6H),3.10-3.21(m,7H),2.90-3.06(m,6H),2.37-2.53(m,2H),1.95-2.22(m,2H),1.70-1.83(m , 4H), 1.53 (d, J=6.8Hz, 3H), 1.47 (d, J=6.8Hz, 3H), 1.11-1.17 (m, 6H).

Example 134: (1S,4S)-5-((2-(((S)-1-(6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)-1 ,2,4-triazin -5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)-N,N-di Methyl-2,5-diazabicyclo [2.2.1]heptane-2-carboxamide

Step 1: (1S,4S)-5-((2-(((S)-1-(6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)-1, 2,4-triazin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)-2,5-diaza Heterobicyclo[2.2.1]heptane-2-carboxylate tert-butyl ester

Referring to the method in Step 1 in Example 83, the target compound was obtained using Intermediate 89 as a starting material. MS m/z [LC-MS]: 786.41 [M+1].

Step 2: 2-((5-((S)-3-((7-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-sulfonyl)- 2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro- N,N-Diisopropylbenzamide Hydrochloride

Referring to the method of step 2 in Example 83, use (1S,4S)-5-((2-(((S)-1-(6-(2-(diisopropylcarbamoyl)-4- Fluorophenoxy)-1,2,4-triazin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl )-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as raw material to obtain the target compound. MS m/z [LC-MS]: 686.36 [M+1].

Step 3: (1S,4S)-5-((2-(((S)-1-(6-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)-1, 2,4-triazin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)-N,N-dimethyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxamide

Referring to the method of step 3 in Example 83, use 2-((5-((S)-3-((7-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane Alkane-2-sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)-1,2,4-triazin-6-yl) Oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride as raw material to obtain the target compound. MS m/z[LC-MS]: 757.40[M+1]. ¹ H NMR (400MHz , CDCl ₃ ): δ＝8.49(s,1H),6.83-7.22(m,3H),4.04-4.56(m,4H),3.70-3.98(m,3H),3.04-3.62(m,12H), 2.78-2.94(m,7H),1.44-2.36(m,14H),1.36(d,J=6.4Hz,3H),1.28(d,J=6.4Hz,3H),1.06-1.09(m,3H) .

Example 135: (S)-2-((5-(3-((7-((4-acryloyl-1,4-diazepan-1-yl)sulfonyl)-2,7 -Diazaspiro [3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N -Diisopropylbenzamide

Step 1: (S)-4-((2-((1-(6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)-1,2,4-triazine -5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)-1,4-diazepane-1 - tert-butyl formate

Referring to the method in step 1 in Example 83, the title compound was obtained by using intermediates 89 and 74 as starting materials. MS m/z [LC-MS]: 788.43 [M+1].

Step 2: (S)-2-((5-(3-((7-((1,4-diazepan-1-yl)sulfonyl)-2,7-diazaspiro[ 3.5] Nonan-2-yl)methyl)pyrrolidin-1-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzene Formamide hydrochloride

Referring to the method of step 2 in Example 83, use (S)-4-((2-((1-(6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)- 1,2,4-Triazin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)-1,4- The target compound was obtained from tert-butyl diazepane-1-carboxylate. MS m/z [LC-MS]: 688.38 [M+1].

Step 3: (S)-2-((5-(3-((7-((4-acryloyl-1,4-diazepan-1-yl)sulfonyl)-2,7- Diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N- Diisopropylbenzamide

Referring to the method of step 3 in Example 83, use (S)-2-((5-(3-((7-((1,4-diazepan-1-yl)sulfonyl)-2 ,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N , N-diisopropylbenzamide hydrochloride as the starting material to obtain the target compound. MS m/z [LC-MS]: 742.39 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.48(s, 1H), 7.18-7.23(m, 1H), 7.06-7.11(m, 1H), 6.93-6.96(m, 1H), 6.49-6.60( m,1H),6.32-6.41(m,1H),5.69-5.75(m,1H),4.30-4.42(m,0.5H),4.07-4.20(m,0.5H),3.48-3.96(m,8H ),3.22-3.46(m,5.5H),2.90-3.16(m,7.5H),2.40-2.62(m,2H),1.88-2.36(m,5H),1.74-1.84(m,4H),1.48 (d, J=6.4Hz, 3H), 1.26-1.30(m, 3H), 1.06-1.07(m, 3H), 0.68-0.73(m, 3H).

Example 136: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((3'-(trifluoromethyl)-5',6'-dihydro -8'H-spiro[piperidin -4,7'-[1,2,4]triazolo[4,3-a]pyridin]-1-yl)methyl)pyrrolidin-1-yl)pyrimidine -5-yl)oxy)benzamide

Referring to the method in Example 36, using intermediates 26 and 90 as starting materials, the title compound was obtained. MS m/z [LC-MS]: 659.34 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.44(s,0.5H),8.43(s,0.5H),7.86(s,0.5H),7.84(s,0.5H),6.86-6.99(m, 2H),6.64-6.68(m,0.5H),6.51-6.55(m,0.5H),3.99-4.16(m,3.5H),3.42-3.88(m,6.5H),2.44-3.22(m,10H ),2.10-2.24(m,1H),1.55-1.72(m,4H),1.53(d,J＝6.8Hz,1.5H),1.46(d,J＝6.8Hz,3H),1.42(d,J =6.8Hz, 1.5H), 1.11-1.18 (m, 6H).

Example 137: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-(pyridin-3-ylamino)-3-azaspiro[5.5 ]undecyl -3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 92, the title compound was obtained using 3-aminopyridine as a starting material. MS m/z [LC-MS]: 644.41 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.41(s,0.5H),8.40(s,0.5H),7.98(d,J=2.8Hz,1H),7.90(d,J=4.0Hz,1H ),7.81(s,1H),7.04(dd,J＝8.0Hz,4.0Hz,1H),6.91-6.99(m,2H),6.81-6.84(m,1H),6.65-6.69(m,0.5H ),6.59-6.63(m,0.5H),3.60-3.91(m,3.5H),3.45-3.55(m,2.5H),3.34-3.44(m,0.5H),3.18-3.28(m,1.5H ),2.27-2.44(m,6H),1.96-2.08(m,2H),1.83-1.92(m,2H),1.60-1.72(m,4H),1.54(d,J＝7.2Hz,3H), 1.47 (d, J=6.4Hz, 3H), 1.37-1.42 (m, 1H), 1.19-1.36 (m, 6H), 1.12-1.17 (m, 6H).

Example 138: (S)-2-((4-(3-((9-((5-cyanopyrimidin-2-yl)amino)-3-azaspiro[5.5]undecane-3- Base)methyl) pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method in Example 92, the title compound was obtained using 2-aminopyrimidine-5-carbonitrile as a starting material. MS m/z [LC-MS]: 670.40 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.50(s,1H),8.40-8.42(m,2H),7.81(s,1H),6.91-6.97(m,2H),6.65-6.68(m, 0.5H),6.59-6.62(m,0.5H),5.57(s,0.5H),5.55(s,0.5H),3.59-3.91(m,4.5H),3.34-3.54(m,2H),3.20 -3.27(m,0.5H),2.24-2.46(m,7H),1.96-2.09(m,1H),1.80-1.90(m,2H),1.58-1.73(m,5H),1.53(d,J =6.8Hz, 3H), 1.47(d, J=6.4Hz, 3H), 1.33-1.44(m, 4H), 1.19-1.29(m, 2H), 1.12-1.15(m, 6H).

Example 139: 2-((4-(7-((1-((4-acryloylpiperazin-1-yl)sulfonyl)piperidin-4-yl)methyl)-2,7-diazepine Heterospiro [3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

Step 1: 4-((4-((2-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7 -Diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)piperazine-1-carboxylic acid tert-butyl ester

Referring to the method in Step 1 in Example 83, the title compound was obtained from Intermediate 83 and tert-butyl 4-(chlorosulfonyl)piperazine-1-carboxylate as starting materials. MS m/z [LC-MS]: 773.42 [M+1].

Step 2: N-Ethyl-5-fluoro-N-isopropyl-2-((4-(7-((1-(piperazin-1-ylsulfonyl)piperidin-4-yl)methyl )-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

Referring to the method of step 2 in Example 83, using 4-((4-((2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine- 4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)piperazine-1-carboxylic acid tert-butyl ester as raw material to obtain the target compound . MS m/z [LC-MS]: 673.37 [M+1].

Step 3: 2-((4-(7-((1-((4-acryloylpiperazin-1-yl)sulfonyl)piperidin-4-yl)methyl)-2,7-diazepine Spiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

Referring to the method of step 3 in Example 83, use N-ethyl-5-fluoro-N-isopropyl-2-((4-(7-((1-(piperazin-1-ylsulfonyl)piper Pyridin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride as starting material to obtain the target compound. MS m/z [LC-MS]: 727.38 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.34(s,1H), 7.74(s,1H), 6.96-7.02(m,2H), 6.71-6.77(m,1H), 6.51(dd,J= 17.2Hz, 10.4Hz, 1H), 6.28(dd, J=17.2Hz, 1.6Hz, 1H), 5.71(dd, J=10.4Hz, 1.6Hz, 1H), 3.78-3.96(m, 5H), 3.53- 3.76(m,6H),3.43-3.52(m,1H),3.18-3.33(m,5H),2.72-2.79(m,2H),2.17-2.36(m,4H),2.10(d,J＝6.0 Hz, 2H), 1.66-1.81(m, 6H), 1.48-1.61(m, 1H), 1.14-1.26(m, 5H), 1.10-1.12(m, 6H).

Example 140: 2-((4-(7-((1-((4-acryloyl-1,4-diazepan-1-yl)sulfonyl)piperidin-4-yl)methyl Base)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

Step 1: 4-((4-((2-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7 -Diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester

Referring to the method of step 1 in Example 83, the title compound was obtained by using intermediates 83 and 74 as starting materials. MS m/z [LC-MS]: 787.43 [M+1].

Step 2: 2-((4-(7-((1-((1,4-diazepan-1-yl)sulfonyl)piperidin-4-yl)methyl)-2,7 -Diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, using 4-((4-((2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine- 4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)-1,4-diazepane-1- The target compound was obtained from tert-butyl formate. MS m/z [LC-MS]: 687.38 [M+1].

Step 3: 2-((4-(7-((1-((4-acryloyl-1,4-diazepan-1-yl)sulfonyl)piperidin-4-yl)methyl )-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

Referring to the method of step 3 in Example 83, use 2-((4-(7-((1-((1,4-diazepan-1-yl)sulfonyl)piperidin-4-yl )methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide Hydrochloride as starting material to obtain the target compound. MS m/z [LC-MS]: 741.39 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.35(s,1H),7.74(s,1H),6.96-7.02(m,2H),6.71-6.77(m,1H),6.48-6.58(m, 1H),6.30-6.39(m,1H),6.67-6.72(m,1H),3.78-3.97(m,4.5H),3.64-3.76(m,4.5H),3.24-3.58(m,8H), 2.64-2.73(m,2H),2.16-2.36(m,4H),2.09(d,J＝6.4Hz,2H),1.89-1.98(m,2H),1.68-1.80(m,6H),1.46- 1.60 (m, 1H), 1.14-1.26 (m, 5H), 1.10-1.13 (m, 6H).

Example 141: 2-((4-(7-((1-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptan-2-yl) Sulfonyl) piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro -N - Isopropylbenzamide

Referring to the method in Step 1 in Example 83, the target compound was obtained using Intermediate 83 as a starting material. MS m/z [LC-MS]: 785.42 [M+1].

Referring to the method of step 2 in Example 83, use (1S,4S)-5-((4-((2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluoro Phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)-2,5-diaza The target compound was obtained from tert-butyl bicyclo[2.2.1]heptane-2-carboxylate. MS m/z [LC-MS]: 685.37 [M+1].

Referring to the method of step 3 in Example 83, use 2-((4-(7-((1-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2- Base)sulfonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5 - Fluoro-N-isopropylbenzamide hydrochloride as the starting material to obtain the target compound. MS m/z [LC-MS]: 739.38 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.35(s,1H),7.75(s,1H),6.96-7.03(m,2H),6.71-6.78(m,1H),6.37-6.42(m, 1.3H),6.23-6.30(m,0.7H),5.69-5.72(m,1H),4.97(s,0.7H),4.61(s,0.3H),4.42(s,0.7H),4.39(s ,0.3H),3.76-3.98(m,5.7H),3.62-3.69(m,2.3H),3.44-3.52(m,2H),3.14-3.37(m,3H),2.66-2.71(m,2H ),2.17-2.38(m,4H),2.09(d,J＝6.4Hz,2H),1.88-2.02(m,2H),1.68-1.83(m,7H),1.47-1.60(m,1H), 1.21-1.27 (m, 4H), 1.11-1.13 (m, 6H).

Example 142: (S)-2-((4-(3-((7-((9-acryloyl-3,9-diazaspiro[5.5]undec-3-yl)sulfonyl) -2,7- diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropyl phenylbenzamide

Step 1: (S)-9-((2-((1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine- 3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester

Referring to the method in step 1 in Example 83, the title compound was obtained by using intermediates 70 and 91 as starting materials. MS m/z [LC-MS]: 841.48 [M+1].

Step 2: (S)-2-((4-(3-((7-((3,9-diazaspiro[5.5]undec-3-yl)sulfonyl)-2,7-di Azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride Salt

Referring to the method of step 2 in Example 83, use (S)-9-((2-((1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine -4-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)-3,9-diazaspiro[5.5]deca The target compound can be obtained from tert-butyl monoalkane-3-carboxylate. MS m/z [LC-MS]: 741.43 [M+1].

Step 3: (S)-2-((4-(3-((7-((9-acryloyl-3,9-diazaspiro[5.5]undec-3-yl)sulfonyl)- 2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropyl benzamide

Referring to the method of step 3 in Example 83, use (S)-2-((4-(3-((7-((3,9-diazaspiro[5.5]undec-3-yl)sulfonyl Acyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-di Cumyl benzamide hydrochloride was used as starting material to obtain the target compound. MS m/z [LC-MS]: 795.44 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.40(s,0.5H),8.39(s,0.5H),7.81(s,1H),6.91-6.99(m,2H),6.64-6.68(m, 0.5H), 6.52-6.61(m, 1.5H), 6.25(dd, J＝16.8Hz, 2.0Hz, 1H), 5.66(dd, J＝10.4Hz, 2.0Hz, 1H), 3.76-3.89(m, 2H),3.58-3.72(m,4H),3.42-3.52(m,3H),3.30-3.40(m,1H),3.10-3.22(m,8H),2.91-3.04(m,4H),2.34- 2.54(m,2H),2.10-2.33(m,2H),1.90-2.07(m,3H),1.73-1.81(m,4H),1.46-1.58(m,12H),1.12-1.17(m,6H ).

Example 143: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-(pyrazin-2-ylamino)-3-azaspiro[ 5.5] Undecyl -3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 92, the title compound was obtained using 2-aminopyrazine as a starting material. MS m/z [LC-MS]: 645.40 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.41(s,0.5H),8.40(s,0.5H),7.94(s,1H),7.82(s,1H),7.81(s,1H),7.74 (d,J=2.8Hz,1H),6.91-6.97(m,2H),6.65-6.68(m,0.5H),6.57-6.61(m,0.5H),4.49(d,J=7.6Hz,1H ),3.59-3.95(m,4.5H),3.34-3.54(m,2H),3.17-3.26(m,0.5H),2.18-2.59(m,7H),1.95-2.13(m,2H),1.84 -1.93(m,2H),1.22-1.72(m,16H),1.12-1.17(m,6H).

Example 144: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-(pyrimidin-5-ylamino)-3-azaspiro[5.5 ]undecyl -3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 92, the title compound was obtained using 5-aminopyrimidine as a starting material. MS m/z [LC-MS]: 645.40 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.53(s, 1H), 8.40(d, J=3.6Hz, 1H), 8.06(s, 2H), 7.81(s, 1H), 6.91-6.98(m ,2H),6.65-6.68(m,0.5H),6.57-6.61(m,0.5H),3.57-3.94(m,4.5H),3.34-3.54(m,2H),3.17-3.30(m,1.5 H), 2.22-2.52 (m, 7H), 1.94-2.12 (m, 2H), 1.83-1.92 (m, 2H), 1.24-1.72 (m, 16H), 1.11-1.17 (m, 6H).

Example 145: (S)-2-((4-(3-((9-((5-chloropyrimidin-2-yl)amino)-3-azaspiro[5.5]undec-3-yl )methyl) pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method in Example 92, the title compound was obtained using 5-chloropyrimidin-2-amine as a starting material. MS m/z [LC-MS]: 679.37 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.41(s,0.5H),8.40(s,0.5H),8.17(s,2H),7.81(s,1H),6.91-6.97(m,2H) ,6.65-6.68(m,0.5H),6.58-6.62(m,0.5H),5.05(d,J＝7.6Hz,1H),3.60-3.93(m,4.5H),3.34-3.54(m,2H ),3.18-3.28(m,0.5H),2.22-2.48(m,7H),1.94-2.10(m,2H),1.81-1.90(m,2H),1.56-1.72(m,4H),1.53( d, J=6.8Hz, 3H), 1.47(d, J=6.8Hz, 3H), 1.18-1.42(m, 6H), 1.11-1.47(m, 6H).

Example 146: (S)-5-fluoro-2-((4-(3-((9-((5-fluoropyrimidin-2-yl)amino)-3-azaspiro[5.5]undecane -3-yl)methyl )pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method in Example 92, the title compound was obtained using 5-fluoropyrimidin-2-amine as a starting material. MS m/z [LC-MS]: 663.39 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.41(s,0.5H),8.40(s,0.5H),8.13(s,2H),7.81(s,1H),6.91-6.97(m,2H) ,6.65-6.68(m,0.5H),6.58-6.62(m,0.5H),4.98(d,J＝7.6Hz,1H),3.60-3.94(m,4.5H),3.34-3.54(m,2H ),3.18-3.27(m,0.5H),2.21-2.48(m,4H),1.95-2.10(m,2H),1.81-1.90(m,2H),1.56-1.71(m,4H),1.53( d, J=6.8Hz, 3H), 1.47(d, J=6.8Hz, 3H), 1.19-1.42(m, 9H), 1.11-1.17(m, 6H).

Example 147: (S)-5-fluoro-2-((4-(3-((9-((5-fluoropyridin-2-yl)amino)-3-azaspiro[5.5]undecane -3-yl)methyl )pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide

Referring to the method in Example 92, the title compound was obtained using 5-fluoropyridin-2-amine as a starting material. MS m/z [LC-MS]: 662.40 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.40(s,0.5H),8.39(s,0.5H),7.91(d,J=2.8Hz,1H),7.80(s,1H),7.13-7.18 (m,1H),6.91-6.96(m,2H),6.64-6.68(m,0.5H),6.58-6.61(m,0.5H),6.28(dd,J＝9.2Hz,3.2Hz,1H), 4.32(d,J＝7.6Hz,1H),3.62-3.94(m,4.5H),3.34-3.53(m,2H),3.20-3.25(m,0.5H),2.22-2.48(m,7H), 1.96-2.10(m,2H),1.81-1.88(m,2H),1.54-1.78(m,4H),1.53(d,J＝6.8Hz,3H),1.46(d,J＝6.8Hz,3H) ,1.20-1.42(m,6H),1.11-1.17(m,6H).

Example 148: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((7-(pyrimidin-2-ylamino)-2-azaspiro[3.5 ]nonan-2- yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Under nitrogen protection, intermediate 66 (108 mg), 2-bromopyrimidine (38 mg), cuprous iodide (11 mg) and cesium carbonate (130 mg) were added to dioxane (5 mL), heated to reflux and stirred for 24 hours. Cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (dichloromethane/methanol, 10:1) to obtain the target compound (70 mg). MS m/z [LC-MS]: 617.37 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.46-8.48(m,1H),8.23-8.38(m,2H),7.96(s,1H),7.587.67(m,0.5H),6.90-7.08 (m,1.5H),6.71-6.74(m,0.5H),6.44-6.51(m,1.5H),4.76(s,1H),4.26-4.34(m,0.5H),3.96-4.07(m, 0.5H),3.08-3.94(m,8.5H),2.68-2.98(m,1.5H),2.36-2.49(m,1H),2.11-2.22(m,2H),1.68-2.05(m,8H) , 1.42-1.56 (m, 7H), 1.14 (d, J=6.4Hz, 3H), 1.01 (d, J=6.4Hz, 3H).

Example 149: (S)-5-fluoro-N,N-diisopropyl-2-((5-(3-((9-(pyrimidin-2-ylamino)-3-azaspiro[5.5 ]undecyl -3-yl)methyl)pyrrolidin-1-yl)-1,2,4-triazin-6-yl)oxy)benzamide

Referring to the method in Example 148, the title compound was obtained using Intermediate 93 as a starting material. MS m/z [LC-MS]: 646.40 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ＝8.52(s, 1H), 8.25(d, J＝3.2Hz, 2H), 7.07-7.30(m, 2H), 6.89-6.97(m, 1H), 6.50 (t,J=4.8Hz,1H),5.03-5.25(brs,1H),3.28-4.32(m,7H),2.70-3.04(m,6H),2.24-2.52(m,2H),1.56-2.16 (m, 13H), 1.36-1.47 (m, 6H), 1.06-1.10 (m, 3H), 0.81-0.85 (m, 3H).

Example 150: 2-((4-(7-((1-((4-acryloyl-1,4-diazepan-1-yl)sulfonyl)piperidin-4-yl)methyl Base)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: 4-((4-((2-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diaze Heterospiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester

Referring to the method in step 1 in Example 83, the title compound was obtained by using intermediates 94 and 74 as starting materials. MS m/z [LC-MS]: 801.45 [M+1].

Step 2: 2-((4-(7-((1-((1,4-diazepan-1-yl)sulfonyl)piperidin-4-yl)methyl)-2,7 -Diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, 4-((4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl )-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)-1,4-diazepane-1-carboxylic acid tert-butyl Esters are used as starting materials to obtain the target compounds. MS m/z [LC-MS]: 701.40 [M+1].

Step 3: 2-((4-(7-((1-((4-acryloyl-1,4-diazepan-1-yl)sulfonyl)piperidin-4-yl)methyl )-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, use 2-((4-(7-((1-((1,4-diazepan-1-yl)sulfonyl)piperidin-4-yl )methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride Salt as starting material to obtain the target compound. MS m/z [LC-MS]: 755.41 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.34(s,1H),7.74(s,1H),6.94-6.99(m,2H),6.73-6.77(m,1H),6.48-6.59(m, 1H),6.30-6.40(m,1H),5.68-5.72(m,1H),3.82-4.02(m,4H),3.64-3.80(m,5H),3.51-3.58(m,2H),3.31- 3.50(m,5H),2.66-2.72(m,2H),2.16-2.37(m,4H),2.09(d,J＝6.8Hz,2H),1.89-1.99(m,2H),1.68-1.80( m, 6H), 1.52 (d, J = 6.4Hz, 3H), 1.46 (d, J = 7.2Hz, 3H), 1.06-1.21 (m, 9H).

Example 151: 2-((4-(7-((1-((4-acryloylpiperazin-1-yl)sulfonyl)piperidin-4-yl)methyl)-2,7-diazepine Heterospiro [3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: 4-((4-((2-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diaze Heterospiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)piperazine-1-carboxylic acid tert-butyl ester

Referring to the method in step 1 in Example 83, the title compound was obtained by using intermediate 94 and tert-butyl 4-(chlorosulfonyl)piperazine-1-carboxylate as starting materials. MS m/z [LC-MS]: 787.43 [M+1].

Step 2: 5-fluoro-N,N-diisopropyl-2-((4-(7-((1-(piperazin-1-ylsulfonyl)piperidin-4-yl)methyl)- 2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

Referring to the method of step 2 in Example 83, 4-((4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl )-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)piperazine-1-carboxylic acid tert-butyl ester as raw material to obtain the target compound. MS m/z [LC-MS]: 687.38 [M+1].

Step 3: 2-((4-(7-((1-((4-acryloylpiperazin-1-yl)sulfonyl)piperidin-4-yl)methyl)-2,7-diazepine Spiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, using 5-fluoro-N,N-diisopropyl-2-((4-(7-((1-(piperazin-1-ylsulfonyl)piperidine- 4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride as starting material to obtain the target compound. MS m/z [LC-MS]: 741.39 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.34(s,1H),7.74(s,1H),6.94-6.99(m,2H),6.73-6.76(m,1H),6.52(dd,J= 16.8Hz, 10.4Hz, 1H), 6.29(dd, J=16.8Hz, 1.6Hz, 1H), 5.72(dd, J=10.4Hz, 1.6Hz, 1H), 3.81-4.01(m, 4H), 3.54- 3.80(m,7H),3.41-3.52(m,1H),3.16-3.25(m,4H),2.72-2.80(m,2H),2.17-2.38(m,4H),2.10(d,J＝6.8 Hz, 2H), 1.67-1.79 (m, 6H), 1.51-1.60 (m, 4H), 1.46 (d, J=6.8Hz, 3H), 1.06-1.21 (m, 8H).

Example 152: 2-((4-(7-((1-((4-acryloylaminopiperidin-1-yl)sulfonyl)piperidin-4-yl)methyl)-2,7-di Azaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: (1-((4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-di Azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)piperidin-4-yl)tert-butyl carbamate

Referring to the method of step 1 in Example 83, the title compound was obtained by using intermediates 94 and 95 as starting materials. MS m/z [LC-MS]: 801.45 [M+1].

Step 2: 2-((4-(7-((1-((4-aminopiperidin-1-yl)sulfonyl)piperidin-4-yl)methyl)-2,7-diazaspiro [3.5]Nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, (1-((4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine-4- Base)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)piperidin-4-yl)tert-butyl carbamate as raw material to obtain target compound. MS m/z [LC-MS]: 701.40 [M+1].

Step 3: 2-((4-(7-((1-((4-acryloylaminopiperidin-1-yl)sulfonyl)piperidin-4-yl)methyl)-2,7-diazepine Heterospiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, 2-((4-(7-((1-((4-aminopiperidin-1-yl)sulfonyl)piperidin-4-yl)methyl)- The target compound. MS m/z [LC-MS]: 755.41 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.34(s,1H),7.74(s,1H),6.95-7.00(m,2H),6.74-6.77(m,1H),6.27(dd,J= 16.8Hz, 1.2Hz, 1H), 6.05(dd, J=16.8Hz, 10.0Hz, 1H), 5.68(d, J=7.6Hz, 1H), 5.63(d, J=10.0Hz, 1H), 3.82- 4.02(m,5H),3.61-3.80(m,5H),3.42-3.52(m,1H),2.86-2.93(m,2H),2.69-2.76(m,2H),2.16-2.40(m,4H ), 2.11 (d, J=6.8Hz, 2H), 1.94-2.01 (m, 2H), 1.66-1.91 (m, 7H), 1.44-1.55 (m, 8H), 1.06-1.21 (m, 8H).

Example 153: (R)-2-((4-(7-((1-((3-acryloylaminopiperidin-1-yl)sulfonyl)piperidin-4-yl)methyl)-2 ,7 -diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: (R)-(1-((4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2 , 7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)piperidin-3-yl)tert-butyl carbamate

Referring to the method of step 1 in Example 83, the title compound was obtained by using intermediates 94 and 96 as starting materials. MS m/z [LC-MS]: 801.45 [M+1].

Step 2: (R)-2-((4-(7-((1-((3-aminopiperidin-1-yl)sulfonyl)piperidin-4-yl)methyl)-2,7- Diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, use (R)-(1-((4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy) Pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)piperidin-3-yl)tert-butyl carbamate The target compound is obtained as a starting material. MS m/z [LC-MS]: 701.40 [M+1].

Step 3: (R)-2-((4-(7-((1-((3-acryloylaminopiperidin-1-yl)sulfonyl)piperidin-4-yl)methyl)-2, 7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, use (R)-2-((4-(7-((1-((3-aminopiperidin-1-yl)sulfonyl)piperidin-4-yl) Methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride The target compound is obtained as a starting material. MS m/z [LC-MS]: 755.41 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.35(s,1H),7.74(s,1H),6.95-7.00(m,2H),6.74-6.77(m,1H),6.27(dd,J= 17.2Hz, 1.2Hz, 1H), 6.05-6.14(m, 2H), 5.64(dd, J=10.4Hz, 1.2Hz, 1H), 4.08-4.16(m, 1H), 3.82-4.04(m, 4H) ,3.72-3.80(m,1H),3.59-3.68(m,2H),3.38-3.50(m,2H),3.20-3.29(m,2H),3.04-3.11(m,1H),2.72-2.78( m,2H),2.18-2.41(m,3H),2.06-2.16(m,2H),1.66-1.84(m,10H),1.55-1.65(m,2H),1.52(d,J＝6.8Hz, 3H), 1.47 (d, J=6.8Hz, 3H), 1.11-1.29 (m, 5H), 1.08 (d, J=6.8Hz, 3H).

Example 154: N-Ethyl-5-fluoro-N-isopropyl-2-((4-(7-(((1r,4r)-4-(pyrimidin-2-ylamino)cyclohexyl)methanol base)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 148, the target compound was obtained by using the product in Step 2 in Example 1 as a starting material. MS m/z [LC-MS]: 617.37 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ＝8.37(s, 1H), 8.23(d, J＝4.8Hz, 2H), 7.77(s, 1H), 6.98-7.02(m, 2H), 6.72-6.78 (m,1H),6.47(t,J=4.8Hz,1H),5.07(d,J=8.0Hz,1H),3.67-4.06(m,6H),3.44-3.53(m,1H),3.25- 3.33 (m, 1H), 2.40-2.62 (m, 8H), 1.66-2.01 (m, 5H), 1.42-1.63 (m, 1H), 1.11-1.28 (m, 14H).

Example 155: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-(pyrido[2,3-d]pyrimidin-4-ylamino )-3- azaspiro[5.5]undecyl-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 92, the target compound was obtained using pyrido[2,3-d]pyrimidin-4-amine as a starting material. MS m/z [LC-MS]: 696.42 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.67(d, J=4.4Hz, 1H), 8.60(s, 1H), 8.41(s, 0.5H), 8.08(s, 0.5H), 8.06(s ,0.5H),7.82(s,0.5H),7.64(dd,J＝8.4Hz,4.4Hz,1H),7.12(d,J＝8.4Hz,1H),6.92-7.01(m,2H),6.55 -6.80(m,1H),4.10-4.22(m,1H),3.76-3.93(m,2H),3.59-3.68(m,3H),3.15-3.55(m,2H),2.25-2.56(m, 5H), 1.90-2.16(m, 3H), 1.42-1.82(m, 15H), 1.28-1.38(m, 2H), 1.11-1.18(m, 8H).

Example 156: (S)-5-Fluoro-N,N-diisopropyl-2-((4-(3-((9-((2-methoxyphenyl)amino)-3-nitro Heterospiro[5.5]undec -3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 92, the title compound was obtained using 2-methoxyaniline as a starting material. MS m/z [LC-MS]: 673.42 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.45(s,0.5H),8.43(s,0.5H),7.86(s,1H),6.90-7.01(m,2H),6.84(t,J= 7.2Hz, 1H), 6.76(d, J=7.2Hz, 1H), 6.58-6.70(m, 2.5H), 6.43-6.52(m, 0.5H), 3.69-3.87(m, 4H), 3.44-3.56 (m,2H),2.70-3.36(m,5H),2.24-2.44(m,3H),1.86-2.05(m,5H),1.40-1.72(m,17H),1.17-1.22(m,2H) ,1.11-1.15(m,6H).

Example 157: (S)-2-((4-(3-((9-((2,6-dimethoxyphenyl)amino)-3-azaspiro[5.5]undecane-3 -yl)methyl ) pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method in Example 92, the title compound was obtained using 2,6-dimethoxyaniline as a starting material. MS m/z [LC-MS]: 703.43 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.40(s,0.5H),8.39(s,0.5H),7.80(s,1H),6.91-6.97(m,2H),6.79(t,J= 8.4Hz, 1H), 6.65-6.68(m, 0.5H), 6.59-6.62(m, 0.5H), 6.51(d, J＝8.4Hz, 2H), 3.62-4.58(m, 11H), 3.34-3.53 (m,2.5H),3.21-3.25(m,0.5H),2.24-2.43(m,7H),1.88-2.08(m,3H),1.46-1.96(m,13H),1.03-1.36(m, 10H).

Example 158: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-((1-methyl-1H-pyrazol-4-yl) Amino)-3-azaspiro [5.5]undec-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 92, the title compound was obtained using 1-methyl-1H-pyrazol-4-amine as a starting material. MS m/z [LC-MS]: 647.42 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.40(s,1H),7.81(s,0.5H),7.80(s,0.5H),7.15(s,1H),6.90-6.98(m,3H) ,6.56-6.64(m,1H),4.42-4.58(brs,1H),3.73-3.85(m,5H),3.57-3.72(m,2.5H),3.41-3.55(m,2H),3.24-3.29 (m,0.5H),2.70-2.88(m,6H),2.26-2.39(m,1H),1.86-2.02(m,1H),1.50-1.77(m,8H),1.42-1.48(m,5H ), 1.20-1.36(m,4H), 1.01-1.18(m,8H).

Example 159: (S)-N-Ethyl-5-fluoro-N-isopropyl-2-((4-(3-((9-(pyrimidin-2-ylamino)-3-azaspiro [5.5] Undecane -3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 148, the title compound was obtained using Intermediate 97 as a starting material. MS m/z [LC-MS]: 631.39 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ＝8.46-8.48(m, 1H), 8.26(d, J＝4.8Hz, 2H), 7.91(s, 1H), 6.89-7.07(m, 2H), 6.69 -6.72(m,0.5H),6.48-6.53(m,1.5H),5.18-5.32(brs,1H),4.14-4.18(m,0.5H),3.74-3.91(m,2H),3.28-3.68 (m, 3.5H), 2.74-3.27(m, 3H), 1.87-2.40(m, 8H), 1.09-1.68(m, 21H).

Example 160: 2-((4-(7-((1-((4-acryloylaminophenyl)sulfonyl)piperidin-4-yl)methyl)-2,7-diazaspiro [ 3.5] Nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: 2-((4-(7-((1-((4-aminophenyl)sulfonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane Alk-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method in Step 1 in Example 83, the title compound was obtained using Intermediate 94 and 4-aminobenzenesulfonyl chloride as starting materials. MS m/z [LC-MS]: 694.36 [M+1].

Step 2: 2-((4-(7-((1-((4-acryloylaminophenyl)sulfonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5 ]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, 2-((4-(7-((1-((4-aminophenyl)sulfonyl)piperidin-4-yl)methyl)-2,7- Diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide was used as starting material to obtain the target compound. MS m/z [LC-MS]: 748.37 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ＝8.37(s, 1H), 7.92-8.21(brs, 1H), 7.79-7.81(m, 3H), 7.67(d, J＝8.0Hz, 2H), 6.94 -7.01(m,2H),6.70-6.76(m,1H),6.46(d,J=16.8Hz,1H),6.22-6.33(m,1H),5.78(d,J=10.4Hz,1H), 3.68-4.05(m,8H),3.45-3.52(m,2H),2.25-2.84(m,6H),1.57-1.72(m,3H),1.52(d,J＝6.4Hz,4H),1.46( d, J = 6.8Hz, 3H), 1.17-1.38 (m, 5H), 1.12 (d, J = 6.4Hz, 3H), 1.09 (d, J = 6.4Hz, 3H).

Example 161: 2-((4-(7-((1-((3-acryloylaminoazetidin-1-yl)sulfonyl)piperidin-4-yl)methyl)-2 , 7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: (1-((4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7 _- di Azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)azetidin-3-yl)carbamate tert-butyl

Referring to the method in step 1 in Example 83, the title compound was obtained using intermediates 94 and 98 as starting materials. MS m/z [LC-MS]: 773.42 [M+1].

Step 2: 2-((4-(7-((1-((3-aminoazetidin-1-yl)sulfonyl)piperidin-4-yl)methyl)-2,7-bis Azaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, (1-((4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine-4- Base)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)azetidin-3-yl)carbamate tert-butyl ester is Starting materials yielded the target compound. MS m/z [LC-MS]: 673.37 [M+1].

Step 3: 2-((4-(7-((1-((3-acryloylaminoazetidin-1-yl)sulfonyl)piperidin-4-yl)methyl)-2,7 -Diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, use 2-((4-(7-((1-((3-aminoazetidin-1-yl)sulfonyl)piperidin-4-yl)methyl Base)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride is Starting materials yielded the target compound. MS m/z [LC-MS]: 727.38 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.35(s,1H),7.75(s,1H),6.95-7.00(m,2H),6.74-6.78(m,1H),6.30(d,J= 16.8Hz, 1H), 6.00-6.11(m, 2H), 5.70(d, J=10.8Hz, 1H), 4.74-4.83(m, 1H), 4.08(t, J=8.0Hz, 2H), 3.84- 4.00(m,4H),3.76-3.80(m,3H),3.68-3.73(m,2H),3.43-3.52(m,1H),2.68-2.74(m,2H),2.18-2.38(m,4H ),2.08-2.14(m,2H),1.68-1.82(m,7H),1.56-1.67(m,2H),1.53(d,J＝7.2Hz,3H),1.47(d,J＝6.8Hz, 3H), 1.12 (d, J=6.4Hz, 3H), 1.08 (d, J=6.4Hz, 3H).

Example 162: (R)-2-((4-(7-((1-((3-acryloylaminopyrrolidin-1-yl)sulfonyl)piperidin-4-yl)methyl) -2 ,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: (R)-(1-((4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2 , 7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)pyrrolidin-3-yl)carbamate tert-butyl

Referring to the method of step 1 in Example 83, the title compound was obtained using intermediates 94 and 99 as starting materials. MS m/z [LC-MS]: 787.43 [M+1].

Step 2: (R)-2-((4-(7-((1-((3-aminopyrrolidin-1-yl)sulfonyl)piperidin-4-yl)methyl)-2,7- Diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, use (R)-(1-((4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy) Pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)pyrrolidin-3-yl)carbamate The target compound is obtained as a starting material. MS m/z [LC-MS]: 687.38 [M+1].

Step 3: (R)-2-((4-(7-((1-((3-acryloylaminopyrrolidin-1-yl)sulfonyl)piperidin-4-yl)methyl)-2, 7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, use (R)-2-((4-(7-((1-((3-aminopyrrolidin-1-yl)sulfonyl)piperidin-4-yl) Methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride The target compound is obtained as a starting material. MS m/z [LC-MS]: 741.39 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.35(s,1H),7.75(s,1H),6.95-7.00(m,2H),6.74-6.77(m,1H),6.27(d,J= 16.8Hz, 1H), 6.03-6.12(m, 2H), 5.65(d, J＝10.4Hz, 1H), 4.53-4.61(m, 1H), 3.84-4.02(m, 4H), 3.67-3.80(m ,3H),3.40-3.51(m,3H),3.27-3.33(m,2H),2.72-2.80(m,2H),2.08-2.36(m,7H),1.93-2.03(m,1H),1.68 -1.83(m,7H),1.52(d,J=6.8Hz,3H),1.47(d,J=6.8Hz,3H),1.14-1.28(m,2H),1.12(d,J=6.4Hz, 3H), 1.08 (d, J=6.8Hz, 3H).

Example 163: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-((5-(trifluoromethyl)pyrimidin-2-yl) Amino)-3- azaspiro[5.5]undec-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 92, the title compound was obtained using 5-(trifluoromethyl)pyrimidin-2-amine as a starting material. MS m/z [LC-MS]: 713.39 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.40-8.50(m,3H),7.79-7.90(m,1H),6.87-7.02(m,2H),6.44-6.70(m,1H),5.31- 5.42(m,1H),3.59-3.93(m,3.5H),3.06-3.56(m,3.5H),2.70-3.00(m,2H),2.22-2.50(m,3H),1.81-2.08(m ,4H), 1.24-1.72(m,18H), 1.11-1.22(m,6H).

Example 164: (S)-2-((4-(3-((9-((4,6-dimethylpyrimidin-2-yl)amino)-3-azaspiro[5.5]undecane -3-yl) methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method in Example 92, the target compound was obtained using 4,6-dimethylpyrimidin-2-amine as a starting material. MS m/z [LC-MS]: 673.44 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.42(s,0.5H),8.40(s,0.5H),7.82(s,1H),6.90-6.99(m,2H),6.65-6.68(m, 0.5H),6.50-6.56(m,0.5H),6.26(s,1H),4.92-4.99(m,1H),3.40-4.06(m,6.5H),3.11-3.20(m,0.5H), 2.37-2.90(m,7H),2.08-2.32(m,8H),1.82-1.93(m,2H),1.56-1.79(m,5H),1.50-1.53(m,3H),1.45(d,J =6.8Hz, 3H), 1.25-1.38(m, 5H), 1.11-1.18(m, 6H).

Example 165: (S)-2-((4-(3-((9-((6-chloropyridazin-3-yl)amino)-3-azaspiro[5.5]undecane-3- Base)methyl) pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method in Example 92, the title compound was obtained using 6-chloropyridazin-3-amine as a starting material. MS m/z [LC-MS]: 679.37 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ):δ=8.41(s,0.5H),8.40(s,0.5H),7.81(s,1H),7.13(d,J=9.6Hz,1H),6.91-6.99 (m,2H),6.65-6.68(m,0.5H),6.54-6.63(m,1.5H),4.69(d,J＝7.2Hz,1H),3.59-3.92(m,4H),3.34-3.54 (m,2.5H),3.16-3.28(m,0.5H),2.24-2.49(m,6H),1.84-2.10(m,5H),1.58-1.72(m,5H),1.53(d,J= 6.8Hz, 3H), 1.47(d, J=6.8Hz, 3H), 1.26-1.43(m, 5H), 1.11-1.18(m, 6H).

Example 166: (R)-2-((5-(7-((1-((3-acryloylaminopiperidin-1-yl)sulfonyl)piperidin-4-yl)methyl)-2 ,7 -diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: (R)-(1-((4-((2-(6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)-1,2,4-tri oxazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)piperidin-3-yl)carbamate tert-butyl

Referring to the method in Step 1 in Example 83, the title compound was obtained using Intermediates 101 and 96 as starting materials. MS m/z [LC-MS]: 802.45 [M+1].

Step 2: (R)-2-((5-(7-((1-((3-aminopiperidin-1-yl)sulfonyl)piperidin-4-yl)methyl)-2,7- Diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, use (R)-(1-((4-((2-(6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy) -1,2,4-Triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)piperidine-3 -yl) tert-butyl carbamate as raw material to obtain the target compound. MS m/z [LC-MS]: 702.39 [M+1].

Step 3: (R)-2-((5-(7-((1-((3-acryloylaminopiperidin-1-yl)sulfonyl)piperidin-4-yl)methyl)-2, 7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, use (R)-2-((5-(7-((1-((3-aminopiperidin-1-yl)sulfonyl)piperidin-4-yl) Methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diiso Propylbenzamide hydrochloride was used as starting material to obtain the target compound. MS m/z [LC-MS]: 756.40 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.50(s, 1H), 7.22-7.28(m, 1H), 7.10-7.16(m, 1H), 6.94-6.96(m, 1H), 6.26(d, J＝16.8Hz, 1H), 6.11(dd, J＝16.8Hz, 10.4Hz, 1H), 6.01-6.07(m, 1H), 5.65(d, J＝10.4Hz, 1H), 4.62-4.71(m, 1H),4.31-4.41(m,1H),4.05-4.14(m,1H),3.92-4.04(m,2H),3.66-3.82(m,4H),3.52-3.62(m,2H),3.27- 3.44(m,3H),3.08-3.19(m,1H),2.71-2.89(m,7H),1.96-2.16(m,5H),1.60-1.82(m,4H),1.48(d,J＝6.0 Hz, 3H), 1.18-1.35 (m, 6H), 1.09 (d, J=6.0Hz, 3H), 0.70 (d, J=6.0Hz, 3H).

Example 167: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-((5-methylpyrimidin-2-yl)amino)-3 -Azaspiro[5.5 ] undec-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 92, the title compound was obtained using 5-methylpyrimidin-2-amine as a starting material. MS m/z [LC-MS]: 659.42 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.41(s,0.5H),8.40(s,0.5H),8.08(s,2H),7.81(s,1H),6.90-6.97(m,2H) ,6.65-6.68(m,0.5H),6.57-6.61(m,0.5H),4.88(d,J＝8.0Hz,1H),3.60-3.96(m,4.5H),3.34-3.52(m,2H ),3.17-3.25(m,0.5H),2.22-2.62(m,7H),1.97-2.14(m,4H),1.82-1.91(m,2H),1.55-1.71(m,5H),1.53( d, J = 7.2Hz, 3H), 1.46 (d, J = 6.8Hz, 3H), 1.22-1.41 (m, 6H), 1.12-1.17 (m, 6H).

Example 168: (S)-2-((4-(3-((9-((5-chloropyridin-2-yl)amino)-3-azaspiro[5.5]undecane-3-yl )methyl) pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method in Example 92, the title compound was obtained using 5-chloropyridin-2-amine as a starting material. MS m/z [LC-MS]: 678.37 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.41(s, 1H), 7.98(d, J=2.4Hz, 1H), 7.82(s, 1H), 7.32(dd, J=9.2Hz, 2.8Hz, 1H),6.91-6.99(m,2H),6.65-6.69(m,0.5H),6.53-6.62(m,0.5H),6.28(d,J＝9.2Hz,1H),4.43(d,J＝ 6.4Hz, 1H), 3.59-3.99(m, 3.5H), 3.35-3.56(m, 3H), 3.13-3.26(m, 0.5H), 2.21-2.54(m, 6.5H), 1.96-2.13(m ,1.5H),1.80-1.92(m,2H),1.55-1.74(m,5H),1.53(d,J＝7.2Hz,3H),1.46(d,J＝6.8Hz,3H),1.20-1.35 (m,6H),1.12-1.18(m,6H).

Example 169: (R)-2-((4-(7-((1-((4-acryloyl-1,4-diazepan-1-yl)sulfonyl)pyrrolidine-3 -yl )methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: (R)-4-((3-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2, tert-Butyl 7-diazaspiro[3.5]nonan-7-yl)methyl)pyrrolidin-1-yl)sulfonyl)-1,4-diazepane-1-carboxylate

Referring to the method in step 1 in Example 83, the title compound was obtained using intermediates 102 and 74 as starting materials. MS m/z [LC-MS]: 787.43 [M+1].

Step 2: (R)-2-((4-(7-((1-((1,4-diazepan-1-yl)sulfonyl)pyrrolidin-3-yl)methyl) -2,7-Diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, use (R)-4-((3-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine -4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)pyrrolidin-1-yl)sulfonyl)-1,4-diazepane-1 - tert-butyl formate is the starting material to obtain the target compound. MS m/z [LC-MS]: 687.38 [M+1].

Step 3: (R)-2-((4-(7-((1-((4-acryloyl-1,4-diazepan-1-yl)sulfonyl)pyrrolidine-3- Base)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, (R)-2-((4-(7-((1-((1,4-diazepan-1-yl)sulfonyl)pyrrolidine -3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzene Formamide hydrochloride was used as starting material to obtain the target compound. MS m/z [LC-MS]: 741.39 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.39(s,1H),7.81(s,1H),6.95-7.01(m,2H),6.70-6.76(m,1H),6.49-6.60(m, 1H),6.30-6.39(m,1H),5.69-5.74(m,1H),3.88-4.10(m,4H),3.62-3.82(m,5H),3.32-3.54(m,7H),3.20- 3.26(m,1H),2.99-3.11(m,1H),2.35-2.95(m,6H),2.09-2.27(m,2H),1.58-2.06(m,7H),1.52(d,J＝6.8 Hz, 3H), 1.46 (d, J = 7.2Hz, 3H), 1.13 (d, J = 6.4Hz, 3H), 1.09 (d, J = 6.4Hz, 3H).

Example 170: (S)-2-((4-(7-((1-((4-acryloyl-1,4-diazepan-1-yl)sulfonyl)pyrrolidine-3 -yl )methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: (S)-4-((3-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2, tert-Butyl 7-diazaspiro[3.5]nonan-7-yl)methyl)pyrrolidin-1-yl)sulfonyl)-1,4-diazepane-1-carboxylate

Referring to the method in Step 1 in Example 83, the title compound was obtained using Intermediates 103 and 74 as starting materials. MS m/z [LC-MS]: 787.43 [M+1].

Step 2: (S)-2-((4-(7-((1-((1,4-diazepan-1-yl)sulfonyl)pyrrolidin-3-yl)methyl) -2,7-Diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, use (S)-4-((3-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine -4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)pyrrolidin-1-yl)sulfonyl)-1,4-diazepane-1 - tert-butyl formate is the starting material to obtain the target compound. MS m/z [LC-MS]: 687.38 [M+1].

Step 3: (S)-2-((4-(7-((1-((4-acryloyl-1,4-diazepan-1-yl)sulfonyl)pyrrolidine-3- Base)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, use (S)-2-((4-(7-((1-((1,4-diazepan-1-yl)sulfonyl)pyrrolidine -3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzene Formamide hydrochloride was used as starting material to obtain the target compound. MS m/z [LC-MS]: 741.39 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.46(s,1H),7.84(s,1H),6.95-7.04(m,2H),6.71-6.81(m,1H),6.50-6.61(m, 1H),6.29-6.38(m,1H),5.69-5.74(m,1H),4.15-428(m,1H),3.90-4.04(m,3H),3.36-3.80(m,12H),3.21- 3.28(m,1H),2.96-3.18(m,2H),2.52-2.95(m,5H),2.24-2.34(m,1H),1.58-2.06(m,8H),1.52(d,J＝6.8 Hz, 3H), 1.46 (d, J = 7.2Hz, 3H), 1.13 (d, J = 6.4Hz, 3H), 1.09 (d, J = 6.4Hz, 3H).

Example 171: (S)-2-((4-(3-((7-((4-acryloylaminopiperidin-1-yl)sulfonyl)-2,7-diazaspiro[3.5] Nonan -2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: (S)-(1-((2-((1-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine -3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)piperidin-4-yl)carbamate tert-butyl

Referring to the method of step 1 in Example 83, the title compound was obtained by using intermediates 70 and 95 as starting materials. MS m/z [LC-MS]: 787.43 [M+1].

Step 2: (S)-2-((4-(3-((7-((4-aminopiperidin-1-yl)sulfonyl)-2,7-diazaspiro[3.5]nonane- 2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, use (S)-(1-((2-((1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy) Pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)piperidin-4-yl)carbamate tert-butyl The target compound is obtained as a starting material. MS m/z [LC-MS]: 687.38 [M+1].

Step 3: (S)-2-((4-(3-((7-((4-acryloylaminopiperidin-1-yl)sulfonyl)-2,7-diazaspiro[3.5]nonyl Alk-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, use (S)-2-((4-(3-((7-((4-aminopiperidin-1-yl)sulfonyl)-2,7-diazepine Heterospiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride The target compound is obtained as a starting material. MS m/z [LC-MS]: 741.39 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.40(s,0.5H),8.39(s,0.5H),7.80(s,1H),6.91-6.97(m,2H),6.64-6.68(m, 0.5H),6.58-6.61(m,0.5H),6.28(dd,J＝16.8Hz,1.6Hz,1H),6.05(dd,J＝16.8Hz,10.4Hz,1H),5.65(dd,J＝ 10.8Hz, 1.2Hz, 1H), 5.48(d, J=7.6Hz, 1H), 3.94-4.03(m, 1H), 3.76-3.89(m, 2H), 3.62-3.73(m, 3H), 3.32- 3.53(m,2H),3.11-3.21(m,5H),2.87-3.02(m,6H),2.36-2.50(m,2H),2.08-2.22(m,1H),1.94-2.05(m,3H ), 1.54-1.81 (m, 7H), 1.53 (d, J=6.8Hz, 3H), 1.47 (d, J=7.2Hz, 3H), 1.12-1.16 (m, 6H).

Example 172: 2-((4-((S)-3-((7-(((R)-3-acryloylaminopiperidin-1-yl)sulfonyl)-2,7-diazepine Spiro[3.5 ] nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: ((R)-1-((2-(((S)-1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine-4- Base) pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)piperidin-3-yl)tert-butyl carbamate

Referring to the method in step 1 in Example 83, the title compound was obtained using intermediates 70 and 96 as starting materials. MS m/z [LC-MS]: 787.43 [M+1].

Step 2: 2-((4-((S)-3-((7-(((R)-3-aminopiperidin-1-yl)sulfonyl)-2,7-diazaspiro[3.5 ]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, use ((R)-1-((2-(((S)-1-(5-(2-(diisopropylcarbamoyl)-4-fluoro Phenoxy)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)piperidin-3-yl)amino The target compound was obtained from tert-butyl formate. MS m/z [LC-MS]: 687.38 [M+1].

Step 3: 2-((4-((S)-3-((7-(((R)-3-acryloylaminopiperidin-1-yl)sulfonyl)-2,7-diazaspiro [3.5] Nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, with 2-((4-((S)-3-((7-(((R)-3-aminopiperidin-1-yl)sulfonyl))-2, 7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzyl Amide hydrochloride as starting material to obtain the target compound. MS m/z [LC-MS]: 741.39 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ):δ=8.40(s,0.5H),8.39(s,0.5H),7.80(s,1H),6.90-6.98(m,2H),6.64-6.68(m, 0.5H),6.58-6.61(m,0.5H),6.26(d,J＝17.2Hz,1H),6.05-6.11(m,2H),5.64(d,J＝10.0Hz,1H),4.08-4.17 (m,1H),3.75-3.90(m,2H),3.57-3.74(m,1.5H),3.32-3.54(m,3H),2.88-3.30(m,11.5H),2.36-2.53(m, 2H),2.08-2.23(m,1H),1.92-2.06(m,1.5H),1.67-1.84(m,6.5H), 1.54-1.65(m,2H),1.53(d,J＝6.8Hz, 3H), 1.46 (d, J=7.2Hz, 3H), 1.12-1.16 (m, 6H).

Example 173: 5-fluoro-2-((4-(7-((1-((4-(2-fluoroacryloyl)-1,4-diazepan-1-yl)sulfonyl )piperidin -4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzyl Amide

Step 3: 5-fluoro-2-((4-(7-((1-((4-(2-fluoroacryloyl)-1,4-diazepan-1-yl)sulfonyl) Piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, use 2-((4-(7-((1-((1,4-diazepan-1-yl)sulfonyl)piperidin-4-yl )methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride Salt as starting material to obtain the target compound. MS m/z [LC-MS]: 773.40 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.35(s,1H),7.75(s,1H),6.95-7.00(m,2H),6.74-6.77(m,1H),5.31(d,J= 47.6Hz, 1H), 5.11(d, J=16.8Hz, 1H), 3.82-4.04(m, 3.5H), 3.62-3.81(m, 4.5H), 3.55-3.61(m, 2H), 3.36-3.51 (m,5H),2.68-2.74(m,2H),2.18-2.40(m,3.5H),2.10-2.12(m,2H),1.94-2.04(m,2.5H),1.70-1.82(m, 6H), 1.56-1.68(m, 1H), 1.53(d, J＝7.2Hz, 3H), 1.47(d, J＝6.4Hz, 3H), 1.11-1.22(m, 6H), 1.08(d, J = 6.4Hz, 3H).

Example 174: 2-((5-(7-((1-((4-acryloyl-1,4-diazepan-1-yl)sulfonyl)piperidin-4-yl)methyl Base)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropyl phenylbenzamide

Step 1: 4-((4-((2-(6-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl )-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester

Referring to the method in Step 1 in Example 83, the title compound was obtained using Intermediates 101 and 74 as starting materials. MS m/z [LC-MS]: 802.45 [M+1].

Step 2: 2-((5-(7-((1-((1,4-diazepan-1-yl)sulfonyl)piperidin-4-yl)methyl)-2,7 -Diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride Salt

Referring to the method of step 2 in Example 83, use 4-((4-((2-(6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)-1,2, 4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)-1,4-diazacyclo The target compound was obtained from tert-butyl heptane-1-carboxylate. MS m/z [LC-MS]: 702.39 [M+1].

Step 3: 2-((5-(7-((1-((4-acryloyl-1,4-diazepan-1-yl)sulfonyl)piperidin-4-yl)methyl )-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropyl benzamide

Referring to the method of step 3 in Example 83, use 2-((5-(7-((1-((1,4-diazepan-1-yl)sulfonyl)piperidin-4-yl )methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-two Cumyl benzamide hydrochloride was used as starting material to obtain the target compound. MS m/z [LC-MS]: 756.40 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ＝8.46(s, 1H), 7.23-7.26(m, 1H), 7.07-7.12(m, 1H), 6.94(dd, J＝8.0Hz, 3.2Hz, 1H ),6.49-6.59(m,1H),6.35-6.40(m,1H),5.69-5.74(m,1H),4.44-4.58(m,1H),4.25-4.34(m,1H),3.83-3.97 (m,2H),3.64-3.81(m,6H),3.54-3.62(m,2H),3.32-3.44(m,5.5H),2.69-2.75(m,2.5H),2.08-2.64(m, 6H), 1.56-2.04(m, 9H), 1.49(d, J=7.2Hz, 3H), 1.36(d, J=6.8Hz, 3H), 1.07(d, J=6.4Hz, 3H), 0.70( d, J=6.0Hz, 3H).

Example 175: 2-((5-(7-((1-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptan-2-yl) Sulfonyl) piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)- 5-fluoro-N,N- diisopropylbenzamide

Step 1: (1S,4S)-5-((4-((2-(6-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)-1,2,4- Triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)-2,5-diazabicyclo[2.2 .1] tert-butyl heptane-2-carboxylate

Referring to the method in step 1 in Example 83, the target compound was obtained using intermediate 101 as a starting material. MS m/z [LC-MS]: 800.43 [M+1].

Step 2: 2-((5-(7-((1-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)sulfonyl)piperidine- 4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N, N-Diisopropylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, use (1S,4S)-5-((4-((2-(6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy )-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)-2, The target compound was obtained from tert-butyl 5-diazabicyclo[2.2.1]heptane-2-carboxylate. MS m/z [LC-MS]: 700.38 [M+1].

Step 3: 2-((5-(7-((1-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)sulfo Acyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5 -Fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, use 2-((5-(7-((1-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2- Base)sulfonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy )-5-fluoro-N,N-diisopropylbenzamide hydrochloride as raw material to obtain the target compound. MS m/z [LC-MS]: 754.39 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.47(s, 1H), 7.23-7.26(m, 1H), 7.07-7.14(m, 1H), 6.95(dd, J=7.6Hz, 3.2Hz, 1H ),6.24-6.43(m,2H),5.71-5.74(m,1H),4.98(s,0.7H),4.26-4.62(m,3.3H),3.83-4.00(m,2H),3.64-3.80 (m,5H),3.46-3.53(m,1.7H),3.30-3.42(m,3H),3.21-3.24(m,0.3H),2.64-2.90(m,4H),1.62-2.50(m, 13H), 1.49(d, J=6.8Hz, 3H), 1.35(d, J=6.0Hz, 3H), 1.07(d, J=6.8Hz, 3H), 0.70(d, J=6.0Hz, 3H) .

Example 176: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-(pyridin-2-ylamino)-3-azaspiro[5.5 ]undecyl -3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 92, the title compound was obtained using 2-aminopyridine as a starting material. MS m/z [LC-MS]: 644.41 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.41(s,0.5H),8.40(s,0.5H),8.04(dd,J=4.8Hz,1.2Hz,1H),7.81(s,1H), 7.35-7.40(m,1H),6.91-6.98(m,2H),6.65-6.68(m,0.5H),6.59-6.62(m,0.5H),6.51(dd,J＝7.2Hz,5.2Hz, 1H), 6.32(d, J=8.4Hz, 1H), 4.44(d, J=7.2Hz, 1H), 3.62-3.92(m, 4H), 3.45-3.56(m, 2H), 3.35-3.44(m ,0.5H),3.21-3.26(m,0.5H),2.24-2.49(m,7H),1.96-2.10(m,1.5H),1.76-1.94(m,3.5H),1.58-1.72(m, 4H), 1.53 (d, J = 6.8Hz, 3H), 1.47 (d, J = 6.4Hz, 3H), 1.19-1.44 (m, 5H), 1.12-1.17 (m, 6H).

Example 177: (S)-5-fluoro-2-((4-(3-((9-((2-fluorophenyl)amino)-3-azaspiro[5.5]undecane-3- Base)methyl) pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide

Referring to the method in Example 92, the title compound was obtained using 2-fluoroaniline as a starting material. MS m/z [LC-MS]: 661.40 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.41(s,0.5H),8.40(s,0.5H),7.81(s,1H),6.91-6.97(m,4H),6.65-6.69(m, 1.5H),6.54-6.62(m,1.5H),3.62-3.96(m,4.5H),3.35-3.52(m,2H),3.18-3.28(m,1.5H),2.20-2.53(m,7H ),1.96-2.10(m,1H),1.84-1.93(m,2H),1.58-1.73(m,5H),1.53(d,J＝6.8Hz,3H),1.47(d,J＝6.4Hz, 3H), 1.19-1.44(m,6H), 1.12-1.16(m,6H).

Example 178: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-((5-methylisoxazol-3-yl)amino) -3-Azaspiro [5.5]undecyl-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 92, using 5-methylisoxazol-3-amine as starting material, the title compound was obtained. MS m/z [LC-MS]: 648.40 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.37(s,0.5H),8.36(s,0.5H),7.77(s,1H),6.87-6.98(m,2H),6.62-6.66(m, 0.5H),6.57-6.60(m,0.5H),5.41(s,1H),3.58-3.88(m,4.5H),3.17-3.50(m,3.5H),2.18-2.42(m,10H), 1.94-2.06(m,1H),1.80-1.90(m,2H),1.54-1.68(m,3H),1.40-1.53(m,8H),1.16-1.38(m,6H),1.09-1.14(m ,6H).

Example 179: (S)-2-((4-(3-((9-((2,6-difluorophenyl)amino)-3-azaspiro[5.5]undec-3-yl )methyl)pyrrolidin -1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method in Example 92, using 2,6-difluoroaniline as a starting material, the title compound was obtained. MS m/z [LC-MS]: 679.39 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.41(s,0.5H),8.40(s,0.5H),7.82(s,1H),6.90-6.99(m,2H),6.54-6.85(m, 4H),3.60-4.02(m,4H),3.36-3.56(m,2H),3.14-3.24(m,1.5H),2.21-2.70(m,7.5H),1.97-2.18(m,1H), 1.82-1.92(m,2H),1.56-1.76(m,5H),1.51-1.54(m,3H),1.41-1.50(m,4H),1.19-1.37(m,5H),1.12-1.18(m ,6H).

Example 180: (S)-2-((4-(3-((9-((4,6-dimethylpyrimidin-5-yl)amino)-3-azaspiro[5.5]undecane -3-yl) methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method in Example 92, using 4,6-dimethylpyrimidin-5-amine as a starting material, the title compound was obtained. MS m/z [LC-MS]: 673.44 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.56(s,1H),8.41(s,0.5H),8.40(s,0.5H),7.81(s,1H),6.91-6.99(m,2H) ,6.65-6.68(m,0.5H),6.55-6.63(m,0.5H),3.61-3.94(m,4H),3.33-3.56(m,2.5H),3.15-3.30(m,0.5H), 2.90-3.00(m,1H),2.52-2.57(m,0.5H),2.25-2.48(m,11H),1.92-2.08(m,1.5H),1.44-1.82(m,15H),1.22-1.40 (m,5H), 1.12-1.17(m,6H).

Example 181: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-((4-methylpyrimidin-5-yl)amino)-3 -Azaspiro[5.5 ] undec-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 92, using 4-methylpyrimidin-5-amine as the starting material, the title compound was obtained. MS m/z [LC-MS]: 659.42 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.46(s,1H),8.41(s,0.5H),8.40(s,0.5H),7.96(s,1H),7.81(s,1H),6.91 -6.99(m,2H),6.65-6.68(m,0.5H),6.57-6.67(m,0.5H),3.58-3.92(m,4H),3.44-3.55(m,2H),3.18-3.38( m,2H),2.28-2.46(m,7H),1.97-2.08(m,1H),1.86-1.96(m,2H),1.53-1.73(m,12H),1.47(d,J＝6.8Hz, 3H), 1.22-1.44(m, 5H), 1.11-1.18(m, 6H).

Example 182: 2-((4-(7-((1-((3-acryloylaminophenyl)sulfonyl)piperidin-4-yl)methyl)-2,7-diazaspiro [ 3.5] Nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: 2-((4-(7-((1-((3-aminophenyl)sulfonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane Alk-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method in step 1 in Example 83, using intermediate 94 and 3-aminobenzenesulfonyl chloride as starting materials, the title compound was obtained. MS m/z [LC-MS]: 694.36 [M+1].

Step 2: 2-((4-(7-((1-((3-acryloylaminophenyl)sulfonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5 ]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, 2-((4-(7-((1-((3-aminophenyl)sulfonyl)piperidin-4-yl)methyl)-2,7- Diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide as starting material to obtain the target compound. MS m/z [LC-MS]: 748.36 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=9.36(s,1H),8.36(s,1H),8.10(d,J=7.2Hz,1H),7.93(s,1H),7.78(s,1H ),7.38-7.45(m,2H),6.93-7.01(m,2H),6.71-6.74(m,1H),6.39-6.49(m,2H),5.70-5.73(m,1H),3.82-4.06 (m,4H),3.72-3.79(m,1H),3.62-3.71(m,2H),3.42-3.51(m,1H),2.42-3.14(m,6H),2.27(t,J＝11.2Hz ,2H),1.80-2.18(m,5H),1.62-1.78(m,1H),1.50(d,J＝6.8Hz,3H),1.43(d,J＝6.4Hz,3H),1.18-1.40( m, 3H), 1.11 (d, J=6.4Hz, 3H), 1.08 (d, J=6.4Hz, 3H).

Example 183: (R)-5-fluoro-2-((4-(7-((1-((3-(2-fluoroacryloylamino)piperidin-1-yl)sulfonyl)piperidine- 4- yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide

Referring to the method in Step 1 in Example 83, using Intermediate 94 and Intermediate 96 as starting materials, the title compound was obtained. MS m/z [LC-MS]: 801.45 [M+1].

Referring to the method of step 2 in Example 83, (R)-(1-((4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy) Pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)piperidin-3-yl)tert-butyl carbamate As raw materials, the target compound was obtained. MS m/z [LC-MS]: 701.40 [M+1].

Step 3: (R)-5-fluoro-2-((4-(7-((1-((3-(2-fluoroacryloylamino)piperidin-1-yl)sulfonyl)piperidine-4 -yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, (R)-2-((4-(7-((1-((3-aminopiperidin-1-yl)sulfonyl)piperidin-4-yl) Methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride As raw materials, the target compound was obtained. MS m/z [LC-MS]: 773.40 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.38(s,1H),7.79(s,1H),6.95-7.02(m,2H),6.74-6.77(m,1H),6.62-6.65(m, 1H), 5.65(dd, J＝47.6Hz, 3.6Hz, 1H), 5.12(dd, J＝15.2Hz, 3.6Hz, 1H), 3.96-4.12(m, 3H), 3.89-3.92(m, 2H) ,3.74-3.81(m,1H),3.63-3.72(m,2H),3.46-3.53(m,1H),3.38(dd,J=12.0Hz,3.2Hz,1H),3.15-3.29(m,2H ),3.09(dd,J＝12.0Hz,6.4Hz,1H),2.79-2.85(m,2H),2.54-2.72(m,3H),1.95-2.13(m,4H),1.58-1.92(m, 8H), 1.52(d, J=7.2Hz, 3H), 1.45(d, J=6.8Hz, 3H), 1.21-1.42(m, 4H), 1.13(d, J=6.8Hz, 3H), 1.10( d, J=6.8Hz, 3H).

Example 184: 2-((5-(7-((1-((4-acryloylpiperazin-1-yl)sulfonyl)piperidin-4-yl)methyl)-2,7-diazepine Heterospiro [3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: 4-((4-((2-(6-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl )-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)piperazine-1-carboxylic acid tert-butyl ester

Referring to the method in step 1 in Example 83, the title compound was obtained from intermediate 101 and tert-butyl 4-(chlorosulfonyl)piperazine-1-carboxylate as starting materials. MS m/z [LC-MS]: 788.43 [M+1].

Step 2: 5-fluoro-N,N-diisopropyl-2-((5-(7-((1-(piperazin-1-ylsulfonyl)piperidin-4-yl)methyl)- 2,7-Diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide hydrochloride

Referring to the method of step 2 in Example 83, with 4-((4-((2-(6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)-1,2, 4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)piperazine-1-carboxylic acid tert-butyl Esters are used as starting materials to obtain the target compounds. MS m/z [LC-MS]: 688.38 [M+1].

Step 3: 2-((5-(7-((1-((4-acryloylpiperazin-1-yl)sulfonyl)piperidin-4-yl)methyl)-2,7-diazepine Spiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, with 5-fluoro-N,N-diisopropyl-2-((5-(7-((1-(piperazin-1-ylsulfonyl)piperidine- 4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)benzamide hydrochloride is raw materials to obtain the target compound. MS m/z [LC-MS]: 742.39 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.47(s, 1H), 7.23-7.27(m, 1H), 7.07-7.14(m, 1H), 6.95(dd, J=7.6Hz, 3.2Hz, 1H ), 6.53(dd, J=16.8Hz, 10.8Hz, 1H), 6.31(dd, J=16.8Hz, 1.6Hz, 1H), 5.74(dd, J=10.8Hz, 1.6Hz, 1H), 4.23-4.39 (m,1H),3.49-4.06(m,11H),3.34-3.44(m,2H),3.18-3.26(m,4H),2.72-2.88(m,2H),1.56-1.90(m,13H) , 1.49 (d, J=6.8Hz, 3H), 1.21-1.34 (m, 6H), 1.08 (d, J=6.8Hz, 3H).

Example 185: 2-((4-(7-(4-((4-acryloyl-1,4-diazepan-1-yl)sulfonyl)benzyl)-2,7-di Azaspiro [3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: 4-((4-((2-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diaze Heterospiro[3.5]nonan-7-yl)methyl)phenyl)sulfonyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester

Referring to the method of step 2 in intermediate 108, with 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro- Starting from N,N-diisopropylbenzamide and intermediate 104, the target compound was obtained. MS m/z [LC-MS]: 794.41 [M+1].

Step 2: 2-((4-(7-(4-((1,4-diazepan-1-yl)sulfonyl)benzyl)-2,7-diazaspiro[3.5] Nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, 4-((4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl )-2,7-diazaspiro[3.5]nonan-7-yl)methyl)phenyl)sulfonyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester as raw material , to obtain the target compound. MS m/z [LC-MS]: 694.36 [M+1].

Step 3: 2-((4-(7-(4-((4-acryloyl-1,4-diazepan-1-yl)sulfonyl)benzyl)-2,7-diazepine Heterospiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, 2-((4-(7-(4-((1,4-diazepan-1-yl)sulfonyl)benzyl)-2,7 -Diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride as starting material to obtain the target compound. MS m/z [LC-MS]: 748.37 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.37(s, 1H), 7.72-7.78(m, 3H), 7.34-7.64(m, 2H), 6.97-7.01(m, 2H), 6.73-6.78( m,1H),6.44-6.54(m,1H),6.27-6.36(m,1H),5.67-5.71(m,1H),3.88-4.10(m,4H),3.73-3.80(m,3H), 3.66-3.70(m,3H),3.45-3.62(m,2H),3.33-3.38(m,2H),3.24-3.27(m,2H),2.24-2.62(m,4H),1.68-2.02(m ,6H),1.54(d,J=7.2Hz,3H),1.46(d,J=6.8Hz,3H),1.13(d,J=6.4Hz,3H),1.08(d,J=6.8Hz,3H ).

Example 186: (R)-2-((4-(7-(4-((3-acryloylaminopiperidin-1-yl)sulfonyl)benzyl)-2,7-diazaspiro [ 3.5] Nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzoyl

Step 1: (R)-(1-((4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2 ,7-diazaspiro[3.5]nonan-7-yl)methyl)phenyl)sulfonyl)piperidin-3-yl)carbamate tert-butyl

Referring to the method of step 2 in intermediate 108, with 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro- Starting from N,N-diisopropylbenzamide and intermediate 105, the target compound was obtained. MS m/z [LC-MS]: 794.41 [M+1].

Step 2: (R)-2-((4-(7-(4-((3-aminopiperidin-1-yl)sulfonyl)benzyl)-2,7-diazaspiro[3.5]nonane Alk-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, (R)-(1-((4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy) Starting from pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)phenyl)sulfonyl)piperidin-3-yl)carbamate, tert-butyl ester gives target compound. MS m/z [LC-MS]: 694.36 [M+1].

Step 3: (R)-2-((4-(7-(4-((3-acryloylaminopiperidin-1-yl)sulfonyl)benzyl)-2,7-diazaspiro[3.5 ]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzoyl

Referring to the method of step 3 in Example 83, (R)-2-((4-(7-(4-((3-aminopiperidin-1-yl)sulfonyl)benzyl)-2,7- Diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride was used as starting material to obtain the target compound. MS m/z [LC-MS]: 748.37 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.37(s,1H),7.78(s,1H),7.52-7.74(m,4H),6.96-7.01(m,2H),6.73-6.76(m, 1H), 6.28(dd, J=16.8Hz, 1.2Hz, 1H), 6.09-6.21(m, 2H), 5.65(dd, J=10.8Hz, 1.2Hz, 1H), 4.16-4.23(m, 1H) ,3.94-4.11(m,2H),3.88-3.90(m,2H),3.68-3.85(m,3H),3.44-3.52(m,1H),3.33-3.43(m,1H),3.18-3.28( m,1H),2.34-2.94(m,6H),1.55-2.06(m,8H),1.53(d,J=6.8Hz,3H),1.45(d,J=6.8Hz,3H),1.12(d , J=6.4Hz, 3H), 1.07(d, J=6.8Hz, 3H).

Example 187: 2-((4-(7-(4-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)sulfo Acyl) benzyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: (1S,4S)-5-((4-((2-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)- 2,7-Diazaspiro[3.5]nonan-7-yl)methyl)phenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

Referring to the method of step 2 in intermediate 108, with 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro- Starting from N,N-diisopropylbenzamide and intermediate 106, the target compound was obtained. MS m/z [LC-MS]: 792.39 [M+1].

Step 2: 2-((4-(7-(4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)sulfonyl)benzyl)- 2,7-Diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, with (1S,4S)-5-((4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy )pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)phenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane The target compound was obtained from tert-butyl alkane-2-carboxylate. MS m/z [LC-MS]: 692.34 [M+1].

Step 3: 2-((4-(7-(4-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)sulfonyl )benzyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, 2-((4-(7-(4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl )sulfonyl)benzyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzyl Amide hydrochloride as starting material to obtain the target compound. MS m/z [LC-MS]: 746.35 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.36(s, 1H), 7.74-7.82(m, 3H), 7.48-7.68(m, 2H), 6.96-7.01(m, 2H), 6.74-6.77( m,1H),6.31-6.37(m,1.3H),6.14(dd,J=16.8Hz,10.4Hz,0.7H),5.65-5.69(m,1H),4.88(s,0.7H),4.53- 4.55(m,1.3H),3.93-4.11(m,2H),3.87-3.89(m,2H),3.58-3.79(m,3H),3.44-3.55(m,3.3H),3.32-3.40(m ,1H),3.20-3.23(m,0.7H),2.24-2.74(m,4H),1.76-2.01(m,4H),1.67(d,J＝9.6Hz,1H),1.52(d,J＝ 7.2Hz, 3H), 1.45(d, J=6.8Hz, 3H), 1.35(d, J=9.6Hz, 1H), 1.12(d, J=6.4Hz, 3H), 1.07(d, J=6.8Hz ,3H).

Example 188: 2-((4-(7-((1-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptan-2-yl) Sulfonyl ) piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N- Diisopropylbenzamide _

Step 1: (1S,4S)-5-((4-((2-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2 ,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxy tert-butyl acid

Referring to the method in Step 1 in Example 83, using Intermediate 94 as a starting material, the title compound was obtained. MS m/z [LC-MS]: 799.43 [M+1].

Step 2: 2-((4-(7-((1-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)sulfonyl)piperidine- 4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzyl Amide hydrochloride

Referring to the method of step 2 in Example 83, (1S,4S)-5-((4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy) Pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)-2,5-diazabicyclo[2.2. 1] Using tert-butyl heptane-2-carboxylate as the starting material to obtain the target compound. MS m/z [LC-MS]: 699.38 [M+1].

Step 3: 2-((4-(7-((1-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)sulfo Acyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-di Cumamide

Referring to the method of step 3 in Example 83, 2-((4-(7-((1-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2- Base)sulfonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N, N-diisopropylbenzamide hydrochloride was used as starting material to obtain the target compound. MS m/z [LC-MS]: 753.39 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.33(s,1H),7.73(s,1H),6.94-6.98(m,2H),6.72-6.76(m,1H),6.37-6.42(m, 1.3H),6.22-6.29(m,0.7H),5.69-5.72(m,1H),4.96(s,0.7H),4.60(s,0.3H),4.41(s,0.7H),4.38(s ,0.3H),3.62-4.02(m,9H),3.41-3.52(m,3H),3.19-3.52(m,2H),2.64-2.72(m,2H),2.16-2.40(m,4H), 2.04-2.15(m,2H),1.86-2.02(m,2H),1.64-1.83(m,7H),1.51(d,J=6.4Hz,3H),1.45(d,J=6.8Hz,3H) , 1.10 (d, J=6.8Hz, 3H), 1.06 (d, J=7.2Hz, 3H).

Example 189: 5-fluoro-2-((4-(7-((1-(((1S,4S)-5-(2-fluoroacryloyl)-2,5-diazabicyclo[2.2. 1] Heptane -2-yl)sulfonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy) -N,N- Diisopropylbenzamide

Referring to the method of step 3 in Example 83, 2-((4-(7-((1-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2- Base)sulfonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N, N-diisopropylbenzamide hydrochloride and 2-fluoroacryloyl chloride were used as raw materials to obtain the target compound. MS m/z [LC-MS]: 771.38 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.34(s,1H),7.74(s,1H),6.95-6.99(m,2H),6.73-6.76(m,1H),5.50-5.68(m, 1H),5.12-5.18(m,1H),4.91(s,0.5H),4.82-4.86(m,0.5H),4.36-4.41(m,1H),3.81-4.04(m,4H),3.73- 3.80(m,1H),3.58-3.72(m,3H),3.43-3.54(m,2H),3.26-3.39(m,2H),2.66-2.73(m,2H),2.19-2.50(m,4H ),2.08-2.18(m,2H),1.66-1.87(m,7H),1.49-1.62(m,4H),1.46(d,J＝7.2Hz,3H),1.26-1.36(m,1H), 1.10-1.20 (m, 5H), 1.07 (d, J=6.8Hz, 3H).

Example 190: 2-((4-(7-((1-(((1R,5R)-6-acryloyl-3,6-diazabicyclo[3.2.0]heptan-3-yl) Sulfonyl )piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N -Diisopropylbenzamide _

Step 1: (1R,5R)-3-((4-((2-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2 ,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)-3,6-diazabicyclo[3.2.0]heptane-6-carboxy tert-butyl acid

Referring to the method in Step 1 in Example 83, using Intermediate 94 and Intermediate 107 as starting materials, the title compound was obtained. MS m/z [LC-MS]: 799.43 [M+1].

Step 2: 2-((4-(7-((1-(((1R,5R)-3,6-diazabicyclo[3.2.0]heptane-3-yl)sulfonyl)piperidine- 4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzyl Amide hydrochloride

Referring to the method of step 2 in Example 83, (1R,5R)-3-((4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy) Pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)-3,6-diazabicyclo[3.2. 0] tert-butyl heptane-6-carboxylate as raw material to obtain the target compound. MS m/z [LC-MS]: 699.38 [M+1].

Step 3: 2-((4-(7-((1-(((1R,5R)-6-acryloyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)sulfo Acyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-di Cumamide

Referring to the method of step 3 in Example 83, 2-((4-(7-((1-(((1R,5R)-3,6-diazabicyclo[3.2.0]heptane-3- Base)sulfonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N, N-diisopropylbenzamide hydrochloride was used as starting material to obtain the target compound. MS m/z [LC-MS]: 753.39 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.42(s, 1H), 7.84(s, 1H), 7.72(d, J=8.4Hz, 2H), 7.18(d, J=8.4Hz, 2H), 6.94-7.03(m,2H),6.70-6.78(m,1H),6.29-6.40(m,1H),6.12-6.18(m,1H),5.67-5.73(m,1H),4.86-4.92(m ,1H),4.25-4.30(m,1H),4.09-4.23(m,1.5H),3.84-4.01(m,4H),3.66-3.81(m,3.5H),3.44-3.62(m,4H) ,3.08-3.24(m,3H),2.62-3.01(m,7H),2.26-2.54(m,6H), 1.26-2.08(m,5H),1.52(d,J＝6.4Hz,3H),1.44 (d, J=6.4Hz, 3H), 1.13 (d, J=6.4Hz, 3H), 1.09 (d, J=6.4Hz, 3H).

Example 191: 2-((4-(7-((1-(((1S,4S)-5-((E)-4-(dimethylamino)but-2-enoyl)-2, 5-diazabicyclo [2.2.1]heptane-2-yl)sulfonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl) Pyrimidin-5-yl)oxy)-5- fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, 2-((4-(7-((1-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2- Base)sulfonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N, N-diisopropylbenzamide hydrochloride and (E)-4-(dimethylamino)but-2-enoyl chloride were used as raw materials to obtain the target compound. MS m/z [LC-MS]: 810.45 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.36(s,1H),7.75(s,1H),6.89-7.00(m,3H),6.74-6.77(m,1H),6.35(d,J= 15.6Hz,0.3H),6.15(d,J＝15.6Hz,0.7H),4.97(s,0.7H),4.66(s,0.3H),4.42(s,0.7H),4.39(s,0.3H ),3.84-4.02(m,4H),3.75-3.81(m,1.4H),3.62-3.70(m,2.6H),3.44-3.54(m,2.3H),3.30-3.37(m,1.4H) ,3.21-3.23(m,0.3H),3.10-3.16(m,2H),2.69(t,J＝12.0Hz,2H),2.19-2.42(m,10H),2.10-2.18(m,3H), 1.87-2.04(m,3H),1.71-1.83(m,7H),1.53(d,J=6.8Hz,3H),1.47(d,J=6.8Hz,3H),1.12(d,J=6.4Hz , 3H), 1.08 (d, J=6.4Hz, 3H).

Example 192: 2-((4-(7-((1-((4-acryloyl-1,4-diazepan-1-yl)sulfonyl)-1,2,3,6 -tetrahydropyridin -4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N- Diisopropylbenzamide

Step 1: 4-((4-((2-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diaze Heterospiro[3.5]nonan-7-yl)methyl)-3,6-dihydropyridin-1(2H)-yl)sulfonyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester

Referring to the method in Step 1 in Example 83, using Intermediate 108 and Intermediate 74 as starting materials, the title compound was obtained. MS m/z [LC-MS]: 799.43 [M+1].

Step 2: 2-((4-(7-((1-((1,4-diazepan-1-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4 -yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide Hydrochloride

Referring to the method of step 2 in Example 83, 4-((4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl )-2,7-diazaspiro[3.5]nonan-7-yl)methyl)-3,6-dihydropyridin-1(2H)-yl)sulfonyl)-1,4-diaza Starting from tert-butyl cycloheptane-1-carboxylate, the target compound was obtained. MS m/z [LC-MS]: 699.38 [M+1].

Step 3: 2-((4-(7-((1-((4-acryloyl-1,4-diazepan-1-yl)sulfonyl)-1,2,3,6- Tetrahydropyridin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diiso Propyl benzamide

Referring to the method of step 3 in Example 83, 2-((4-(7-((1-((1,4-diazepan-1-yl)sulfonyl)-1,2,3 ,6-tetrahydropyridin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N -diisopropylbenzamide hydrochloride as raw material to obtain the target compound. MS m/z [LC-MS]: 753.39 [M+1]. ¹ H NMR (400 MHz, CDCl ₃ ): δ=.

Example 193: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-((1-methylpiperidin-4-yl)amino)- 3-Azaspiro[5.5 ] undecyl-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 148, using Intermediate 76 and 1-methylpiperidin-4-one as starting materials, the title compound was obtained. MS m/z [LC-MS]: 664.47 [M+1]. ¹ H NMR (400MHz, DMSO-d ₆ ): δ=10.59-10.73 (brs, 1H), 10.31-10.49 (brs, 1H), 9.36-9.63 (brs, 2H), 8.66 (s, 1H), 8.02 ( s,1H),7.17-7.34(m,3H),2.90-3.96(m,19H),2.61-2.82(m,4H),2.08-2.28(m,4H),1.52-2.03(m,10H), 1.20-1.44 (m, 9H), 1.09 (d, J=6.8Hz, 3H), 0.96-0.99 (m, 3H).

Example 194: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-(pyridin-4-ylamino)-3-azaspiro[5.5 ]undecyl -3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 92, using 4-aminopyridine as a starting material, the title compound was obtained. MS m/z [LC-MS]: 644.41 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.43(s,0.5H),8.42(s,0.5H),8.05(d,J=6.8Hz,2H),7.83(s,1H),6.92-6.99 (m,2H),6.66-6.69(m,0.5H),6.54-6.62(m,2.5H),3.60-4.01(m,4H),3.31-3.56(m,3H),3.14-3.22(m, 1H), 2.40-2.78(m, 8H), 2.06-2.18(m, 2H), 1.38-1.92(m, 17H), 1.13-1.19(m, 6H).

Example 195: (S)-5-fluoro-2-((4-(3-((9-((3-fluorophenyl)amino)-3-azaspiro[5.5]undecane-3- Base)methyl) pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide

Referring to the method in Example 92, using 3-fluoroaniline as a starting material, the title compound was obtained. MS m/z [LC-MS]: 661.40 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.40(s,0.5H),8.39(s,0.5H),7.80(s,1H),7.01-7.07(m,1H),6.90-6.97(m, 2H),6.64-6.68(m,0.5H),6.57-6.61(m,0.5H),6.28-6.33(m,2H),6.21-6.25(m,1H),3.61-3.93(m,4H), 3.34-3.54(m,2.5H),3.13-3.25(m,1.5H),2.16-2.65(m,7H),1.96-2.10(m,1H),1.80-1.91(m,2H),1.36-1.68 (m,13H), 1.11-1.33(m,10H).

Example 196: 2-((4-(7-((1-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptan-2-yl) Sulfonyl )-4-fluoropiperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro -N,N- Diisopropylbenzamide

Step 1: (1S,4S)-5-((4-((2-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)- 2,7-diazaspiro[3.5]nonan-7-yl)methyl)-4-fluoropiperidin-1-yl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane tert-butyl alkane-2-carboxylate

Referring to the method in step 1 in Example 83, using intermediate 109 as a starting material, the title compound was obtained. MS m/z [LC-MS]: 817.42 [M+1].

Step 2: 2-((4-(7-((1-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)sulfonyl)-4- Haloperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diiso Propylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, (1S,4S)-5-((4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy )pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)-4-fluoropiperidin-1-yl)sulfonyl)-2,5-diazo The target compound was obtained from tert-butyl heterobicyclo[2.2.1]heptane-2-carboxylate. MS m/z [LC-MS]: 717.37 [M+1].

Step 3: 2-((4-(7-((1-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)sulfo Acyl)-4-fluoropiperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N ,N-Diisopropylbenzamide

Referring to the method of step 3 in Example 83, 2-((4-(7-((1-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2- Base)sulfonyl)-4-fluoropiperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5- Fluoro-N,N-diisopropylbenzamide hydrochloride was used as starting material to obtain the target compound. MS m/z [LC-MS]: 771.38 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.35(s,1H),7.74(s,1H),6.95-7.00(m,2H),6.73-6.77(m,1H),6.36-6.47(m, 1.3H), 6.27(dd, J＝16.8Hz, 10.0Hz, 0.7H), 5.71-5.74(m, 1H), 4.98(s, 0.7H), 4.62(s, 0.3H), 4.43(s, 0.7 H),4.40(s,0.3H),3.74-4.04(m,5.5H),3.64-3.67(m,0.3H),3.44-3.61(m,4.5H),3.38(d,J＝9.2Hz, 0.7H), 3.33(dd, J=9.2Hz, 2.0Hz, 0.7H), 3.24(d, J=9.2Hz, 0.3H), 2.98-3.09(m, 2H), 2.30-2.54(m, 5H) ,1.55-2.03(m,11H),1.52(d,J=6.4Hz,3H),1.46(d,J=6.8Hz,3H),1.12(d,J=6.8Hz,3H),1.08(d, J=6.8Hz, 3H).

Example 197: 2-((4-(7-(((S)-1-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptane- 2-yl)sulfonyl )pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro- N,N-Diisopropyl benzamide

Step 1: (1S,4S)-5-(((S)-3-((2-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine-4 -yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)pyrrolidin-1-yl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane tert-butyl alkane-2-carboxylate

Referring to the method in Step 1 in Example 83, the title compound was obtained using Intermediate 103 as a starting material. MS m/z [LC-MS]: 785.42 [M+1].

Step 2: 2-((4-(7-(((S)-1-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)sulfonyl )pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diiso Propylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, with (1S,4S)-5-(((S)-3-((2-(5-(2-(diisopropylcarbamoyl)-4- Fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)pyrrolidin-1-yl)sulfonyl)-2,5-diazo The target compound was obtained from tert-butyl heterobicyclo[2.2.1]heptane-2-carboxylate. MS m/z [LC-MS]: 685.37 [M+1].

Step 3: 2-((4-(7-(((S)-1-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptane-2 -yl)sulfonyl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N ,N-Diisopropylbenzamide

Referring to the method of step 3 in Example 83, 2-((4-(7-(((S)-1-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane Alkyl-2-yl)sulfonyl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5- Fluoro-N,N-diisopropylbenzamide hydrochloride was used as starting material to obtain the target compound. MS m/z [LC-MS]: 739.37 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.35(s,1H),7.74(s,1H),6.95-6.99(m,2H),6.73-6.77(m,1H),6.35-6.47(m, 1.3H), 6.27(dd, J=16.8Hz, 10.0Hz, 0.7H), 5.70-5.73(m, 1H), 4.97(s, 0.7H), 4.61(s, 0.3H), 4.44(s, 0.7 H),4.41(s,0.3H),3.73-4.02(m,5.7H),3.64-3.67(m,0.3H),3.22-3.52(m,7H),2.96-3.01(m,1H),2.16 -2.48(m,6H),1.66-2.04(m,8H),1.56-1.65(m,1H),1.52(d,J＝6.8Hz,3H),1.46(d,J＝6.8Hz,3H), 1.11 (d, J=6.8Hz, 3H), 1.07 (d, J=6.8Hz, 3H).

Example 198: (S)-2-((4-(3-((9-((4-cyanophenyl)amino)-3-azaspiro[5.5]undec-3-yl)methyl Base) pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method in Example 92, using 4-cyanoaniline as a starting material, the title compound was obtained. MS m/z [LC-MS]: 668.41 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.38(s,0.5H),8.37(s,0.5H),7.81-7.86(m,4H),7.79(s,1H),6.77-6.96(m, 2H),6.61-6.65(m,0.5H),6.54-6.58(m,0.5H),3.72-3.86(m,2.5H),3.54-3.68(m,1.5H),3.26-3.51(m,2.5 H),2.76-3.14(m,9H),2.34-2.54(m,2.5H),2.06-2.23(m,1H),1.91-2.02(m,1.5H),1.73-1.88(m,4.5H) ,1.47-1.60(m,5H),1.42-1.44(m,3H),1.22-1.28(m,1H),1.11-1.15(m,6H).

Example 199: (S)-2-((4-(3-((9-((3-cyanophenyl)amino)-3-azaspiro[5.5]undec-3-yl)methyl Base) pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method in Example 92, using 3-cyanoaniline as a starting material, the title compound was obtained. MS m/z [LC-MS]: 668.41 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.37(s, 0.5H), 8.36(s, 0.5H), 8.01(s, 1H), 7.95(d, J=8.4Hz, 1H), 7.86(d ,J=8.0Hz,1H),7.78(s,1H),7.67(t,J=8.0Hz,1H),6.84-6.96(m,2H),6.61-6.64(m,0.5H),6.54-6.58 (m,0.5H),3.72-3.86(m,2.5H),3.55-3.67(m,1.5H),3.26-3.52(m,2.5H),2.72-3.18(m,9H),2.26-2.60( m,2.5H),2.04-2.20(m,1H),1.89-2.02(m,1.5H),1.74-1.88(m,4.5H),1.47-1.59(m,5H),1.42-1.44(m, 3H), 1.21-1.31(m, 1H), 1.10-1.14(m, 6H).

Example 200: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-(oxetan-3-ylamino)-3-azepine spiro[5.5] undec-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 92, using 3-oxetanamine as the starting material, the title compound was obtained. MS m/z [LC-MS]: 623.41 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.38(s 0.5H), 8.37(s, 0.5H), 7.79(s, 1H), 6.89-6.96(m, 2H), 6.63-6.66(m, 0.5 H),6.57-6.60(m,0.5H),4.78(t,J＝6.8Hz,2H),4.55-4.63(m,0.5H),4.38(t,J＝6.4Hz,2H),3.99-4.06 (m,1H),3.59-3.88(m,4.5H),3.31-3.51(m,2.5H),3.19-3.23(m,0.5H),2.22-2.45(m,9H),1.94-2.07(m ,1H), 1.44-1.64(m,11H), 1.26-1.36(m,2H), 0.98-1.22(m,10H).

Example 201: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-((tetrahydro-2H-pyran-4-yl)amino) -3-Azaspiro [5.5]undecyl-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 92, using tetrahydro-2H-pyran-4-amine as starting material, the title compound was obtained. MS m/z [LC-MS]: 651.44 [M+1]. ¹ H NMR (400MHz, DMSO-d ₆ ): δ=9.06-9.27(m,2H),7.17-7.33(m,3H),3.96-4.28(m,1H),3.84-3.90(m,2H), 3.46-3.75(m,4H),2.91-3.42(m,11H),2.68-2.82(m,1H),2.08-2.26(m,2H),1.50-2.03(m,12H),1.24-1.42(m , 9H), 1.09 (d, J=6.0Hz, 3H), 0.93-1.06 (m, 4H).

Example 202: 2-((4-(7-(((S)-1-(((1S,4S)-5-((E)-4-(dimethylamino)but-2-enoyl )-2,5-diazabicyclo [2.2.1]heptane-2-yl)sulfonyl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonane -2-yl)pyrimidin-5-yl)oxy )-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 196, 2-((4-(7-(((S)-1-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane Alkyl-2-yl)sulfonyl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5- Fluoro-N,N-diisopropylbenzamide hydrochloride and (E)-4-(dimethylamino)but-2-enoyl chloride were used as starting materials to obtain the target compound. MS m/z [LC-MS]: 796.43 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.36(s,1H),7.75(s,1H),6.89-7.00(m,3H),6.74-6.78(m,1H),6.35(d,J= 14.8Hz,0.3H),6.15(d,J＝14.8Hz,0.7H),4.97(s,0.7H),4.67(s,0.3H),4.44(s,0.7H),4.41(s,0.3H ),3.72-4.02(m,5.7H),3.65(d,J＝11.6Hz,0.3H),3.22-3.54(m,7H),3.07-3.16(m,2H),2.96-3.03(m,1H ),2.20-2.48(m,13H),1.95-2.03(m,2H),1.70-1.90(m,5H),1.59-1.64(m,1H),1.53(d,J＝7.2Hz,3H), 1.47 (d, J=6.8Hz, 3H), 1.12 (d, J=6.4Hz, 3H), 1.08 (d, J=6.8Hz, 3H).

Example 203: (R,E)-2-((4-(7-((1-((3-(4-(Dimethylamino)but-2-enamido)pyrrolidin-1-yl )sulfonyl) piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N -Diisopropylbenzamide _

Referring to the method in Step 1 in Example 83, using Intermediate 94 and Intermediate 99 as starting materials, the title compound was obtained. MS m/z [LC-MS]: 787.43 [M+1].

Referring to the method of step 2 in Example 83, (R)-(1-((4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy) Pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)pyrrolidin-3-yl)carbamate As raw materials, the target compound was obtained. MS m/z [LC-MS]: 687.38 [M+1].

Step 3: (R,E)-2-((4-(7-((1-((3-(4-(Dimethylamino)but-2-enamido)pyrrolidin-1-yl) Sulfonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N- Diisopropylbenzamide

Referring to the method of step 3 in Example 83, (R)-2-((4-(7-((1-((3-aminopyrrolidin-1-yl)sulfonyl)piperidin-4-yl) Methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride and (E)-4-(dimethylamino)but-2-enoyl chloride as raw materials to obtain the target compound. MS m/z [LC-MS]: 798.45 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.36(s,1H),7.76(s,1H),6.96-7.01(m,2H),6.73-6.85(m,2H),6.07-6.18(brs, 1H),6.02(d,J＝15.2Hz,1H),4.51-4.59(m,1H),3.90-4.06(m,2H),3.85-3.88(m,2H),3.67-3.81(m,3H) ,3.41-3.53(m,3H),3.27-3.34(m,2H),3.13-3.21(m,2H),2.77(td,J＝12.0Hz,2.0Hz,2H),2.28-2.48(m,9H ), 2.14-2.22(m, 2H), 1.56-2.06(m, 12H), 1.53(d, J=6.8Hz, 3H), 1.47(d, J=6.8Hz, 3H), 1.12(d, J= 6.4Hz, 3H), 1.09 (d, J = 6.4Hz, 3H).

Example 204: 2-((4-(7-((1-((4-acryloylamino-3-fluorophenyl)sulfonyl)piperidin-4-yl)methyl)-2,7-di Azaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: 2-((4-(7-((1-((4-amino-3-fluorophenyl)sulfonyl)piperidin-4-yl)methyl)-2,7-diazaspiro [3.5] Nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method in Step 1 in Example 83, using Intermediate 94 and 4-amino-3-fluorobenzenesulfonyl chloride as starting materials, the title compound was obtained. MS m/z [LC-MS]: 712.35 [M+1].

Step 2: 2-((4-(7-((1-((4-acryloylamino-3-fluorophenyl)sulfonyl)piperidin-4-yl)methyl)-2,7-diazepine Heterospiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, 2-((4-(7-((1-((4-amino-3-fluorophenyl)sulfonyl)piperidin-4-yl)methyl)- 2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide as starting material to obtain the target compound. MS m/z [LC-MS]: 766.36 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.65(t, J=8.0Hz, 1H), 8.34(s, 1H), 7.74(s, 1H), 7.71(d, J=3.6Hz, 1H), 7.49-7.55(m,2H),6.95-6.99(m,2H),6.73-6.76(m,1H),6.49(d,J=17.2Hz,1H),6.30(dd,J=17.2Hz,10.4Hz ,1H),5.86(d,J＝10.4Hz,1H),3.70-4.04(m,7H),3.43-3.50(m,1H),2.06-2.38(m,9H),1.56-1.82(m,8H ), 1.51 (d, J=6.4Hz, 3H), 1.45 (d, J=7.2Hz, 3H), 1.11 (d, J=6.8Hz, 3H), 1.07 (d, J=6.8Hz, 3H).

Example 205: 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(pyrimidin-2-ylamino)cyclohexyl)methyl) -2,7- diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide

Step 1: ((1r,4r)-4-((2-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7 -Diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)carbamate tert-butyl

Referring to the method of step 1 in Example 1, with 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro- N,N-Diisopropylbenzamide was used as starting material to obtain the target compound. MS m/z [LC-MS]: 653.42 [M+1].

Step 2: 2-((4-(7-(((1r,4r)-4-aminocyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidine- 5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 2 in Example 1, with ((1r,4r)-4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine- 4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)carbamate tert-butyl ester as raw material to obtain the target compound. MS m/z [LC-MS]: 553.37 [M+1].

Step 3: 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(pyrimidin-2-ylamino)cyclohexyl)methyl)- 2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide

With reference to the method of step 3 in Example 1, 2-((4-(7-(((1r,4r)-4-aminocyclohexyl)methyl)-2,7-diazaspiro[3.5]nonane Alk-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide and (E)-4-(dimethylamino)but-2-enoyl chloride As raw materials, the target compound was obtained. MS m/z [LC-MS]: 631.39 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ):δ=8.36(s,1H), 8.23(d,J=4.8Hz,2H),7.75(s,1H),6.96-7.00(m,2H),6.74-6.78 (m,1H),6.47(t,J=4.8Hz,1H),4.95(d,J=8.4Hz,1H),3.84-4.04(m,4H),3.68-3.82(m,2H),3.41- 3.51(m,1H),2.06-2.50(m,7H),1.60-1.94(m,8H),1.53(d,J=7.2Hz,3H),1.47(d,J=6.4Hz,3H),1.15 -1.35 (m, 4H), 1.12 (d, J=6.4Hz, 3H), 1.08 (d, J=6.4Hz, 3H).

Example 206: 2-((4-(7-((1-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptan-2-yl) Sulfonyl )-1,2,3,6-tetrahydropyridin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy base)-5-fluoro-N,N- diisopropylbenzamide

Step 1: (1S,4S)-5-((4-((2-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)- 2,7-diazaspiro[3.5]nonan-7-yl)methyl)-3,6-dihydropyridin-1(2H)-yl)sulfonyl)-2,5-diazabicyclo[ 2.2.1] tert-butyl heptane-2-carboxylate

Referring to the method in step 1 in Example 83, the title compound was obtained using intermediate 108 as a starting material. MS m/z [LC-MS]: 797.42 [M+1].

Step 2: 2-((4-(7-((1-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)sulfonyl)-1, 2,3,6-tetrahydropyridin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro- N,N-Diisopropylbenzamide Hydrochloride

Referring to the method of step 2 in Example 83, (1S,4S)-5-((4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy )pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)-3,6-dihydropyridin-1(2H)-yl)sulfonyl)-2 , 5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester was used as raw material to obtain the target compound. MS m/z [LC-MS]: 697.37 [M+1].

Step 3: 2-((4-(7-((1-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)sulfo Acyl)-1,2,3,6-tetrahydropyridin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy) -5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, 2-((4-(7-((1-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2- Base)sulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl) Oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride as raw material to obtain the target compound. MS m/z [LC-MS]: 751.38 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.36(s,1H),7.75(s,1H),6.96-7.00(m,2H),6.74-6.78(m,1H),6.36-6.47(m, 1.3H), 6.27(dd, J=16.8Hz, 10.4Hz, 0.7H), 5.71-5.74(m, 1H), 5.44-5.64(m, 1H), 4.98(s, 0.7H), 4.62(s, 0.3H),4.44(s,0.7H),4.42(s,0.3H),3.82-4.06(m,4H),3.63-3.81(m,4H),3.42-3.53(m,2H),3.21-3.38 (m,4H),2.70-2.94(m,2H),2.08-2.44(m,5H),1.60-2.05(m,7H),1.53(d,J＝6.8Hz,3H),1.47(d,J =6.8Hz, 3H), 1.12(d, J=6.4Hz, 3H), 1.08(d, J=6.8Hz, 3H).

Example 207: 2-((4-(7-(4-(((1S,4S)-5-((E)-4-(dimethylamino)but-2-enoyl)-2,5 -Diazabicyclo [2.2.1]heptane-2-yl)sulfonyl)benzyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy )-5-fluoro-N,N- diisopropylbenzamide

Referring to the method of step 3 in Example 83, 2-((4-(7-(4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl )sulfonyl)benzyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzyl Starting from amide hydrochloride and (E)-4-(dimethylamino)but-2-enoyl chloride, the title compound was obtained. MS m/z [LC-MS]: 803.41 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ＝8.32(s, 1H), 7.72-7.74(m, 3H), 7.46(d, J＝8.4Hz, 2H), 6.94-6.98(m, 2H), 6.81 -6.91(m,1H),6.72-6.76(m,1H),6.24(d,J=15.2Hz,0.3H),6.02(d,J=15.2Hz,0.7H),4.85(s,0.7H) ,4.55(s,0.3H),4.52(s,0.7H),4.45(s,0.3H),3.81-4.08(m,4H),3.71-3.78(m,1H),3.64-3.69(m,2H ),3.33-3.56(m,4H),3.16(d,J＝8.8Hz,1H),3.03-3.07(m,2H),2.08-2.58(m,11H),1.74-1.76(m,4H), 1.61(d, J=10.8Hz, 1H), 1.51(d, J=6.8Hz, 3H), 1.44(d, J=6.8Hz, 3H), 1.10(d, J=6.8Hz, 3H), 1.05( d, J=6.4Hz, 3H).

Example 208: 2-((5-(7-(4-(((1S,4S)-5-((E)-4-(dimethylamino)but-2-enoyl)-2,5 -Diazabicyclo [2.2.1]heptane-2-yl)sulfonyl)benzyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-tri Oxyzin-6-yl)oxy)-5-fluoro -N,N-diisopropylbenzamide

Step 1: (1S,4S)-5-((4-((2-(6-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)-1,2,4- Triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)phenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane tert-butyl alkane-2-carboxylate

Referring to the method of step 2 in intermediate 108, using intermediate 106 and intermediate 110 as raw materials, the target compound was obtained. MS m/z [LC-MS]: 793.39 [M+1].

Step 2: 2-((5-(7-(4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)sulfonyl)benzyl)- 2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzyl Amide hydrochloride

Referring to the method of step 2 in Example 83, (1S,4S)-5-((4-((2-(6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy )-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)phenyl)sulfonyl)-2,5-diazo The target compound was obtained from tert-butyl heterobicyclo[2.2.1]heptane-2-carboxylate. MS m/z [LC-MS]: 693.33 [M+1].

Step 3: 2-((5-(7-(4-(((1S,4S)-5-((E)-4-(dimethylamino)but-2-enoyl)-2,5- Diazabicyclo[2.2.1]heptane-2-yl)sulfonyl)benzyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazine -6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, 2-((5-(7-(4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl )sulfonyl)benzyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N, N-diisopropylbenzamide hydrochloride and (E)-4-(dimethylamino)but-2-enoyl chloride were used as raw materials to obtain the target compound. MS m/z [LC-MS]: 804.40 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.44(s, 1H), 7.74-7.77(m, 2H), 7.51-7.56(m, 2H), 7.22-7.24(m, 1H), 7.15(d, J＝15.2Hz, 0.4H), 7.06-7.11(m, 1H), 6.94(dd, J＝8.0Hz, 2.8Hz, 1H), 6.74-6.89(m, 1H), 6.50(d, J＝15.2Hz ,0.6H),4.94(s,0.4H),4.86(s,0.6H),4.48-4.54(m,2H),4.26-4.32(m,1H),3.82-3.94(m,2H),3.30- 3.80(m,8.4H),3.18-3.20(m,0.6H),2.86-2.91(m,1H),2.75(s,3H),2.63(s,3H),2.30-2.60(m,4H), 1.65-1.98(m,6H),1.47(d,J=6.4Hz,3H),1.34(d,J=6.8Hz,3H),1.06(d,J=7.2Hz,3H),0.69(d,J = 6.4Hz, 3H).

Example 209: 2-((5-(7-(((S)-1-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptane- 2-yl)sulfonyl )pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl) Oxy)-5-fluoro-N,N- diisopropylbenzamide

Step 1: (1S,4S)-5-(((S)-3-((2-(6-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)-1, 2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)pyrrolidin-1-yl)sulfonyl)-2,5-diazo Heterobicyclo[2.2.1]heptane-2-carboxylate tert-butyl ester

Referring to the method in step 1 in Example 83, the title compound was obtained using intermediate 111 as a starting material. MS m/z [LC-MS]: 786.41 [M+1].

Step 2: 2-((5-(7-(((S)-1-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)sulfonyl )pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5- Fluoro-N,N-diisopropylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, (1S,4S)-5-(((S)-3-((2-(6-(2-(diisopropylcarbamoyl)-4- Fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)pyrrolidin-1-yl)sulfonyl )-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as raw material to obtain the target compound. MS m/z [LC-MS]: 686.36 [M+1].

Step 3: 2-((5-(7-(((S)-1-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptane-2 -yl)sulfonyl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy base)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, 2-((5-(7-(((S)-1-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane Alkyl-2-yl)sulfonyl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazine-6- base)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride as raw material to obtain the target compound. MS m/z [LC-MS]: 740.37 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.43(s, 1H), 7.21-7.25(m, 1H), 7.06-7.11(m, 1H), 6.93(dd, J=7.6Hz, 2.8Hz, 1H ),6.35-6.47(m,1.3H),6.27(dd,J＝16.8Hz,10.0Hz,0.7H),5.69-5.73(m,1H),4.97(s,0.7H),4.61(s,0.3 H), 4.41-4.47(m, 2H), 4.26(d, J=10.0Hz, 1H), 3.74-3.89(m, 3.7H), 3.66(d, J=11.2Hz, 0.3H), 3.22-3.52 (m,7H),2.97-3.02(m,1H),2.17-2.49(m,6H),1.56-2.03(m,9H),1.48(d,J＝6.8Hz,3H),1.36(d,J =6.8Hz, 3H), 1.06(d, J=6.8Hz, 3H), 0.69(d, J=6.8Hz, 3H).

Example 210: 2-((5-(7-(((R)-1-(((1S,4S)-5-((E)-4-(dimethylamino)but-2-enoyl )-2,5-diazabicyclo [2.2.1]heptane-2-yl)sulfonyl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonane -2-yl)-1,2,4-triazin-6- yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: (1S,4S)-5-(((R)-3-((2-(6-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)-1, 2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)pyrrolidin-1-yl)sulfonyl)-2,5-diazo Heterobicyclo[2.2.1]heptane-2-carboxylate tert-butyl ester

Referring to the method in step 1 in Example 83, the title compound was obtained using intermediate 112 as a starting material. MS m/z [LC-MS]: 786.41 [M+1].

Step 2: 2-((5-(7-(((R)-1-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)sulfonyl )pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5- Fluoro-N,N-diisopropylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, (1S,4S)-5-(((R)-3-((2-(6-(2-(diisopropylcarbamoyl)-4- Fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)pyrrolidin-1-yl)sulfonyl )-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as raw material to obtain the target compound. MS m/z [LC-MS]: 686.36 [M+1].

Step 3: 2-((5-(7-(((R)-1-(((1S,4S)-5-((E)-4-(dimethylamino)but-2-enoyl) -2,5-diazabicyclo[2.2.1]heptane-2-yl)sulfonyl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-2 -yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, 2-((5-(7-(((R)-1-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane Alkyl-2-yl)sulfonyl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazine-6- base)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride and (E)-4-(dimethylamino)but-2-enoyl chloride as raw materials to obtain the target compound. MS m/z [LC-MS]: 797.43 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.44(s, 1H), 7.22-7.25(m, 1H), 7.06-7.11(m, 1H), 6.90-6.96(m, 2H), 6.28(d, J＝15.6Hz, 0.3H), 6.11(d, J＝15.6Hz, 0.7H), 4.97(s, 0.7H), 4.64(s, 0.3H), 4.38-4.47(m, 2H), 4.26(d ,J=10.0Hz,1H),3.74-3.90(m,3.7H),3.65(d,J=11.2Hz,0.3H),3.22-3.53(m,7H),3.07-3.09(m,2H), 2.98-3.02(m,1H),2.21-2.48(m,12H),1.56-2.04(m,9H),1.48(d,J＝6.8Hz,3H),1.36(d,J＝6.8Hz,3H) , 1.06 (d, J=6.8Hz, 3H), 0.70 (d, J=6.8Hz, 3H).

Example 211: 2-((5-(7-((1-(((1S,4S)-5-(cyclopent-1-ene-1-formyl)-2,5-diazabicyclo[ 2.2.1] Heptane -2-yl)sulfonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4- Triazin-6-yl)oxy)-5-fluoro -N,N-diisopropylbenzamide

Referring to the method in step 1 in Example 83, the title compound was obtained using intermediate 101 as a starting material. MS m/z [LC-MS]: 800.43 [M+1].

Referring to the method of step 2 in Example 83, (1S,4S)-5-((4-((2-(6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy )-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)-2, 5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester was used as raw material to obtain the target compound. MS m/z [LC-MS]: 700.38 [M+1].

Step 3: 2-((5-(7-((1-(((1S,4S)-5-(cyclopent-1-ene-1-formyl)-2,5-diazabicyclo[2.2 .1] heptane-2-yl)sulfonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-tri Oxyzin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, 2-((5-(7-((1-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2- Base)sulfonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy )-5-fluoro-N,N-diisopropylbenzamide hydrochloride and cyclopent-1-ene-1-carbonyl chloride as raw materials to obtain the target compound. MS m/z [LC-MS]: 794.42 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.44(s, 1H), 7.22-7.25(m, 1H), 7.06-7.11(m, 1H), 6.94(dd, J=7.6Hz, 3.2Hz, 1H ),6.17(s,0.6H),6.00(s,0.4H),4.90(s,0.6H),4.63(s,0.4H),4.46(d,J＝10.0Hz,1H),4.35-4.39( m,1H),4.26(d,J＝10.0Hz,1H),3.74-3.90(m,4H),3.65-3.73(m,2H),3.34-3.54(m,3H),3.24-3.30(m, 1H), 2.43-2.73(m, 6H), 2.22-2.41(m, 4H), 2.12(d, J=6.8Hz, 2H), 1.68-2.02(m, 11H), 1.48(d, J=6.8Hz , 3H), 1.37(d, J=6.8Hz, 3H), 1.12-1.22(m, 2H), 1.06(d, J=6.8Hz, 3H), 0.70(d, J=6.8Hz, 3H).

Example 212: 2-((4-(7-((1-(((1S,5S)-6-acryloyl-3,6-diazabicyclo[3.2.0]heptan-3-yl) Sulfonyl) piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N- Diisopropylbenzamide _

Step 1: (1S,5S)-3-((4-((2-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)- 2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)-3,6-diazabicyclo[3.2.0]heptane-6- tert-butyl carboxylate

Referring to the method in Step 1 in Example 83, using Intermediate 101 and Intermediate 113 as raw materials, the title compound was obtained. MS m/z [LC-MS]: 799.43 [M+1].

Step 2: 2-((4-(7-((1-(((1S,5S)-3,6-diazabicyclo[3.2.0]heptane-3-yl)sulfonyl)piperidine- 4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzyl Amide hydrochloride

Referring to the method of step 2 in Example 83, (1S,5S)-3-((4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy )pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)-3,6-diazabicyclo[3.2 .0] tert-butyl heptane-6-carboxylate as raw material to obtain the target compound. MS m/z [LC-MS]: 699.38 [M+1].

Step 3: 2-((4-(7-((1-(((1S,5S)-6-acryloyl-3,6-diazabicyclo[3.2.0]heptane-3-yl)sulfo Acyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-di Cumamide

Referring to the method of step 3 in Example 83, 2-((4-(7-((1-(((1S,5S)-3,6-diazabicyclo[3.2.0]heptane-3- Base)sulfonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N, N-diisopropylbenzamide hydrochloride was used as starting material to obtain the target compound. MS m/z [LC-MS]: 753.39 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.34(s,1H),7.74(s,1H),6.95-7.00(m,2H),6.74-6.77(m,1H),6.29-6.40(m, 1H),6.09-6.18(m,1H),5.66-5.71(m,1H),4.87-4.92(m,1H),4.26-4.30(m,0.7H),4.14-4.19(m,0.3H), 3.70-4.02(m,9H),3.44-3.62(m,2H),3.10-3.22(m,2H),2.95-2.99(m,1H),2.69-2.81(m,2H),2.16-2.38(m ,4H),2.10(d,J=6.4Hz,2H),1.64-1.83(m,9H),1.52(d,J=6.4Hz,3H),1.47(d,J=6.8Hz,3H),1.12 (d, J=6.8Hz, 3H), 1.08 (d, J=6.8Hz, 3H).

Example 213: 2-((4-(7-(((R)-1-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptane- 2-yl)sulfonyl )pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro- N,N-Diisopropyl benzamide

Step 1: (1S,4S)-5-(((R)-3-((2-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine-4 -yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)pyrrolidin-1-yl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane tert-butyl alkane-2-carboxylate

Referring to the method in step 1 in Example 83, the title compound was obtained by using intermediate 114 as a starting material. MS m/z [LC-MS]: 785.42 [M+1].

Step 2: 2-((4-(7-(((R)-1-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)sulfonyl )pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diiso Propylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, (1S,4S)-5-(((R)-3-((2-(5-(2-(diisopropylcarbamoyl)-4- Fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)pyrrolidin-1-yl)sulfonyl)-2,5-diazo The target compound was obtained from tert-butyl heterobicyclo[2.2.1]heptane-2-carboxylate. MS m/z [LC-MS]: 685.37 [M+1].

Step 3: 2-((4-(7-(((R)-1-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptane-2 -yl)sulfonyl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N ,N-Diisopropylbenzamide

Referring to the method of step 3 in Example 83, 2-((4-(7-(((R)-1-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane Alkyl-2-yl)sulfonyl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5- Fluoro-N,N-diisopropylbenzamide hydrochloride was used as starting material to obtain the target compound. MS m/z [LC-MS]: 739.37 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.35(s,1H),7.74(s,1H),6.95-7.00(m,2H),6.74-6.77(m,1H),6.35-6.47(m, 1.3H),6.27(dd,J＝17.2Hz,10.0Hz,0.7H),5.70-5.73(m,1H),4.98(s,0.7H),4.62(s,0.3H),4.44(s,0.7 H),4.42(s,0.3H),3.84-4.02(m,4H),3.73-3.82(m,1.7H),3.65(d,J＝11.6Hz,0.3H),3.21-3.52(m,7H ),2.96-3.02(m,1H),2.18-2.45(m,6H),1.95-2.04(m,2H),1.68-1.91(m,6H),1.56-1.65(m,1H),1.52(d , J=6.4Hz, 3H), 1.46 (d, J=7.2Hz, 3H), 1.12 (d, J=6.8Hz, 3H), 1.07 (d, J=6.8Hz, 3H).

Example 214: 2-((5-(7-(((R)-1-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptane- 2-yl)sulfonyl )pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl) Oxy)-5-fluoro-N,N- diisopropylbenzamide

Referring to the method of step 3 in Example 83, 2-((5-(7-(((R)-1-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane Alkyl-2-yl)sulfonyl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazine-6- base)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride as raw material to obtain the target compound. MS m/z [LC-MS]: 740.37 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.43(s, 1H), 7.23(dd, J=8.8Hz, 4.4Hz, 1H), 7.05-7.11(m, 1H), 6.93(dd, J=8.0 Hz, 3.2Hz, 1H), 6.35-6.47(m, 1.3H), 6.26(dd, J=16.8Hz, 10.0Hz, 0.7H), 5.69-5.72(m, 1H), 4.97(s, 0.7H) ,4.61(s,0.3H),4.39-4.47(m,2H),4.26(d,J=10.4Hz,1H),3.71-3.88(m,3.7H),3.65(d,J=11.6Hz,0.3 H),3.21-3.52(m,7H),2.97-3.03(m,1H),2.17-2.48(m,6H),1.70-2.04(m,8H),1.56-1.65(m,1H),1.48( d, J = 6.4Hz, 3H), 1.36 (d, J = 6.4Hz, 3H), 1.05 (d, J = 6.4Hz, 3H), 0.69 (d, J = 6.4Hz, 3H).

Example 215: (R)-2-((5-(7-((1-((4-acryloyl-1,4-diazepan-1-yl)sulfonyl)pyrrolidine-3 -yl )methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N -Diisopropylbenzamide

Step 1: (R)-4-((3-((2-(6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)-1,2,4-triazine -5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)pyrrolidin-1-yl)sulfonyl)-1,4-diazepane-1 - tert-butyl carboxylate

Referring to the method in Step 1 in Example 83, using Intermediate 112 and Intermediate 74 as raw materials, the title compound was obtained. MS m/z [LC-MS]: 788.43 [M+1].

Step 2: (R)-2-((5-(7-((1-((1,4-diazepan-1-yl)sulfonyl)pyrrolidin-3-yl)methyl) -2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzene Formamide hydrochloride

Referring to the method of step 2 in Example 83, (R)-4-((3-((2-(6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)- 1,2,4-Triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)pyrrolidin-1-yl)sulfonyl)-1,4- Starting from tert-butyl diazepane-1-carboxylate, the target compound was obtained. MS m/z [LC-MS]: 688.38 [M+1].

Step 3: (R)-2-((5-(7-((1-((4-acryloyl-1,4-diazepan-1-yl)sulfonyl)pyrrolidine-3- Base)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N- Diisopropylbenzamide

Referring to the method of step 3 in Example 83, (R)-2-((5-(7-((1-((1,4-diazepan-1-yl)sulfonyl)pyrrolidine -3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N , N-diisopropylbenzamide hydrochloride raw material to obtain the target compound. MS m/z [LC-MS]: 742.39 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.43(s, 1H), 7.22-7.25(m, 1H), 7.06-7.11(m, 1H), 6.94(dd, J=8.0Hz, 3.2Hz, 1H ),6.49-6.59(m,1H),6.30-6.40(m,1H),5.68-5.73(m,1H),4.46(d,J=10.0Hz,1H),4.26(d,J=10.0Hz, 1H),3.66-3.90(m,7H),3.18-3.45(m,8H),2.92-2.99(m,1H),2.18-2.48(m,6H),1.90-2.04(m,3H),1.70- 1.85(m,5H),1.57-1.66(m,1H),1.48(d,J=6.4Hz,3H),1.36(d,J=6.4Hz,3H),1.06(d,J=6.8Hz,3H ), 1.09 (d, J=6.4Hz, 3H).

Example 216: (R)-2-((5-(7-((1-((3-acrylamidopyrrolidin-1-yl)sulfonyl)piperidin-4-yl)methyl)-2 ,7 -diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: (R)-(1-((4-((2-(6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)-1,2,4-tri oxazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)pyrrolidin-3-yl)carbamate tert-butyl

Referring to the method in Step 1 in Example 83, using Intermediate 101 and Intermediate 99 as raw materials, the title compound was obtained. MS m/z [LC-MS]: 788.43 [M+1].

Step 2: (R)-2-((5-(7-((1-((3-aminopyrrolidin-1-yl)sulfonyl)piperidin-4-yl)methyl)-2,7- Diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, (R)-(1-((4-((2-(6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy) -1,2,4-Triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)pyrrolidine-3 -yl) tert-butyl carbamate as raw material to obtain the target compound. MS m/z [LC-MS]: 688.38 [M+1].

Step 3: (R)-2-((5-(7-((1-((3-acrylamidopyrrolidin-1-yl)sulfonyl)piperidin-4-yl)methyl)-2, 7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, (R)-2-((5-(7-((1-((3-aminopyrrolidin-1-yl)sulfonyl)piperidin-4-yl) Methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diiso Propylbenzamide hydrochloride was used as starting material to obtain the target compound. MS m/z [LC-MS]: 742.39 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.44(s, 1H), 7.22-7.26(m, 1H), 7.07-7.12(m, 1H), 6.94(dd, J=8.0Hz, 3.2Hz, 1H ),6.27(dd,J=16.8Hz,1.2Hz,1H),6.03-6.10(m,2H),5.65(dd,J=10.8Hz,1.2Hz,1H),4.53-4.60(m,1H), 4.47(d, J=10.0Hz, 1H), 4.27(d, J=10.0Hz, 1H), 3.68-3.90(m, 5H), 3.28-3.52(m, 5H), 2.77(td, J=12.4Hz ,2.0Hz,2H),2.09-2.44(m,7H),1.94-2.02(m,1H),1.68-1.86(m,7H),1.49(d,J＝6.8Hz,3H),1.37(d, J=6.8Hz, 3H), 1.13-1.27(m, 2H), 1.07(d, J=6.4Hz, 3H), 0.70(d, J=6.4Hz, 3H).

Example 217: (R,E)-2-((5-(7-((1-((3-(4-(Dimethylamino)but-2-enamido)pyrrolidin-1-yl )sulfonyl) piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy) -5-fluoro-N,N- diisopropylbenzamide

Referring to the method of step 3 in Example 83, (R)-2-((5-(7-((1-((3-aminopyrrolidin-1-yl)sulfonyl)piperidin-4-yl) Methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diiso Propylbenzamide hydrochloride and (E)-4-(dimethylamino)but-2-enoyl chloride were used as starting materials to obtain the target compound. MS m/z [LC-MS]: 799.45 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.44(s, 1H), 7.22-7.26(m, 1H), 7.07-7.11(m, 1H), 6.94(dd, J=8.0Hz, 3.2Hz, 1H ),6.78-6.85(m,1H),5.91-5.97(m,2H),4.53-4.60(m,1H),4.47(d,J=10.0Hz,1H),4.27(d,J=10.0Hz, 1H), 3.68-3.90(m, 5H), 3.26-3.50(m, 5H), 3.05(d, J=6.4Hz, 2H), 2.76(td, J=12.0Hz, 2.0Hz, 2H), 2.12- 2.41(m,13H),1.92-2.00(m,1H),1.72-1.86(m,7H),1.49(d,J＝6.8Hz,3H),1.37(d,J＝6.8Hz,3H),1.14 -1.24 (m, 2H), 1.07 (d, J=6.4Hz, 3H), 0.71 (d, J=6.4Hz, 3H).

Example 218: 2-((5-(7-((1-(((1S,4S)-5-((E)-4-(dimethylamino)but-2-enoyl)-2, 5-diazabicyclo [2.2.1]heptane-2-yl)sulfonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl) -1,2,4-Triazin-6-yl)oxy )-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, 2-((5-(7-((1-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2- Base)sulfonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy )-5-fluoro-N,N-diisopropylbenzamide hydrochloride and (E)-4-(dimethylamino)but-2-enoyl chloride as raw materials to obtain the target compound. MS m/z [LC-MS]: 811.45 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.43(s, 1H), 7.21-7.25(m, 1H), 7.05-7.10(m, 1H), 6.88-6.95(m, 2H), 6.35(d, J＝15.2Hz, 0.3H), 6.14(d, J＝15.2Hz, 0.7H), 4.95(s, 0.7H), 4.66(s, 0.3H), 4.38-4.47(m, 2H), 4.26(d ,J＝10.4Hz,1H),3.61-3.90(m,6H),3.20-3.53(m,4H),3.09-3.13(m,2H),2.66-2.72(m,2H),2.21-2.42(m ,10H),2.12(d,J=7.2Hz,2H),1.71-2.00(m,8H),1.50-1.61(m,1H),1.48(d,J=6.4Hz,3H),1.36(d, J=6.4Hz, 3H), 1.10-1.22(m, 2H), 1.05(d, J=6.4Hz, 3H), 0.69(d, J=6.4Hz, 3H).

Example 219: (E)-2-((5-(7-((1-((4-(4-(Dimethylamino)but-2-enoyl)-1,4-diazacyclo Heptane-1-yl) sulfonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazine-6 -yl)oxy)-5-fluoro-N,N- diisopropylbenzamide

Referring to the method of step 3 in Example 83, 2-((5-(7-((1-((1,4-diazepan-1-yl)sulfonyl)piperidin-4-yl )methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-two Isopropylbenzamide hydrochloride and (E)-4-(dimethylamino)but-2-enoyl chloride were used as starting materials to obtain the target compound. MS m/z [LC-MS]: 813.46 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.45 (s, 1H), 7.22-7.25 (m, 1H), 7.07-7.12 (m, 1H), 6.83-6.96 (m, 2H), 6.45-6.51 ( m,1H),4.47(d,J=10.0Hz,1H),4.27(d,J=10.0Hz,1H),3.66-3.90(m,7H),3.53-3.60(m,2H),3.32-3.46 (m,5H),3.12-3.22(m,2H),2.68-2.74(m,2H),2.24-2.42(m,11H),2.14(d,J＝7.2Hz,2H),1.92-1.98(m ,2H),1.75-1.86(m,5H),1.53-1.63(m,1H),1.49(d,J=7.2Hz,3H),1.37(d,J=7.2Hz,3H),1.11-1.22( m, 2H), 1.07 (d, J=6.8Hz, 3H), 0.70 (d, J=6.8Hz, 3H).

Example 220: 2-((5-(7-(((S)-1-(((R)-3-acrylamidopyrrolidin-1-yl)sulfonyl)pyrrolidin-3-yl)methan Base)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropyl phenylbenzamide

Step 1: ((R)-1-(((S)-3-((2-(6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)-1,2 ,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)pyrrolidin-1-yl)sulfonyl)pyrrolidin-3-yl)amino tert-butyl formate

Referring to the method in Step 1 in Example 83, using Intermediate 111 and Intermediate 99 as raw materials, the title compound was obtained. MS m/z [LC-MS]: 774.41 [M+1].

Step 2: 2-((5-(7-(((S)-1-(((R)-3-aminopyrrolidin-1-yl)sulfonyl)pyrrolidin-3-yl)methyl)- 2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzyl Amide hydrochloride

Referring to the method of step 2 in Example 83, ((R)-1-(((S)-3-((2-(6-(2-(diisopropylcarbamoyl)-4-fluoro Phenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)pyrrolidin-1-yl)sulfonyl) Pyrrolidin-3-yl) tert-butyl carbamate as starting material to obtain the target compound. MS m/z [LC-MS]: 674.36 [M+1].

Step 3: 2-((5-(7-(((S)-1-(((R)-3-acrylamidopyrrolidin-1-yl)sulfonyl)pyrrolidin-3-yl)methyl )-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropyl benzamide

Referring to the method of step 3 in Example 83, 2-((5-(7-(((S)-1-(((R)-3-aminopyrrolidin-1-yl)sulfonyl)pyrrolidine- 3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N, N-diisopropylbenzamide hydrochloride was used as starting material to obtain the target compound. MS m/z [LC-MS]: 728.37 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.45(s, 1H), 7.23-7.26(m, 1H), 7.07-7.12(m, 1H), 6.95(dd, J=7.6Hz, 3.2Hz, 1H ),6.28(d,J=16.8Hz,1H),5.99-6.13(m,2H),5.66(d,J=10.4Hz,1H),4.55-4.63(m,1H),4.43-4.53(m, 1H), 4.28(d, J=10.0Hz, 1H), 3.75-3.92(m, 3H), 3.28-3.55(m, 8H), 3.00-3.10(m, 1H), 2.16-2.52(m, 8H) ,1.95-2.08(m,2H),1.72-1.88(m,3H),1.54-1.68(m,2H),1.49(d,J＝6.8Hz,3H),1.37(d,J＝7.2Hz,3H ), 1.07 (d, J=6.8Hz, 3H), 0.70 (d, J=6.4Hz, 3H).

Example 221: (E)-4-((1S,4S)-5-((4-((2-(6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy )-1,2,4- triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)-2, 5-diazabicyclo[2.2.1]heptane -2-yl)-4-oxobut-2-enoic acid ethyl ester

Referring to the method of step 3 in Example 83, 2-((5-(7-((1-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2- Base)sulfonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy )-5-fluoro-N,N-diisopropylbenzamide hydrochloride and monoethyl fumaric acid chloride as raw materials to obtain the target compound. MS m/z [LC-MS]: 826.41 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ＝8.43(s, 1H), 7.19-7.26(m, 1.3H), 7.03-7.11(m, 1.7H), 6.94(dd, J＝8.0Hz, 2.8Hz ,1H),6.85-6.89(m,1H),4.97(s,0.7H),4.69(s,0.3H),4.41-4.47(m,2H),4.21-4.28(m,3H),3.66-3.90 (m,6H),3.57(dd,J=9.2Hz,2.0Hz,0.7H)3.48-3.51(m,0.7H),3.31-3.40(m,2.3H),3.22(d,J=9.2Hz, 0.3H), 2.65-2.74(m, 2H), 2.20-2.45(m, 4H), 2.12(d, J=6.8Hz, 2H), 1.68-2.06(m, 11H), 1.48(d, J=6.4 Hz,3H),1.36(d,J=6.8Hz,3H),1.30(t,J=7.2Hz,3H),1.06(d,J=6.8Hz,3H),0.69(d,J=6.8Hz, 3H).

Example 222: 2-((5-(7-(4-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)sulfo Acyl) benzyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N- Diisopropylbenzamide

Referring to the method of step 3 in Example 83, 2-((5-(7-(4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl )sulfonyl)benzyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N, N-diisopropylbenzamide hydrochloride and (E)-4-(dimethylamino)but-2-enoyl chloride were used as raw materials to obtain the target compound. MS m/z [LC-MS]: 747.35 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.44(s, 1H), 7.76(d, J=8.0Hz, 2H), 7.48(d, J=8.0Hz, 2H), 7.22-7.26(m, 1H ),7.07-7.12(m,1H),6.95(dd,J＝8.0Hz,3.2Hz,1H),6.33-6.37(m,1.3H),6.15(dd,J＝16.8Hz,10.0Hz,0.7H ),5.66-5.70(m,1H),4.89(s,0.7H),4.48-4.56(m,2.3H),4.29(d,J＝10.4Hz,1H),3.75-3.91(m,3H), 3.64(d, J=9.2Hz, 0.7H), 3.33-3.58(m, 5.6H), 3.22(dd, J=9.2Hz, 2.0Hz, 0.7H), 2.24-2.54(m, 4H), 1.58- 1.89(m,6H),1.48(d,J=6.4Hz,3H),1.35(d,J=6.4Hz,3H),1.06(d,J=6.8Hz,3H),0.69(d,J=6.8 Hz, 3H).

Example 223: 2-((5-((S)-3-((7-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptane- 2-yl)sulfonyl )-2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)-1,2,4-triazin-6-yl) Oxy)-5-fluoro-N,N- diisopropylbenzamide

Referring to the method of step 3 in Example 83, use 2-((5-((S)-3-((7-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane Alkane-2-sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)-1,2,4-triazin-6-yl) Oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride was used as raw material to obtain the target compound. MS m/z[LC-MS]: 740.37[M+1]. ¹ H NMR( 400MHz, CDCl ₃ ):δ＝8.47(s,1H),7.18-7.25(m,1H),7.06-7.11(m,1H),6.92-6.97(m,1H),6.39-6.43(m,1.3H ),6.27(dd,J＝16.8Hz,10.0Hz,0.7H),5.71-5.74(m,1H),4.97(s,0.7H),4.62(s,0.3H),4.30-4.42(m,1.3 H),4.07-4.20(m,0.7H),3.70-3.86(m,3H),3.45-3.65(m,2.7H),3.26-3.39(m,3H),3.21(d,J＝9.2Hz, 0.3H), 3.10-3.18(m, 4H), 2.94-3.06(m, 4H), 2.42-2.58(m, 2H), 1.54-2.34(m, 12H), 1.48(d, J＝6.4Hz, 3H ), 1.06 (d, J=6.4Hz, 3H), 0.68-0.74 (m, 3H).

Example 224: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-(methyl(pyridin-2-yl)amino)-3-nitro heterospiro[5.5] undec-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide .

Referring to the method in Example 92, using N-picoline-2-amine as starting material, the title compound was obtained. MS m/z [LC-MS]: 658.42 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ＝8.43(s, 1H), 8.13(d, J＝3.6Hz, 1H), 7.86(s, 1H), 7.39-7.43(m, 1H), 6.91-6.99 (m,2H),6.67-6.70(m,0.5H),6.54-6.60(m,0.5H),6.45-6.51(m,2H),4.33-4.44(m,1H),3.59-4.06(m, 4H),3.40-3.56(m,2H),2.85(s,3H),2.32-2.78(m,7H),2.06-2.22(m,1H),1.51-1.89(m,14H),1.46(d, J=6.8Hz, 3H), 1.21-1.36(m, 2H), 1.12-1.18(m, 6H).

Example 225: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-(methyl(5-methylisoxazol-3-yl) Amino)-3- azaspiro[5.5]undec-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 92, using N,5-dimethylisoxazol-3-amine as a raw material, the title compound was obtained. MS m/z [LC-MS]: 662.42 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.41(s,0.5H),8.40(s,0.5H),7.81(s,1H),6.91-7.01(m,2H),6.65-6.68(m, 0.5H),6.58-6.61(m,0.5H),5.55(s,1H),3.60-3.94(m,3.5H),3.34-3.54(m,3H),3.19-3.25(m,0.5H), 2.76(s,3H),2.18-2.57(m,10H),1.96-2.12(m,1H),1.49-1.81(m,12H),1.46(d,J＝6.8Hz,3H),1.31-1.39( m,2H), 1.04-1.20(m,8H).

Example 226: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-(piperidin-4-ylamino)-3-azaspiro[ 5.5] Undecyl -3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

Step 1: (S)-4-((3-((1-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine- 3-yl)methyl)-3-azaspiro[5.5]undec-9-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

Referring to the method in Example 92, using tert-butyl 4-aminopiperidine-1-carboxylate as starting material, the title compound was obtained. MS m/z [LC-MS]: 750.51 [M+1].

Step 2: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-(piperidin-4-ylamino)-3-azaspiro[5.5 ]undecyl-3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride

Referring to the method of step 2 in Example 83, (S)-4-((3-((1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine -4-yl)pyrrolidin-3-yl)methyl)-3-azaspiro[5.5]undec-9-yl)amino)piperidine-1-carboxylic acid tert-butyl ester as raw material to obtain the target compound . MS m/z [LC-MS]: 650.46 [M+1]. ¹ H NMR (400MHz, DMSO-d ₆ ):δ=10.54-10.66(brs,1H),9.42-9.56(m,2H),9.26-9.35(m,1H),8.92-9.04(m,1H), 8.68(s,1H),8.01(s,1H),7.22-7.33(m,3H),3.86-4.10(m,1H),3.23-3.74(m,9H),2.66-3.22(m,8H), 2.09-2.26(m,4H),1.94-2.04(m,1H),1.54-1.92(m,10H),1.20-1.46(m,10H),1.08(d,J＝6.4Hz,3H),0.95- 0.98 (m,3H).

Example 227: (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-((2-methoxyethyl)amino)-3-nitro Heterospiro[5.5]undec -3-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)benzamide

Referring to the method in Example 92, using 2-methoxyethylamine as the starting material, the title compound was obtained. MS m/z [LC-MS]: 625.42 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.41(s,0.5H),8.39(s,0.5H),7.85(s,1H),6.91-7.01(m,2H),6.69(dd,J= 9.2Hz, 4.4Hz, 0.5H), 6.50(dd, J＝8.4Hz, 4.0Hz, 0.5H), 4.07-4.12(m, 0.5H), 3.72-3.88(m, 4.5H), 3.41-3.60( m,3H),3.34(s,3.5H),2.92-3.28(m,7.5H),2.73-2.90(m,1H),2.23-2.33(m,1H),1.80-2.20(m,8H), 1.54-1.78 (m, 3H), 1.48-1.51 (m, 3H), 1.42-1.45 (m, 3H), 1.11-1.31 (m, 9H).

Example 228: (S)-5-fluoro-N,N-diisopropyl-2-((5-(3-((9-(pyrimidin-5-ylamino)-3-azaspiro[5.5 ]undecyl -3-yl)methyl)pyrrolidin-1-yl)-1,2,4-triazin-6-yl)oxy)benzamide

Referring to the method in Example 148, using intermediate 93 and 5-bromopyrimidine as starting materials, the title compound was obtained. MS m/z [LC-MS]: 646.40 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.55(s,1H),8.52(s,1H),8.07(s,2H),7.23-7.30(m,0.5H),7.18-7.21(m,0.5 H),7.08-7.15(m,1H),6.89-6.96(m,1H),4.38-4.80(m,0.5H),3.98-4.34(m,1.5H),2.76-3.90(m,12H), 1.74-2.52(m,10H),1.39-1.72(m,9H),1.16-1.36(m,2H),1.08(d,J=6.4Hz,3H),0.72(d,J=6.4Hz,3H) .

Example 229: 2-((5-(7-((1-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptan-2-yl) Sulfonyl )-1,2,3,6-tetrahydropyridin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4- Triazin-6-yl)oxy)-5-fluoro -N,N-diisopropylbenzamide

Step 1: (1S,4S)-5-((4-((2-(6-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)-1,2,4- Triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)-3,6-dihydropyridin-1(2H)-yl)sulfonyl)-2 , tert-Butyl 5-diazabicyclo[2.2.1]heptane-2-carboxylate

Referring to the method in step 1 in Example 83, using intermediate 115 as a starting material, the title compound was obtained. MS m/z [LC-MS]: 798.41 [M+1].

Step 2: 2-((5-(7-((1-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)sulfonyl)-1, 2,3,6-tetrahydropyridin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl) Oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, with (1S,4S)-5-((4-((2-(6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy )-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)-3,6-dihydropyridine-1(2H) -yl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as raw material to obtain the target compound. MS m/z [LC-MS]: 678.36 [M+1].

Step 3: 2-((5-(7-((1-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)sulfo Acyl)-1,2,3,6-tetrahydropyridin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazine -6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, 2-((5-(7-((1-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2- Base)sulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4 -Triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride as starting material to obtain the target compound. MS m/z [LC-MS]: 753.37 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.45(s, 1H), 7.23-7.26(m, 1H), 7.07-7.12(m, 1H), 6.95(dd, J=7.6Hz, 3.2Hz, 1H ),6.37-6.43(m,1.3H),6.28(dd,J＝16.8Hz,10.0Hz,0.7H),5.71-5.74(m,1H),5.51-5.57(m,1H),4.98(s, 0.7H), 4.63(s, 0.3H), 4.42-4.48(m, 2H), 4.27(d, J=10.4Hz, 1H), 3.64-3.90(m, 6H), 3.22-3.54(m, 6H) ,2.81(s,2H),2.12-2.39(m,4H),1.90-2.04(m,2H),1.72-1.85(m,5H),1.58-1.68(m,1H),1.49(d,J= 6.8Hz, 3H), 1.37(d, J=6.8Hz, 3H), 1.07(d, J=6.8Hz, 3H), 0.70(d, J=6.8Hz, 3H).

Example 230: (S)-5-fluoro-2-((5-(3-((9-((2-fluorophenyl)amino)-3-azaspiro[5.5]undecane-3- Base)methyl) pyrrolidin-1-yl)-1,2,4-triazin-6-yl)oxy)-N,N-diisopropylbenzamide

Referring to the method in Example 148, using intermediate 93 and 1-bromo-2-fluorobenzene as starting materials, the title compound was obtained. MS m/z [LC-MS]: 662.40 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.51 (s, 1H), 7.18-7.22 (m, 1H), 7.07-7.14 (m, 1H), 6.93-6.98 (m, 3H), 6.64-6.68 ( m,1H),6.56-6.62(m,1H),3.72-3.88(m,2H),3.17-3.68(m,6H),2.62-3.08(m,4H),0.98-2.56(m,26H), 0.72 (d, J=6.8Hz, 3H).

Example 231: (S)-5-fluoro-N,N-diisopropyl-2-((5-(3-((9-(pyridin-3-ylamino)-3-azaspiro[5.5 ]undecyl -3-yl)methyl)pyrrolidin-1-yl)-1,2,4-triazin-6-yl)oxy)benzamide

Referring to the method in Example 148, using Intermediate 93 and 3-bromopyridine as starting materials, the title compound was obtained. MS m/z [LC-MS]: 645.40 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ):δ=8.52(s,1H),8.20(s,1H),7.86(s,1H),7.18-7.31(m,2H),7.01-7.16(m,2H) ,6.90-6.96(m,1H),3.71-3.89(m,2H),3.12-3.68(m,6H),2.70-3.10(m,4H),1.02-2.52(m,26H),0.72(d, J=6.8Hz, 3H).

Example 232: (S)-5-fluoro-N,N-diisopropyl-2-((5-(3-((9-(pyrazin-2-ylamino)-3-azaspiro[ 5.5] Undecyl -3-yl)methyl)pyrrolidin-1-yl)-1,2,4-triazin-6-yl)oxy)benzamide

Referring to the method in Example 148, using Intermediate 93 and 2-bromopyrazine as starting materials, the title compound was obtained. MS m/z [LC-MS]: 646.40 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.51(s, 1H), 7.94(s, 1H), 7.83(s, 1H), 7.76(d, J=2.8Hz, 1H), 7.24-7.30(m ,0.3H),7.18-7.21(m,0.7H),7.08-7.14(m,1H),6.90-6.96(m,1H),4.64-4.77(m,0.3H),4.40-4.59(m,1H ),4.26-4.37(m,0.7H),3.98-4.18(m,1H),3.66-3.90(m,4H),3.50-3.64(m,2H),2.68-3.46(m,9H),1.64- 2.52 (m, 11H), 1.44-1.47 (m, 6H), 1.07-1.09 (m, 3H), 0.72 (d, J=6.4Hz, 3H).

Example 233: 2-((5-((S)-3-((7-(((R)-3-acrylamidinylpiperidin-1-yl)sulfonyl)-2,7-diazepine Spiro[3.5] nonan-2-yl)methyl)pyrrolidin-1-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropyl phenylbenzamide

Step 1: ((R)-1-((2-(((S)-1-(6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)-1,2 ,4-triazin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)piperidin-3-yl)amino tert-butyl formate

Referring to the method in Step 1 in Example 83, using Intermediate 89 and Intermediate 96 as raw materials, the title compound was obtained. MS m/z [LC-MS]: 788.43 [M+1].

Step 2: 2-((5-((S)-3-((7-(((R)-3-aminopiperidin-1-yl)sulfonyl)-2,7-diazaspiro[3.5 ]nonan-2-yl)methyl)pyrrolidin-1-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzyl Amide hydrochloride

Referring to the method of step 2 in Example 83, ((R)-1-((2-(((S)-1-(6-(2-(diisopropylcarbamoyl)-4-fluoro Phenoxy)-1,2,4-triazin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl) Piperidin-3-yl) tert-butyl carbamate as starting material to obtain the target compound. MS m/z [LC-MS]: 688.38 [M+1].

Step 3: 2-((5-((S)-3-((7-(((R)-3-acrylamidinylpiperidin-1-yl)sulfonyl)-2,7-diazaspiro [3.5] Nonan-2-yl)methyl)pyrrolidin-1-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropyl benzamide

Referring to the method of step 3 in Example 83, with 2-((5-((S)-3-((7-(((R)-3-aminopiperidin-1-yl)sulfonyl))-2, 7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N, N-diisopropylbenzamide hydrochloride was used as starting material to obtain the target compound. MS m/z [LC-MS]: 742.39 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.47(s, 1H), 7.17-7.24(m, 1H), 7.06-7.11(m, 1H), 6.93-6.96(m, 1H), 6.27(d, J＝17.2Hz, 1H), 6.05-6.12(m, 2H), 5.65(d, J＝10.4Hz, 1H), 4.02-4.22(m, 2H), 3.68-3.94(m, 3H), 3.48-3.63 (m,1H),2.94-3.44(m,13H),2.44-2.58(m,2H),2.16-2.33(m,1H),2.01-2.15(m,1H),1.54-1.86(m,12H) , 1.48 (d, J=6.4Hz, 3H), 1.06-1.08 (m, 3H), 0.68-0.74 (m, 3H).

Example 234: 2-((5-((S)-3-((7-(((R)-3-acrylamidopyrrolidin-1-yl)sulfonyl)-2,7-diazepine Spiro[3.5 ] nonan-2-yl)methyl)pyrrolidin-1-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropyl phenylbenzamide

Step 1: ((R)-1-((2-(((S)-1-(6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)-1,2 ,4-triazin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)pyrrolidin-3-yl)amino tert-butyl formate

Referring to the method in Step 1 in Example 83, using Intermediate 89 and Intermediate 99 as raw materials, the title compound was obtained. MS m/z [LC-MS]: 774.41 [M+1].

Step 2: 2-((5-((S)-3-((7-(((R)-3-aminopyrrolidin-1-yl)sulfonyl)-2,7-diazaspiro[3.5 ]nonan-2-yl)methyl)pyrrolidin-1-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzyl Amide hydrochloride

Referring to the method of step 2 in Example 83, ((R)-1-((2-(((S)-1-(6-(2-(diisopropylcarbamoyl)-4-fluoro Phenoxy)-1,2,4-triazin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl) Pyrrolidin-3-yl) tert-butyl carbamate as starting material to obtain the target compound. MS m/z [LC-MS]: 674.36 [M+1].

Step 3: 2-((5-((S)-3-((7-(((R)-3-acrylamidopyrrolidin-1-yl)sulfonyl)-2,7-diazaspiro [3.5] Nonan-2-yl)methyl)pyrrolidin-1-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropyl benzamide

Referring to the method of step 3 in Example 83, with 2-((5-((S)-3-((7-(((R)-3-aminopyrrolidin-1-yl)sulfonyl)-2, 7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N, N-diisopropylbenzamide hydrochloride was used as starting material to obtain the target compound. MS m/z [LC-MS]: 728.37 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.48(s, 1H), 7.16-7.24(m, 1H), 7.06-7.11(m, 1H), 6.92-6.95(m, 1H), 6.27(d, J＝16.4Hz,1H),5.88-6.10(m,2H),5.59-5.69(m,1H),4.49-4.61(m,1H),4.01-4.20(m,1H),3.68-3.98(m, 3H),3.24-3.62(m,6H),3.14-3.23(m,4H),2.94-3.08(m,4H), 2.44-2.58(m,2H),1.93-2.33(m,5H),1.76- 1.84 (m, 3H), 1.56-1.74 (m, 4H), 1.48 (d, J=6.8Hz, 3H), 1.06-1.07 (m, 3H), 0.69-0.74 (m, 3H).

Example 235: (S)-2-((5-(3-((7-((4-acrylamidopiperidin-1-yl)sulfonyl)-2,7-diazaspiro[3.5] Nonan -2-yl)methyl)pyrrolidin-1-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: (S)-(1-((2-((1-(6-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)-1,2,4-tri oxazin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)piperidin-4-yl)carbamate tert-butyl

Referring to the method in Step 1 in Example 83, using Intermediate 89 and Intermediate 95 as starting materials, the title compound was obtained. MS m/z [LC-MS]: 788.43 [M+1].

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

Referring to the method of step 2 in Example 83, (S)-(1-((2-((1-(6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy) -1,2,4-triazin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)piperidine-4 -yl) tert-butyl carbamate as raw material to obtain the target compound. MS m/z [LC-MS]: 688.38 [M+1].

Step 3: (S)-2-((5-(3-((7-((4-acrylamidinylpiperidin-1-yl)sulfonyl)-2,7-diazaspiro[3.5]nonyl Alk-2-yl)methyl)pyrrolidin-1-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, (S)-2-((5-(3-((7-((4-aminopiperidin-1-yl)sulfonyl)-2,7-diazepine Heterospiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diiso Propylbenzamide hydrochloride was used as starting material to obtain the target compound. MS m/z [LC-MS]: 742.39 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.47(s, 1H), 7.18-7.25(m, 1H), 7.06-7.11(m, 1H), 6.94(dd, J=8.0Hz, 2.8Hz, 1H ), 6.28(dd, J=17.2Hz, 1.2Hz, 1H), 6.05(dd, J=17.2Hz, 10.4Hz, 1H), 5.65(dd, J=10.4Hz, 1.2Hz, 1H), 5.48(d ,J＝8.0Hz,1H),4.07-4.20(m,0.5H),3.92-4.04(m,1H),3.64-3.86(m,4.5H),3.48-3.63(m,1H),3.22-3.42 (m,2H),3.10-3.20(m,4H),2.96-3.08(m,4H),2.86-2.96(m,2H),2.44-2.58(m,2H),2.16-2.34(m,1H) ,1.90-2.15(m,4H),1.76-1.83(m,3H),1.56-1.74(m,4H),1.44-1.55(m,5H),1.06-1.07(m,3H),0.69-0.75( m,3H).

Example 236: 2-((4-(7-((1-(((1S,4S)-5-(cyclopent-1-en-1-acyl)-2,5-diazabicyclo[2.2 .1] heptane-2- yl)sulfonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy )-5-fluoro-N,N- diisopropylbenzamide

Referring to the method of step 3 in Example 83, 2-((4-(7-((1-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2- Base)sulfonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N, N-diisopropylbenzamide hydrochloride and cyclopent-1-ene-1-acyl chloride were used as raw materials to obtain the target compound. MS m/z [LC-MS]: 793.42 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.34(s,1H),7.73(s,1H),6.95-6.99(m,2H),6.73-6.77(m,1H),6.14-6.18(m, 0.6H),5.97-6.03(m,0.4H),4.90(s,0.6H),4.62(s,0.4H),4.38(s,0.4H),4.34(s,0.6H),3.63-4.08( m,8H),3.40-3.55(m,4H),3.22-3.30(m,1H),2.42-2.76(m,6H),2.17-2.36(m,3H),2.10(d,J＝6.4Hz, 2H), 1.66-2.01(m, 11H), 1.52(d, J＝6.8Hz, 3H), 1.46(d, J＝6.8Hz, 3H), 1.12-1.21(m, 2H), 1.11(d, J =6.8Hz, 3H), 1.07(d, J=6.8Hz, 3H).

Example 237: 2-((5-(7-((1-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptan-2-yl) Sulfonyl )-4-fluoropiperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl )oxy)-5-fluoro-N,N- diisopropylbenzamide

Step 1: (1S,4S)-5-((4-((2-(6-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)-1,2,4- Triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)-4-fluoropiperidin-1-yl)sulfonyl)-2,5-diazepine Heterobicyclo[2.2.1]heptane-2-carboxylate tert-butyl ester

Referring to the method in step 1 in Example 83, the title compound was obtained using intermediate 116 as a starting material. MS m/z [LC-MS]: 818.42 [M+1].

Step 2: 2-((5-(7-((1-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)sulfonyl)-4- Haloperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5- Fluoro-N,N-diisopropylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, (1S,4S)-5-((4-((2-(6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy )-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)-4-fluoropiperidin-1-yl)sulfonyl )-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as raw material to obtain the target compound. MS m/z [LC-MS]: 718.37 [M+1].

Step 3: 2-((5-(7-((1-(((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)sulfo Acyl)-4-fluoropiperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy base)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, 2-((5-(7-((1-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2- Base)sulfonyl)-4-fluoropiperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazine-6- base)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride as raw material to obtain the target compound. MS m/z [LC-MS]: 772.38 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.45(s, 1H), 7.22-7.26(m, 1H), 7.07-7.12(m, 1H), 6.95(dd, J=7.6Hz, 3.2Hz, 1H ),6.37-6.47(m,1.3H),6.28(dd,J＝16.8Hz,10.4Hz,0.7H),5.71-5.74(m,1H),4.99(s,0.7H),4.62(s,0.3 H),4.38-4.48(m,2H),4.22-4.31(m,1H),3.72-3.90(m,3.7H),3.64-3.68(m,0.3H),3.48-3.63(m,3.4H) ,3.32-3.41(m,2.3H),3.24(d,J＝9.2Hz,0.3H),3.00-3.11(m,2H),2.34-2.60(m,6H),1.90-2.04(m,3.3H ),1.58-1.85(m,6.7H),1.49(d,J=6.8Hz,3H),1.37(d,J=6.8Hz,3H),1.07(d,J=6.4Hz,3H),0.72( d, J=6.4Hz, 3H).

Example 238: (E)-2-((4-(7-((1-(N-(3-chloro-2-(4-(dimethylamino)but-2-enamido)propyl )sulfonamido) piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N, N - Diisopropylbenzamide

Step 1: (1-((4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-di Azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)azetidin-3-yl)carbamate tert-butyl

Referring to the method in Step 1 in Example 83, using Intermediate 94 and Intermediate 98 as starting materials, the title compound was obtained. MS m/z [LC-MS]: 773.42 [M+1].

Step 2: 2-((4-(7-((1-(N-(2-amino-3-chloropropyl)sulfonamido)piperidin-4-yl)methyl)-2,7-bis Azaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, (1-((4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine-4- Base)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)azetidin-3-yl)carbamate tert-butyl ester is The raw materials were stirred at room temperature for 14 hours to obtain the target compound. MS m/z [LC-MS]: 709.34 [M+1].

Step 3: (E)-2-((4-(7-((1-(N-(3-chloro-2-(4-(dimethylamino)but-2-enamido)propyl) Sulfonamido)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N -Diisopropylbenzamide

Referring to the method of step 3 in Example 83, 2-((4-(7-((1-(N-(2-amino-3-chloropropyl)sulfonamido)piperidin-4-yl)methyl Base)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride and Starting from (E)-4-(dimethylamino)but-2-enoyl chloride, the target compound was obtained. MS m/z [LC-MS]: 820.41 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.35(s,1H),7.75(s,1H),6.94-7.00(m,2H),6.74-6.88(m,2H),6.65-6.73(brs, 1H),6.08(d,J＝14.8Hz,1H),5.24-5.42(brs,1H),4.28-4.37(m,1H),3.83-4.02(m,4H),3.60-3.80(m,5H) ,3.44-3.51(m,1H),3.14-3.42(m,3H),3.06-3.12(m,1H),2.66-2.73(m,3H),2.24-2.42(m,9H),2.11-2.18( m,2H),1.72-1.85(m,7H),1.54-1.64(m,2H),1.53(d,J＝6.8Hz,3H),1.47(d,J＝6.8Hz,3H),1.12(d , J=6.4Hz, 3H), 1.08(d, J=6.4Hz, 3H).

Example 239: 2-((4-(7-((1-((2-acryloyl-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)piperidine-4- Base) methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: 7-((4-((2-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diaze Heterospiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester

Referring to the method in Step 1 in Example 83, using Intermediate 94 and Intermediate 73 as starting materials, the title compound was obtained. MS m/z [LC-MS]: 827.47 [M+1].

Step 2: 2-((4-(7-((1-((2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)piperidin-4-yl)methyl)- 2,7-Diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, 7-((4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl )-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)-2,7-diazaspiro[3.5]nonane-2- Using tert-butyl carboxylate as starting material, the target compound was obtained. MS m/z [LC-MS]: 727.41 [M+1].

Step 3: 2-((4-(7-((1-((2-acryloyl-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)piperidin-4-yl )methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, 2-((4-(7-((1-((2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)piperidine- 4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzyl Amide hydrochloride as starting material to obtain the target compound. MS m/z [LC-MS]: 781.42 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.34(s,1H),7.74(s,1H),6.95-7.00(m,2H),6.73-6.77(m,1H),6.33(dd,J= 16.8Hz, 1.6Hz, 1H), 6.16(dd, J=16.8Hz, 10.0Hz, 1H), 5.67(dd, J=10.0Hz, 1.6Hz, 1H), 3.83-4.01(m, 6H), 3.73- 3.80(m,3H),3.61-3.68(m,2H),3.44-3.50(m,1H),3.10-3.24(m,4H),2.68-2.76(m,2H),2.20-2.38(m,3H ), 2.11(d, J=7.2Hz, 2H), 1.68-1.88(m, 12H), 1.52(d, J=6.8Hz, 3H), 1.46(d, J=6.8Hz, 3H), 1.12-1.20 (m, 2H), 1.11 (d, J=6.8Hz, 3H), 1.07 (d, J=6.8Hz, 3H).

Example 240: 2-((4-(7-((1-((6-acryloyl-2,6-diazaspiro[3.3]heptane-2-yl)sulfonyl)piperidine-4- Base) methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Step 1: 6-((4-((2-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diaze Heterospiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

Referring to the method in Step 1 in Example 83, using Intermediate 94 and Intermediate 84 as raw materials, the title compound was obtained. MS m/z [LC-MS]: 799.43 [M+1].

Step 2: 2-((4-(7-((1-((2,6-diazaspiro[3.3]heptan-2-yl)sulfonyl)piperidin-4-yl)methyl)- 2,7-Diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride

Referring to the method of step 2 in Example 83, 6-((4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl )-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2- Using tert-butyl carboxylate as starting material, the target compound was obtained. MS m/z [LC-MS]: 699.38 [M+1].

Step 3: 2-((4-(7-((1-((6-acryloyl-2,6-diazaspiro[3.3]heptan-2-yl)sulfonyl)piperidin-4-yl )methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, 2-((4-(7-((1-((2,6-diazaspiro[3.3]heptane-2-yl)sulfonyl)piperidine- 4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzyl Amide hydrochloride as starting material to obtain the target compound. MS m/z [LC-MS]: 753.39 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.34(s,1H),7.74(s,1H),6.95-6.99(m,2H),6.73-6.73(m,1H),6.32(d,J= 16.8Hz, 1H), 6.12(dd, J＝16.8Hz, 10.4Hz, 1H), 5.68(d, J＝10.4Hz, 1H), 4.29(s, 2H), 4.16(s, 2H), 3.83-3.99 (m,8H),3.73-3.80(m,1H),3.67-3.70(m,2H),3.43-3.50(m,1H),2.70(td,J＝12.0Hz,1.6Hz,2H),2.20- 2.34(m, 3H), 2.10(d, J=6.8Hz, 2H), 1.69-1.88(m, 8H), 1.52(d, J=6.8Hz, 3H), 1.46(d, J=6.8Hz, 3H ), 1.12-1.20 (m, 2H), 1.11 (d, J=6.8Hz, 3H), 1.07 (d, J=6.8Hz, 3H).

Example 241: 2-((4-(7-((1-(((1S,4S)-5-((E)-2-cyano-4,4-dimethylpent-2-enoyl )-2,5-diazabicyclo [2.2.1]heptane-2-yl)sulfonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane -2-yl)pyrimidin-5-yl)oxy )-5-fluoro-N,N-diisopropylbenzamide

Referring to the method of step 3 in Example 83, 2-((4-(7-((1-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2- Base)sulfonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N, N-diisopropylbenzamide hydrochloride and (E)-2-cyano-4,4-dimethylpent-2-enoyl chloride were used as raw materials to obtain the target compound. MS m/z [LC-MS]: 834.45 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.34(s,1H),7.73(s,1H),7.33(s,0.6H),7.30(s,0.4H),6.94-6.99(m,2H) ,6.73-6.76(m,1H),4.80(s,1H),4.42(s,0.4H),4.37(s,0.6H),3.64-4.02(m,8H),3.55(s,1H),3.41 -3.49(m,2.4H),3.28(dd,J=9.2Hz,2.0Hz,0.6H),2.66-2.72(m,2H),2.16-2.38(m,3H),2.09(d,J=6.8 Hz, 2H), 1.66-2.04(m, 9H), 1.51(d, J=6.8Hz, 3H), 1.46(d, J=7.2Hz, 3H), 1.29(s, 3.6H), 1.28(s, 5.4H), 1.12-1.20 (m, 3H), 1.11 (d, J=6.8Hz, 3H), 1.07 (d, J=6.8Hz, 3H).

Example 242: (S)-2-((4-(3-((9-((3,6-dichloro-1,2,4-triazin-5-yl)amino)-3-aza Spiro[5.5]undec-3- yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Add intermediate 76 (57mg), 3,5,6-trichloro-1,2,4-triazine (20mg) diisopropylethylamine (39mg) into dichloromethane (5mL), stir at room temperature 2 hours. After filtration, the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (dichloromethane/methanol, 15:1) to obtain the target compound (48 mg). MS m/z [LC-MS]: 714.32 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.43(s,0.5H),8.42(s,0.5H),7.84(s,1H),6.91-7.01(m,2H),6.66-6.69(m, 0.5H),6.46-6.61(m,0.5H),5.70-5.81(m,1H),3.093-4.06(m,1H),3.60-3.88(m,3H), 3.40-3.56(m,2H), 3.04-3.28 (m, 1H), 2.15-3.01 (m, 6H), 1.85-2.07 (m, 4H), 1.39-1.82 (m, 15H), 1.12-1.22 (m, 8H).

Example 243: (S)-N-Ethyl-2-((5-(3-((7-(ethylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methanol Base) pyrrolidin-1-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N-isopropylbenzamide

Referring to the method in step 1 in Example 83, using intermediate 117 and ethylsulfonyl chloride as starting materials, the title compound was obtained. MS m/z [LC-MS]: 618.32 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.49(s, 1H), 7.17-7.25(m, 1H), 7.08-7.15(m, 1H), 6.97-7.04(m, 1H), 3.99-4.36( m,2H),2.94-3.98(m,13H),1.81-2.82(m,11H),1.46-1.78(m,5H),1.35(t,J＝7.6Hz,3H),1.02-1.12(m, 6H).

Example 244: (S)-N-ethyl-2-((5-(3-((9-(ethylsulfonamido)-3-azaspiro[5.5]undec-3-yl) Methyl) pyrrolidin-1-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N-isopropylbenzamide

Step 1: (S)-2-((3-Chloro-5-(3-((9-(ethanesulfonamido)-3-azaspiro[5.5]undec-3-yl)methyl) Pyrrolidin-1-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

Referring to the method of step 2 in Example 82, with (S)-N-(3-((1-(3,6-dichloro-1,2,4-triazin-5-yl)pyrrolidin-3- Base) methyl)-3-azaspiro[5.5]undec-9-yl)ethanesulfonamide and N-ethyl-5-fluoro-2-hydroxyl-N-isopropylbenzamide as raw materials, to obtain the target compound. MS m/z [LC-MS]: 680.32 [M+1].

Step 2: (S)-N-Ethyl-2-((5-(3-((9-(ethylsulfonamido)-3-azaspiro[5.5]undecane-3-yl)methanol Base) pyrrolidin-1-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N-isopropylbenzamide

Referring to the method of step 3 in Example 82, (S)-2-((3-chloro-5-(3-((9-(ethanesulfonamido)-3-azaspiro[5.5]undecane -3-yl)methyl)pyrrolidin-1-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide As raw materials, the target compound was obtained. MS m/z [LC-MS]: 646.32 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.49(s, 1H), 7.17-7.25(m, 1H), 7.08-7.16(m, 1H), 6.97-7.04(m, 1H), 4.18-4.37( m,1H),4.07(d,J＝7.2Hz,1H),2.99-3.97(m,9H),2.37-2.70(m,6H),1.95-2.24(m,6H),1.52-1.88(m, 9H), 1.34-1.48(m,6H), 1.02-1.09(m,6H).

Example 245: 5-fluoro-2-((5-(7-((1-(((1S,4S)-5-(2-fluoroacryloyl)-2,5-diazabicyclo[2.2. 1] Heptane -2-yl)sulfonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazine -6-yl)oxy)-N,N- diisopropylbenzamide

Referring to the method of step 3 in Example 83, 2-((5-(7-((1-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2- Base)sulfonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy )-5-fluoro-N,N-diisopropylbenzamide hydrochloride and 2-fluoroacryloyl chloride as raw materials to obtain the target compound. MS m/z [LC-MS]: 772.38 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ): δ=8.45(s, 1H), 7.23-7.26(m, 1H), 7.06-7.12(m, 1H), 6.95(dd, J=7.6Hz, 3.2Hz, 1H ),5.52-5.69(m,1H),5.13-5.20(m,1H),4.92(s,0.6H),4.84-4.88(m,0.4H),4.43-4.51(m,1H),4.38-4.42 (m,1H),4.24-4.31(m,1H),3.82-3.92(m,2H),3.74-3.81(m,1H),3.47-3.72(m,4H),3.28-3.42(m,3H) ,2.71(t,J=12.0Hz,2H),2.22-2.42(m,3H),2.12(d,J=7.2Hz,2H),1.95-2.02(m,2H),1.76-1.88(m,7H ),1.52-1.68(m,3H),1.49(d,J=6.8Hz,3H),1.37(d,J=6.8Hz,3H),1.07(d,J=6.8Hz,3H),0.70(d , J=6.8Hz, 3H).

biological test

Biochemical Detection of Compounds Inhibiting the Binding of Menin and MLL

Wild-type Menin can bind with high affinity to the N-terminal conserved sequence of MLL, and the compound binds to Menin by competing with the N-terminus of MLL. FITC-MLL (4-43) (synthesized by GenScript) contains the conserved sequence of MLL binding to Menin. Through the Fluorescence Polarization Binding Assay (FP Assay), we constructed a detection method for the binding activity of Menin and MLL and used it to detect the inhibitory binding activity of the compound. The specific method is as follows:

Compounds were serially diluted 5-fold starting from 1 mM with 100% DMSO (8 concentrations in total). Take 2 μl of each concentration and add to 48 μl of reaction buffer (50mM NaCl, 50mM Tris (pH 7.5), 0.05% Tween-20, 1mM DTT) and mix well as 4* compounds (final concentrations are 10000, 2000, 400, 80, 16, 3.2, 0.64, OnM) for use. Prepare 2*Menin with reaction buffer, the final concentration is 5nM, 4*FITC-MLL(4-43), the final concentration is 2nM. Take 5 μl of the 4* compound and add it to a 384-well plate (OptiPlate-384, purchased from PerkinElmer), add 10 μl of 2*Menin, centrifuge, then add 5 μl of FITC-MLL (4-43), centrifuge to start the reaction, and keep at 23°C. Light reaction for 1 hour. After the reaction, the signal value (excitation wavelength 480 nm/emission wavelength 535 nm) was read on EnVison2104 Multilabel Reader (purchased from PerkinElmer). The data is processed by the data analysis software GraphPad Prism and the _IC50 value of the compound is obtained

Determination of cell proliferation activity of compounds:

MV-4-11 cells are human acute myeloid leukemia cells, which contain MLL-AF4 fusion protein. In this experiment, after incubating different concentrations of compounds with MV-4-11 cells, Promega’s

Detection Reagent A screening method for MV-4-11 cell proliferation inhibition was established.

MV-4-11 cells were cultured with 1640 (Biological Industries, Cat. No. 01-100-1ACS) medium containing 10% fetal calf serum (Biological Industries, Cat. CO ₂ . Subculture 2-3 times a week. Seed cells at 5000 cells/well in 96-well cell culture plate

Medium, 195 μL/well, and cultured at 37°C, 5% CO ₂ . After 24 hours, the compound was serially diluted 3 times with 100% DMSO starting from 10 mM and mixed (10 concentrations in total), and then 4 μL of each concentration was added to 96 μL of RPMI-1640 medium for dilution and mixed. 5 μL of each concentration of the diluted compound was added to the paved cell suspension, and the compound and the cells were co-incubated for 72 hours (3 days) in the cell culture incubator. Afterwards, 35 μL of CellTiter-Blue (Promega, Cat. No. G8082) reagent was added, and reacted at 37° C., 5% CO ₂ for 4 hours. The chemiluminescence value was read on the BMG Clariostar Microplate Reader, the data was processed using GraphPad Prism software, and the IC ₅₀ value of the compound on cell proliferation inhibition was calculated.

Note: * refers to multiplication, indicating multiples.

Table 1. Example compounds bind to Menin-MLL protein and inhibit activity of MV-4-11 cell proliferation

Table 1 lists the IC ₅₀ values of the inhibitory activity of the compounds of the examples of the present invention on Menin-MLL protein binding and MV-4-11 cell proliferation. The data show that the compounds provided by the present invention all have good binding inhibitory activity to Menin-MLL protein, and also have good inhibitory activity on the proliferation of MLL-AF4 positively expressing MV-4-11 cells.

Determination of pharmacokinetic data of compounds in SD rats

Male SD rats were derived from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., and the rats were divided into groups, 3 in each group, and the suspension of the sample to be tested was orally administered respectively (10 mg/kg, the suspension was 0.5% MC +0.1% SDS). The animals were fasted overnight before the experiment, and the fasting time was from 10 hours before administration to 4 hours after administration. Blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. After being anesthetized with isoflurane using a small animal anesthesia machine, 0.3mL whole blood was collected through the fundus venous plexus and placed in a heparin anticoagulant tube. The sample was centrifuged at 4°C and 4000rpm for 5min, and the plasma was transferred to a centrifuge tube and placed at -80°C. Store at °C until analysis. Plasma samples were extracted by protein precipitation, and the extract was analyzed by LC/MS. The test results of some compounds are shown in Table 2.

The pharmacokinetic parameter of table 2 embodiment compound

Table 2 lists the pharmacokinetic data of the reference substance and the compounds of the embodiments of the present invention in SD rats. It shows that the compound provided by the invention has a better metabolic level in vivo.

Determination of Compounds' Inhibition of CYP450 Subtype 3A4

The relative activity of the test substance and the positive control to the main subtype CYP3A4 metabolite of the mixed human liver microsomal CYP450 enzyme was detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the positive control substance and the test substance were calculated for their relative activity. The IC50 value of the inhibitory effect of mixed human liver microsomal cytochrome P450 enzymes was used to evaluate the in vitro inhibitory effect of the test substance on the main subtype of CYP450 enzymes, CYP3A4.

The experiment was divided into a positive control group and a test object group. Positive controls or test substances were incubated with human liver microsomes and probe substrates for CYP3A4 enzymes, including human liver microsomes (0.05mg/mL), NADPH (1.5mM), PBS buffer (100mM, PH=7.4) , probe substrates (midazolam 4 μM or testosterone 40 μM) and inhibitors (final concentrations of test substances are 0, 1, 2.5, 5.0, 10.0, 25.0 μM; positive control ketoconazole final concentrations are 0, 0.0025, 0.005 , 0.01, 0.025, 0.05, 0.1, 0.25μM.), the total volume of incubation is 100μL. The specific operation steps are as follows:

2.1 Preparation of liver microsome dilution

The 20 mg/mL stock solution of human liver microsomes was thawed on ice, and diluted 40 times with PBS buffer (100 mM, pH=7.4) to prepare a 0.5 mg/mL dilution of liver microsomes.

2.2 Preparation of mixed incubation solution

A mixed incubation solution containing liver microsome dilution and substrate solution (midazolam or testosterone) was prepared using PBS buffer (100 mM, pH=7.4).

2.3 Pre-incubate the mixed incubation solution in a constant temperature shaker at 37°C and 100 rpm for 5 minutes.

2.4 After pre-incubation, add different concentrations of test substance working solution or positive control ketoconazole working solution (the final concentration of test substance is 0, 1, 2.5, 5.0, 10.0, 25.0 μM; the final concentration of positive control ketoconazole is 0, 0.0025, 0.005, 0.01, 0.025, 0.05, 0.1, 0.25μM.), vortex and mix well, add NADPH (final concentration 1.5mM) to start the reaction, and continue to place it in a constant temperature shaker at 37°C and 100rpm. The total volume of incubation is 100 μL, the concentration of organic solvent in the incubation system is within 1%. After incubation for a certain period of time (10 minutes for the solution whose probe substrate is midazolam, and 15 minutes for the solution whose probe substrate is testosterone), add 150 μL ice internal standard After vortex shaking, centrifuge at 12000rpm for 10 minutes, take 200 μL of supernatant and analyze it by UPLC-MS/MS, and calculate the peak area of each metabolite and internal standard propranolol by MassLynx V4.1 SCN962 software , and then use Excel software to calculate the peak area ratio of each metabolite (metabolite peak area/internal standard peak area). The inhibitory IC50 values of the positive control group and the test substance were obtained by directly calculating the two concentration points in Excel, or by Graphpad Prism (version 6.01) software.

Table 3 Example Compounds Inhibition of CYP450 Enzyme Main Subtype Subtype 3A4

实施例Example	IC ₅₀(μM) _IC50 (μM)
191191	>25>25
202202	>25>25
203203	2525
216216	>25>25
217217	>25>25
218218	>25>25
219219	>25>25
221221	>25>25
223223	>25>25
243243	>25>25
244244	>25>25

Table 3 lists the IC ₅₀ values of the inhibitory effect of the compounds of the examples of the present invention on the main subtype 3A4 of CYP450 enzymes (with midazolam as the substrate). The data show that the compound provided by the invention has a very weak inhibitory effect on the main subtype 3A4 of CYP450 enzymes, which is beneficial to avoid potential drug-drug interaction risks and improve the safety of clinical medication.

Claims

A compound of formula (III) or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof,

in,

Y 3 is NR 6 or

X is

L is a bond, -(CO)-, or -CR 11 R 12 -,

V is N or CH,

U is N or CR 16 ,

Ring A is a 3-12 membered carbocyclic ring or a 3-12 membered heterocyclic ring,

Ring B is a benzene ring or a 5-6 membered heteroaromatic ring,

The C ring is a 3-12 member nitrogen-containing heterocycle,

Y 1 is -O-, -S-, -NR 13 -, or -CR 11 R 12 -,

Y 2 is a bond, -O-, -S-, or -NR 13 -,

R 6 is -CN, C 1-6 alkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -(CO)-CH=CH 2 ,
or
The alkyl, aryl and heteroaryl groups can be optionally substituted by halogen, CF 3 , C 1-6 alkyl, -NR 13 R 14 or -OR 1 ,

R 7 is hydrogen, -OR 13 , -NR 13 R 14 , C 1-6 alkyl, or C 3-8 cycloalkyl, and the C 1-6 alkyl or C 3-8 cycloalkyl can be optionally replaced by halogen,

Z is -(CO)-NR 13 R 14 or -(CO)-OR 13 ,

R 1 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CF 3 , -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) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS(O) 2 R 15 , -NR 13 -S(O) 2 R 15 ,
or

R 2 are each independently hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl , CF 3 , -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) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS (O) 2 R 15 , -NR 13 -S(O) 2 R 15 ,
or

R3 is halogen,

R 4 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CF 3 , -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) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS(O) 2 R 15 , -NR 13 -S(O) 2 R 15 ,
or

R 5 are each independently hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl , CF 3 , -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) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS (O) 2 R 15 , -NR 13 -S(O) 2 R 15 ,
or

R 11 and R 12 are each independently selected from H, halogen, CN, OH, C 1-6 alkyl, C 1-6 alkyl-O-, C 3-8 cycloalkyl, amino, C 1-6 alkane Baseamino or C 2-8 dialkylamino; said C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkylamino or C 2-8 dialkylamino can optionally be halogen substitution,

R 15 are each independently selected from H, 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, the C 1-6 alkyl, C 3-8 cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered hetero Aryl, C 2-6 alkenyl or C 2-6 alkynyl 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 is substituted,

R 41 is H or C 1-6 alkyl, the alkyl may be optionally substituted by -NR 13 R 14 or -OR 13 ,

R 42 and R 43 are each independently selected from H and halogen,

R 13 and R 14 are each independently selected from hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl, said C 1-6 alkyl or C 3-8 cycloalkyl may be optionally substituted by halogen ,

R 16 is selected from H, halogen, CN, OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, amino, C 1-6 alkylamino or C 2-8 di Alkylamino; the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 1-6 alkylamino or C 2-8 dialkylamino can optionally be halogen substitution,

R 30 and R 31 are each independently selected from hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl,

R 40 is selected from hydrogen, -CN, -(CO)-CH═CH 2 , C 1-6 alkyl and C 3-8 cycloalkyl, the C 1-6 alkyl or C 3-8 cycloalkyl optionally substituted by halogen,

m is each independently 0, 1, or 2,

n is each independently 0, 1, 2, or 3,

p is each independently 0 or 1.
The compound according to claim 1 or its pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug, wherein

Y 3 is NR 6 or

X is

L is a bond, -(CO)-, or -CR 11 R 12 -,

V is N or CH,

U is N or CR 16 ,

Ring A is a 3-12 membered carbocyclic ring or a 3-12 membered heterocyclic ring,

Ring B is a benzene ring or a 5-6 membered heteroaromatic ring,

The C ring is a 3-12 member nitrogen-containing heterocycle,

Y 1 is -O-, -S-, -NR 13 -, or -CR 11 R 12 -,

Y 2 is a bond, -O-, -S-, or -NR 13 -,

R 6 is -CN, C 1-6 alkyl, 5-12 membered heteroaryl, -(CO)-CH=CH 2 ,
or
The alkyl group can be optionally substituted by halogen,

R 7 is hydrogen, -OR 13 , -NR 13 R 14 , C 1-6 alkyl, or C 3-8 cycloalkyl, and the C 1-6 alkyl or C 3-8 cycloalkyl can be optionally replaced by halogen,

Z is -(CO)-NR 13 R 14 or -(CO)-OR 13 ,

R 1 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CF 3 , -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) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS(O) 2 R 15 , -NR 13 -S(O) 2 R 15 ,
or

R 2 are each independently hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl , CF 3 , -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) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS (O) 2 R 15 , -NR 13 -S(O) 2 R 15 ,
or

R3 is halogen,

R 4 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CF 3 , -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) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS(O) 2 R 15 , -NR 13 -S(O) 2 R 15 ,
or

R 5 are each independently hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl , CF 3 , -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) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS (O) 2 R 15 , -NR 13 -S(O) 2 R 15 ,
or

R 11 and R 12 are each independently selected from H, halogen, CN, OH, C 1-6 alkyl, C 1-6 alkyl-O-, C 3-8 cycloalkyl, amino, C 1-6 alkane Baseamino or C 2-8 dialkylamino; said C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkylamino or C 2-8 dialkylamino can optionally be halogen substitution,

R 15 are each independently selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, 3-12 membered heterocycloalkyl, C 2-6 alkenyl and C 2-6 alkynyl, the C 1-6 alkyl, C 3-8 cycloalkyl, 3-12 membered heterocycloalkyl, C 2-6 alkenyl or C 2-6 alkynyl can be optionally replaced by halogen, -(CO)-R 41 , or -(CO)-CH=CHR 41 substituted,

R 41 is H or C 1-6 alkyl, the alkyl may be optionally substituted by -NR 13 R 14 or -OR 13 ,

R 13 and R 14 are each independently selected from hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl, said C 1-6 alkyl or C 3-8 cycloalkyl may be optionally substituted by halogen ,

R 16 is selected from H, halogen, CN, OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, amino, C 1-6 alkylamino or C 2-8 di Alkylamino; the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 1-6 alkylamino or C 2-8 dialkylamino can optionally be halogen substitution,

R 30 and R 31 are each independently selected from hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl,

R 40 is selected from hydrogen, -CN, -(CO)-CH═CH 2 , C 1-6 alkyl and C 3-8 cycloalkyl, the C 1-6 alkyl or C 3-8 cycloalkyl optionally substituted by halogen,

m is each independently 0, 1, or 2,

n is each independently 0, 1, 2, or 3,

p is each independently 0 or 1.
According to claim 1 or its pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug of the compound described in claim 1, said compound has the structure shown in formula (II),

in,

X is

L is a key or -CR 11 R 12 -,

V is N or CH,

U is N or CR 16 ,

Ring A is a 3-12 membered carbocyclic ring or a 3-12 membered heterocyclic ring,

Ring B is a benzene ring or a 5-6 membered heteroaromatic ring,

The C ring is a 3-12 member nitrogen-containing heterocycle,

Y 1 is -O-, -S-, -NR 13 -, or -CR 11 R 12 -,

Y 2 is a bond, -O-, -S-, or -NR 13 -,

R 6 is C 1-6 alkyl,
or
The alkyl group can be optionally substituted by halogen,

R 7 is hydrogen, -OR 13 , -NR 13 R 14 , C 1-6 alkyl, or C 3-8 cycloalkyl, and the C 1-6 alkyl or C 3-8 cycloalkyl can be optionally replaced by halogen,

Z is -(CO)-NR 13 R 14 or -(CO)-OR 13 ,

R 1 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CF 3 , -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) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS(O) 2 R 15 , -NR 13 -S(O) 2 R 15 ,
or

R 2 are each independently hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl , CF 3 , -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) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS (O) 2 R 15 , -NR 13 -S(O) 2 R 15 ,
or

R3 is halogen,

R 4 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CF 3 , -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) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS(O) 2 R 15 , -NR 13 -S(O) 2 R 15 ,
or

R 5 are each independently hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl , CF 3 , -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) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS (O) 2 R 15 , -NR 13 -S(O) 2 R 15 ,
or

R 11 and R 12 are each independently selected from H, halogen, CN, OH, C 1-6 alkyl, C 1-6 alkyl-O-, C 3-8 cycloalkyl, amino, C 1-6 alkane Baseamino or C 2-8 dialkylamino; said C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkylamino or C 2-8 dialkylamino can optionally be halogen substitution,

R 13 and R 14 are each independently selected from hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl, said C 1-6 alkyl or C 3-8 cycloalkyl may be optionally substituted by halogen ,

R 15 are each independently selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, C 2-6 alkenyl and C 2-6 alkynyl, the C 1-6 alkyl, C 3- 8 cycloalkyl, C 2-6 alkenyl or C 2-6 alkynyl may be optionally substituted by halogen,

R 16 is selected from H, halogen, CN, OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, amino, C 1-6 alkylamino or C 2-8 di Alkylamino; the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 1-6 alkylamino or C 2-8 dialkylamino can optionally be halogen substitution,

R 30 and R 31 are each independently selected from hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl,

m is each independently 0, 1, or 2,

n is each independently 0, 1, 2, or 3,

p is each independently 0 or 1.
According to claim 1 or its pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug of the compound described in claim 1, said compound has the structure shown in formula (I),

in,

X is

U is N or CR 16 , the A ring is a 3-12 membered carbocyclic ring or a 3-12 membered heterocyclic ring,

Ring B is a benzene ring or a 5-6 membered heteroaromatic ring,

The C ring is a 3-12 member nitrogen-containing heterocycle,

Y 1 is -O-, -S-, -NR 13 -, or -CR 11 R 12 -,

Y 2 is a bond, -O-, -S-, or -NR 13 -,

R6 is
or

R 7 is hydrogen, -OR 13 , -NR 13 R 14 , C 1-6 alkyl, or C 3-8 cycloalkyl, and the C 1-6 alkyl or C 3-8 cycloalkyl can be optionally replaced by halogen,

Z is -(CO)-NR 13 R 14 or -(CO)-OR 13 ,

R 1 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CF 3 , -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) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS(O) 2 R 15 , -NR 13 -S(O) 2 R 15 ,
or

R 2 are each independently hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl , CF 3 , -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) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS (O) 2 R 15 , -NR 13 -S(O) 2 R 15 ,
or

R3 is halogen,

R 4 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CF 3 , -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) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS(O) 2 R 15 , -NR 13 -S(O) 2 R 15 ,
or

R 5 are each independently hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl , CF 3 , -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) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS (O) 2 R 15 , -NR 13 -S(O) 2 R 15 ,
or

R 11 and R 12 are each independently selected from H, halogen, 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 dialkyl The amino group can be optionally substituted by halogen, R 13 and R 14 are each independently selected from hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl, the C 1-6 alkyl or C 3-8 ring Alkyl can be optionally substituted by halogen,

R 15 is selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, C 2-6 alkenyl and C 2-6 alkynyl, the C 1-6 alkyl, C 3-8 cycloalkane Base, C 2-6 alkenyl or C 2-6 alkynyl may be optionally substituted by halogen,

R 16 is selected from H, halogen, CN, OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, amino, C 1-6 alkylamino or C 2-8 di Alkylamino; the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 1-6 alkylamino or C 2-8 dialkylamino can optionally be halogen substitution

m is each independently 0, 1, or 2,

n is each independently 0, 1, 2, or 3,

p is each independently 0 or 1.
The compound according to claim 4 or its pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug, wherein

X is

U is N or CR 16 , the A ring is a 3-12 membered carbocyclic ring or a 3-12 membered heterocyclic ring,

Ring B is a benzene ring or a 5-6 membered heteroaromatic ring,

The C ring is a 3-8 membered nitrogen-containing heterocycle,

Y 1 is -O-, -S-, -NR 13 -, or -CR 11 R 12 -,

Y 2 is -O-, -S-, or -NR 13 -,

R6 is
or

R 7 is hydrogen, -OR 13 , -NR 13 R 14 , C 1-6 alkyl, or C 3-8 cycloalkyl, and the C 1-6 alkyl or C 3-8 cycloalkyl can be optionally replaced by halogen,

Z is -(CO)-NR 13 R 14 or -(CO)-OR 13 ,

R 1 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CF 3 , -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) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS(O) 2 R 15 , -NR 13 -S(O) 2 R 15 ,
or

R 2 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CF 3 , -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) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS(O) 2 R 15 , -NR 13 -S(O) 2 R 15 ,
or

R3 is halogen,

R 4 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CF 3 , -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) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS(O) 2 R 15 , -NR 13 -S(O) 2 R 15 ,
or

R 5 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CF 3 , -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) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS(O) 2 R 15 , -NR 13 -S(O) 2 R 15 ,
or

R 11 and R 12 are each independently selected from H, halogen, 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 dialkyl The amino group can be optionally substituted by halogen, R 13 and R 14 are each independently selected from hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl, the C 1-6 alkyl or C 3-8 ring Alkyl can be optionally substituted by halogen,

R 15 is selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, C 2-6 alkenyl and C 2-6 alkynyl, the C 1-6 alkyl, C 3-8 cycloalkane Base, C 2-6 alkenyl or C 2-6 alkynyl may be optionally substituted by halogen,

R 16 is selected from H, halogen, CN, OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, amino, C 1-6 alkylamino or C 2-8 di Alkylamino; the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 1-6 alkylamino or C 2-8 dialkylamino can optionally be halogen substitution

m is each independently 0, 1, or 2,

n is each independently 0, 1, 2, or 3,

p is each independently 0 or 1.
The compound according to claim 1 or its pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug, wherein Y 3 is
L is a bond, V is N, p is 1, Z is -(CO)-NR 13 R 14 , Y 1 is -NR 13 -, Y 2 is a bond or -NR 13 -, R 16 is H, R 6 is
R 3 is fluorine, R 40 , R 13 , R 14 and R 15 are as defined in claim 1.
The compound according to claim 1 or its pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug, wherein m is each independently 0 or 1, n each independently ground is 0 or 1.
The compound according to claim 1 or its pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug, wherein R 1 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl.
The compound according to claim 1 or its pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug, wherein

R 2 are each independently hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl , CF 3 , -NR 13 R 14 , or -OR 13 .

R 4 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CF 3 , -NR 13 R 14 , or -OR 13 .

R 5 are each independently hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl , CF 3 , -NR 13 R 14 , or -OR 13 ,

R 13 and R 14 are as defined in claim 1 .
The compound according to claim 1 or its pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug, wherein

R 11 and R 12 are hydrogen,

R 13 and R 14 are each independently selected from hydrogen and C 1-6 alkyl,

R 15 is selected from C 1-6 alkyl and C 3-8 cycloalkyl.
According to any one of claims 1-10, the compound or its pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug, wherein,

C ring is
The following compounds or pharmaceutically acceptable salts, solvates, polymorphs, tautomers, metabolites or prodrugs thereof:
A pharmaceutical composition comprising a compound according to any one of claims 1-12 or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof , and optionally include a pharmaceutically acceptable carrier.
The compound according to any one of claims 1-12 or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof, or according to claim 13 Use of the pharmaceutical composition of the invention in the preparation of a medicament for treating diseases associated with MLL activity.
The use according to claim 14, wherein the disease associated with MLL activity is cancer, preferably acute leukemia (comprising 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 myelogenous leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma (including B-cell lymphoma), myeloma (including multiple myeloma), Brain tumors, head and neck cancers, esophageal cancers, thyroid cancers, small cell lung cancers, non-small cell lung cancers, breast cancers, stomach cancers, gallbladder and bile duct cancers, liver cancers, hepatocellular carcinomas, pancreatic cancers, colon cancers, rectal cancers, anal cancers, villi Membranous epithelioma, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, urothelial cancer, 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.