WO2020114474A1

WO2020114474A1 - Heterocyclic compound, application thereof and pharmaceutical composition containing same

Info

Publication number: WO2020114474A1
Application number: PCT/CN2019/123479
Authority: WO
Inventors: 胡永韩; 吴冬冬; 彭薇; 卢亮; 李昕; 张秀春; 王入志; 朱升; 黄彬; 刘涛; 朱金莲; 吴予川
Original assignee: 苏州信诺维医药科技有限公司
Priority date: 2018-12-06
Filing date: 2019-12-06
Publication date: 2020-06-11
Also published as: CN111285875A; CN111285875B

Abstract

Disclosed are a heterocyclic compound, an application thereof and a pharmaceutical composition containing same. The structure of the compound is as shown in formula I-0, and the inhibitory effect of the compound to RET kinase is better.

Description

Heterocyclic compound, its application and pharmaceutical composition containing it

This application requires the priority of the Chinese patent application 201811487386.8 with the filing date of December 6, 2018. This application requires the priority of Chinese patent application 201910361420.5 with an application date of April 30, 2019. This application cites the entire text of the aforementioned Chinese patent application.

Technical field

The invention relates to a heterocyclic compound, its application and pharmaceutical composition containing the same.

Background technique

The RET gene was transformed and cultured in mouse NTH3T3 cells by Takahashi et al. (Takahashi M, Ritz J, Cooper GM. Activation, of novel human, transforming gene, ret, by DNA rearrangement. Cell, 1985, 42(2): 581-588) Found in and named RET gene. The RET gene is a proto-oncogene located on the long arm of chromosome 10 (10q11.2). The encoded RET protein is a tyrosine kinase receptor composed of a cysteine-rich cadherin-like extracellular region, The three parts of the transmembrane domain and the intracellular domain with tyrosine kinase activity are 37% amino acid identical to the ALK kinase domain. RET protein stimulates receptor dimerization through ligand-receptor binding, and autophosphorylation and intracellular substrate phosphorylation occur in the intracellular region, thereby activating downstream signals, which play an important role in the process of cell proliferation, migration and differentiation effect.

Under normal physiological conditions, RET is related to kidney development and gastrointestinal nervous system development. However, mutations in the RET gene lead to ligand-independent, abnormal activation of constitutive RET kinase, leading to tumorigenesis. There are two main mechanisms for RET kinase activation: 1. RET gene point mutation; 2. RET gene rearrangement. RET missense mutations may occur on extracellular Cys residues (eg C620R, C634R/W), causing abnormal kinase activation. Mutations may also occur in the intracellular kinase active domain (eg: V804L/M, M918T), this mutation will promote ligand-independent RET kinase activation (Romei C, Ciampi R, Elisei RA, comprehensive overview of the role of the RET) proto-oncogene in thyroid carcinoma. Nat Rev Endocrinol 2016; 12:192-202.). Point mutations of RET in medullary thyroid carcinoma (MTC) are very common and are present in approximately 50% of sporadic MTCs and almost all familial MTCs. The RET gene recombines by breaking itself and joining with other genes to become a new fusion gene, so that the activation of RET tyrosine kinase escapes the regulation of ligand and further self-phosphorylates, thereby enhancing signal transduction function and promoting kinase activation , Triggering tumor formation. In 10-20% of papillary thyroid carcinoma (PTC), 1-2% of non-small cell lung cancer (NSCLC) and many other cancers, such as colon cancer and breast cancer, have RET fusion. The above results indicate that dysregulation of the RET signaling pathway is an important driving cause of many tumor diseases.

There are currently no specific inhibitors for RET on the market, but some multi-target tyrosine kinase inhibitors have been used in clinical studies of patients with RET gene mutations, such as: vandetanib, carbotinib, and lovastib Nepal etc. At present, multi-target tyrosine kinase inhibitors in patients with RET fusion NSCLC are worse than other NSCLC driver genes in terms of effectiveness and survival data. In addition, patients with long-term exposure to RET TKIs have a high incidence of grade 3-4 toxicity due to the inhibition of VEGFR kinase. Therefore, the development of RET-specific inhibitors with higher selectivity and stronger activity will increase efficacy and limit toxicity, and are expected to become a new method for the treatment of various malignant tumors such as thyroid cancer and NSCLC.

Blueprint Medicines patent WO2017079140 contains the clinically RET inhibitor compound BLU-667

Blueprint Medicines patent WO2018017983 discloses another class of compounds. The structure of compound 218 is as follows:

Summary of the invention

The technical problem to be solved by the present invention is that the structure of the existing compound is relatively simple. For this reason, the present invention provides a heterocyclic compound, its application and a pharmaceutical composition containing the same. The compound has better inhibitory effect on RET kinase.

The present invention provides a heterocyclic compound represented by Formula I-0, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystal form thereof;

Wherein R ¹ is hydrogen, fluorine, difluoromethyl, methoxy, cyclopropyl or C ₁ ～C ₄ alkyl;

Y ¹ is N or CH;

Y ² is N, CH, C(F), C(Cl) or C(CN);

R ⁹ is hydrogen, methyl or difluoromethyl;

middle

Is a single or double bond; when

When it is a single bond, X ¹ is N, CH, C(OH), C(F) or C(OCH ₃ ); when

When it is a double bond, X ¹ is C;

s is 0 or 1; t is 0 or 1;

middle

Is a single or double bond; when

When it is a single bond, X ³ is N, X ² is CH ₂ or C (=O); when

When it is a double bond, X ³ is C and X ² is N;

X ⁴ is

{Wherein, b with ends X ³ X ^4} connector

A ¹ is N;

A ² is N or CR ^{^3;} R ³ is hydrogen, cyano, amino, C ₁ ~ C ₄ alkyl, fluoro-substituted C ₁ ~ C ₄ alkyl, substituted C ₃ ~ C ₆ cycloalkyl, or fluoro C ₃ ～C ₆ cycloalkyl;

A ³ is C(═O), NR ⁴ , CH ₂ , O or S; R ⁴ is hydrogen, C ₁ ～C ₄ alkyl, fluorine substituted C ₁ ～C ₄ alkyl, C ₃ ～C ₆ cycloalkane C ₁ -C ₄ alkyl group substituted by C ₁ group, C ₃ -C ₆ cycloalkyl group, or C ₃ -C ₆ cycloalkyl group substituted by fluorine

A ⁴ is NR ⁵ , C(═O), C(═S) or CH ₂ ; R ⁵ is hydrogen, C ₁ ～C ₄ alkyl, fluorine substituted C ₁ ～C ₄ alkyl, C ₃ ～C ₆ Cycloalkyl, or C ₃ ～C ₆ cycloalkyl substituted with fluorine;

n is 0 or 1;

A ⁵ is NR ¹⁰ , CH ₂ , O or S; R ¹⁰ is hydrogen, C ₁ ～C ₄ alkyl, fluorine substituted C ₁ ～C ₄ alkyl, C ₃ ～C ₆ cycloalkyl substituted C ₁ ～ C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₃ -C ₆ cycloalkyl substituted with fluorine;

A ⁶ is C (=O) or CH ₂ ;

A ⁷ is

Or CR ¹¹ R ¹² ; R ¹¹ and R ^{12 are} independently hydrogen or C ₁ ˜C ₄ alkyl, but R ¹¹ and R ^{12 are} not hydrogen at the same time;

X ⁶ is C (=O) or CHR ² ;

R ² is hydrogen or C ₁ ～C ₄ alkyl;

X ⁵ is N or CH;

R ⁶ is hydrogen, halogen, cyclopropyl, or, unsubstituted or halogen-substituted C ₁ ～C ₄ alkyl;

R ⁷ is hydrogen or halogen;

R ⁸ is hydrogen, halogen, cyclopropyl, or unsubstituted or halogen-substituted C ₁ to C ₄ alkyl.

In a certain technical solution, the heterocyclic compound I-0, its pharmaceutically acceptable salt, its solvate, the solvate of its pharmaceutically acceptable salt, or certain groups in its crystalline form The definition of can be as follows, and the definition of an unspecified group is as described in any of the previous schemes (hereinafter referred to as “in a certain technical scheme”): R ¹ is C ₁ ˜C ₄ alkyl.

In a technical solution: R ¹ is methyl.

In a certain technical solution: Y ¹ is CH.

In a certain technical solution: Y ² is N or CH.

In a certain technical solution: Y ² is N.

In a certain technical solution: R ⁹ is hydrogen or methyl.

In a certain technical solution: R ⁹ is methyl.

In a technical solution:

middle

Is a single or double bond; when

When it is a single bond, X ¹ is N or CH; when

When it is a double bond, X ¹ is C.

In a technical solution:

middle

Is a single key; when

When it is a single bond, X ¹ is N or CH.

In a technical solution: s is 1; t is 1.

In a technical solution: X ⁴ is

In a technical solution: when X ⁴ is

In this case, A ² is CR ³ ; R ³ is hydrogen, amino, or C ₁ -C ₄ alkyl.

In a technical solution: when X ⁴ is

In this case, A ² is CR ³ ; R ³ is amino or C ₁ ˜C ₄ alkyl.

In a technical solution: when X ⁴ is

, A ² is CR ³ ; R ³ is amino, methyl or isopropyl.

In a technical solution: when X ⁴ is

, A ³ is NR ⁴ , CH ₂ , O or S; R ⁴ is hydrogen, C ₁ ～C ₄ alkyl, fluorine substituted C ₁ ～C ₄ alkyl, C ₃ ～C ₆ cycloalkyl substituted C ₁ to C ₄ alkyl, C ₃ to C ₆ cycloalkyl, or C ₃ to C ₆ cycloalkyl substituted with fluorine.

In a technical solution: when X ⁴ is

, A ³ is NR ⁴ , CH ₂ , O or S; R ⁴ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH ₂ CF ₃ , cyclopropane, -CH ₂ -Cyclopropane.

In a technical solution: when X ⁴ is

At this time, A ⁴ is C (=O), C (=S) or CH ₂ .

In a technical solution: when X ⁴ is

, A ⁴ is C (=O) or CH ₂ .

In a technical solution: when X ⁴ is

, A ⁴ is C (=O).

In a technical solution: when X ⁴ is

When, A ⁵ is NR ¹⁰ , CH ₂ , O or S; R ¹⁰ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH ₂ CF ₃ , cyclopropane, -CH ₂ -Cyclopropane.

In a technical solution: n is 1.

In a certain technical solution: X ⁶ is CHR ² .

In a technical solution: R ² is C ₁ ˜C ₄ alkyl.

In a certain technical solution: R ² is hydrogen or methyl.

In a technical solution: X ⁵ is CH.

In a technical solution: R ⁶ is hydrogen.

In a technical solution: R ⁷ is halogen.

In a technical solution: R ⁷ is F.

In a technical solution: R ⁸ is hydrogen.

In a certain technical scheme: R ¹ is C ₁ ～C ₄ alkyl;

Y ¹ is CH;

Y ² is N or CH;

R ⁹ is hydrogen or methyl;

middle

Is a single or double bond; when

When it is a single bond, X ¹ is N or CH; when

When it is a double bond, X ¹ is C;

s is 0 or 1; t is 0 or 1;

middle

Is a single or double bond; when

When it is a single bond, X ³ is N, X ² is CH ₂ or C (=O); when

When it is a double bond, X ³ is C and X ² is N;

X ⁴ is

{Wherein, b with ends X ³ X ^4} connector

A ¹ is N;

A ² is CR ³ ; R ³ is hydrogen, amino or C ₁ ～C ₄ alkyl;

A ⁴ is C (=O), C (=S) or CH ₂ ;

n is 0 or 1;

A ⁶ is C (=O) or CH ₂ ;

A ⁷ is

X ⁶ is C (=O) or CHR ² ;

R ² is hydrogen or C ₁ ～C ₄ alkyl;

X ⁵ is CH;

R ⁶ is hydrogen;

R ⁷ is halogen;

R ⁸ is hydrogen.

In a certain technical scheme: R ¹ is C ₁ ～C ₄ alkyl;

Y ¹ is CH;

Y ² is N or CH;

R ⁹ is hydrogen or methyl;

middle

Is a single or double bond; when

When it is a single bond, X ¹ is N or CH; when

When it is a double bond, X ¹ is C;

s is 0 or 1; t is 0 or 1;

middle

Is a single or double bond; when

When it is a single bond, X ³ is N, X ² is CH ₂ or C (=O); when

When it is a double bond, X ³ is C and X ² is N;

X ⁴ is

{Wherein, b with ends X ³ X ^4} connector

A ¹ is N;

A ² is CR ³ ; R ³ is amino or C ₁ ～C ₄ alkyl;

A ³ is NR ⁴ , CH ₂ , O or S; R ⁴ is hydrogen, C ₁ ～C ₄ alkyl, fluorine substituted C ₁ ～C ₄ alkyl, C ₃ ～C ₆ cycloalkyl substituted C ₁ ～ C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or C ₃ -C ₆ cycloalkyl substituted with fluorine;

A ⁴ is C (=O) or CH ₂ ;

n is 0 or 1;

A ⁶ is C (=O) or CH ₂ ;

A ⁷ is

X ⁶ is C (=O) or CHR ² ;

R ² is hydrogen or C ₁ ～C ₄ alkyl;

X ⁵ is CH;

R ⁶ is hydrogen;

R ⁷ is halogen;

R ⁸ is hydrogen.

In a technical solution: R ¹ is methyl;

Y ¹ is CH;

Y ² is N or CH;

R ⁹ is hydrogen or methyl;

middle

Is a single or double bond; when

When it is a single bond, X ¹ is N or CH; when

When it is a double bond, X ¹ is C;

s is 0 or 1; t is 0 or 1;

middle

Is a single or double bond; when

When it is a single bond, X ³ is N, X ² is CH ₂ or C (=O); when

When it is a double bond, X ³ is C and X ² is N;

X ⁴ is

{Wherein, b with ends X ³ X ^4} connector

A ¹ is N;

A ² is CR ³ ; R ³ is amino, methyl or isopropyl;

A ³ is NR ⁴ , CH ₂ , O or S; R ⁴ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH ₂ CF ₃ , cyclopropane, -CH ₂ -ring Propane

A ⁴ is C (=O) or CH ₂ ;

n is 0 or 1;

A ⁵ is NR ¹⁰ , CH ₂ , O or S; R ¹⁰ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH ₂ CF ₃ , cyclopropane, -CH ₂ -ring Propane

A ⁶ is C (=O) or CH ₂ ;

A ⁷ is

Or CR ¹¹ R ¹² ; R ¹¹ and R ^{12 are} independently hydrogen or methyl, but R ¹¹ and R ^{12 are} not hydrogen at the same time;

X ⁶ is C (=O) or CHR ² ;

R ² is hydrogen or methyl;

X ⁵ is CH;

R ⁶ is hydrogen;

R ⁷ is F;

R ⁸ is hydrogen.

In a technical solution: R ¹ is methyl;

Y ¹ is CH;

Y ² is N;

R ⁹ is methyl;

middle

Is a single key; when

When it is a single bond, X ¹ is N or CH;

s is 1; t is 1;

middle

Is a single key; when

When it is a single bond, X ³ is N and X ² is C (=O);

X ⁴ is

{Wherein, b with ends X ³ X ^4} connector

A ⁴ is C (=O);

n is 1;

X ⁶ is CHR ² ;

R ² is C ₁ ～C ₄ alkyl;

X ⁵ is CH;

R ⁶ is hydrogen;

R ⁷ is halogen;

R ⁸ is hydrogen.

In a certain technical solution: R ¹ is hydrogen, fluorine, difluoromethyl, methoxy, cyclopropyl or C ₁ ～C ₄ alkyl;

Y ¹ is N or CH;

Y ² is N, CH, C(F), C(Cl) or C(CN);

R ⁹ is hydrogen, methyl or difluoromethyl;

middle

Is a single or double bond; when

When it is a single bond, X ¹ is N, CH, C(OH), C(F) or C(OCH ₃ ); when

When it is a double bond, X ¹ is C;

s is 0 or 1; t is 0 or 1;

middle

Is a single or double bond; when

When it is a single bond, X ³ is N, X ² is CH ₂ or C (=O); when

When it is a double bond, X ³ is C and X ² is N;

X ⁴ is

{Wherein, b with ends X ³ X ^4} connector

A ⁶ is C (=O) or CH ₂ ;

A ⁷ is

X ⁶ is C (=O) or CHR ² ;

R ² is hydrogen or C ₁ ～C ₄ alkyl;

X ⁵ is N or CH;

R ⁷ is hydrogen or halogen;

In a certain technical solution: when R ¹ is C ₁ -C ₄ alkyl, the C ₁ -C ₄ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec Butyl, isobutyl or tert-butyl.

In a certain technical solution: when R ¹ is C ₁ -C ₄ alkyl, the C ₁ -C ₄ alkyl is methyl.

In a technical solution: when

When it is a double bond,

for

In a technical solution: when

When it is a single bond and X ¹ is CH, C(OH), C(F) or C(OCH ₃ ),

for

In a certain technical solution: when R ³ is a C ₁ -C ₄ alkyl group, the C ₁ -C ₄ alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary Butyl, isobutyl or tert-butyl.

In a certain technical solution: when R ³ is C ₁ -C ₄ alkyl, the C ₁ -C ₄ alkyl is methyl or isopropyl.

In a certain technical solution: when R ³ is a C ₁ -C ₄ alkyl group substituted with fluorine, the number of the fluorine is one or more.

In a certain technical solution: when R ³ is a fluorine-substituted C ₁ -C ₄ alkyl group, the number of the fluorine is 1, 2, or 3.

In a certain technical solution: when R ³ is a fluorine-substituted C ₁ -C ₄ alkyl group, the C ₁ -C ₄ alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl Group, sec-butyl, isobutyl or tert-butyl.

In a certain technical solution: when R ³ is fluorine-substituted C ₁ -C ₄ alkyl, the fluorine-substituted C ₁ -C ₄ alkyl is trifluoromethyl.

In a certain technical solution: when R ³ is C ₃ -C ₆ cycloalkyl, the C ₃ -C ₆ cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In a certain technical solution: when R ³ is a C ₃ -C ₆ cycloalkyl substituted with fluorine, the number of the fluorine is one or more.

In a certain technical solution: when R ³ is a C ₃ -C ₆ cycloalkyl substituted with fluorine, the number of the fluorine is 1, 2, or 3.

In a certain technical solution: when R ³ is a fluorine-substituted C ₃ ～C ₆ cycloalkyl, the C ₃ ～C ₆ cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl .

In a certain technical solution: when R ⁴ is C ₁ -C ₄ alkyl, the C ₁ -C ₄ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec Butyl, isobutyl or tert-butyl.

In a certain technical solution: when R ⁴ is C ₁ -C ₄ alkyl, the C ₁ -C ₄ alkyl is methyl, ethyl, n-propyl or n-butyl.

In a certain technical solution: when R ⁴ is a C ₁ -C ₄ alkyl group substituted with fluorine, the number of the fluorine is one or more.

In a certain technical solution: when R ⁴ is a fluorine-substituted C ₁ -C ₄ alkyl group, the number of said fluorine is 1, 2, or 3.

In a certain technical solution: when R ⁴ is a fluorine-substituted C ₁ -C ₄ alkyl group, the C ₁ -C ₄ alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl Group, sec-butyl, isobutyl or tert-butyl.

In a certain technical solution: when R ⁴ is fluorine-substituted C ₁ -C ₄ alkyl, the fluorine-substituted C ₁ -C ₄ alkyl is 2,2,2-trifluoroethyl or 2, 2-difluoroethyl.

In one aspect: when R ⁴ is a C ₃ ~ C ₆ cycloalkyl substituted with C ₁ ~ C ₄ alkyl, said C ₃ ~ C ₆ cycloalkyl group number is 1.

In one aspect: when R ⁴ is a C ₃ ~ C ₆ cycloalkyl substituted with C ₁ ~ C ₄ alkyl, said C ₃ ~ C ₆ cycloalkyl group is cyclopropyl, cyclobutyl, Cyclopentyl or cyclohexyl.

In a certain technical solution: when R ⁴ is C ₁ -C ₄ alkyl substituted with C ₃ -C ₆ cycloalkyl, the C ₁ -C ₄ alkyl is methyl, ethyl, n-propyl , Isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

In one aspect: when R ⁴ is a C ₃ ~ C ₆ cycloalkyl substituted with C ₁ ~ C ₄ alkyl, said C ₃ ~ C ₆ cycloalkyl substituted with C ₁ ~ C ₄ alkyl group It is cyclopropylmethyl.

In a certain technical solution: when R ⁴ is C ₃ -C ₆ cycloalkyl, the C ₃ -C ₆ cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In a certain technical solution: when R ⁴ is C ₃ -C ₆ cycloalkyl, the C ₃ -C ₆ cycloalkyl is cyclopropyl.

In a certain technical solution: when R ⁴ is a C ₃ -C ₆ cycloalkyl substituted with fluorine, the number of the fluorine is one or more.

In a certain technical solution: when R ⁴ is a C ₃ ˜C ₆ cycloalkyl substituted with fluorine, the number of the fluorine is 1, 2, or 3.

In a certain technical solution: when R ⁴ is a fluorine-substituted C ₃ -C ₆ cycloalkyl, the C ₃ -C ₆ cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl .

In a certain technical solution: when R ⁵ is C ₁ ˜C ₄ alkyl, the C ₁ ˜C ₄ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec Butyl, isobutyl or tert-butyl.

In a certain technical solution: when R ⁵ is C ₁ -C ₄ alkyl, the C ₁ -C ₄ alkyl is methyl.

In a certain technical solution: when R ⁵ is a C ₁ -C ₄ alkyl substituted with fluorine, the number of the fluorine is one or more.

In a certain technical solution: when R ⁵ is C ₁ -C ₄ alkyl substituted with fluorine, the number of fluorine is 1, 2, or 3.

In a certain technical solution: when R ⁵ is a fluorine-substituted C ₁ -C ₄ alkyl group, the C ₁ -C ₄ alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl Group, sec-butyl, isobutyl or tert-butyl.

In a certain technical solution: when R ⁵ is fluorine-substituted C ₁ -C ₄ alkyl, the fluorine-substituted C ₁ -C ₄ alkyl is trifluoromethyl.

In a certain technical solution: when R ⁵ is C ₃ -C ₆ cycloalkyl, the C ₃ -C ₆ cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In a certain technical solution: when R ⁵ is a C ₃ -C ₆ cycloalkyl substituted with fluorine, the number of the fluorine is one or more.

In a certain technical solution: when R ⁵ is fluorine-substituted C ₃ ˜C ₆ cycloalkyl, the number of said fluorine is 1, 2, or 3.

In a certain technical solution: when R ⁵ is fluorine-substituted C ₃ -C ₆ cycloalkyl, the C ₃ -C ₆ cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl .

In a certain technical solution: when R ¹⁰ is C ₁ -C ₄ alkyl, the C ₁ -C ₄ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec Butyl, isobutyl or tert-butyl.

In a certain technical solution: when R ¹⁰ is C ₁ -C ₄ alkyl, the C ₁ -C ₄ alkyl is methyl, ethyl, n-propyl or n-butyl.

In a certain technical solution: when R ¹⁰ is a fluorine-substituted C ₁ -C ₄ alkyl group, the number of the fluorine is one or more.

In a certain technical solution: when R ¹⁰ is a C ₁ -C ₄ alkyl group substituted with fluorine, the number of said fluorine is 1, 2, or 3.

In a certain technical solution: when R ¹⁰ is a fluorine-substituted C ₁ -C ₄ alkyl group, the C ₁ -C ₄ alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl Group, sec-butyl, isobutyl or tert-butyl.

In a certain technical solution: when R ¹⁰ is a fluorine-substituted C ₁ -C ₄ alkyl group, the fluorine-substituted C ₁ -C ₄ alkyl group is 2,2,2-trifluoroethyl or 2, 2-difluoroethyl.

In one aspect: when R ¹⁰ is C ₃ ~ C ₆ cycloalkyl substituted with C ₁ ~ C ₄ alkyl, said C ₃ ~ C ₆ cycloalkyl group number is 1.

In one aspect: when R ¹⁰ is C ₃ ~ C ₆ cycloalkyl substituted with C ₁ ~ C ₄ alkyl, said C ₃ ~ C ₆ cycloalkyl group is cyclopropyl, cyclobutyl, Cyclopentyl or cyclohexyl.

In a certain technical solution: when R ¹⁰ is C ₁ -C ₄ alkyl substituted with C ₃ -C ₆ cycloalkyl, the C ₁ -C ₄ alkyl is methyl, ethyl, n-propyl , Isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

In one aspect: when R ¹⁰ is C ₃ ~ C ₆ cycloalkyl substituted with C ₁ ~ C ₄ alkyl, said C ₃ ~ C ₆ cycloalkyl substituted with C ₁ ~ C ₄ alkyl group It is cyclopropylmethyl.

In a certain technical solution: when R ¹⁰ is C ₃ -C ₆ cycloalkyl, the C ₃ -C ₆ cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In a certain technical solution: when R ¹⁰ is C ₃ -C ₆ cycloalkyl, the C ₃ -C ₆ cycloalkyl is cyclopropyl.

In a certain technical solution: when R ¹⁰ is a C ₃ -C ₆ cycloalkyl substituted with fluorine, the number of said fluorine is one or more.

In a certain technical solution: when R ¹⁰ is a C ₃ -C ₆ cycloalkyl substituted with fluorine, the number of the fluorine is 1, 2, or 3.

In a certain technical solution: when R ¹⁰ is a fluorine-substituted C ₃ -C ₆ cycloalkyl, the C ₃ -C ₆ cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl .

In a certain technical solution: when R ¹¹ is C ₁ -C ₄ alkyl, the C ₁ -C ₄ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec Butyl, isobutyl or tert-butyl.

In a certain technical solution: when R ¹¹ is C ₁ -C ₄ alkyl, the C ₁ -C ₄ alkyl is methyl, ethyl, n-propyl or n-butyl.

In a certain technical solution: when R ¹² is C ₁ -C ₄ alkyl, the C ₁ -C ₄ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec Butyl, isobutyl or tert-butyl.

In a certain technical solution: when R ¹² is C ₁ -C ₄ alkyl, the C ₁ -C ₄ alkyl is methyl, ethyl, n-propyl or n-butyl.

In a technical solution: when X ⁶ is CHR ² ,

for

In a technical solution: when X ⁶ is CHR ² ,

When it is a double bond,

for

One or more of them.

In a technical solution: when X ⁶ is CHR ² ,

When it is a single bond and X ¹ is CH, C(OH), C(F) or C(OCH ₃ ),

for

One or more of them.

In a technical solution: when X ⁶ is CHR ² ,

When it is a single bond and X ¹ is N,

for

In a certain technical solution: when R ² is C ₁ -C ₄ alkyl, the C ₁ -C ₄ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec Butyl, isobutyl or tert-butyl.

In a certain technical solution: when R ² is C ₁ -C ₄ alkyl, the C ₁ -C ₄ alkyl is methyl.

In a certain technical solution: when R ⁶ is halogen, the halogen is fluorine, chlorine, bromine or iodine.

In a certain technical solution: when R ⁶ is halogen, the halogen is fluorine.

In a certain technical solution: when R ⁶ is halogen substituted C ₁ ˜C ₄ alkyl, the number of the “halogen” is one or more.

In a certain technical solution: when R ⁶ is a halogen-substituted C ₁ ˜C ₄ alkyl group, the number of the “halogen” is 1, 2, or 3.

In a certain technical solution: when R ⁶ is halogen-substituted C ₁ -C ₄ alkyl, the “halogen” is independently fluorine, chlorine, bromine or iodine.

In a certain technical solution: when R ⁶ is halogen substituted C ₁ ˜C ₄ alkyl, the “halogen” is fluorine.

In a technical solution: when R ⁶ is an unsubstituted or halogen-substituted C ₁ -C ₄ alkyl group, the C ₁ -C ₄ alkyl group is methyl, ethyl, n-propyl, isopropyl , N-butyl, sec-butyl, isobutyl or tert-butyl.

In a certain technical solution: when R ⁶ is unsubstituted or halogen-substituted C ₁ -C ₄ alkyl, the C ₁ -C ₄ alkyl is methyl.

In a certain technical solution: when R ⁶ is halogen-substituted C ₁ -C ₄ alkyl, the halogen-substituted C ₁ -C ₄ alkyl is difluoromethyl.

In a certain technical solution: when R ⁷ is halogen, the halogen is fluorine, chlorine, bromine or iodine.

In a certain technical solution: when R ⁷ is halogen, the halogen is fluorine.

In a technical solution: when R ⁸ is halogen, the halogen is fluorine, chlorine, bromine or iodine.

In a certain technical solution: when R ⁸ is halogen, the halogen is fluorine.

In a certain technical solution: when R ⁸ is halogen substituted C ₁ ˜C ₄ alkyl, the number of the “halogen” is one or more.

In a certain technical solution: when R ⁸ is a halogen-substituted C ₁ -C ₄ alkyl group, the number of the “halogen” is 1, 2, or 3.

In a certain technical solution: when R ⁸ is halogen substituted C ₁ ˜C ₄ alkyl, the “halogen” is independently fluorine, chlorine, bromine or iodine.

In a certain technical solution: when R ⁸ is halogen substituted C ₁ ˜C ₄ alkyl, the “halogen” is fluorine.

In a certain technical solution: when R ⁸ is unsubstituted or halogen-substituted C ₁ ～C ₄ alkyl, the C ₁ ～C ₄ alkyl is methyl, ethyl, n-propyl, isopropyl , N-butyl, sec-butyl, isobutyl or tert-butyl.

In a certain technical solution: when R ⁸ is unsubstituted or halogen-substituted C ₁ -C ₄ alkyl, the C ₁ -C ₄ alkyl is methyl.

In a certain technical solution: when R ⁸ is halogen-substituted C ₁ -C ₄ alkyl, the halogen-substituted C ₁ -C ₄ alkyl is difluoromethyl.

In a certain technical solution: except for the part whose stereo configuration has been determined, the rest of the heterocyclic compound I-0 is a mixture of various stereo configurations.

In a certain technical solution: all atoms in the heterocyclic compound I-0 are atoms with abundance of natural isotopes.

Y ¹ is N or CH;

Y ² is N, CH, C(F), C(Cl) or C(CN);

R ⁹ is hydrogen, methyl or difluoromethyl;

middle

Is a single or double bond; when

When it is a single bond, X ¹ is N, CH, C(OH), C(F) or C(OCH ₃ ); when

When it is a double bond, X ¹ is C;

s is 0 or 1; t is 0 or 1;

middle

Is a single or double bond; when

When it is a single bond, X ³ is N, X ² is CH ₂ or C (=O); when

When it is a double bond, X ³ is C and X ² is N;

X ⁴ is

{Wherein, b with ends X ³ X ^4} connector

A ¹ is N;

A ⁴ is NR ⁵ , C(═O) or CH ₂ ; R ⁵ is hydrogen, C ₁ -C ₄ alkyl, fluorine-substituted C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or, Fluorine-substituted C ₃ ～C ₆ cycloalkyl;

n is 0 or 1;

X ⁶ is C (=O) or CHR ² ;

R ² is hydrogen or C ₁ ～C ₄ alkyl;

X ⁵ is N or CH;

R ⁷ is hydrogen or halogen;

Y ¹ is N or CH;

Y ² is N, CH, C(F), C(Cl) or C(CN);

R ⁹ is hydrogen, methyl or difluoromethyl;

middle

Is a single or double bond; when

When it is a single bond, X ¹ is N, CH, C(OH), C(F) or C(OCH ₃ ); when

When it is a double bond, X ¹ is C;

s is 0 or 1; t is 0 or 1;

middle

Is a single or double bond; when

When it is a single bond, X ³ is N, X ² is CH ₂ or C (=O); when

When it is a double bond, X ³ is C and X ² is N;

X ⁴ is

{Wherein, b with ends X ³ X ^4} connector

A ¹ is N;

n is 0 or 1;

X ⁶ is C (=O) or CHR ² ;

R ² is hydrogen or C ₁ ～C ₄ alkyl;

X ⁵ is N or CH;

R ⁷ is hydrogen or halogen;

R ⁸ is hydrogen or halogen.

In a technical solution: when

When it is a double bond,

for

In a technical solution: when

When it is a single bond and X ¹ is CH, C(OH), C(F) or C(OCH ₃ ),

for

In a certain technical solution: when R ⁴ is C ₁ -C ₄ alkyl, the C ₁ -C ₄ alkyl is methyl or ethyl.

In a certain technical solution: when R ⁴ is fluorine-substituted C ₁ -C ₄ alkyl, the fluorine-substituted C ₁ -C ₄ alkyl is 2,2,2-trifluoroethyl.

In a technical solution: when X ⁶ is CHR ² ,

for

In a certain technical solution: R ¹ is C ₁ ˜C ₄ alkyl.

In a certain technical solution: Y ¹ is CH.

In a certain technical solution: Y ² is N.

In a technical solution: R ⁹ is methyl or difluoromethyl.

In a technical solution: when

middle

When it is a single bond, X ¹ is N or CH.

In a technical solution: s is 1; t is 1.

In a technical solution:

middle

Is a single key.

In a technical solution: X ⁴ is

{Wherein, b end is connected to the X-X ^4} ^3.

In a certain technical solution: A ² is CR ³ ; R ³ is amino or C ₁ ˜C ₄ alkyl.

In a certain technical scheme: A ³ is NR ⁴ , CH ₂ , O or S; R ⁴ is hydrogen, C ₁ -C ₄ alkyl, or C ₁ -C ₄ alkyl substituted with fluorine;

A ⁴ is C (=O) or CH ₂ .

When A ³ is NR ⁴ , A ⁴ is C (=O) or CH ₂ ; when A ³ is CH ₂ , O, or S, A ⁴ is CH ₂ .

In a technical solution:

middle

Is a single bond; X ³ is N, X ² is CH ₂ or C (=O);

When X ² is CH ₂ , A ³ is NR ⁴ and A ⁴ is C (=O);

When X ² is C (=O), A ³ is NR ⁴ , A ⁴ is C (=O) or CH ₂ , or when A ³ is CH ₂ , O, or S, A ⁴ is CH ₂ .

In a technical solution: n is 1.

In a certain technical solution: X ⁶ is CHR ² .

In a technical solution: X ⁵ is CH.

In a technical solution: R ⁶ is hydrogen; R ⁷ is halogen; R ⁸ is hydrogen.

In a certain technical scheme: R ¹ is C ₁ ～C ₄ alkyl;

Y ¹ is CH; Y ² is N; R ⁹ is methyl or difluoromethyl;

middle

Is a single or double bond; when

When it is a single bond, X ¹ is N or CH; when

When it is a double bond, X ¹ is C;

s is 0 or 1; t is 0 or 1;

middle

Is a single or double bond; when

When it is a single bond, X ³ is N, X ² is CH ₂ or C (=O); when

When it is a double bond, X ³ is C and X ² is N;

X ⁴ is

{Wherein, b with ends X ³ X ^4} connector

A ¹ is N;

A ² is CR ³ ; R ³ is amino or C ₁ ～C ₄ alkyl;

A ³ is NR ⁴ , CH ₂ , O or S; R ⁴ is hydrogen, C ₁ -C ₄ alkyl, or C ₁ -C ₄ alkyl substituted with fluorine;

A ⁴ is C (=O) or CH ₂ ;

n is 0 or 1;

X ⁶ is C (=O) or CHR ² ;

R ² is hydrogen or C ₁ ～C ₄ alkyl;

X ⁵ is CH;

R ⁶ is hydrogen; R ⁷ is halogen; R ⁸ is hydrogen.

In a certain technical scheme: R ¹ is C ₁ ～C ₄ alkyl;

Y ¹ is CH; Y ² is N; R ⁹ is methyl or difluoromethyl;

middle

Is a single or double bond; when

When it is a single bond, X ¹ is N or CH; when

When it is a double bond, X ¹ is C;

s is 0 or 1; t is 0 or 1;

middle

Is a single or double bond; when

When it is a single bond, X ³ is N, X ² is CH ₂ or C (=O); when

When it is a double bond, X ³ is C and X ² is N;

X ⁴ is

{Wherein, b with ends X ³ X ^4} connector

A ¹ is N;

A ² is CR ³ ; R ³ is amino or C ₁ ～C ₄ alkyl;

When A ³ is NR ⁴ , A ⁴ is C (=O) or CH ₂ ; when A ³ is CH ₂ , O or S, A ⁴ is CH ₂ ;

n is 0 or 1;

X ⁶ is C (=O) or CHR ² ;

R ² is hydrogen or C ₁ ～C ₄ alkyl;

X ⁵ is CH;

R ⁶ is hydrogen; R ⁷ is halogen; R ⁸ is hydrogen.

In a certain technical scheme: R ¹ is C ₁ ～C ₄ alkyl;

Y ¹ is CH; Y ² is N; R ⁹ is methyl or difluoromethyl;

middle

Is a single or double bond; when

When it is a single bond, X ¹ is N or CH; when

When it is a double bond, X ¹ is C;

s is 1; t is 1;

middle

Is a single bond; X ³ is N, X ² is CH ₂ or C (=O);

X ⁴ is

{Wherein, b with ends X ³ X ^4} connector

A ⁴ is C (=O) or CH ₂ ;

n is 1;

X ⁶ is CHR ² ;

R ² is hydrogen or C ₁ ～C ₄ alkyl;

X ⁵ is CH;

R ⁶ is hydrogen; R ⁷ is halogen; R ⁸ is hydrogen.

In a certain technical scheme: R ¹ is C ₁ ～C ₄ alkyl;

Y ¹ is CH; Y ² is N; R ⁹ is methyl or difluoromethyl;

middle

Is a single or double bond; when

When it is a single bond, X ¹ is N or CH; when

When it is a double bond, X ¹ is C;

s is 1; t is 1;

middle

Is a single bond; X ³ is N, X ² is CH ₂ or C (=O);

X ⁴ is

{Wherein, b with ends X ³ X ^4} connector

n is 1;

X ⁶ is CHR ² ;

R ² is hydrogen or C ₁ ～C ₄ alkyl;

X ⁵ is CH;

R ⁶ is hydrogen; R ⁷ is halogen; R ⁸ is hydrogen.

In a certain technical scheme: R ¹ is C ₁ ～C ₄ alkyl;

Y ¹ is CH; Y ² is N; R ⁹ is methyl or difluoromethyl;

middle

Is a single or double bond; when

When it is a single bond, X ¹ is N or CH; when

When it is a double bond, X ¹ is C;

s is 1; t is 1;

middle

Is a single bond; X ³ is N, X ² is CH ₂ or C (=O);

X ⁴ is

{Wherein, b with ends X ³ X ^4} connector

When X ² is CH ₂ , A ³ is NR ⁴ and A ⁴ is C (=O);

When X ² is C (=O), A ³ is NR ⁴ , A ⁴ is C (= O) or CH ₂ , or, when A ³ is CH ₂ , O or S, A ⁴ is CH ₂ ;

n is 1;

X ⁶ is CHR ² ;

R ² is hydrogen or C ₁ ～C ₄ alkyl;

X ⁵ is CH;

R ⁶ is hydrogen; R ⁷ is halogen; R ⁸ is hydrogen.

In a technical solution: the heterocyclic compound I-0 is

Wherein R ¹ is hydrogen, fluorine, difluoromethyl, methoxy, cyclopropyl or C ₁ -C ₄ alkyl {for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary Butyl, isobutyl or tert-butyl, for example methyl};

Y ¹ is N or CH;

Y ² is N, CH, C(F), C(Cl) or C(CN);

middle

Is a single or double bond; when

When it is a single bond, X ¹ is N, CH, C(OH), C(F) or C(OCH ₃ ); when

When it is a double bond, X ¹ is C;

middle

Is a single or double bond; when

When it is a single bond, X ³ is N, X ² is CH ₂ or C (=O); when

When it is a double bond, X ³ is C and X ² is N;

X ⁴ is

{Wherein, b with ends X ³ X ^4} connector

A ¹ is N;

A ² is N or CR ³ ; R ³ is hydrogen, cyano, amino, C ₁ ～C ₄ alkyl {for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso Butyl or tert-butyl, for example, methyl or isopropyl}, fluorine-substituted C ₁ ～C ₄ alkyl {the number of fluorine is one or more [such as 2 or 3]; "C ₁ -C ₄ alkyl" as mentioned above, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl}, C ₃ -C ₆ naphthenic Radical {for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl}, or, fluorine-substituted C ₃ -C ₆ cycloalkyl {the number of fluorine is one or more [for example 2 or 3]; the "C ₃ -C ₆ cycloalkyl" such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl}

A ³ is C(═O), NR ⁴ , CH ₂ , O or S; R ⁴ is hydrogen, C ₁ ～C ₄ alkyl {for example, methyl, ethyl, n-propyl, isopropyl, n-butyl , Sec-butyl, iso-butyl or tert-butyl, for example, methyl}, fluorine-substituted C ₁ -C ₄ alkyl {the number of fluorine is one or more [for example, 2 or 3] ; "C ₁ -C ₄ alkyl" such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl}, C ₃ ~ C ₆ {number cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group}, or fluorine-substituted C ₃ ~ C ₆ cycloalkyl group {said one or more fluorine [2 e.g. 3 or 3]; the “C ₃ ～C ₆ cycloalkyl” such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl};

A ⁴ is NR ⁵ , C(═O) or CH ₂ ; R ⁵ is hydrogen, C ₁ ～C ₄ alkyl {eg methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl , Isobutyl or tert-butyl, for example methyl}, fluorine-substituted C ₁ ～C ₄ alkyl {the number of fluorine is one or more [such as 2 or 3]; "C ₁ -C ₄ alkyl" such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl}, C ₃ -C ₆ cycloalkyl{ For example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl}, or fluorine-substituted C ₃ ～C ₆ cycloalkyl {the number of fluorine is one or more [such as 2 or 3 ]; The "C ₃ ~ C ₆ cycloalkyl" such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl};

n is 0 or 1;

R ² is hydrogen or C ₁ -C ₄ alkyl {for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, and for example methyl};

X ⁵ is N or CH;

R ⁶ is hydrogen, halogen {for example, fluorine, chlorine, bromine or iodine, and for example fluorine}, cyclopropyl, or, unsubstituted or halogen-substituted C ₁ ˜C ₄ alkyl {the number of “halogens” It is one or more [the "pluralities" such as 2 or 3], when there are multiple "halogens", the "halogens" are the same or different. The "halogen" may independently be fluorine, chlorine, bromine, or iodine, or fluorine. The "C ₁ -C ₄ alkyl group" is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, and is also methyl, for example. The "halogen substituted C ₁ -C ₄ alkyl group" such as difluoromethyl};

R ⁷ is hydrogen or halogen {for example fluorine, chlorine, bromine or iodine, for example fluorine};

R ⁸ is hydrogen, halogen {for example fluorine, chlorine, bromine or iodine, for example fluorine}, cyclopropyl, or, unsubstituted or halogen-substituted C ₁ ～C ₄ alkyl {the number of “halogen” It is one or more [the "pluralities" such as 2 or 3], when there are multiple "halogens", the "halogens" are the same or different. The "halogen" may independently be fluorine, chlorine, bromine, or iodine, or fluorine. The "C ₁ -C ₄ alkyl group" is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, and is also methyl, for example. The "halogen substituted C ₁ -C ₄ alkyl group" such as difluoromethyl};

R ⁹ is hydrogen, methyl or difluoromethyl.

In a certain technical solution, the definition of certain groups in the heterocyclic compound I, its pharmaceutically acceptable salt, its solvate, the solvate of its pharmaceutically acceptable salt or its crystal form It can be described as follows (unspecified group definition is as described in any of the previous schemes):

for

when

middle

Is a single bond, when X ¹ is CH, C(OH), C(F) or C(OCH ₃ );

for

when

middle

Is a double bond, when X ¹ is C;

for

for

for

for

R ¹ is C ₁ ～C ₄ alkyl;

Y ¹ is CH;

Y ² is N;

middle

Is a single or double bond; when

When it is a single bond, X ¹ is N or CH; when

When it is a double bond, X ¹ is C;

middle

Is a single key; when

When it is a single bond, X ³ is N and X ² is C (=O);

X ⁴ is

A ¹ is N;

A ² is CR ³ ; R ³ is amino or C ₁ ～C ₄ alkyl;

A ³ is NR ⁴ , CH ₂ , O or S; R ⁴ is hydrogen or C ₁ ～C ₄ alkyl;

A ⁴ is C (=O) or CH ₂ ;

n is 0;

R ² is C ₁ ～C ₄ alkyl;

X ⁵ is N or CH;

R ⁶ is hydrogen;

R ⁷ is halogen;

R ⁸ is hydrogen;

R ⁹ is methyl.

R ¹ is fluorine, difluoromethyl, methoxy, cyclopropyl or C ₁ ～C ₄ alkyl;

Y ¹ is CH;

Y ² is N, CH, C(F), C(Cl) or C(CN).

middle

Is a single or double bond; when

When it is a single bond, X ¹ is N, CH, C(OH), C(F) or C(OCH ₃ ); when

When it is a double bond, X ¹ is C;

middle

Is a single key; when

When it is a single bond, X ³ is N and X ² is C (=O);

X ⁴ is

A ¹ is N;

A ² is CR ³ ; R ³ is amino, C ₁ -C ₄ alkyl, fluorine-substituted C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or fluorine-substituted C ₃ -C ₆ ring alkyl;

A ³ is NR ⁴ , CH ₂ , O or S; R ⁴ is hydrogen, C ₁ ～C ₄ alkyl, fluorine substituted C ₁ ～C ₄ alkyl, C ₃ ～C ₆ cycloalkyl, or fluorine substituted C ₃ ～C ₆ cycloalkyl;

n is 0;

R ² is C ₁ ～C ₄ alkyl;

X ⁵ is N or CH;

R ⁶ is hydrogen, cyclopropyl, or unsubstituted or halogen substituted C ₁ ～C ₄ alkyl;

R ⁷ is halogen;

R ⁸ is hydrogen, cyclopropyl, or unsubstituted or halogen substituted C ₁ ～C ₄ alkyl;

R ⁹ is hydrogen, methyl or difluoromethyl.

R ¹ is fluorine, difluoromethyl, methoxy, cyclopropyl, or C ₁ -C ₄ alkyl.

R ¹ is C ₁ to C ₄ alkyl.

Y ¹ is CH.

Y ² is N.

middle

Is a single key; when

In the case of a single bond, X ³ is N and X ² is C (=O).

X ⁴ and X ³ is connected to the b-side.

A ² is CR ³ ; R ³ is amino, C ₁ -C ₄ alkyl, fluorine-substituted C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, or fluorine-substituted C ₃ -C ₆ ring alkyl.

A ² is CR ³ ; R ³ is amino or C ₁ ˜C ₄ alkyl.

A ³ is NR ^4, CH _2, O, or S; R ⁴ is hydrogen, C ₁ ~ C ₄ alkyl, fluoro-substituted C ₁ ~ C ₄ alkyl group, C ₃ ~ C ₆ cycloalkyl group, or fluorine-substituted C ₃ ～C ₆ cycloalkyl.

A ³ is NR ⁴ , CH ₂ , O or S; R ⁴ is hydrogen or C ₁ ˜C ₄ alkyl.

A ⁴ is C (=O) or CH ₂ .

n is 0.

R ² is C ₁ -C ₄ alkyl.

X ⁵ is N or CH.

R ⁶ is hydrogen, cyclopropyl, or unsubstituted or halogen-substituted C ₁ to C ₄ alkyl.

R ⁶ is hydrogen.

R ⁷ is halogen.

R ⁸ is hydrogen, cyclopropyl, or unsubstituted or halogen-substituted C ₁ to C ₄ alkyl.

R ⁸ is hydrogen.

R ⁹ is methyl.

In a certain technical solution, in the heterocyclic compound I-0, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof or a crystal form thereof, the The heterocyclic compound I-0 may be any of the following compounds:

In the heterocyclic compound I-0, its pharmaceutically acceptable salt, its solvate, the solvate of its pharmaceutically acceptable salt or its crystalline form, the heterocyclic compound I-0 It can also be any of the following compounds:

Under the following HPLC conditions, the retention time is 5.79min

Instrument: Waters Acquity ARC (UHPLC); Column: XSelect CSH ^TM C18 2.5μm, 4.6*150mm Column XP; mobile phase A: 0.1% aqueous ammonia solution; mobile phase B: acetonitrile; flow rate: 1ml/min; wavelength: 282nm; Column temperature: 30°C; blank solvent: methanol; sample solution: dissolve the appropriate amount of the analyte in methanol and filter with 0.22 μm filter membrane; gradient elution:

时间(min)Time(min)	A(％)A(%)	B(％)B (%)
00	7575	2525
44	3535	6565
77	2020	8080
1313	2020	8080
13.113.1	7575	2525
1818	7575	2525

Under the following HPLC conditions, the retention time is 6.24min

Under the following HPLC conditions, the retention time is 6.07min

Instrument: Waters Acquity ARC (UHPLC); Column: Xselect CSH ^TM C18 2.5μm, 4.6*150mm Column XP; mobile phase A: 0.1% formic acid aqueous solution; mobile phase B: acetonitrile; flow rate: 1ml/min; wavelength: 290nm; Column temperature: 30°C; blank solvent: methanol; sample solution: dissolve the appropriate amount of the analyte in methanol and filter with 0.22 μm filter membrane; gradient elution:

时间(min)Time(min)	A(％)A(%)	B(％)B (%)
00	7575	2525
1010	5555	4545
1313	2020	8080
13.113.1	7575	2525
1818	7575	2525

Under the following HPLC conditions, the retention time is 6.35min

Under the following HPLC conditions, the retention time is 6.49min

Apparatus: Waters Acquity ARC (UHPLC); Column: XSelect CSH ^TM C ₁₈ 2.5um 4.6*150mm Column XP; mobile phase A: 0.1% aqueous ammonia solution; mobile phase B: acetonitrile; flow rate: 1ml/min; wavelength: 254nm; Column temperature: 30°C; blank solvent: methanol; sample solution: dissolve the appropriate amount of the analyte in methanol and filter with 0.22 μm filter membrane; gradient elution:

Under the following HPLC conditions, the retention time is 5.68min

Instrument: Waters Acquity ARC (UHPLC); Column: XSelect CSH ^TM C ₁₈ 2.5um 4.6*150mm Column XP; Mobile phase A: 0.1% aqueous ammonia solution; Mobile phase B: Acetonitrile; Flow rate: 1ml/min; Wavelength: 254nm; Column temperature: 30°C; blank solvent: methanol; sample solution: dissolve the appropriate amount of the analyte in methanol and filter with 0.22 μm filter membrane; gradient elution:

Under the following HPLC conditions, the retention time is 6.32min

Under the following HPLC conditions, the retention time is 7.53min

Instrument: Waters Acquity ARC (UHPLC); Column: XSelect CSH ^TM C ₁₈ 3.5um 4.6*150mm Column XP; mobile phase A: 0.1% aqueous ammonia solution; mobile phase B: acetonitrile; flow rate: 1.0ml/min; wavelength: 287nm ; Column temperature: 30 ℃; blank solvent: methanol; sample solution: dissolve the appropriate amount of the test substance with methanol, filter with 0.22um filter membrane, and gradient elution:

时间(min)Time(min)	A(％)A(%)	B(％)B (%)
00	7575	2525
1010	37.537.5	62.562.5
1515	2020	8080
15.115.1	7575	2525
1818	7575	2525

Under the following HPLC conditions, the retention time is 8.45min

Under the following HPLC conditions, the retention time is 5.95min

Instrument: Waters Acquity ARC (UHPLC); Column: XSelect CSH ^TM C ₁₈ 2.5um 4.6*150mm Column XP; Mobile phase A: 0.1% aqueous ammonia solution; Mobile phase B: Acetonitrile; Flow rate: 1.0 ml/min; Wavelength: PDA Full wavelength, 254nm, 220nm; column temperature: 30°C; blank solvent: methanol; sample solution: dissolve the appropriate amount of analyte with methanol, filter with 0.22um filter membrane, and gradient elution:

Under the following HPLC conditions, the retention time is 6.43min

Instrument: Waters Acquity ARC (UHPLC); Column: XSelect CSH ^TM C ₁₈ 2.5um 4.6*150mm Column XP; Mobile phase A: 0.1% aqueous ammonia solution; Mobile phase B: Acetonitrile; Flow rate: 1.0ml/min; Wavelength: PDA Full wavelength, 254nm, 220nm; column temperature: 30°C; blank solvent: methanol; sample solution: dissolve the appropriate amount of analyte with methanol, filter with 0.22um filter membrane, and gradient elution:

Under the following HPLC conditions, the retention time is 5.574min

Instrument: Waters Acquity ARC (UHPLC); Column: XSelect CSH ^TM C18 3.5μm, 4.6*150mm Column XP; mobile phase A: 0.1% aqueous ammonia solution; mobile phase B: acetonitrile; flow rate: 1ml/min; wavelength: 282nm; Column temperature: 30°C; blank solvent: methanol; sample solution: dissolve the appropriate amount of the analyte in methanol and filter with 0.22 μm filter membrane; gradient elution:

Under the following HPLC conditions, the retention time is 5.363min

Under the following HPLC conditions, the retention time is 8.737min

时间(min)Time(min)	A(％)A(%)	B(％)B (%)
00	7575	2525
1515	2020	8080
1818	2020	8080
18.118.1	7575	2525
23twenty three	7575	2525

Under the following HPLC conditions, the retention time is 9.444min

Under the following HPLC conditions, the retention time is 5.21min

Under the following HPLC conditions, the retention time is 6.066min

Time(min)	A(%)	B (%)
0	75	25
4	35	65
7	20	80
13	20	80
13.1	75	25
18	75	25

.

The present invention also provides a heterocyclic compound I-0, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof or a crystal form thereof in the preparation of a RET inhibitor Applications.

The present invention also provides an application of the above-mentioned heterocyclic compound I-0, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof or a crystal form thereof in the preparation of a medicament The drugs are used to prevent and/or treat diseases mediated by abnormal expression of RET.

The "diseases mediated by abnormal expression of RET" such as cancer, for example, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma (MTC), pheochromocytoma (PC), pancreatic ductal adenocarcinoma, multiple endocrine Tumor (MEN2A or MEN2B), breast cancer (also for example metastatic breast cancer), testicular cancer, small cell lung cancer, non-small cell lung cancer, chronic myelomonocytic leukemia, colon cancer, rectal cancer, ovarian cancer or salivary adenocarcinoma.

The present invention also provides an application of the above-mentioned heterocyclic compound I-0, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof or a crystal form thereof in the preparation of a medicament , The drugs are used to prevent and/or treat cancer.

The “cancer” includes, for example, thyroid papillary carcinoma (PTC), medullary thyroid carcinoma (MTC), pheochromocytoma (PC), pancreatic ductal adenocarcinoma, multiple endocrine tumors (MEN2A or MEN2B), breast cancer (also For example, metastatic breast cancer), testicular cancer, small cell lung cancer, non-small cell lung cancer, chronic myelomonocytic leukemia, colon cancer, rectal cancer, ovarian cancer, or salivary adenocarcinoma.

The present invention also provides a pharmaceutical composition comprising the above-mentioned heterocyclic compound I-0, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystal form thereof , And, medicinal accessories.

The present invention also provides an application of the above-mentioned heterocyclic compound I-0, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof or a crystal form thereof in the preparation of a medicament .

The present invention also provides a method for inhibiting RET, which comprises administering to a patient a therapeutically effective amount of the above-mentioned heterocyclic compound I-0, a pharmaceutically acceptable salt thereof, a solvate thereof, a pharmaceutically acceptable salt thereof Solvate or its crystalline form.

The present invention also provides a method for treating or preventing RET-mediated diseases, which comprises administering to a patient a therapeutically effective amount of the above-mentioned heterocyclic compound I-0, a pharmaceutically acceptable salt thereof, a solvate thereof, A solvate of a pharmaceutically acceptable salt or its crystalline form.

The present invention also provides a method of treating or preventing cancer, which comprises administering to a patient a therapeutically effective amount of the above-mentioned heterocyclic compound I-0, a pharmaceutically acceptable salt thereof, a solvate thereof, a pharmaceutically acceptable thereof Solvate of the salt or its crystalline form.

Unless otherwise specified, the terms in the present invention have the following meanings:

The term "alkyl" refers to a linear or branched alkyl group having the specified number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl and It is similar to alkyl.

The term "cycloalkyl" refers to having a ring atoms indicated (e.g., C ₃ -C ₆ cycloalkyl) and fully saturated hydrocarbon ring. "Cycloalkyl" also means bicyclic and polycyclic hydrocarbon rings, such as, for example, spiro[2.3]hexane and the like.

The term "halogen" refers to a fluorine, chlorine, bromine or iodine atom.

The term "one or more" refers to one to four. In one embodiment, it refers to one to three. In further embodiments, it refers to one or two. In a further embodiment, it refers to one.

The term "pharmaceutically acceptable salt" refers to a salt of a compound prepared by a compound of the present invention and a pharmaceutically acceptable, relatively non-toxic acid or base.

When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting prototypes of such compounds with a sufficient amount of the desired base in the absence of a solvent or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganese salts, potassium salts, sodium Salt, zinc salt and similar salts. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines including substituted amines, cyclic amines, naturally occurring amines, and the like, such as refined Amino acid, betaine, caffeine, choline, N,N'-benzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- Ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucosamine, Porphyrin, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting prototypes of such compounds with a sufficient amount of the desired acid in the absence of a solvent or in a suitable inert solvent. The acid can be an inorganic acid, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphoric acid, sulfuric acid, monohydrogen sulfuric acid, hydroiodic acid or phosphorous acid and similar inorganic acid. The acid can be an organic acid, such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonate Acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid and similar organic acids.

The term "solvate" refers to a substance formed by combining a compound of the present invention with a stoichiometric or non-stoichiometric solvent. The solvent molecules in the solvate may exist in an ordered or unordered arrangement. The solvent includes but is not limited to: water, methanol, ethanol and the like.

The terms "pharmaceutically acceptable salts" and "solvates" in the term "solvates of pharmaceutically acceptable salts" as described above refer to the compounds of the present invention and 1, and the relatively non-toxic, pharmaceutically acceptable 2. It is prepared from the acid or base that is accepted, and is formed by combining with stoichiometric or non-stoichiometric solvent. The "solvate of pharmaceutically acceptable salts" includes but is not limited to the hydrochloric acid monohydrate of the compound of the present invention.

The term "crystalline form" means that the ions or molecules are strictly arranged in three-dimensional space in a certain way, and have a regular recurrence interval at a certain distance; due to the difference of the above-mentioned periodic arrangement, there can be many Crystal form, that is, polymorphism.

Certain compounds in the present invention have chiral carbon atoms, double bonds, carbocyclic or heterocyclic rings, and the resulting configuration isomers {optical isomers (such as enantiomers, diastereomers, etc.), Cis-trans isomers, etc.} and their mixtures (e.g. racemates) are within the scope of the present invention. When certain compounds in the present invention indicate a specific configuration, it means a compound in which the configuration isomer exists and is substantially free of other isomers.

The atoms in the compounds of the present invention may be atoms with abundance of natural isotopes or atoms with abundance of unnatural isotopes. That is, one or more atoms in the compounds of the present invention may be atoms of unnatural isotope abundance. The resulting isotopic variants are all within the scope of the present invention. In an abundance of unnatural isotopes, the amount of any one isotope can be between 0% and 100%. Taking hydrogen (H) as an example, it may be a hydrogen atom with abundance of natural isotopes (99.985% ¹ H+0.015% ² H+ less than 0.001% ³ H), or an atom with abundance of unnatural isotopes (eg, greater than 95 % ² H).

When any variable (such as halogen) appears multiple times in the definition of a compound, the definition appearing at each position of the variable is independent of the definitions appearing at the remaining positions, and their meanings are independent of each other and do not affect each other. Therefore, if a group is substituted with 1, 2, or 3 halogens, that is, the group may be substituted with up to 3 halogens, the definition of halogen at a certain position and the definition of halogen at other positions are mutually independent. In addition, combinations of substituents and/or variables are only allowed when the combination produces stable compounds.

The term "inhibitor" refers to molecules that reduce, block, prevent, delay activation, inactivation, desensitization, or downregulate, for example, genes, proteins, ligands, receptors, or cells.

The term "abnormal expression of RET" is an increase in RET activity caused by signaling through RET.

The term "prevention" refers to the reduced risk of acquiring or developing a disease or disorder.

The term "treating" any disease or disorder in one embodiment refers to improving the disease or disorder (ie, preventing the disease, or, reducing the degree or severity of its clinical symptoms). In another embodiment, "treatment" refers to improving at least one physical parameter, which may not be noticed by the subject. In another embodiment, "treatment" refers to adjusting the disease or disorder physically (eg, stabilizing distinguishable symptoms), physiologically (eg, stabilizing physical parameters), or both. In another embodiment, "treatment" refers to slowing disease progression.

The term "cancer" refers to malignant or benign growth of cells in skin or body organs, such as but not limited to breast, prostate, lung, kidney, pancreas, stomach, or intestine. Cancer tends to infiltrate adjacent tissues and spread (metastasize) to distant organs, such as bone, liver, lung, or brain. The term cancer as used herein includes metastatic tumor cell types (such as but not limited to melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mast cell tumor) and tissue cancer types (such as but not limited to colorectal cancer, prostate cancer , Small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, kidney cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, prostate cancer and uterine leiomyosarcoma). In particular, the term "cancer" refers to acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix tumors, astrocytoma, atypical teratoid/rhabdoid tumor (atypical teratoid/rhabdoid tumor), basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumor, brain and spinal cord tumor, breast cancer, bronchial tumor, Burkitt lymphoma Tumor, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumor, endometrial cancer, ependymal blast Tumors (ependymoblastoma), ependymoma, esophageal cancer, tumor Ewing sarcoma family, eye cancer, retinoblastoma, gallbladder cancer, stomach (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, blastoma, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer (hypopharyngeal cancer), intraocular Melanoma, islet cell tumor (endocrine pancreas), Kaposi's sarcoma, kidney cancer, Langerhans cell hyperplasia, laryngeal cancer, leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic Myeloid leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Burkitt lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenstrom giant Globulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, oral cancer, chronic myeloid leukemia, myeloid leukemia, multiple myeloma, nasopharyngeal carcinoma (asopharyngeal) cancer), neuroblastoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, bone malignant fibrous histiocytoma, ovarian cancer, ovarian epithelioma, ovarian germ cell tumor, ovarian low-grade potential malignant tumor, pancreas Cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, intermediate differentiated pineal tumors (pineal parenchymal tumors of intermediate differentiation), pineal gland cell tumors and supratentorial primitive neuroectodermal tumors (supratentorial primitive neuroma neuroectodermal tumors), pituitary tumors, plasma cell tumors/multiple myeloma, pleural lung blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (renal) cancer, retinoblastoma, striated muscle Sarcoma, salivary gland cancer, sarcoma, tumor Ewing sarcoma family, sarcoma, Kaposi, Sezary syndrome, skin cancer, Small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (stomach) cancer, suprasuperior primitive neuroectodermal tumor, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymic cancer, Thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, and Wilms tumor.

The term "pharmaceutical excipients" refers to excipients and additives used in the production of pharmaceuticals and the formulation of prescriptions; it is a safety evaluation that has been reasonably evaluated in addition to the active ingredient or precursor, and is included in pharmaceutical preparations substance.

On the basis of not violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred examples of the present invention.

The reagents and raw materials used in the present invention are commercially available.

The positive effect of the present invention is that the compound has a better inhibitory effect on RET kinase.

detailed description

The present invention is further described by way of examples below, but does not limit the present invention to the scope of the described examples. The experimental methods without specific conditions in the following examples are selected according to conventional methods and conditions, or according to the product description.

The parameters of the LCMS analysis method of the embodiments of the present invention are as follows:

Column: CORTECS C ₁₈ 2.7μm, 4.6*50mm Column;

Mobile phase A: 0.1% formic acid in water;

Mobile phase B: 0.1% formic acid in acetonitrile;

时间(min)Time(min)	A(％)A(%)	B(％)B (%)
00	9090	1010
0.70.7	9090	1010
2.52.5	1010	9090
44	1010	9090
4.14.1	9090	1010
6.56.5	9090	1010

Flow rate: 1ml/min;

Wavelength: PDA full wavelength, 220nm, 254nm;

Column temperature: 30℃;

Sample tray: no temperature control;

MS: Positive ion mode, ESI (scan from 100 to 800).

Example 1 SZ-9312: (S)-8-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-3-(1 -Phenylethyl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one

step 1:

Add 1 (17g, 69.6mmol) and anhydrous dichloromethane (500ml) to the reaction flask, stir, then add N,N-isopropylethylamine (22.5g, 174mmol), stir at room temperature for 30 minutes, slowly Trimethylchlorosilane (15.1 g, 140 mmol) was added dropwise, and then heated to reflux for 3 h, during which argon gas was bubbled for 30 seconds every 30 minutes to remove hydrogen chloride gas generated by the reaction. The reaction was cooled to -10°C, Fmoc-Cl (16.7g, 64.6mmol), EDCI·HCl (21.1g, 0.11mol) were added, and stirring was continued for 3h, during which argon gas was bubbled for 30 seconds every 30 minutes to remove the reaction. Hydrogen chloride gas. The reaction solution was added with 2.5% Na ₂ CO ₃ aqueous solution (1000 ml), extracted with ether (100 ml x 2), the aqueous phase was adjusted to pH 2 with 2N hydrochloric acid, extracted with ethyl acetate (300 ml x 3), and the organic phase was extracted with anhydrous sulfuric acid Sodium was dried, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 9307A1 (24.4 g, 85%, white foamy solid), which was directly subjected to the next reaction without purification. LCMS: [M+H] ⁺ 367.08 (De-Boc).

Step 2:

Add 9307A1 (4.5g, 9.6mmol) and DMF (30ml) to the reaction flask, stir, then add S-(-)-phenethylamine (1.17g, 9.6mmol), DIPEA (2.5g, 19.3mmol), and finally add HATU (4.4g, 11.6mmol), react at 20°C for 2 hours. The reaction solution was added with water (400ml), extracted with EA (50ml x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography (EA/PE 0-50%) Purification gave 9307A2 (4.5 g, 82%, white foam solid). LCMS: [M+Na] ⁺ 592.18.

Step 3:

9307A2 (4.5g, 7.9mmol) and methanol (30ml) were added to the reaction flask, stirred, then ethylenediamine (30ml) was added, and reacted at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography (EA/PE 50-100%) to obtain 9307A3 (2.5 g, 91%, colorless oily liquid). LCMS: [M+H] ⁺ 348.12.

Step 4:

Compound 9307A3 (2.5g, 7.2mmol) was dissolved in acetic acid (3ml) and triethyl orthoformate (6ml) and stirred under microwave at 100 degrees for 1 hour, concentrated to remove the solvent, the residue was purified by flash silica gel column chromatography (PE / EA 50%-100%) purification to give compound 9307A4 (2.3g, 89%, colorless oily liquid). LCMS: [M+H] ⁺ 358.09.

Step 5:

Compound 9307A4 (1g, 2.8mmol) was dissolved in dichloromethane (5ml), trifluoroacetic acid (1ml) was added, stirred at room temperature for 2 hours, concentrated to remove the solvent to obtain crude 9307A5, the next step was carried out without purification. LCMS: [M+H] ⁺ 258.07.

Step 6:

Compound 9307A5 (178 mg, 0.5 mol), compound 2 (112 mg, 0.5 mmol) and potassium carbonate (276 mg, 2 mmol) were added to DMSO (5 ml) and stirred at 110° C. for 16 hours. Water (50 mL) was added to the system, extracted with ethyl acetate (10 ml x 3), and the organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by medium-pressure reversed-phase column chromatography (ACN-0.1% HCO ₂ H aqueous solution) and lyophilized To give SZ-9312 (18.6 mg, 9%, white solid). LCMS: [M+H] ⁺ 445.14. ¹ H NMR (400MHz, DMSO-d6) δ 9.21 (s, 1H), 8.31 (s, 1H), 8.15 (s, 1H), 7.38 (dd, J=9.9, 4.9Hz, 2H), 7.34–7.27 (m, 3H), 6.24 (s, 1H), 6.08 (s, 1H), 5.10 (q, J = 7.3Hz, 1H), 4.50 (t, J = 12.3Hz, 2H), 3.46-3.34 (m, 1H), 2.18 (s, 3H), 2.13 (s, 3H), 1.75-1.57 (m, 5H), 1.40 (d, J = 13.2 Hz, 1H), 1.29 (d, J = 13.4 Hz, 1H).

Example 2 SZ-9315: (S)-3-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-methyl-8- (4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,3,8-triazaspiro[4.5]dec-1- En-4-one

step 1:

Add 9307A1 (932mg, 1mmol) and DMF (5ml) to the reaction flask, stir, and then add (S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethane Amine (prepared according to WO2017079140) (412 mg, 1 mmol), DIPEA (516 mg, 2 mmol), and finally HATU (912 mg, 2 mmol) was added and reacted at 20° C. for 1 hour. The reaction solution was added with water (40ml), extracted with EA (10ml x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography (EA/PE 0-50%) Purification gave 9315A0 (900 mg, 69%, white foam). LCMS: [M+H] ⁺ 654.20.

Step 2:

9315A0 (900 mg, 7.9 mmol) and methanol (3 ml) were added to the reaction flask, stirred, and then ethylenediamine (3 ml) was added, and reacted at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography (EA/PE 50-100%) to obtain 9315A1 (500 mg, 85%, colorless oily liquid). LCMS: De-Boc[M+H] ⁺ 333.10.

Step 3: tert-butyl(S)-3-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-methyl-4- Carbonyl-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate (9315A2)

Compound 9315A1 (330 mg, 0.76 mmol) was dissolved in acetic acid (3 ml) and triethyl orthoacetate (6 ml) and stirred under microwave at 100 degrees for 1 hour, concentrated to remove the solvent, and the residue was purified by flash silica gel column chromatography (PE/EA 50%-100%) purification to give compound 9315A2 (230 mg, 66%, colorless oily liquid). LCMS: [M+H] ⁺ 457.12@3.60min.

Step 4: (S)-3-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-methyl-1,3,8 -Triazaspiro[4.5]dec-1-en-4-one (9315A3)

Compound 9315A2 (230 mg, 0.50 mmol) was dissolved in dichloromethane (5 ml), trifluoroacetic acid (1 ml) was added, stirred at room temperature for 2 hours, and concentrated to remove the solvent to obtain crude 9315A3, which was directly reacted without purification. LCMS: [M+H] ⁺ 357.08@2.70min.

Step 5: (S)-3-(1-(6-(4-Fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-methyl-8-(4- Methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,3,8-triazaspiro[4.5]dec-1-ene-4 -Ketone (SZ-9315)

Compound 9315A3 (170 mg, 0.50 mol), compound 3 (110 mg, 0.50 mmol) (prepared according to WO2017079140) and potassium carbonate (207 mg, 1.50 mmol) were added to DMSO (5 ml) and stirred at 110° C. for 16 hours. Water (50ml) was added to the system, extracted with ethyl acetate (20mlx3), the organic phase was concentrated under reduced pressure to obtain crude product, purified by flash silica gel column chromatography (DCM/EA 50%-100%), the product was dissolved in acetonitrile and water , And freeze-dried to obtain SZ-9315 (160 mg, 58%, light yellow solid). LCMS: [M+H] ⁺ 544.16@3.03min. ¹ H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 9.21 (s, 1H), 8.68 (d, J=4.5 Hz, 1H), 8.43 (d, J=2.1 Hz, 1H), 7.97-7.89(m, 3H), 6.24(brs, 1H), 6.08(brs, 1H), 5.30(q, J=7.0Hz, 1H), 4.55-4.45(m, 2H), 3.48-3.38(m, 2H), 2.18 (s, 6H), 2.13 (s, 3H), 1.77 (d, J = 7.0 Hz, 3H), 1.73-1.58 (m, 2H), 1.44-1.30 (m, 2H).

Example 3 SZ-9316: (S)-3-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-isopropyl-8 -(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,3,8-triazaspiro[4.5]dec-1 -En-4-one

Step 1: tert-butyl(S)-3-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-isopropyl-4 -Carbonyl-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate (9316A1)

Compound 9315A1 (330mg, 0.76mmol) was dissolved in acetic acid (3ml) and triethyl isobutyrate (6ml), and stirred at 100 degrees under microwave for 1 hour, concentrated to remove the solvent, and the residue was purified by flash silica gel column chromatography (PE /EA 50%-100%) purification to give compound 9316A1 (240 mg, 65%, colorless oily liquid). LCMS: [M+H] ⁺ 485.13@4.05min.

Step 2: (S)-3-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-isopropyl-1,3, 8-Triazaspiro[4.5]dec-1-en-4-one (9316A2)

Compound 9316A1 (240 mg, 0.50 mmol) was dissolved in dichloromethane (5 ml), trifluoroacetic acid (1 ml) was added, stirred at room temperature for 2 hours, and concentrated to remove the solvent to obtain crude 9316A2, which was directly reacted without purification. LCMS: [M+H] ⁺ 385.13@2.82min.

Step 3: (S)-3-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-isopropyl-8-(4 -Methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,3,8-triazaspiro[4.5]dec-1-ene- 4-ketone (SZ-9316)

Compound 9316A2 (190 mg, 0.50 mol), compound 3 (110 mg, 0.50 mmol) and potassium carbonate (207 mg, 1.50 mmol) were added to DMSO (5 ml) and stirred at 110° C. for 16 hours. Water (50ml) was added to the system, extracted with ethyl acetate (20ml x 3), and the organic phase was concentrated under reduced pressure to obtain the crude product, which was purified by flash silica gel column chromatography (DCM/EA 50%-100%). The water was dissolved and lyophilized to obtain SZ-9316 (160 mg, 58%, light yellow solid). LCMS: [M+H] ⁺ 572.18@3.40min. ¹ H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 9.22 (s, 1H), 8.68 (d, J=4.4 Hz, 1H), 8.40 (d, J=1.6 Hz, 1H), 7.95-7.90(m, 3H), 6.23(brs, 1H), 6.11(brs, 1H), 5.33(q, J=7.0Hz, 1H), 4.50-4.40(m, 2H), 3.50-3.40(m, 2H), 2.96-2.88(m, 1H), 2.19(s, 3H), 2.13(s, 3H), 1.78(d, J=7.0Hz, 3H), 1.71-1.56(m, 2H), 1.40-1.23 (m, 2H), 1.17 (d, J = 6.7 Hz, 3H), 1.13 (d, J = 6.7 Hz, 3H).

Example 4 SZ-9336 (SZ-9336A and SZ-9336B): (S)-3-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl )-8-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,3-diazaspiro[4.5]decane -2,4-dione

SZ-9367(9305A12); 3-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-8-(4-methyl -6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,3-diazaspiro[4.5]dec-7-ene-2,4-di ketone

Step 1: Diethyl 1,4-dioxaspiro[4.5]decane-8,8-dicarboxylate (9305A2)

Compound 9305A1 (50g, 0.2mol) was dissolved in anhydrous toluene (400ml), ethylene glycol (13.6ml) and p-toluenesulfonic acid monohydrate (400mg, 2mmol) were added in this order, and then the water separator was refluxed for 2 hours The system was cooled to room temperature and saturated sodium bicarbonate was added until pH=8, the aqueous phase was separated, the organic phase was dried over sodium sulfate, and concentrated to obtain 9305A2 (70g, colorless oil).

Step 2: 8-(ethyl ester <ethoxycarbonyl>)-1,4-dioxaspiro[4.5]decane-8-carboxylic acid (9305A3)

9305A2 (70g, 0.2mol) was dissolved in methanol (400ml), added 1N sodium hydroxide (250ml) and stirred at room temperature for 16 hours, then concentrated to remove methanol, the pH of the system was adjusted with 1N hydrochloric acid = 4-5, followed by ethyl acetate The ester (300 ml) was extracted and the organic phase was dried over sodium sulfate and concentrated to give 9305A3 (50 g, 94% in two steps, colorless oil). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.22 (q, J=8.5 Hz, 2H), 3.94 (s, 4H), 2.18-2.22 (m, 4H), 1.68-1.73 (m, 4H), 1.27 ( t, J = 8.5 Hz, 3H).

Step 3: Ethyl 8-(((benzyloxy)carbonyl)amino)-1,4-dioxaspiro[4.5]decane-8-carboxylate (9305A4)

9305A3 (45g, 0.17mol) was dissolved in toluene (200ml), triethylamine (52g, 0.51mol) and DPPA (0.17mol) were added, the reaction temperature was controlled not to exceed 30 degrees and stirred for 1 hour, followed by stirring at 100 degrees 2 Hours, and finally benzyl alcohol (17.6 g, 0.17 mol) was added and stirred at this temperature overnight. The reaction system was cooled and purified by flash silica gel column chromatography (PE/EA 20%-30%) to obtain 9305A4 (19 g, 53%, colorless oil). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.26-7.35 (m, 5H), 5.08 (s, 2H), 4.97 (s, 1H), 4.14 (q, J = 5.5 Hz, 2H), 3.94 (s, 4H), 2.11-2.19 (m, 4H), 1.69-1.72 (m, 4H), 1.20 (t, J = 5.5 Hz, 3H).

Step 4: Ethyl 1-(((benzyloxy)carbonyl)amino)-4-carbonyl cyclohexanoate (9305A5)

9305A4 (19g, 62.9mmol) was dissolved in dioxane (200ml), 6N hydrochloric acid (100ml) was added at room temperature and stirred at this temperature for 16 hours. After the reaction was completed, ethyl acetate (300 ml) was added for extraction. The organic phase was dried over sodium sulfate and concentrated to obtain 9305A5 (16 g, 97%, colorless oil).

Step 5: ethyl 1-(((benzyloxy)carbonyl)amino)-4-(((trifluoromethyl)sulfonyl)oxo)cyclohex-3-ene carboxylate (9305A6)

9305A5 (2.0g, 6.26mol) was dissolved in anhydrous tetrahydrofuran (20ml), the system was cooled to -70 degrees under the protection of argon and LiHMDS (7.5ml, 1mol/L) was slowly dropped into it, and then stirred at this temperature After 1 hour, phenylbis(trifluoromethanesulfonyl)imide (3.3 g, 9.3 mmol) in tetrahydrofuran (10 ml) was quickly added to the system and the temperature was raised to 0 degree and stirred for 3 hours. After the reaction was completed, saturated ammonium chloride (20ml) was added to quench, extracted with ethyl acetate (50ml), the organic phase was dried over sodium sulfate, concentrated and purified by flash silica gel column chromatography (PE/EA 10%-20%) to obtain 9305A6 (1.6g, 57%, colorless oil).

Step 6: ethyl 1-(((benzyloxy)carbonyl)amino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl ) Cyclohex-3-ene carboxylate (9305A7)

9305A6 (1.6g, 3.5mmol) and pinacol boronic acid with (0.9,3.5mmol), Pd (dppf) 2 Cl 2 · DCM (144mg, 5%), potassium acetate (1.0g, 10.6mmol) under argon protection Mix in dioxane (30ml) and heat to 80 degrees and stir for 4 hours. After the reaction was completed, it was cooled, concentrated to remove the solvent, and purified by flash silica gel column chromatography (PE/EA 10%-20%) to obtain 9305A7 (1.0 g, 62%, colorless oil). LCMS: [M+H] ⁺ 430.13.

Step 7: ethyl 1-(((benzyloxy)carbonyl)amino)-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidine- 2-yl)cyclohex-3-ene carboxylate (9305A9)

9305A7 (0.5g, 1.2mmol) and 3 (259mg, 1.2mmol), Pd (PPh 3) 4 (100mg, 5%), potassium carbonate (400mg, 3.0mmol) were mixed in dioxane under argon protection ( 6ml) and water (2ml), stirred at 125 degrees microwave for 5 hours, the resulting reaction solution was concentrated and purified by flash silica gel column chromatography (PE/EA 50%-70%) to obtain 9305A9 (500mg, 85%, colorless oil) Thing). LCMS: [M+H] ⁺ 491.10.

Step 8: 1-(((benzyloxy)carbonyl)amino)-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidine-2- Group) cyclohex-3-ene carboxylic acid (9305A10)

9305A9 (0.5g, 1.0mmol) and lithium hydroxide monohydrate (125mg, 3.1mmol) were dissolved in tetrahydrofuran (2ml), methanol (2ml) and water (2ml), the system was heated to 60 degrees and stirred for 3 hours, the reaction was completed After cooling and concentration, the resulting 9305A10 was not further purified. LCMS: [M+H] ⁺ 463.07.

Step 9: 3-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-8-(4-methyl-6- ((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,3-diazaspiro[4.5]dec-7-ene-2,4-dione (9305A12 ; SZ-9367)

9305A10 and (S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethylamine (270 mg, 0.97 mmol), HATU (555 mg, 1.46 mmol), DIPEA ( 0.46ml, 2.91mmol) was mixed in DMF (4ml) and stirred at room temperature for 16 hours. After the reaction was completed, DMF was concentrated under reduced pressure, and then purified by flash silica gel column chromatography (EA) to obtain 9305A12 (SZ-9367) (60 mg, white solid). LCMS: [M+H] ⁺ 543.10, HPLC: t _R =6.49 min. ¹ H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.54 (s, 1H), 8.72 (s, 1H), 8.68 (d, J=5.5 Hz, 1H), 8.43 (d, J =2.0Hz, 1H), 7.90-8.01(m, 3H), 7.08(s, 1H), 6.83(s, 1H), 6.22(s, 1H), 5.33(q, J=9.0Hz, 1H), 2.86 -2.90(m,1H),2.64-2.73(m,1H),2.50-2.50(m,1H),2.32-2.35(m,1H),2.27(s,3H),2.20(s,3H),1.83 -1.89 (m, 2H), 1.78 (d, J = 9.0 Hz, 3H).

SZ-9367HPLC analysis method

Instrument: Waters Acquity ARC (UHPLC)

Column: XSelect CSH ^TM C ₁₈ 2.5um 4.6*150mm Column XP

Mobile phase A: 0.1% aqueous ammonia solution

Mobile phase B: Acetonitrile

Gradient elution:

Flow rate: 1ml/min

Wavelength: 254nm

Column temperature: 30℃

Blank solvent: methanol

Sample solution: Dissolve the appropriate amount of SZ-9367 with methanol, filter with 0.22um filter membrane, and enter liquid chromatography for analysis.

Step 10: (S)-3-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-8-(4-methyl-6- ((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,3-diazaspiro[4.5]decane-2,4-dione (SZ-9336: (SZ-9336A and SZ-9336B)

9305A12 (20 mg) was suspended in ethanol (2 ml), 2 drops of acetic acid was added dropwise to dissolve, and stirred at 60 degrees overnight under a hydrogen atmosphere. After the reaction was completed, the pH of the system was adjusted to about 9 with saturated sodium carbonate, extracted with dichloromethane, the organic phase was concentrated and separated and purified using a preparation plate to obtain two isomers SZ-9336A (6mg) and SZ-9336B (1.2mg).

SZ-9336A: LCMS: [M+H] ⁺ 545.10, HPLC t _R =5.79 min. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.40 (dd. J ₁ =0.5 Hz, J ₂ =5.0 Hz, 1H), 8.36 (d, J=2.5 Hz, 1H), 7.93 (d, J=10.0 Hz, 1H), 7.82 (d, J = 10.5 Hz, 1H), 7.56 (d, J = 5.0 Hz, 1H), 6.54 (s, 1H), 6.42 (s, 1H), 5.26-5.36 (m, 1H ), 2.62-2.66 (m, 1H), 2.34-2.44 (m, 1H), 2.22 (s, 3H), 2.17 (s, 3H), 1.90-1.97 (m, 2H), 1.76-1.77 (m, 2H) ), 1.77 (d, J = 9.0 Hz, 3H), 1.58-1.66 (m, 2H).

SZ-9336B: LCMS: [M+H] ⁺ 545.10, HPLC: t _R =6.24 min. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.40 (d, J=5.0 Hz, 1H), 8.35 (d, J = 3.0 Hz, 1H), 7.92 (dd, J ₁ = 3.5 Hz, J ₂ = 10.5 Hz, 1H), 7.81 (d, J = 10.5 Hz, 1H), 7.58 (d, J = 5.5 Hz, 1H) , 6.61(s, 1H), 6.04(s, 1H), 5.30(q, J=9.5Hz, 1H), 2.65-2.70(m, 2H), 2.23(s, 3H), 2.18(s, 3H), 1.79-1.92 (m, 6H), 1.73 (d, J = 9.0 Hz, 1H), 1.57-1.65 (m, 2H).

SZ-9336A and SZ-9336B HPLC analysis conditions are as follows:

Example 5 SZ-9384: (S)-3-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-8-(4-methyl -6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2-thio-1,3,8-triazaspiro[4.5]decane-4 -ketone

step 1:

Compound 9315A1 (1 g, 2.3 mmol) was dissolved in THF (20 ml), and triethylamine (1 g, 10 mmol) and thiocarbonyldiimidazole (1.78 g, 10 mmol) were added and stirred at 60° C. for 16 hours. Water (50 ml) was added to the system, extracted with ethyl acetate (50 ml x 2), the organic phase was concentrated under reduced pressure, and the resulting residue was separated and purified using a preparation plate (DCM:CH ₃ OH=20:1) to obtain compound 9384A1 ( 200 mg, 18%, yellow solid). LCMS: [M+H] ⁺ 475.03.

Step 2:

Compound 9384A1 (100mg, 0.21mmol) was dissolved in dichloromethane (2ml), trifluoroacetic acid (0.5ml) was added, stirred at room temperature for 2 hours, concentrated to remove the solvent to obtain 9384A2, the next step was carried out without purification. LCMS: [M+H] ⁺ 375.05.

Step 3:

Compound 9384A2 (100 mg, 0.27 mol), compound 3 (60 mg, 0.27 mmol) and potassium carbonate (186 mg, 1.35 mmol) were added to DMSO (5 ml) and stirred at 110° C. for 16 hours. Water (50ml) was added to the system, extracted with ethyl acetate (20ml x 3), the organic phase was concentrated under reduced pressure to obtain the crude product, purified by high-pressure reversed-phase column chromatography (ACN-0.1% HCO ₂ H aqueous solution), and freeze-dried. SZ-9384 (23.5 mg, 16%, white solid) was obtained. LCMS: [M+H] ⁺ 562.08. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.53–8.49 (m, 2H), 8.05 (dd, J=8.6, 2.3 Hz, 1H), 7.92 (d, J=8.6 Hz, 1H), 7.70 (d , J=4.0Hz, 1H), 6.26(s, 1H), 6.23–6.10(m, 2H), 4.45–4.25(m, 2H), 3.78–3.59(m, 2H), 2.29(s, 3H), 2.28(s, 3H), 2.08–1.98(m, 1H), 1.89(d, J=7.3Hz, 3H), 1.87–1.76(m, 1H), 1.73–1.63(m, 1H), 1.39–1.28( m,1H).

Example 6 SZ-9333: (S)-2-amino-3-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-8-( 4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,3,8-triazaspiro[4.5]dec-1-ene -4-one

step 1:

Compound SZ-9384 (50 mg, 0.089 mmol) was dissolved in methanol (3 ml), and 7M ammonia methanol solution (0.1 ml) and 70% tert-butyl hydroperoxide (0.1 ml) were added. Water (10 ml) was added to the system, extracted with ethyl acetate (10 ml x 3), and the organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by high-pressure reversed-phase column chromatography (ACN-0.1% HCO ₂ H aqueous solution) and lyophilized to obtain SZ-9333 (3.2 mg, 6%, white solid). LCMS: [M+H] ⁺ 545.12. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.54 (d, J=4.4 Hz, 1H), 8.50 (d, J=2.3 Hz, 1H), 8.04 (dd, J=8.6, 2.3 Hz, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.73 (d, J = 4.4 Hz, 1H), 6.15 (d, J = 12.9 Hz, 2H), 5.47–5.39 (m, 1H), 4.42–4.22 (m , 2H), 3.79–3.61(m, 2H), 2.28(s, 3H), 2.24(s, 3H), 2.09–1.98(m, 1H), 1.95(d, J=7.1Hz, 3H), 1.89– 1.85(m,1H), 1.82-1.75(m,1H),1.71-1.59(m,1H).

Example 7 SZ-9334: (S)-3-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-8-(4-methyl -6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,3,8-triazaspiro[4.5]dec-2,4-dione

step 1:

9307A1 (1g, 2.13mmol), (S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethylamine (prepared according to WO2017079140) (0.3 g, 2.13 mmol) and DIPEA (0.9 ml, 4.26 mmol), stirred to dissolve. Finally, HATU (0.91g, 1.1mmol) was added and the reaction was carried out at 23-26°C for 16 hours. The reaction solution was added with water (30 ml) and extracted with EA (30 ml x 3). The organic phases were combined and washed with saturated brine (30 ml x 3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography ( PE: EA=3:1～EA, DCM:MeOH=10:1; Rf=0.3) purification to obtain 9334A0 (860 mg, 61.9%, off-white solid). LCMS: [M+H] ⁺ 655.19@4.19min.

Step 2:

9334A0 (730 mg, 1.11 mmol) and methanol (6 ml) were added to the reaction flask, and stirred to dissolve. Then, diethylamine (6 ml) was added in portions and the reaction was carried out at 26°C for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography (PE:EA=1:1～EA, DCM:MeOH=10:1; Rf=0.3) to obtain 9334A1 (0.426g, 53.3%, light yellow oil) (The material becomes solid overnight). LCMS: De-Boc[M+H] ⁺ 333.08@2.85min.

Step 3: tert-butyl(S)-3-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2,4-dicarbonyl- 1,3,8-Triazaspiro[4.5]dec-8-carboxylate (9334A2)

Compound 9334A1 (399 mg, 0.91 mmol), carbonyldiimidazole (1.8 g) and dioxane (9 ml) were added to the reaction flask, and the resulting reaction mixture was heated to 110° C. and stirring was continued for 16 hours. The reaction solution was cooled to room temperature and quenched with water (30ml), and then extracted with ethyl acetate (30mlx3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to remove the solvent. The residue was purified by flash silica gel column chromatography (PE:EA=3:1~EA, DCM:MeOH=10:1; Rf=0.3). Compound 9334A2 was obtained (0.3 g, 71.6%, white solid). LCMS: [M+H] ⁺ 459.07@3.72min.

Step 4: (S)-3-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-methyl-1,3,8 -Triazaspiro[4.5]dec-2,4-dione; trifluoroacetate (9334A3)

Compound 9334A2 (91 mg, 0.19 mmol) was dissolved in dichloromethane (3 ml), trifluoroacetic acid (3 ml) was added, stirred at 23 degrees Celsius for 1 hour, and the solvent was concentrated under reduced pressure to obtain crude 9334A3, which was directly used in the next reaction. LCMS: [M+H] ⁺ 359.06@2.72min.

Step 5: (S)-3-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-8-(4-methyl-6- ((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,3,8-triazaspiro[4.5]dec-2,4-dione (SZ-9334 )

Compound 9334A3 (91 mg, 0.19 mol), compound 3 (133 mg, 0.60 mmol) (prepared according to WO2017079140) and potassium carbonate (0.26 g, 1.8 mmol) were added to DMSO (6 ml) and stirred at 110° C. for 39 hours. Water (30ml) was added to the system and extracted with ethyl acetate (30mlx3). The combined organic phase was washed with saturated brine (30 ml×3), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Purified by preparative thin layer chromatography (EA; Rf=0.5) to obtain crude product SZ-9334 (0.1 g). It was then purified using column chromatography [(PE:EA=3:1 to EA, DCM:MeOH=10:1 (3V/V%ammonia added))] to obtain crude product SZ-9334 (30 mg). It was then purified using high-pressure preparative chromatography to obtain SZ-9334 (14 mg, 14.29%, white solid). LCMS: [M+H] ⁺ 546.10@3.16min. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.51 (s, 1H), 8.50 (s, 1H), 8.46 (d, J=4.0 Hz, 1H), 8.04-8.01 (dd, J1=8.0 Hz, J2 = 4.0 Hz, 1H), 7.93-7.91 (d, J=8.0 Hz, 1H), 7.69-7.68 (d, J=4.0 Hz, 1H), 5.43-5.36 (q, J=8.0 Hz, 1H), 4.46 -4.43(m, 2H), 3.56-3.43(m, 2H), 2.26(s, 3H), 2.21(s, 3H), 1.98-1.91(m, 2H), 1.87-1.85(d, J=8.0Hz , 3H), 1.68-1.63 (m, 2H).

Example 8 SZ-9335: (S)-3-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methyl-8- (4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,3,8-triazaspiro[4.5]dec-2, 4-dione

Step 1: tert-butyl(S)-3-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methyl-2, 4-Dicarbonyl-1,3,8-triazaspiro[4.5]dec-8-carboxylate (9335A1)

NaH (0.16 g, 60 wt%) was added portionwise to the DMF solution of compound 9334A2 (190 mg, 0.39 mmol) at 23 degrees Celsius, and the resulting reaction mixture was continued to stir at 23 degrees Celsius for 1 hour. Then, methyl iodide (0.6 g) was added dropwise to the above reaction solution. The resulting reaction mixture was continued to stir for half an hour. Then, a saturated aqueous ammonium chloride solution (3 ml) was added dropwise to quench the reaction, and then diluted with water (30 ml), and extracted with ethyl acetate (30 ml×3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to remove the organic solvent. The crude product was obtained by preparative thin layer chromatography (PE: EA = 1:1; Rf = 0.6) to obtain compound 9335A1 (0.13 g, 69.8%, White solid). LCMS: [M+H] ⁺ 473.07@3.91min.

Step 2: (S)-3-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methyl-1,3,8 -Triazaspiro[4.5]dec-2,4-dione; trifluoroacetate (9335A2)

Compound 9335A1 (119 mg, 26 umol) was dissolved in dichloromethane (3.3 ml), trifluoroacetic acid (3.6 ml) was added, stirred at 23 degrees Celsius for 1 hour, the water pump was concentrated to remove the solvent, and then the oil pump was used for three minutes. The resulting crude product (9335A2) was directly used in the next reaction. LCMS: [M+H] ⁺ 373.08@2.73min.

Step 3: (S)-3-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methyl-8-(4- Methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,3,8-triazaspiro[4.5]dec-2,4-di Ketone (SZ-9335)

Compound 9335A2 (136 mg, 0.29 mol), compound 3 (130 mg, 0.60 mmol) and potassium carbonate (0.39 g, 0.3 mmol) were added to DMSO (6 ml) and stirred at 180°C for 1.5 hours. After the resulting reaction mixture was cooled to room temperature, water (30 ml) was added to the system, and extracted with ethyl acetate (30 ml×3). The organic phases were combined, washed with saturated brine (30 ml×3), dried over anhydrous magnesium sulfate, and filtered. The organic phase was concentrated under reduced pressure to obtain a crude product, which was separated once by medium-pressure preparative chromatography to obtain the crude product, and then purified using high-pressure preparative chromatography to obtain SZ-9335 (2.1 mg, 1.3%, white solid). LCMS: [M+H] ⁺ 560.1 0@3.33min. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.51-8.50 (d, J=4.0 Hz 1H), 8.47-8.46 (d, J=4.0 Hz 1H), 8.05-8.02 (dd, J1=8.0 Hz, J2 = 4.0 Hz, 1H), 7.93-7.91 (d, J=8.0 Hz, 1H), 7.69-7.68 (d, 4.0 Hz 1H), 6.12-6.10 (d, J=8.0 Hz, 2H), 5.46-5.41 ( q, J=8.0Hz, 1H), 4.69-4.60(m, 2H), 3.6-3.46(m, 2H), 2.25(s, 3H), 2.19(s, 3H), 2.03-1.96(m, 2H) , 1.88-1.86 (d, J=8.0Hz, 3H), 1.69-1.61 (m, 2H).

Example 9 SZ-9306 (SZ-9306A and SZ-9306B): (S)-3-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl )-1-methyl-8-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,3-diazaspiro [4.5]decane-2,4-dione

step 1:

To the reaction flask, compound 9306A0 (8g, 40mmol), NaOH (3.2g, 80mmol) and THF (100ml), water (100ml) were stirred, then di-tert-butyl dicarbonate (13g, 60mmol) was added, and the mixture was stirred at room temperature overnight The reaction solution was adjusted to pH 2 with 1N hydrochloric acid, extracted with ethyl acetate (300ml x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 9306A1 (10.8g, 85%, white foam) Solid), proceed to the next reaction without purification. LCMS: De-Boc[M+H] ⁺ 201.06.

Step 2:

9306A1 (9g, 30mmol), (S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethylamine (prepared according to WO2017079140) (6.18g , 30mmol) and DIPEA (10ml, 60mmol), stirred to dissolve. Finally, HATU (13.68g, 36mmol) was added, and the reaction was carried out at 23-26°C for 16 hours. The reaction solution was added with water (300ml) and extracted with EA (100mlx3). The organic phases were combined and washed with saturated brine (100mlx3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography 9306A2 (12g, 81%, white foamy solid). LCMS:[M+H] ⁺ 490.07

Step 3:

9306A2 (9.78g, 20mmol), NaOH (4.8g, 120mmol) and DMF (100ml) were added to the reaction flask, and the reaction was heated to 60°C and stirred for 3 hours. Water (300 ml) was added to the reaction solution and filtered to obtain crude 9306A3 (7 g, 84%, white powdery solid). LCMS:[M+H] ⁺ 416.02

Step 4:

9306A3 (4.15g, 10mmol) and DMF (30ml) were added to the reaction flask, NaH (480mg, 20mmol) was added in portions at 0°C, stirred for 1 hour, and then iodomethane (2.82g, 20mmol) was added dropwise and stirred at 26°C React overnight. Water (300 ml) was added to the reaction solution and filtered to obtain crude 9306A4 (3.9 g, 90%, white powdery solid). LCMS:M+H] ⁺ 430.04

Step 5:

9306A4 (3.5g, 8.16mmol) and Dioxane (100ml) were added to the reaction bottle, 6N hydrochloric acid (100ml) was added at 0°C, and stirred overnight at 26°C. The reaction solution was adjusted to pH with saturated sodium carbonate solution, = 9. Extracted with EA (100mlx3), the organic phases were combined and washed with saturated brine (100mlx3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography to obtain 9306A5 (2.9g, 92%) , White foamy solid). LCMS: De-Boc[M+H] ⁺ 386.01

Step 6:

9306A5 (2.9g, 7.53mol) was dissolved in anhydrous tetrahydrofuran (50ml), the system was cooled to -70°C under the protection of argon and LiHMDS (15ml, 1mol/L) was slowly dropped, and then stirred again at the temperature for 1 hour Then, phenylbis(trifluoromethanesulfonyl)imide (5.4g, 15mmol) in tetrahydrofuran (30ml) was quickly added to the system and the temperature was raised to 0°C and stirred for 3 hours. After the reaction was completed, 20 ml of saturated ammonium chloride was added to quench, extracted with 50 ml of ethyl acetate. The organic phase was dried over sodium sulfate, concentrated and purified by flash silica gel column chromatography to obtain a colorless oil 9305A6 (2.9 g, 75%, white foam) solid). LCMS: De-Boc[M+H] ⁺ 517.94

Step 7:

9306A6 pinacol (1.7g, 36.72mmol), Pd ( dppf) 2 Cl 2 · DCM (228mg, 5%) (2.9g, 5.6mmol) and the boronic acid with potassium acetate (1.65g, 16.8mmol) under argon Under protection, mix in dioxane (50ml) and heat to 80 degrees and stir for 4 hours. After the reaction was completed, the solvent was cooled and removed, and purified by flash silica gel column chromatography to obtain a colorless oil 9305A7 (2.0 g, 72%, white foamy solid). LCMS: [M+H] ⁺ 496.06.

Step 8:

9306A7 (0.5g, 1mmol), and 9305A8 (237mg, 1mmol), Pd (PPh 3) 4 (100mg, 5%), potassium carbonate (345mg, 2.5mmol) were mixed in dioxane (6ml) under argon protection After stirring with water (2ml) at 125°C for 5 hours, the resulting reaction solution was concentrated and purified by flash silica gel column chromatography (PE/EA 50%-70%) to obtain a colorless oil 9306A8 (370mg, 66%) . LCMS: [M+H] ⁺ 557.07.

Step 9:

9306A8 (330 mg) was suspended in ethanol (10 ml), acetic acid (5 ml) was added dropwise to dissolve, and stirred at 60 degrees overnight under a hydrogen atmosphere. After the reaction is completed, the pH of the system is adjusted to about 9 with saturated sodium carbonate, EA extraction, the organic phase is concentrated and concentrated under reduced pressure to obtain the crude product, purified by high-pressure reversed-phase column chromatography (ACN-0.1% ammonium carbonate aqueous solution), and freeze-dried Two isomers SZ-9306A (60 mg) and SZ-9306B (12 mg) were obtained. LCMS: [M+H] ⁺ 559.04

SZ-9306A: HPLC t _R = 6.07 min. ¹ H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 9.55 (s, 1H), 8.68 (d, J=4.4 Hz, 1H), 8.43 (d, J=1.9 Hz, 1H), 7.95 (ddd, J = 18.9, 11.7, 5.4 Hz, 3H), 6.67 (s, 2H), 5.34 (q, J = 7.1 Hz, 1H), 2.81 (s, 3H), 2.64 (t, J = 12.3 Hz , 1H), 2.38-2.26 (m, 2H), 2.21 (d, J = 22.5 Hz, 6H), 1.95 (dd, J = 18.0, 8.8 Hz, 2H), 1.89-1.64 (m, 7H).

SZ-9306B: HPLC t _R = 6.35 min. ¹ H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 9.55 (s, 1H), 8.68 (d, J=4.4 Hz, 1H), 8.41 (s, 1H), 8.13–7.69 (m , 3H), 6.85(s, 1H), 6.15(s, 1H), 5.35(q, J=6.9Hz, 1H), 2.99–2.76(m, 4H) 2.36–1.90(m, 12H), 1.83–1.56 (m,5H).

SZ-9306A and SZ-9306B HPLC analysis method

Instrument: Waters Acquity ARC (UHPLC)

Column: XSelect CSH ^TM C ₁₈ 2.5um 4.6*150mm Column XP

Mobile Phase A: 0.1% formic acid in water

Mobile Phase B: Acetonitrile

Flow rate: 1ml/min

Wavelength: 290nm

Column temperature: 30℃

Blank solvent: methanol

Sample solution: Dissolve the appropriate amount of SZ-9306A or SZ-9306B with methanol, filter with 0.22um filter membrane, and enter liquid chromatography for analysis.

Example 10 SZ-9386: (S)-2-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-8-(4-methyl -6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2,8-diazaspiro[4.5]dec-1-one

step 1:

LiHMDS (69 ml, 69 mmol) was added dropwise to a solution of compound 1 (11 g, 42.6 mmol) in THF (160 ml) at -78 degrees Celsius. The resulting reaction mixture was further stirred at -78-23 degrees Celsius for half an hour. After cooling to -78 degrees Celsius, allyl bromide (6.9 g, 60 mmol) was added dropwise to the above reaction solution. The resulting reaction mixture was further stirred at -78-23 degrees Celsius for 16 hours. The resulting reaction mixture was quenched with saturated aqueous NH ₄ Cl (160 ml) and diluted with water (30 ml). After separating the organic phase, the aqueous phase was extracted with ethyl acetate (0.1 Lx3). Combine the organic phases, dry with anhydrous MgSO4, filter, and concentrate to remove the organic solvent. The obtained crude product was purified by flash silica gel column chromatography (PE: EA=10:1; Rf=0.1) to obtain a yellow liquid product 9386A0 (11 g, 87.3%).

Step 2:

9334A0 (6.3 g, 21 mmol) was added to a mixed solution of water (80 ml) and acetonitrile (80 ml) at 23 degrees Celsius, followed by NaIO4 (14.6 g) and RuCl3 solid (0.13 g). The resulting reaction mixture was further stirred at 23 degrees Celsius for 3 hours. The resulting dark brown suspension was diluted with water (110 ml) and extracted with ethyl acetate (0.3 Lx3). Combine the organic phases, dry with anhydrous MgSO4, filter, and concentrate to remove the organic solvent. The obtained crude product was purified by flash silica gel column chromatography (PE: EA=10:1 to 1:1; Rf=0.3) to obtain 9386A1 (1.8 g, 28.6%, pale yellow liquid).

Step 3: tert-butyl (S)-2-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-carbonyl-2,8 -Triazaspiro[4.5]dec-8-carboxylate (9386A2)

NaBH(OAc)3 (3.9g) was added in portions at 23 degrees Celsius to compound 9386A1 (1.8g, 0.59mmol) and compound 2 in 1,2-dichloroethane solution, the resulting reaction mixture was continued at 16-23 degrees Celsius Stir for 16 hours. The resulting reaction mixture was then heated to 110 degrees Celsius and stirring continued for 1 hour. The resulting reaction mixture was concentrated to remove the organic solvent, and the residue was quenched with saturated NH 4 Cl aqueous solution (30 ml), followed by ethyl acetate extraction (30 m×3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to remove the solvent. The residue was purified by flash silica gel column chromatography (PE:EA=3:1~1:3; Rf=0.3) to obtain compound 9386A2 as off-white solid (1.6g, 67.8%). LCMS: [M+Na] ⁺ 466.01@3.79min.

Step 4: (S)-2-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2,8-triazaspiro[4.5 ]Dec-1-one; trifluoroacetate (9386A3)

Compound 9386A2 (0.6 g, 1.39 mmol) was dissolved in dichloromethane (3 ml), trifluoroacetic acid (3 ml) was added, stirred at 21 degrees Celsius for 1 hour, the water pump was concentrated to remove the solvent, and then the oil pump was used for three minutes. The resulting crude product 9386A3 (0.6g) was directly reacted in the next step. LCMS: [M+H] ⁺ 344.06@2.683min.

Step 5: (S)-2-(1-(6-(4-Fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-8-(4-methyl-6- ((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2,8-diazaspiro[4.5]dec-1-one (SZ-9386)

Compound 9386A3 (0.6 g, 1.39 mol), compound 3 (0.58 g, 2.58 mmol) and potassium carbonate (1.1 g, 7.8 mmol) were sequentially added to DMSO (6 ml), and stirred at 110°C for 3 hours. Water (30ml) was added to the system and extracted with ethyl acetate (30mlx3). The combined organic phase was washed with saturated brine (30 ml×3), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. It was then purified using high-pressure preparative chromatography to obtain SZ-9386 (110 mg, 14.9%, white solid). LCMS: [M+H] ⁺ 531.10@3.103min. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.51 (d, J=4.0 Hz, 1H), 8.35 (s, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.87 (d, J=8.0 Hz, 1H), 6.15(br,, 1H), 6.07(br, 1H), 5.41(q, J=4.0Hz, 1H), 4.69-4.39(m, 2H), 3.56-3.39(m, 2H), 3.16-3.09(m,3H), 2.25(s,3H), 2.19(s,3H), 2.13-2.09(m,1H), 2.09-2.01(m,1H),,1.89-1.73(m,2H) , 1.61 (d, J = 4.0 Hz, 3H), 1.5 (d, J = 12.0 Hz, 1 H), 1.41 (d, J = 12.0 Hz, 1 H).

Example 11 SZ-013004: (S)-2-(2(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2,8-di Azaspiro[4.5]dec-8-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)amino)pyrimidine-4-amine

Step 1: tert-butyl(S)-2-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2,8-diaza Spiro[4.5]dec-8-carboxylate (013004A1)

At 23 degrees Celsius, LAH (0.16 g, 4.19 mmol) was added to the THF solution of compound 9386A2 (0.3 g, 0.67 mmol) in portions, and then THF (3 ml) was added to dilute the reaction system. The resulting reaction mixture was continued to stir at 23 degrees Celsius for 30 minutes. The resulting reaction mixture was cooled to 1-3°C, and THF (13 ml) was added to dilute the reaction system. Then water (0.16 ml), aqueous NaOH solution (0.16 ml; 16 wt%) and water (0.5 ml) were added to quench the reaction system. The resulting reaction mixture was continued to stir for half an hour. It was then filtered and the solid was washed with THF (6mlx3). The filtrates were combined and concentrated under reduced pressure, and the obtained crude product was subjected to preparative thin layer chromatography (PE: EA = 1:1; Rf = 0.6) to obtain 013004A1 (30 mg, 10.3%) as a pale yellow oil. LCMS: [M+H ⁺ ] 430.12@2.98min.

Step 2: (S)-2-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2,8-diazaspiro[4.5 ] Decane; trifluoroacetate (013004A2)

Compound 013004A1 (30mg, 69.8umol) was dissolved in dichloromethane (3ml), trifluoroacetic acid (3ml) was added, stirred at 21 degrees Celsius for 1 hour, the water pump was concentrated to remove the solvent, and then the oil pump was used for three minutes. The resulting crude product 013004A2 (31 mg, 98%) was directly reacted in the next step. LCMS: [M+H] ⁺ 330.07@0.873min.

Step 3: (S)-2-(2-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2,8-diaza Spiro[4.5]dec-8-yl)-6-methyl-N-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidine-4-amine (SZ-013004)

Compound 013004A2 (31 mg, 69 umol), compound 3 (31 mg, 0.13 mmol) and potassium carbonate (0.126 g, 0.9 mmol) were added to DMSO (3 ml) and stirred at 110° C. for 16 hours. After the resulting reaction mixture was cooled to room temperature, water (30 ml) was added to the system, and extracted with ethyl acetate (30 ml×3). The organic phases were combined, washed with saturated brine (30 ml×3), dried over anhydrous magnesium sulfate, and filtered. The organic phase was concentrated under reduced pressure to obtain a crude product, which was separated and purified by high-pressure preparative chromatography to obtain SZ-013004 (6.3 mg, 18%, white solid). LCMS: [M+H] ⁺ 517.10@2.23min. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.49 (d, J = 4.0 Hz 1H), 8.37 (d, J = 4.0 Hz 1H), 7.95 (dd, J1 = 16.0 Hz, J2 = 8.0 Hz, 1H) , 7.91 (d, J = 16.0 Hz, 1H), 7.68 (d, J = 4.0 Hz, 1H), 3.79-3.73 (m, 2H), 3.69-3.63 (m, 3H), 3.43-3.36 (m, 1H) ), 2.81-2.75 (m, 1H), 2.58 (d, J = 8.0Hz, 1H), 2.56-2.51 (m, 1H), 2.32 (d, J = 8.0Hz, 1H), 2.25 (s, 3H) , 2.17 (s, 3H), 1.76-1.69 (m, 2H), 1.63-1.53 (m, 4H), 1.37 (d, J = 4.0 Hz, 3H).

Example 12 SZ-9391: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methyl-9- (4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,4,9-triazaspiro[5.5]undecane- 2,5-dione

Step 1: tert-butyl-(S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methyl-2 ,5-dicarbonyl-1,4,9-triazaspiro[5.5]undecane-9-carboxylate

Add 013002A4 (560mg, 1.2mmol) and THF (20ml) to the reaction flask, cool to 0°C under stirring, then slowly add NaH (95mg, 2.4mmol), and then warm to room temperature after stirring for 20 minutes. Finally, MeI (185 mg, 1.3 mmol) was added and reacted at 20°C for 12 hours. The reaction solution was quenched with saturated ammonium chloride solution, and then water (100 ml) was added, extracted with EA (50 ml*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography Method (EA/PE 0-50%) purification to obtain 9391A1 (270mg, 46%, white solid). LCMS: [M+H]+487.03.

Step 2: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methyl-1,4,9 -Triazaspiro[5.5]undecane-2,5-dione

Compound 9391A1 (270 mg, 0.55 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, stirred at room temperature for 2 hours, and concentrated to remove the solvent to obtain crude product 9391A2, which was directly reacted without purification.

Step 3: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methyl-9-(4- Methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,4,9-triazaspiro[5.5]undecane-2,5 -Diketone

Compound 9391A2 (214 mg, 0.55 mol), intermediate 2 (122 mg, 0.55 mmol) and potassium carbonate (303 mg, 2.2 mmol) were added to DMSO (5 mL), and stirred at 110° C. for 16 hours. 50mL of water was added to the system, and extracted three times with ethyl acetate (20ml). The organic phase was spin-dried under reduced pressure to obtain the crude product. The product was then subjected to reversed-phase column chromatography with acetonitrile/0.1% formic acid water and freeze-dried to obtain SZ-9391 , 32%, white solid). LCMS: [M+H] ⁺ 574.5.

¹ H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 8.70 (d, J = 4.5 Hz, 1H), 8.40 (s, 1H), 7.99-7.89 (m, 3H), 6.29-6.01 (m, 2H), 5.77 (q, J = 7.0 Hz, 1H), 4.55-4.45 (m, 2H), 4.14 (d, J = 17.8 Hz, 1H), 3.69 (d, J = 17.8 Hz, 1H) , 3.58-3.33(m, 2H), 2.84(s, 3H), 2.20(s, 3H), 2.13(s, 3H), 2.10-2.01(m, 2H), 1.98-1.85(s, 2H), 1.58 (d, J = 7.0 Hz, 3H).

Example 13 SZ-9380: (S)-3-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-8-(4-methyl -6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,3,8-triazaspiro[4.5]decane-2-one

Step 1: tert-butyl-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-formyl piperidine-1-carboxylate

Compound 9380A0 (1.4g, 3.1mmol), PCC (1.34g, 6.2mmol) and DCM (40ml) were added to the reaction flask and stirred. The reaction was stirred at 25°C for 12 hours. The diatom was filtered, and the filtrate was concentrated under reduced pressure. Silica gel column chromatography purification gave 9380A1 (1.1 g, 79%, white foamy solid). LCMS: De-Boc[M+H] ⁺ 451.48.

Step 2: tert-butyl-(S)-4-(((((9H-fluoren-9-yl)methoxy)carbonyl)amino)amino)-4-(((1-(6-(4-fluoro- 1H-pyrazol-1-yl)pyridin-3-yl)ethyl)amino)methyl)piperidine-1-carboxylate

9380A1 (1.1g, 2.4mmol), (S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethylamine (prepared according to WO2017079140) was added to the reaction flask 0.5g, 2.4mmol), acetic acid (0.1mL), DCM (20mL), stirred to dissolve. Finally, sodium triacetoxyborohydride (1.56g, 7.3mmol) was added and reacted at 23-26°C for 6 hours. The reaction solution was added with saturated ammonium chloride solution (100ml) and extracted with EA (30ml*3). The organic phases were combined and washed with saturated brine (30ml*3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product And purified by flash silica gel column chromatography to obtain 9380A2 (800 mg, 52%, white foamy solid). LCMS: [M+H] ⁺ 641.28.

Step 3: tert-Butyl-(S)-4-amino-4-(((1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)amino )Methyl)piperidine-1-carboxylate

9380A2 (0.8g, 1.25mmol), diethylamine (5mL) and methanol (20mL) were added to the reaction bottle, and the reaction was stirred at 25°C for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography to obtain 9380A3 (400 mg, 78%, white foamy solid). LCMS: [M+H] ⁺ 348.19.

The fourth step: tert-butyl-(S)-4-((tert-butoxycarbonyl)amino)-4-(((1-(6-(4-fluoro-1H-pyrazol-1-yl) Pyridin-3-yl) ethyl) amino) methyl) piperidine-1-carboxylate

9380A3 (0.4g, 1.15mmol), di-tert-butyl dicarbonate (0.3g, 1.38mmol) and DCM (20mL) were added to the reaction flask, stirred at 25 ℃ for 1 hour, the reaction solution was added saturated ammonium chloride solution ( 50ml), extracted with EA (15ml*3), the organic phases were combined and washed with saturated brine (15ml*3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography 9380A4 (460 mg, 77%, white foamy solid). LCMS: [M+H] ⁺ 519.33.

The fifth step: tert-butyl-(S)-3-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-carbonyl-1, 3,8-Triazaspiro[4.5]decane-8-carboxylate

9380A4 (460mg, 0.89mmol), NaOH (213mg, 5.32mmol) and DMF (5mL) were added to the reaction bottle, and the reaction was stirred at 60°C for 3 hours. The reaction solution was added with water (60mL) and EA (15ml*3) ) Extraction, the organic phases were combined and washed with saturated brine (15ml*3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography to obtain 9380A5 (330mg, 84%, white foam) Solid). LCMS: [M+H] ⁺ 445.16.

Step 6: (S)-3-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1,3,8-triazaspiro [4.5]decane-2-one

9380A5 (330mg, 0.74mmol) was added to the reaction flask, dissolved in dichloromethane (5mL), trifluoroacetic acid (1mL) was slowly added dropwise, and stirred at 25°C for 2 hours. The solvent was spin-dried without purification to obtain 9380A6 (360mg, crude product) ), go directly to the next step. LCMS: [M+H] ⁺ 345.23.

Step 7: (S)-3-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-8-(4-methyl-6- ((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,3,8-triazaspiro[4.5]decane-2-one

Compound 9380A6 (256 mg, 0.74 mol), 9305A8 (165 mg, 0.74 mmol) and potassium carbonate (410 mg, 3 mmol) were added to DMSO (5 mL) and stirred at 110° C. for 16 hours. Water (50 mL) was added to the system, extracted with ethyl acetate (10*3 ml), and the organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by medium-pressure reversed-phase column chromatography (ACN-0.1% HCO2H aqueous solution) and lyophilized to obtain SZ-9380 (180 mg, 46%, white solid). LCMS: [M+H+] 532.1.

¹ H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 9.19 (s, 1H), 8.69 (dd, J=4.6, 0.7 Hz, 1H), 8.39 (s, 1H), 8.02-7.78 (m, 3H), 7.04 (s, 1H), 6.13 (d, J = 43.1 Hz, 2H), 5.10 (q, J = 7.1 Hz, 1H), 3.91–3.74 (m, 2H), 3.74–3.55 ( m, 2H), 3.28 (d, J = 9.0 Hz, 1H), 2.89 (d, J = 9.0 Hz, 1H), 2.18 (s, 3H), 2.09 (s, 3H), 1.59 (dd, J = 11.0 , 6.5 Hz, 2H), 1.51 (d, J=7.2 Hz, 5H).

Example 14 SZ-013011: (S)-3-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methyl-8- (4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,3-diazaspiro[4.5]decane-2-one

Step 1: Methyl-8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate

Compound 013011A0 (18g, 90mmol) was dissolved in hydrochloric acid methanol solution (400mL), and then reacted under reflux for 6 hours. The system was cooled to room temperature, and the reaction solution was spin-dried under reduced pressure to obtain crude 013011A1 (25g, colorless oil), without Need to be purified and proceed directly to the next reaction. LCMS: [M+H] ⁺ 216.08.

Step 2: Methyl-8-((tert-butoxycarbonyl)amino)-1,4-dioxaspiro[4.5]decane-8-carboxylate

013011A1 (15g, 40mmol) was dissolved in tetrahydrofuran (100mL) and water (100mL), potassium carbonate (11g, 80mmol) was added and stirred at room temperature for 16 hours, then water (400mL) was added, followed by extraction with ethyl acetate (300mL) The organic phase was dried over sodium sulfate and then spin-dried to obtain a crude product, and 013011A2 (8g, 63%, colorless oil) was obtained by flash silica gel column chromatography. LCMS: [M+H] ⁺ 316.06.

Step 3: tert-butyl(8-hydroxymethyl)-1,4-dioxaspiro[4.5]dec-8-yl)carbamate

013011A2 (8g, 0.025mol) was dissolved in THF (100ml) was added portionwise LiAlH ₄ (1g, 0.025mol), reaction temperature does not exceed 25 degrees and stirred for 1 h, TLC to monitor disappearance of starting material, quenched with saturated ammonium chloride Then, it was extracted with ethyl acetate (300 mL), and the organic phase was dried over sodium sulfate and spin-dried to obtain a crude product, and 013011A3 (3.3 g, 46%, colorless oily liquid) was obtained by flash silica gel column chromatography. LCMS: [M+H] ⁺ 288.08.

Step 4: tert-Butyl (8-formyl-1,4-dioxane [4.5]dec-8-yl) carbamate

013011A3 (2.87g, 0.01mol) was dissolved in DCM (30ml), PCC (6.46g, 0.03mol) was added, and stirred at 25°C for 4 hours. The reaction solution was added with silica gel to prepare samples, and 013011A4 was obtained by flash silica gel column chromatography. 2g, 70%, white solid). LCMS: [M+H] ⁺ 285.99.

Step 5: tert-butyl-(8-(((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)amino)methyl)-1,4-di Oxa spiro[4.5]dec-8-yl)carbamate

013011A4 (2g, 7mmol) was dissolved in DCE (30ml), glacial acetic acid (1mL) and sodium triacetoxyborohydride (4.45g, 21mmol) were added, stirred at 25°C for 4 hours, the reaction solution was added to silica gel to sample, Flash silica gel column chromatography gave 013011A5 (2.3 g, 70%, white solid). LCMS: [M+H] ⁺ 476.12.

Step 6: (S)-3-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-9,12-dioxa-1, 3-diazabispiro[4.2.4 ⁸ .2 ⁵ ]tetradecane-2-one

013011A5 (2.3g, 4.84mmol) was dissolved in DMF (30ml), sodium hydroxide (1.16g, 29mmol) was added, stirred at 60°C for 4 hours, then water (100mL) was added, followed by ethyl acetate (30* 3mL) extraction, the organic phase was dried over sodium sulfate and spin-dried to obtain the crude product, and 013011A6 (1.6 g, 82%, white solid) was obtained by flash silica gel column chromatography. LCMS: [M+H] ⁺ 402.07.

Step 7: (S)-3-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methyl-9,12-di Oxa-1,3-diazabispiro[4.2.4 ⁸ .2 ⁵ ]tetradecane-2-one

013011A6 (1.6g, 4mmol) was dissolved in DMF (20ml), sodium hydride (0.16g, 4mmol) was added, stirred at 0°C for 1 hour, then iodomethane (0.85g, 6mmol) was added, and stirred at 40°C 4 Hours, then water (100 mL) was added, followed by extraction with ethyl acetate (30*3 mL), the organic phase was dried over sodium sulfate and spin-dried to give the crude product, and flash silica gel column chromatography was used to obtain 013011A7 (1.45 g, 87%, white solid) ). LCMS: [M+H] ⁺ 416.10.

Step 8: (S)-3-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methyl-1,3-di Azaspiro[4.5]decane-2,8-dione

013011A7 (1.45g, 3.5mmol) was dissolved in Dioxane (30ml), 4N hydrochloric acid (9mL) was added, stirred at 40°C for 6 hours, then water (100mL) was added, followed by extraction with ethyl acetate (30*3mL), The organic phase was dried over sodium sulfate and then spin-dried to obtain a crude product, which was obtained by flash silica gel column chromatography to obtain 013011A8 (1 g, 77%, white solid). LCMS: [M+H] ⁺ 372.12.

Step 9: 3-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methyl-2-carbonyl-1 ,3-diazaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate

013011A8 (1.0g, 2.7mmol) was dissolved in anhydrous tetrahydrofuran (20mL), the system was cooled to -70°C under the protection of argon and LiHMDS (3mL, 1mol/L) was slowly dropped, and then stirred at this temperature for 1 After that, phenylbis(trifluoromethanesulfonyl)imide (1 g, 2.7 mmol) in tetrahydrofuran (10 mL) was quickly added to the system and the temperature was raised to 0°C and stirred for 3 hours. After the reaction was completed, 100 mL of saturated ammonium chloride was added to quench, extracted with 50 mL of ethyl acetate. The organic phase was dried over sodium sulfate, spin-dried and purified by flash silica gel column chromatography to obtain 013011A9 (0.8 g, 59%, white solid). LCMS: [M+H] ⁺ 504.02.

Step 10: 3-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methyl-8-(4, 4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3-diazaspiro[4.5]dec-7-en-2-one

013011A9 pinacol (0.8g, 1.6mmol) and the United boronic acid (0.4g, 1.6mmol), Pd ( dppf) 2 Cl 2 · DCM (65mg, 5%), potassium acetate (0.47g, 4.8mmol) under argon Under protection, mix in dioxane (30 mL) and heat to 80 degrees and stir for 4 hours. After the reaction was completed, the solvent was cooled and removed, and purified by flash silica gel column chromatography to obtain 013011A10 (0.6 g, 78%, white solid). LCMS: [M+H] ⁺ 482.16.

Step 11: 3-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methyl-8-(4- Methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,3-diazaspiro[4.5]dec-7-en-2-one

013011A10 (0.6g, 1.25mmol), and 9305A8 (279mg, 1.25mmol), Pd (PPh 3) 4 (72mg, 5%), potassium carbonate (518mg, 3.75mmol) were mixed in dioxane under argon protection ( 6 mL) and water (2 mL), stirred under microwave at 125° C. for 5 hours, and the resulting reaction solution was spin-dried and purified by flash silica gel column chromatography to obtain 013011A11 (600 mg, 89%, white solid). LCMS: [M+H] ⁺ 542.16.

Step 12: (S)-3-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methyl-8-(4- Methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,3-diazaspiro[4.5]decane-2-one

013011A11 (0.6g, 1.1mmol) was dissolved in methanol (10mL), ammonium formate (0.7g, 11mmol) and palladium hydroxide/C (100mg) were added, stirred at 60°C for 3 hours, filtered, and the organic phase was decompressed The crude product was obtained by spin-drying, which was purified by medium-pressure reversed-phase column chromatography (ACN-0.1% HCO ₂ H aqueous solution) and lyophilized to obtain SZ-013011A (150 mg, white solid) and SZ-013011B (50 mg, white solid). LCMS: [M+H] ⁺ 545.7.

SZ-013011A: LCMS t _R = 2.059 min, HPLC t _R = 5.68 min, ¹ H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 9.50 (s, 1H), 8.69 (d, J= 4.1Hz, 1H), 8.40(d, J=2.0Hz, 1H), 8.05–7.80(m, 3H), 6.81(s, 1H), 6.13(s, 1H), 5.14(q, J=7.0Hz, 1H), 3.27 (d, J = 8.8Hz, 1H), 2.90 (d, J = 8.8Hz, 1H), 2.63 (s, 3H), 2.55 (d, J = 11.3Hz, 1H), 2.21 (s, 3H), 2.14 (s, 3H), 1.86 (dt, J = 28.4, 13.2 Hz, 4H), 1.71-1.48 (m, 6H), 1.40 (d, J = 12.1 Hz, 1H).

SZ-013011B: LCMS t _R = 2.100 min, HPLC t _R = 6.32 min, ¹ H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 9.51 (s, 1H), 8.76-8.62 (m, 1H), 8.39(s, 1H), 7.97–7.85(m, 3H), 6.87(s, 1H), 6.87(s, 1H), 6.14(s, 1H), 6.14(s, 1H), 5.11(q , J = 7.1 Hz, 1H), 5.11 (q, J = 7.1 Hz, 1H), 3.31 (d, J = 9.0 Hz, 1H), 2.93–2.77 (m, 2H), 2.47–2.28 (m, 5H) , 2.26 (s, 3H), 2.18 (s, 3H), 1.99-1.57 (m, 4H), 1.52 (d, J = 7.2Hz, 3H), 1.32 (d, J = 11.9Hz, 1H), 1.15 ( d, J = 12.4 Hz, 1H).

The HPLC analysis methods of SZ-013011A and SZ-013011B are as follows:

Instrument: Waters Acquity ARC (UHPLC); Column: XSelect CSHTMC18 2.5um 4.6*150mm Column XP; Mobile phase A: 0.1% aqueous ammonia solution; Mobile phase B: Acetonitrile; Flow rate: 1ml/min; Wavelength: PDA full wavelength, 254nm , 220nm; Column temperature: 30°C; Blank solvent: methanol; Sample solution: Dissolve the appropriate amount of analyte in methanol and filter with 0.22μm filter membrane; Gradient elution:

Example 15 SZ-013002: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-9-(4-methyl -6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,4,9-triazaspiro[5.5]undecane-2,5-di ketone

Step 1: tert-Butyl(S)-4-(((((9H-fluoren-9-yl)methoxy)carbonyl)amino)amino)-4-((1-(6-(4-fluoro-1H -Pyrazol-1-yl)pyridin-3-yl)ethyl)carbamoyl)piperidine-1-carboxylate (013002A1)

Add 9307A1 (2.3g, 5mmol) and DMF (20ml) to the reaction flask, stir, then add (S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl) Ethylamine (prepared according to WO2017079140) (1.0 g, 5 mmol), DIPEA (1.9 g, 15 mmol), and finally HATU (2.3 g, 6 mmol) was added and reacted at 20° C. for 1 hour. The reaction solution was added with water (100ml), extracted with EA (50mlx3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography (EA/PE 0-50%) 013002A1 (2.0 g, 61%, white solid). LCMS: [M+H] ⁺ 655.06.

Step 2: tert-Butyl(S)-4-amino-4-((1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)carbamate Acyl)piperidine-1-carboxylate (013002A2)

Compound 013002A1 (2.0g, 3.0mmol) and methanol (5ml) were stirred, and then ethylenediamine (10ml) was added and reacted at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography (EA/PE 50-100%) to obtain 013002A2 (1.1 g, 85%, colorless oily liquid). LCMS: [M+H] ⁺ 433.08.

Step 3: tert-Butyl(S)-4-(2-chloroacetamido)-4-((1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl )Ethyl)carbamoyl)piperidine-1-carboxylate (013002A3)

Add 013002A2 (1.1g, 2.5mmol) and anhydrous THF (20ml) to the reaction flask, stir, then add triethylamine (500mg, 5mmol), cool to 0°C, and add chloroacetyl chloride (316mg, 2.8mmol) dropwise. After dripping, the temperature was raised to 20°C and reacted for 12 hours. The reaction solution was added with water (40ml), extracted with EA (10mlx3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography (EA/PE 50-100%) 013002A3 (500 mg, 39%, white solid). LCMS: [M+H] ⁺ 509.04.

Step 4: tert-Butyl(S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2,5-dicarbonyl -1,4,9-Triazaspiro[5.5]undecane-9-carboxylate (013002A4)

Add 013002A3 (500mg, 1.0mmol) and anhydrous THF (10ml) to the reaction flask, stir and cool to 0°C, then add sodium hydride (60% adsorbed to mineral oil, 80mg, 2.0mmol), slowly warm to 60°C and stir React for 20 minutes. After the reaction was completed, it was cooled to room temperature, and the reaction was quenched with 2 ml of water. The reaction solution was added with water (40ml), extracted with EA (10mlx3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography (EA/PE 50-100%) 013002A4 (400 mg, 85%, white solid). LCMS: [M+H] ⁺ 473.01.

Step 5: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1,4,9-triazaspiro [5.5] Undecane-2,5-dione (013002A5)

Compound 013002A4 (200mg, 0.42mmol) was dissolved in dichloromethane (5ml), trifluoroacetic acid (1ml) was added, stirred at room temperature for 2 hours, concentrated to remove the solvent to obtain the crude product 013002A5, the next step was carried out without purification. LCMS: [M+H] ⁺ 373.06.

Step 6: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-9-(4-methyl-6- ((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,4,9-triazaspiro[5.5]undecane-2,5-dione (SZ -013002)

Compound 013002A5 (157 mg, 0.42 mol), intermediate 2 (93 mg, 0.42 mmol) and potassium carbonate (231 mg, 1.68 mmol) were added to DMSO (5 ml) and stirred at 110° C. for 16 hours. Add 50ml of water to the system, extract with ethyl acetate (20mlx3), and concentrate the organic phase under reduced pressure to obtain the crude product. Purify by flash silica gel column chromatography (DCM/EA 50%). The product is dissolved in acetonitrile/water and freeze-dried to obtain SZ-013002 (110 mg, 47%, white solid). LCMS: [M+H] ⁺ 560.15; ¹ H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 9.25 (s, 1H), 8.70 (d, J=4.4 Hz, 1H), 8.64 ( s,1H),8.38(s,1H),7.96-7.89(m,3H),6.29-6.03(m,2H),5.76(q,J=7.0Hz,1H),4.28-4.17(m,2H) , 4.05 (d, J = 17 Hz, 1H), 3.63-3.51 (m, 3H), 2.20 (s, 3H), 2.12 (s, 3H), 2.04-1.92 (m, 2H), 1.74.1.61 (m, 2H), 1.56 (d, J = 7.1 Hz, 3H).

Example 16 SZ-013005: (S)-2-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-8-(4-methyl -6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2,8-diazaspiro[4.5]decane-3-one

Step 1: tert-butyl 4-(2-methoxy-2-oxoethyl)-4-(nitromethyl)piperidine-1-carboxylate

A solution of TBAF in tetrahydrofuran (15 mL, 15 mmol, 1 M) was added portionwise to a solution of compound 1 (1.29 g, 5 mmol) and nitromethane (0.8 mL, 15 mmol) in THF (3 mL) at 23 degrees Celsius. The resulting reaction mixture was heated to 86 degrees Celsius and stirring was continued for 16 hours. The resulting reaction mixture was cooled to room temperature, quenched with saturated aqueous NH ₄ Cl (30 mL), and extracted with ethyl acetate (30 mL*3). After combining the organic phases, dry with anhydrous Mg ₂ SO 4, filter and spin-dry the organic solvent. The obtained crude product was purified by silica gel column chromatography (PE: EA=30:1->10:1; Rf=0.3) to obtain 013005A0 (1.1 g, crude product) as a colorless oily product.

Step 2: tert-butyl 4-formyl-4-(2-methoxy-2-oxyethyl)piperidine-1-carboxylate

A solution of KOH (0.126 g, 1.1 mmol) in methanol (3.6 mL) was added dropwise to a solution of 013005A0 (0.6 g, 1.8 mmol) in methanol (6 mL) at 1-3 degrees Celsius. The resulting reaction mixture was further stirred at 1-3 degrees Celsius for 30 minutes. Then, a solution of Mg ₂ SO 4 (0.19 g, 1.36 mmol) and potassium permanganate (0.216 g, 1.36 mmol) in water (30 mL) was added dropwise to the above reaction solution. The resulting reaction mixture was further stirred at 1-3 degrees Celsius for 1 hour. The resulting suspension was filtered through celite, and the filtrate was combined with the spin-dried solvent, and then concentrated under reduced pressure using an oil pump to obtain a light yellow oil 013005A1 (0.29 g, crude product) which was directly used in the next reaction.

Step 3: tert-butyl-(S)-2-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-3-oxo-2, 8-Diazaspiro[4.5]decane-8-carboxylate

NaBH(OAc) ₃ (0.63 g, 3 mmol) was added in portions to the suspension of 1,2-dichloroethane (6 mL) of compound 013005A1 (0.29 g, 1 mmol) and compound 2 (0.23 g, 1 mmol) at 23°C in portions. In the liquid, the resulting reaction mixture was stirred for 16 hours at 16-23 degrees Celsius. The resulting reaction mixture was quenched with saturated aqueous ammonium chloride solution (30 mL), and extracted with dichloromethane (30 mL*3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to remove the solvent. The residue was purified by flash silica gel column chromatography (PE: EA=10:1->3:1->1:1->EA->EA: MeOH=10:1; Rf=0.3) purification to obtain 013005A2 (0.3g, 67%) as off-white solid. LCMS: [M+H] ⁺ 444.04@3.686min.

Step 4: (S)-2-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2,8-diazaspiro[4.5 ]Dec-3-one; trifluoroacetate

Trifluoroacetic acid (3 mL) was added portionwise to the dichloromethane solution (3 mL) of compound 013005A2 (0.3 g, 0.669 mmol) at 23 degrees Celsius. The resulting reaction mixture was continued to stir at 23 degrees Celsius for one hour. The resulting reaction mixture was spin-dried the solvent, and then concentrated under reduced pressure using an oil pump to obtain the product 013005A3 (0.23 g, 99%) as a pale yellow oil, which was directly used in the next reaction. LCMS: [M+H] ⁺ 344.04@2.593min.

Step 5: (S)-2-(1-(6-(4-Fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-8-(4-methyl-6- ((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2,8diazaspiro[4.5]decane-3-one

The suspension of compound 013005A3 (0.23 g, 0.67 mmol), compound 3 (0.16 g, 0.73 mmol), potassium carbonate (0.56 g, 3.9 mmol) and DMSO (6 mL) was heated to 180 degrees Celsius and stirring was continued for 1 hour. The resulting reaction mixture was cooled to 21 degrees Celsius and then diluted with water (30 mL) and extracted with ethyl acetate (30 mL*3). The organic phases were combined, washed with saturated brine (30 mL*3), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Then use column chromatography (PE: EA=10:1->3:1->1:1->EA->DCM:MeOH=10:1 (add 3V/V% concentrated ammonia to help elute), Rf = 0.1) to give impure compound SZ-013005 (50 mg). It was then purified using high-pressure preparative chromatography to obtain the white solid compound SZ-013005 (3.6 mg, 46.9%). LCMS: [M+H] ⁺ 531.13@3.001min. 1H NMR (400MHz, CD ₃ OD) δ 8.54 (dd, J1 = 8.0Hz, J2 = 4.0Hz, 1H), 8.43 (s, 1H), 7.98-7.96 (m, 2H), 7.72 (dd, J1 = 4.0Hz, J2=2.0Hz, 1H), 6.13(s, 1H), 6.15(br, 1H), 6.10(s, 1H), 5.49(q, J=8.0Hz) 3.98-3.91(m, 1H), 3.86-3.78(m, 1H), 3.73-3.63(m, 2H), 3.41(d, J=8.0Hz, 1H), 3.04(d, J=8.0Hz, 1H) 2.46(d, J=4.0Hz, 2H), 2.27 (s, 3H), 2.21 (s, 3H), 1.73-1.69 (m, 2H), 1.63 (d, J=8.0Hz, 3H) 1.63-1.46 (m, 2H).

Example 17 SZ-9387: (S)-2-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-8-(4-methyl -6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2-azaspiro[4.5]decane-1-one

Step 1: Ethyl-1,4-dioxaspiro[4,5]decane-8-carboxylate

LiHMDS (51 mL, 51 mmol) was added dropwise to a solution of compound 1 (6.5 g, 30 mmol) in THF (60 mL) at -78 degrees Celsius. The resulting reaction mixture was further stirred at -78 to 16 degrees Celsius for one hour. After cooling to -78 degrees Celsius, allyl bromide (3.39 mL, 39 mmol) was added dropwise to the above reaction solution. The resulting reaction mixture was stirred at -78 to 16 degrees Celsius for 16 hours. The resulting reaction mixture was quenched with saturated aqueous NH ₄ Cl (90 mL) and diluted with water (30 mL). After the organic phase was separated, the aqueous phase was extracted with ethyl acetate (0.1L*3). After combining the organic phases, add anhydrous MgSO4 to dry, filter and spin-dry the organic solvent. It was then pumped with an oil pump for three minutes to obtain 9387A0 (8 g, crude product) as a yellow liquid.

Step 2: Ethyl 8-allyl-1,4-dioxaspiro[4,5]decane-8-carboxylate

9387A0 (5.18 g, 21 mmol) was added to a mixed solution of water (93 mL) and acetonitrile (96 ml) at 13 degrees Celsius, and then NaIO4 (13.9 g) and RuCl ₃ solid (0.129 g) were sequentially added in portions. The resulting reaction mixture was continued to stir at 13 degrees Celsius for 1.6 hours. The obtained off-white suspension was diluted with water (390 mL) and extracted with ethyl acetate (0.3 L*3). After combining the organic phases, add anhydrous MgSO4 to dry, filter and spin-dry the organic solvent. It was then pumped for three minutes using an oil pump to obtain 9387A1 (3.9 g, crude product) as a pale yellow oil.

Step 3: (S)-10-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1,4-diox-10-nitrogen Heterospiro[4.2.4 ⁸ .2 ⁵ ]tetradecyl-9-one

NaBH(OAc) ₃ (9g, 42.6mmol) was added in portions at 18 degrees Celsius to a solution of compound 9387A1 (3.9g, 15.3mmol) and compound 2 (3g, 15.3mmol) in 1,2-dichloroethane to obtain The reaction mixture was continuously stirred at 9 to 18 degrees Celsius for 16 hours. The resulting reaction mixture was then heated to 110°C and stirring continued for 1.6 hours. The resulting reaction mixture was quenched with water (300 mL), followed by ethyl acetate extraction (100 mL*3). The organic phases were combined, dried with anhydrous magnesium sulfate, filtered, and concentrated to remove the solvent. The residue was purified by flash silica gel column chromatography (PE: EA=10:1->3:1->1:1->1:3->EA->EA:MeOH=10:1; Rf=0.3) purification to obtain 9387A2 (2.6g, 42.3%) as yellow oil. LCMS: [M+H] ⁺ 401.26@3.503min.

Step 4: (S)-2-(1-(6-(4-Fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-azaspiro[4.5]dec- 1,8-diketone

Compound 9387A2 (2.6g, 6.48mmol) was dissolved in 1,4-dioxane (29mL), hydrochloric acid (30mL, 6M) was added to the reaction portionwise at 13 degrees Celsius, heated to 69 degrees Celsius and stirred for 16 hours . The resulting reaction mixture was cooled to 13 degrees Celsius and the pH of the system was adjusted to >9 using solid Na ₂ CO ₃ (if a large amount of insoluble solids appeared, appropriate water was added to dissolve, but please keep the system saturated with Na ₂ CO ₃ ). This mixture was extracted with ethyl acetate (60 mL*3), and the organic phases were combined and dried with anhydrous MgSO ₄ , filtered, and the organic solvent was spin-dried to obtain a white solid product 9387A3 (1.96 g, 86%) which was directly used in the next reaction. LCMS: [M+H] ⁺ 357.19@3.280min.

Step 5: 2-((S)1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-carbonyl-2-azaspiro[4.5 ]Dec-7-ene-8-yl trifluoromethanesulfonate

LiHMDS (16.5 mL, 16.5 mmol) was added portionwise to a solution of compound 9387A3 (1.96 g, 5.5 mol) in tetrahydrofuran at -78 degrees Celsius with a syringe. The resulting reaction mixture was further stirred at -78 degrees Celsius for 1 hour. Then a solution of PhNTf2 (2.16 g, 6.1 mmol) in tetrahydrofuran (13 mL) was slowly added at -78 degrees Celsius. The resulting reaction mixture was heated to -78 degrees Celsius at -78 and stirring was continued for 16 hours. Then, a saturated aqueous NH ₄ Cl solution (100 mL) was added to the system to quench the reaction and extracted with ethyl acetate (60 ml*3). The organic phases are combined and dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Next, purification using column chromatography (PE: EA=10:1->3:1->1:1, Rf=0.3) gave compound 9387A4 (1.26 g, 46.9%) as a white solid. LCMS: [M+H ⁺ ] 489.16@3.987mi.

Step 6: 2-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-8-(4,4,5,5 -Tetramethyl-1,3,2-dioxaborate-2-yl)-2-azaspiro[4.5]dec-7-en-1-one

At 18 degrees Celsius, put 9387A4 (1.26g, 2.58mmol), double-linked pinacol borate (0.8g, 3.1mmol), potassium acetate (0.8g, 8mmol), 1,4-dioxane (26mL) The suspension with PdCl ₂ (dppf) DCM (68 mg) was replaced with nitrogen three times with stirring, then heated to 90° C. under nitrogen protection and stirring was continued for 3 hours. The resulting reaction mixture was cooled to 19 degrees Celsius, and then quenched by adding water (60 mL). Extract with ethyl acetate (60 mL*3). After combining the organic phases, dry with anhydrous MgSO ₄ , filter, and spin-dry the organic solvent. The crude product was purified by flash column chromatography (PE: EA=10:1->3:1->1:1->1:3->EA; Rf=0.3) to give the white solid product 9387A5 (1.01g, 83.7%) . LCMS: [M+H ⁺ ] 467.30@4.101min.

Step 7: 2-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-8-(4-methyl-6- ((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2-azaspiro[4.5]dec-7-en-1-one

Pd(PPh ₃ ) ₄ (69 mg) was added to compound 9387A5 (0.8 g, 1.6 mmol), compound 3 (0.39 g, 1.6 mmol), potassium carbonate (0.69 g, 5.3 mmol), 1, at 16 degrees Celsius In a suspension of 4-dioxane (13 mL) and water (3 mL). Nitrogen was replaced three times, and the resulting reaction mixture was reacted in a Biotage microwave reactor: 130 degrees Celsius for one hour. The resulting red-yellow solution was cooled to room temperature, quenched with water (60 mL), and extracted with ethyl acetate (60 mL*3). After combining the organic phases, dry with anhydrous MgSO ₄ , filter, and spin-dry the organic solvent. The crude product was purified by flash silica gel column chromatography (PE:EA=3:1->1:1->1:3->EA->EA:MeOH=30:1->16:1; Rf=0.1) to give white Solid product 9387A6 (0.39 g, 46.19%). LCMS: [M+H ⁺ ] 528.32@3.208min.

Step 8: (S)-2-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-8-(4-methyl-6- ((5-methyl-1H))pyrazol-3-yl)amino)pyrimidin-2-yl)-2-azaspiro[4.5]decane-1-one.

Compound 9387A6 (300 mg, 0.568 mmol) was added to a black suspension of Pd(OH) ₂ /C (300 mg) in methanol (60 mL) at 16 degrees Celsius, followed by solid ammonium formate (16 g). The resulting reaction mixture was heated to 69 degrees Celsius and stirring continued for one hour. After cooling to room temperature, it was filtered through celite and washed with methanol (30 mL*3). After combining the filtrates, the solvent was vortexed and then dissolved in water (60 mL). This solution was basified by adding solid Na ₂ CO ₃ until saturated. Then extract with ethyl acetate (60 mL*3), combine the organic phases, add anhydrous MgSO _{4 to} dry, filter and spin to dry the organic solvent. This crude product was purified by high-pressure preparative liquid chromatography to obtain two diastereomers:

SZ-9387A (86 mg, 28%, white solid). LCMS: [M+H ⁺ ] 530.32@3.217min. HPLC t _R =7.53 min. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.42 (d, J=4.0 Hz, 1H), 8.28 (d, J=4.0 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.8( dd, J1 = 8.0Hz, J2 = 4.0Hz, 1H), 7.60 (d, J = 4.0Hz, 1H), 6.63 (br, 1H), 6.15 (br, 1H), 5.34 (q, J = 4.0Hz, 1H), 3.42-3.36 (m, 1H), 3.03-2.96 (m, 1H), 2.61 (br, 1H), 2.23 (s, 3H), 2.18 (s, 3H), 2.06-1.91 (m, 2H) , 1.89-1.76 (m, 2H), 1.76-1.63 (m, 4H), 1.61-1.56 (m, 1H), 1.53 (d, J=8.0Hz, 3H), 1.46-1.43 (m, 1H).

SZ-9387B (110 mg, 37%, white solid). LCMS: [M+H+] 530.32@3.349min. HPLC t _R = 8.45 min. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.53 (dd, J1 = 4.0 Hz, J2 = 2.0 Hz, 1H), 8.40 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.91 ( dd, J1 = 4.0 Hz, J2 = 2.0 Hz, 1H), 7.71 (d, J = 4.0 Hz, 1H), 6.75 (br, 1H), 6.44 (br, 1H), 5.44 (q, J = 4.0 Hz, 1H), 3.53-3.43 (m, 1H), 3.10-3.03 (m, 1H), 2.78 (br, 1H), 2.56-2.41 (m, 2H), 2.35 (s, 3H), 2.32 (s, 3H) , 2.13-2.03 (m, 1H), 1.98-1.89 (m, 3H), 1.86-1.76 (m, 2H), 1.63 (d, J=8.0Hz, 3H), 1.56-1.39 (m, 2H).

The HPLC analysis conditions of SZ-9387A and SZ-9387B are as follows:

Instrument: Waters Acquity ARC (UHPLC); chromatographic column: XSelect CSH ^TM C ₁₈ 3.5um 4.6*150mm Column XP;

Mobile phase A: 0.1% aqueous ammonia solution; mobile phase B: acetonitrile; flow rate: 1.0 ml/min;

Wavelength: 287nm; column temperature: 30℃; blank solvent: methanol;

Sample solution: Dissolve the appropriate amount of SZ-9387 with methanol, filter with 0.22um filter membrane, and enter liquid chromatography for analysis.

Example 18 SZ-9329: 2-(2-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3-methyl-1,4,8 -Triazaspiro[4.5]dec-1,3-dien-8-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine

Step 1: 6-methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(1,4-dioxa-8-azaspiro[4.5]decane-8 -Yl)pyrimidine-4-amine

4-piperidone ketal (470 mg, 3.2 mol), intermediate 2 (670 mg, 3.0 mmol) and potassium carbonate (1.2 g, 9.0 mmol) were added to DMSO (5 mL) and stirred at 110° C. for 16 hours. Add 50mL of water to the system, extract with ethyl acetate (20ml*3), and spin-dry the organic phase under reduced pressure to obtain the crude product. Flash silica gel column chromatography (MeOH/EA 10%) to obtain 9329A1 (1.0g, 99%, white) solid). [M+H] ⁺ 331.18.

Step 2: 1-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)piperidin-4-one

Compound 9329A1 (1.0 g, 3.0 mmol) was dissolved in 1,4-dioxane (15 mL), 6N concentrated hydrochloric acid (5 mL, 30 mmol) was added with stirring, and the reaction was carried out at 20°C for 2 hours. The reaction solution was neutralized with saturated sodium bicarbonate, extracted with ethyl acetate (20ml*3), and the organic phase was spin-dried under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography (EA/PE 0-10%) to obtain 9329A2 (700mg, 81%, white solid). LCMS: [M+H] ⁺ 287.08.

Step 3: 2-(2-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3-methyl-1,4,8-triaza Heterospiro[4.5]dec-1,3-dien-8-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidine-4-amine

Compound 013037A4 (350 mg, 1.4 mmol) was dissolved in toluene (20 mL), 9329A2 (400 mg, 1.4 mmol) and ammonium acetate (540 mg, 7.0 mmol) were added, and the mixture was heated to reflux for 12 hours under stirring. After the reaction was completed, the solvent was dried to obtain a crude product. Purification by flash silica gel column chromatography (EA/PE 50-100%) gave SZ-9329 (15 mg, 2%, white solid). LCMS: [M+H] ⁺ 514.32.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.86 (s, 1H), 9.23 (s, 1H), 8.70-8.68 (m, 1H), 8.40-8.38 (m, 1H), 7.94-7.85 (m , 3H), 6.25 (s, 1H), 6.10 (s, 1H), 4.11-4.03 (m, 4H), 3.98-3.91 (m, 2H), 2.20 (s, 3H), 2.18 (s, 3H), 2.13 (s, 3H), 1.63-1.55 (m, 2H), 1.52-1.44 (m, 2H).

Example 19 SZ-013037: (6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)(3-methyl-8-(4-methyl-6-((5- Methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,4,8-triazaspiro[4.5]dec-1,3-dien-2-yl)methanone

Step 1: (6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methanol

Add 2-chloro-5-hydroxymethylpyridine (4.3g, 30mmol), 4-fluoro-1H-pyrazole (2.6g, 20mmol), cesium carbonate (9.6g, 30mmol) and DMSO (100ml), Heat to 140°C and stir for 16h. The reaction solution was added with water (200ml), extracted with EA (150ml*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography (EA/PE 0-50%) Purification gave 013037A1 (5.0 g, 87%, white solid). LCMS: [M+H] ⁺ 194.03.

Step 2: 5-(chloromethyl)-2-(4-fluoro-1H-pyrazol-1-yl)pyridine

Compound 013037A1 (5.0 g, 26 mmol) and DCM (50 ml) were cooled to 0° C. with stirring, and then added sulfoxide chloride (6.1 g, 52 mmol), and the temperature was raised to 20° C. for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography (EA/PE 0-10%) to obtain 013037A2 (4.0 g, 73%, white solid). LCMS: [M+H] ⁺ 212.02.

Step 3: 3-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)pentane-2,4-dione

Add 013037A2 (3.6g, 19mmol), potassium iodide (2.8g, 19mmol), lithium hydroxide monohydrate (1.8g, 42mmol) and DMF (20ml) to the reaction flask, stir, then add acetylacetone (19g, 190mmol), After the addition, the temperature was raised to 75°C for 3 hours. The reaction solution was stirred with water (200 ml), and then filtered to obtain 013037A3 (3.2 g, 61%, white solid). LCMS: [M+H] ⁺ 276.10.

Step 4: 1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)butane-2,3-dione

013037A3 (3.2g, 11.6mmol) and anhydrous THF (20ml) were added to the reaction flask, cooled to 0°C with stirring, sodium hydride (500mg, 12.8mmol) was added, and then raised to 20°C for 20 minutes. The system was cooled to -78°C, and nitrosobenzene (1.5g, 12.8mmol, dissolved in 15mL of THF) was slowly added. After the addition was completed, the reaction temperature was raised to 20°C for 1h. Saturated ammonium chloride quenches the reaction. The reaction solution was added with water (40ml), extracted with EA (10ml*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by flash silica gel column chromatography (EA/PE 50-100%) Purification gave 013037A4 (1 g, 35%, white solid).

Step 5: tert-butyl 2-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3-methyl-1,4,8-triaza Heterospiro[4.5]dec-1,3-diene-8-carboxylate

Compound 013037A4 (1g, 4.0mmol) was dissolved in toluene (20mL), N-Boc piperidone (800mg, 4.0mmol) and ammonium acetate (1.5g, 20mmol) were added, and the mixture was heated to reflux for 12 hours with stirring. The dry solvent gave the crude product, which was purified by flash silica gel column chromatography (EA/PE 50-100%) to give 013037A5 (600 mg, 35%, white solid). LCMS: [M+H] ⁺ 427.25.

Step 6: 2-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3-methyl-1,4,8-triazaspiro[ 4.5]dec-1,3-diene

Compound 013037A5 (600mg, 1.4mol) was dissolved in dichloromethane (5mL), trifluoroacetic acid (1mL) was added, stirred at room temperature for 2 hours, concentrated to remove the solvent to obtain crude product 013037A6, the next step was carried out without purification. LCMS: [M+H] ⁺ 327.19.

Step 7: (6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)(3-methyl-8-(4-methyl-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,4,8-triazaspiro[4.5]dec-1,3-dien-2-yl)methanone

Compound 013037A6 (460 mg, 1.4 mol), intermediate 2 (310 mg, 1.4 mmol) and potassium carbonate (770 mg, 5.6 mmol) were added to DMSO (5 mL), and stirred at 110° C. for 16 hours. 50mL of water was added to the system, and extracted three times with ethyl acetate (20ml). The organic phase was spin-dried under reduced pressure to obtain the crude product, which was purified by flash silica gel column chromatography (MeOH/EA 10%). Phase column chromatography and lyophilization gave SZ-013037 (60 mg, 8%, white solid). LCMS: [M+H] ⁺ 528.30.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.87 (s, 1H), 9.27 (s, 1H), 9.19-9.17 (m, 1H), 8.84 (d, J = 4.4 Hz, 1H), 8.65 ( dd, J=8.8, 2.4Hz, 1H), 8.12-8.07(m, 2H), 6.29(s, 1H), 6.12(s, 1H), 4.15-4.02(m, 4H), 2.44(s, 3H) , 2.19 (s, 3H), 2.15 (s, 3H), 1.78-1.72 (m, 4H).

Example 20 SZ-013038: 2-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-9-(4-methyl-6-((5 -Methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2,9-diazaspiro[5.5]undecane-1-one

Step 1: tert-butyl 2-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-1-carbonyl-2,9-diazaspiro[ 5.5] Undecane-9-carboxylate

1-Oxo-2,9-diazaspiro[5.5]undecane-9-carboxylic acid tert-butyl ester (270mg, 1.0mmol), potassium iodide (166mg, 1.0mmol) and THF (10ml) were added to the reaction flask After cooling to 0°C with stirring, sodium hydride (80mg, 2.0mmol) was added. After stirring for 20 minutes, 013037A2 (211mg, 1.0mmol) was added and the temperature was raised to 20°C for 3 hours. The reaction solution was quenched with saturated ammonium chloride solution, added water (20ml), extracted with EA (15ml*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product, which was purified by flash silica gel column chromatography (EA/PE 0-50%) purification gave 013038A1 (360 mg, 81%, white solid). LCMS: [M+H] ⁺ 444.23.

Step 2: 2-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-2,9-diazaspiro[5.5]undecane-1 -ketone

Compound 013038A1 (360 mg, 0.81 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, stirred at room temperature for 2 hours, and concentrated to remove the solvent to obtain crude product 013038A2, which was directly reacted without purification. LCMS: [M+H] ⁺ 344.21.

Step 3: 2-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-9-(4-methyl-6-((5-methyl -1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2,9-diazaspiro[5.5]undecane-1-one

Compound 013038A2 (278 mg, 0.81 mol), intermediate 2 (180 mg, 0.81 mmol) and potassium carbonate (447 mg, 3.24 mmol) were added to DMSO (5 mL), and stirred at 110° C. for 16 hours. Add 50mL of water to the system, extract with ethyl acetate (20ml*3), and spin-dry the organic phase under reduced pressure to obtain the crude product. Purify by flash silica gel column chromatography (MeOH/EA 10%). The product is then acetonitrile/0.1% formic acid water Reverse phase column chromatography and lyophilization gave SZ-013038 (180 mg, 42%, white solid). LCMS: [M+H] ⁺ 531.32.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.85 (s, 1H), 9.21 (s, 1H), 8.69 (d, J=4.6 Hz, 1H), 8.32 (d, J=1.9 Hz, 1H) , 7.94-7.87(m, 2H), 7.84-7.81(m, 1H), 6.29-6.04(m, 2H), 4.53(s, 2H), 4.38-4.30(m, 2H), 3.31-3.15(m, 4H), 2.19(s, 3H), 2.12(s, 3H), 2.00-1.76(m, 6H), 1.53-1.45(m, 2H).

Example 21 SZ-013039: 2-(2-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-2,9-diazaspiro[5.5 ]Undec-9-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine

Step 1: tert-butyl 2-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-2,9-diazaspiro[5.5]undec Alkane-9-carboxylate

To the reaction flask were added 013037A2 (211mg, 1.0mmol), 2,9-diazaspiro[5.5] undecane-2-carboxylic acid tert-butyl ester (250mg, 1.0mmol), potassium iodide (166mg, 1.0mmol), DIPEA ( 380mg, 3.0mmol) and acetonitrile (10ml), heated to 80 °C with stirring for 2 hours. Add water (20ml), extract with EA (15ml*3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. Purify by flash silica gel column chromatography (EA/PE0-50%) to obtain 013039A1 (400 mg, 93%, white solid). LCMS: [M+H] ⁺ 430.38.

Step 2: 2-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-2,9-diazaspiro[5.5]undecane

Compound 013039A1 (400mg, 0.93mmol) was dissolved in dichloromethane (5mL), trifluoroacetic acid (1mL) was added, stirred at room temperature for 2 hours, concentrated to remove the solvent to obtain crude product 013039A2, the next step was carried out without purification. LCMS: [M+H] ⁺ 330.22.

Step 3: 2-(2-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-2,9-diazaspiro[5.5]eleven Alkane-9-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine

Compound 013039A2 (300 mg, 0.93 mol), intermediate 2 (210 mg, 0.93 mmol) and potassium carbonate (510 mg, 3.72 mmol) were added to DMSO (5 mL), and stirred at 110° C. for 16 hours. Add 50mL of water to the system, extract with ethyl acetate (20ml*3), and spin-dry the organic phase under reduced pressure to obtain the crude product. Purify by flash silica gel column chromatography (MeOH/EA 10%). The product is then acetonitrile/0.1% formic acid water Reverse phase column chromatography and lyophilization gave SZ-013039 (140 mg, 29%, white solid). LCMS: [M+H] ⁺ 517.29. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.16 (s, 1H), 8.69-8.66 (m, 1H), 8.38-8.35 (m, 1H), 8.16 (s, 1H), 7.93-7.86 (m , 3H), 6.20-6.03(m, 2H), 3.75-3.66(m, 2H), 3.57-3.52(m, 2H), 2.39(s, 2H), 2.20(s, 5H), 2.08(s, 3H ), 1.61-1.30 (m, 8H).

Example 22 SZ-9399: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-9-(4-methyl -6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-5- ketone

Step 1: 1-tert-butyl-4-methyl-4-(allyloxy)piperidine-1,4-dicarboxylate (9399A2)

9399A1 (4.8 g, 18.4 mmol) was dissolved in DMF (50 mL), sodium hydride (1.6 g, 60% in oil, 27.1 mmol) was added in portions, and stirring was continued for 10 min after the addition. Allyl bromide (3.2g, 26.6mmol) was added at once and stirred at room temperature for 1 hour. The reaction solution was added with water (50ml), extracted with EA (50mLx2), the organic phase was spin-dried and flash silica gel column chromatography (EA: PE = 1:4) Purification gave 9399A2 as a colorless oil (3.7 g, 61%). LCMS: [M-100] ⁺ 199.13.

Step 2: 1-tert-butyl-4-methyl 4-(2-carbonylethoxy)piperidine-1,4-dicarboxylate (9399A3)

9399A2 (1g, 5mmol) was dissolved in 15mL of acetonitrile and 15mL of water, sodium periodate (2.1g, 9.8mmol) and a catalytic amount of ruthenium trichloride (1%) were added in sequence, and the reaction solution was stirred at room temperature for 2 hours Water (50 ml) was added, extracted with EA (50 mL), and the organic phase was spin-dried to give 1 g of crude 9399A3. LCMS: [M+H] ⁺ 301.21.

Step 3: (S)-1-tert-butyl-4-methyl 4-(2-((1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl) Ethyl)amino)ethoxy)piperidine-1,4-dicarboxylate (9399A5)

9399A3 (500mg crude) and 9399A4 (460mg, 1.65mmol) were suspended in dichloroethane (15mL), sodium triacetoxyborohydride (690mg, 3.3mmol) was added to the system, the reaction solution was gradually clear, after 3 hours Sodium carbonate was added to adjust the pH of the system to about 8, DCM (50 mL) was extracted, the organic phase was spin-dried and purified by flash silica gel column chromatography (EA: MeOH=10:1) to obtain 9399A5 (400 mg) as a colorless oil. LCMS: [M+H] ⁺ 491.11.

Step 4: (S)-tert-butyl-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-5-carbonyl-1- Oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (9399A6)

9399A5 (400 mg, 0.81 mmol) was dissolved in 10 mL of anhydrous methanol, 0.4 mL of a saturated solution of sodium methoxide in methanol was added all at once, and the reaction solution was stirred at 50 degrees for 20 hours. After spinning off the solvent, flash silica gel column chromatography ( EA: PE = 1:1) purification gave 9399A6 (220 mg) as a colorless oil. LCMS: [M+H] ⁺ 459.03.

Step 5: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxa-4,9-di Azaspiro[5.5]undecane-5-one (9399A7)

9399A6 (220 mg) was dissolved in DCM (5 mL) and TFA (2 mL) was added. After 2 hours, the solvent was removed to obtain 9399A7, which was directly reacted in the next step. LCMS: [M+H] ⁺ 359.18.

Step 6: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-9-(4-methyl-6- ((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-5-one (SZ -9399)

The 9399A7 and 9399A8 (97mg, 0.43mmol) and potassium carbonate (237mg, 1.7mmol) obtained in the previous step were dissolved in DMSO and stirred at 115 degrees for 6 hours. After the reaction, the crude product was directly subjected to high-pressure reversed-phase column chromatography (ACN- 0.1% ammonium carbonate aqueous solution) was purified and lyophilized to obtain SZ-9399 (66 mg, 28%). LCMS: [M+H] ⁺ 546.21. HPLC t _R = 7.25 min. ¹ H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 9.22 (s, 1H), 8.66 (dd, J ₁ =4.4 Hz, J ₂ =0.8 Hz, 1H), 8.35 (s, 1H ), 7.89-7.94 (m, 3H), 6.10-6.30 (m 2H), 5.76 (q, J=6.8Hz, 1H), 4.48-4.53 (m, 2H), 3.81-3.90 (m, 2H), 3.36 -3.42(m, 2H), 2.93-3.06(m, 2H), 2.19(s, 3H), 2.11(s, 3H), 1.78-2.01(m, 4H), 1.53(d, J=6.8Hz, 1H ).

Example 23 SZ-013043: (S)-1-ethyl-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-9- (4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,4,9-triazaspiro[5.5]undecane- 2,5-dione

Step 1: tert-butyl-(S)-4-(ethylamino)-4-((1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethane Yl)carbamoyl)piperidine-1-carboxylate

Add 013002A2 (2.1g, 5mmol) and acetaldehyde (5M in THF) (2mL, 10mmol) to DCM (25mL), add sodium triacetoxyborohydride (3.0g, 15mmol) with stirring, 20℃ React for 2 hours. The reaction solution was added with water (100ml), extracted with EA (50ml*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography (EA/PE 0-50%) Purification gave 013043A1 (800 mg, 34%, white solid). LCMS: [M+H] ⁺ 461.32.

Step 2: tert-butyl-(S)-4-(2-chloro-N-ethylacetamido)-4-((1-(6-(4-fluoro-1H-pyrazol-1-yl) Pyridin-3-yl)ethyl)carbamoyl)piperidine-1-carboxylate

Add 013043A1 (800mg, 1.7mmol) and anhydrous THF (20ml) to the reaction flask, stir, then add triethylamine (500mg, 5mmol), cool to 0°C, add chloroacetyl chloride (214mg, 1.9mmol) dropwise The temperature was raised to 20°C for 12 hours. The reaction solution was added with water (40ml), extracted with EA (10ml*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography (EA/PE 50-100%) Purification gave 013043A2 (550 mg, 60%, white solid). LCMS: [M+H] ⁺ 537.26.

Step 3: tert-butyl-(S)-1-ethyl-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2 ,5-dicarbonyl-1,4,9-triazaspiro[5.5]undecane-9-carboxylate

Add 013043A2 (550mg, 1.03mmol), potassium iodide (170mg, 1.0mmol) and anhydrous THF (10ml) to the reaction flask, stir and cool to 0°C, then add sodium hydride (60% adsorbed to mineral oil, 80mg, 2.0mmol) ), slowly raise the temperature to 60°C and stir the reaction for 20 minutes. Cool to room temperature and quench the reaction with saturated ammonium chloride solution. The reaction solution was added with water (40ml), extracted with EA (10ml*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography (EA/PE 50-100%) Purification gave 013043A3 (220 mg, 44%, white solid). LCMS: [M+H] ⁺ 501.25.

Step 4: (S)-1-ethyl-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1,4,9 -Triazaspiro[5.5]undecane-2,5-dione

Compound 013043A3 (220mg, 0.44mmol) was dissolved in dichloromethane (5mL), trifluoroacetic acid (1mL) was added, stirred at room temperature for 2 hours, concentrated to remove the solvent to obtain the crude product 013043A4, the next step was carried out without purification. LCMS: [M+H] ⁺ 401.24.

Step 5: (S)-1-ethyl-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-9-(4- Methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,4,9-triazaspiro[5.5]undecane-2,5 -Diketone

Compound 013043A4 (200 mg, 0.44 mol), intermediate 2 (110 mg, 0.5 mmol) and potassium carbonate (270 mg, 2.0 mmol) were added to DMSO (5 mL), and stirred at 110° C. for 16 hours. 50mL of water was added to the system, and extracted three times with ethyl acetate (20ml). The organic phase was spin-dried under reduced pressure to obtain the crude product, which was purified by flash silica gel column chromatography (MeOH/EA 10%). Phase column chromatography and lyophilization gave SZ-013043 (70 mg, 27%, white solid). LCMS: [M+H] ⁺ 588.34. ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.87 (s, 1H), 9.24 (s, 1H), 8.72-8.69 (m, 1H), 8.40 (d, J=2.0 Hz, 1H), 7.98-7.90 ( m, 3H), 6.29-6.03 (m, 2H), 5.76 (q, J = 7.0 Hz, 1H), 4.58 (d, J = 12.5 Hz, 2H), 4.14 (d, J = 17.5 Hz, 1H), 3.69 (d, J = 17.5 Hz, 1H), 3.51-3.37 (m, 4H), 2.20 (s, 3H), 2.12 (s, 3H), 2.10-2.01 (m, 2H), 1.91-1.79 (m, 2H), 1.58 (d, J = 7.23 Hz, 3H), 0.99 (t, J = 7.10 Hz, 3H).

Example 24 SZ-013049: (S)-2-(4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1,4, 9-Triazaspiro[5.5]undec-9-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidine-4-amine

Step 1: tert-Butyl-(S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl) 1,4,9-tri Azaspiro[5.5]undecane-9-carboxylate

A solution of borane in tetrahydrofuran (21 mL, 21 mmol, 1M) was added portionwise to a solution of compound 013049A0 (1 g, 2.1 mmol) in THF (16 mL) at 21 degrees Celsius. The resulting reaction mixture was heated to 69 degrees Celsius and stirring continued for 1.8 hours. The resulting reaction mixture was cooled to room temperature, quenched with saturated aqueous NH ₄ Cl (10 mL), and then diluted with water (30 mL). The resulting solution was added with solid Na ₂ CO ₃ until saturated, and extracted with ethyl acetate (30 mL*3). After combining the organic phases, add anhydrous Mg ₂ SO _{4 to} dry, filter and spin-dry the organic solvent. The obtained crude product was purified by silica gel column chromatography (PE: EA=10:1->3:1; Rf=0.3) to obtain the product 013005A1 (90 mg) as a pale yellow oil. LCMS: [M+H] ⁺ 445.24@3.916min.

Step 2: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1,4,9-triazaspiro [5.5] Undecane; trifluoroacetate

Trifluoroacetic acid (3 mL) was added portionwise to the dichloromethane solution (3 mL) of compound 013049A1 (90 mg, 0.19 mmol) at 21 degrees Celsius. The resulting reaction mixture was further stirred at 21 degrees Celsius for one hour. The resulting reaction mixture was spin-dried to a solvent, and then concentrated under reduced pressure using an oil pump to obtain a yellow oily product 013049A2 (90 mg), which was directly used in the next reaction. LCMS: [M+H] ⁺ 345.18@2.177min.

Step 3:: (S)-2-(4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1,4,9- Triazaspiro[5.5]undecane-9-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidine-4-amine

The suspension of compound 013049A2 (90 mg, 0.19 mmol), compound 1 (60 mg, 0.269 mmol), potassium carbonate (0.3 g, 2.16 mmol) and DMSO (3 mL) was heated to 169 degrees Celsius and stirring was continued for 90 minutes. The resulting reaction mixture was cooled to 21 degrees Celsius and then diluted with water (10 mL) and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine (10 mL*3), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. It was then purified using high-pressure preparative chromatography to obtain the white solid compound SZ-013049 (6 mg, 6%). LCMS: [M+H] ⁺ 532.35@2.513min. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.54 (d, J = 4.0 Hz, 1H), 8.46 (d, J = 2.0 Hz, 1 H), 8.03 (dd, J1 = 8.0 Hz, J ₂ = 2.0 Hz , 1H), 7.99 (d, J=8.0Hz, 1H), 7.73(d, J=4.0Hz, 1H), 6.16(s, 1H), 6.15(s, 1H), 4.49-4.39(m, 2H) 3.87(q, J=8.0Hz, 1H), 3.36-3.29(m, 3H), 3.18-3.11(m, 2H), 2.96-2.76(m, 3H), 2.33(s, 3H) 2.25(s, 3H ), 2.21-2.16 (m, 2H), 1.73-1.69 (m, 2H), 1.85-1.78 (m, 2H) 1.53 (d, J = 4.0 Hz, 3H).

Example 25 SZ-013048: (S)-6-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-(4-methyl -6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2,6-diazaspiro[3.4]octan-5-one

Step 1: 1-(tert-butyl) 3-methyl 3-allyl azetidine-1,3-dicarboxylate

Add 1-(tert-butyl)3-methylazetidine-1,3-dicarboxylate (2.0g, 9.3mmol) and anhydrous THF (20ml) to the reaction flask, cool to 0°C, and add LDA with stirring (2M in THF, 10mL, 20mmol), gradually raised to 20 °C for 1 hour. Then allyl bromide (1.35g, 11mmol) was added dropwise to continue the reaction for 12h. The reaction was quenched with saturated ammonium chloride, added with water (100ml), extracted with EA (50ml*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by flash silica gel column chromatography (EA /PE 0-20%) purification to obtain 013048A1 (0.6g, 25%, colorless oily liquid). LCMS: [M+H] ⁺ 256.08.

Step 2: 1-(tert-butyl) 3-methyl 3-(2-carbonylethyl) azetidine-1,3-dicarboxylate

In the reaction flask, compound 013048A1 (0.6g, 2.3mmol), ruthenium chloride (5mg, 0.02mml), acetonitrile (5mL) and water (3ml) were added, and sodium periodate (dissolved in 2mL water, 1.5g) was added with stirring , 7.0mml), react at 20°C for 1 hour. The reaction solution was added with water (30 mL) and extracted with EA (50 ml*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 013048A2 (0.5 g, 87%, colorless oily liquid). Next step. LCMS: [M+H] ⁺ 258.04.

Step 3: tert-Butyl(S)-6-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-5-carbonyl-2, 6-diazaspiro[3.4]octane-2-carboxylate

013048A2 (0.5g, 2.0mmol), (S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethylamine (prepared according to WO2017079140) was added to the reaction flask 480mg, 2.4mmol), HOAc (0.5mL), 1,2-dichloroethane (10mL), and finally added sodium triacetoxyborohydride (1.2g, 6.0mmol), react at 20 ℃ for 2 hours, and then heated to reflux React for 12 hours. The reaction solution was added with water (100 mL), extracted with EA (50 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography (EA/PE 0-50%) Purification gave 013048A3 (400 mg, 48%, white solid). LCMS: [M+H] ⁺ 416.2.

Step 4: (S)-6-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2,6-diazaspiro[3.4 ]Octan-5-one

Compound 013048A3 (400 mg, 1 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, stirred at room temperature for 2 hours, and concentrated to remove the solvent to obtain crude product 013048A4, which was directly reacted without purification. LCMS: [M+H] ⁺ 316.14.

Step 5: (S)-6-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-(4-methyl-6- ((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2,6-diazaspiro[3.4]octan-5-one

Compound 013048A4 (300 mg, 1.0 mmol), intermediate 2 (223 mg, 1.0 mmol) and potassium carbonate (500 mg, 4.0 mmol) were added to DMSO (5 mL) and stirred at 110° C. for 16 hours. Add 50 mL of water to the system and extract three times with ethyl acetate (20 mL). The organic phase was spin-dried under reduced pressure to obtain the crude product. Purified by flash silica gel column chromatography (DCM/EA50%). The product was dissolved in acetonitrile/water and lyophilized. To give SZ-013048 (200 mg, 40%, white solid). LCMS: [M+H] ⁺ 503.40.

¹ H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 9.39 (s, 1H), 8.71 (dd, J=4.6, 0.7 Hz, 1H), 8.41 (d, J=1.5 Hz, 1H ), 7.98-7.91 (m, 3H), 6.38-6.11 (m, 2H), 5.34 (q, J=7.3Hz, 1H), 4.16-4.07 (m, 2H), 3.96-3.85 (m, 2H), 3.46-3.38(m, 1H), 3.11-3.03(m, 1H), 2.44-2.30(m, 2H), 2.20(s, 3H), 2.13(s, 3H), 1.57(d, J=7.1Hz, 3H).

Example 26 SZ-013050: (S)-8-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-(4-methyl -6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2,5,8-triazaspiro[3.5]nonane-6,9-dione

Step 1: 1-(tert-butyl) 3-ethyl 3-(((benzyloxy)carbonyl)amino) azetidine-1,3-dicarboxylate

1-(tert-butyl) 3-ethyl 3-aminoazetidine-1,3-dicarboxylate (1.0g, 4mmol), DIPEA (1.5g, 12mmol) and DCM (10mL) were added to the reaction flask, Cbz-Cl (0.85g, 5mmol) was added with stirring, and reacted at 20°C for 12 hours. The reaction solution was added with water (100 mL), extracted with EA (50 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography (EA/PE 0-20%) Purification gave 013050A1 (1.5 g, 99%, white solid). LCMS: [M+H] ⁺ 379.13.

Step 2: 3-(((benzyloxy)carbonyl)amino)-1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid

Compound 013050A1 (1.5g, 3.9mmol) and methanol (10mL) were added to the reaction flask, and water (3mL) was stirred. Then lithium hydroxide monohydrate (1.6g, 39mmol) was added, and the reaction was carried out at 20°C for 2 hours. The reaction solution was neutralized with 1M hydrochloric acid to neutrality, extracted with EA (50mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography (EA/PE 0) -50%) purification to obtain 013050A2 (1.1 g, 81%, colorless oily liquid). LCMS: [M+H] ⁺ 251.05 (de-Boc).

Step 3: tert-Butyl (S)-3-(((benzyloxy)carbonyl)amino)-3-((1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridine- 3-yl)ethyl)carbamoyl)azidine-1-carboxylate

Add 013050A2 (1.1g, 3.1mmol) and DMF (15ml) to the reaction flask, stir, then add (S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl ) Ethylamine (prepared according to WO2017079140) (0.64g, 3.1mmol), DIPEA (1.5g, 12mmol), and finally HATU (1.2g, 3.1mmol) was added and reacted at 20°C for 1 hour. The reaction solution was added with water (100 mL), extracted with EA (50 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography (EA/PE 0-50%) Purification gave 013050A3 (2.0 g, 95%, white solid). LCMS: [M+H] ⁺ 539.21.

Step 4: tert-butyl(S)-3-amino-3-((1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)carbamoyl ) Azetidine-1-carboxylate

013050A3 (2.0g, 3.7mmol), palladium on carbon (10%, 300mg) and methanol (20mL) were added to the reaction flask, and the reaction was replaced with hydrogen under vacuum three times with stirring, and then reacted under a hydrogen atmosphere for 4 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 013050A4 (1.5 g, 100%, white solid) which was directly used in the next step. LCMS: [M+H] ⁺ 405.18.

Step 5: tert-butyl(S)-3-(2-chloroacetamido)-3-((1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl) Ethyl)carbamoyl)azetidine-1-carboxylate

Compound 013050A4 (1.5g, 3.7mmol) was dissolved in anhydrous THF (20ml), stirred, then added triethylamine (1.1g, 11mmol), cooled to 0 ℃, dropwise added chloroacetyl chloride (500mg, 4.4mmol), drop The temperature was raised to 20°C for 12 hours. The reaction solution was added with water (40 mL), extracted with EA (10 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography (EA/PE 50-100%) Purification gave 013050A5 (1.5 g, 84%, white solid). LCMS: [M+H] ⁺ 481.17.

Step 6: tert-butyl (S)-8-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-6,9-dicarbonyl- 2,5,8-Triazaspiro[3.5]nonane-2-carboxylic acid ester

Add 013050A5 (1.5g, 3.1mmol), potassium iodide (500mg, 3.1mmol) and anhydrous THF (20mL) to the reaction flask, stir and cool to 0°C, then add sodium hydride (60% adsorbed to mineral oil, 250mg, 6.2) mmol), slowly warm to 60°C and stir the reaction for 20 minutes. After the reaction, it was cooled to room temperature and quenched with saturated ammonium chloride solution. The reaction solution was added with water (50 mL), extracted with EA (30 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography (EA/PE 50-100%) Purification gave 013050A6 (1.2 g, 87%, white solid). LCMS: [M+H] ⁺ 445.19.

Step 7: (S)-8-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2,5,8-triazaspiro [3.5]nonane-6,9-dione

Compound 013050A6 (440 mg, 1 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, stirred at room temperature for 2 hours, and concentrated to remove the solvent to obtain crude product 013050A7, which was directly reacted without purification. LCMS: [M+H] ⁺ 345.18.

Step 8:

(S)-8-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-(4-methyl-6-((5- Methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2,5,8-triazaspiro[3.5]nonane-6,9-dione

Compound 013050A7 (320 mg, 1.0 mmol), intermediate 2 (223 mg, 1.0 mmol) and potassium carbonate (500 mg, 4.0 mmol) were added to DMSO (5 mL), and stirred at 110° C. for 16 hours. Add 50 mL of water to the system, extract three times with ethyl acetate (20 mL), and spin-dry the organic phase under reduced pressure to obtain the crude product. Purify by flash silica gel column chromatography (DCM/EA 50%). The product was dissolved in acetonitrile/water and lyophilized. To give SZ-013050 (200 mg, 37%, white solid). LCMS: [M+H] ⁺ 532.38.

¹ H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 9.42 (s, 1H), 9.22 (s, 1H), 8.72 (d, J=4.5 Hz, 1H), 8.45 (d, J =2.0Hz, 1H), 8.02-7.91(m, 3H), 6.45-6.11(m, 2H), 5.81(q, J=7.1Hz, 1H), 4.45(s, 2H), 4.09-4.00(m, 3H), 3.55 (d, J = 17.1 Hz, 1H), 2.22 (s, 3H), 2.15 (s, 3H), 1.60 (d, J = 7.2 Hz, 3H).

Example 27 SZ-9397 (SZ-9397A and SZ-9397B): (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl )-9-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1-oxa-4-azaspiro[5.5] Undecane-5-one

Step 1: 4-((tert-butyldimethylsilyl)oxo)cyclohexanone

9397A1 (10g, 87.7mmol), imidazole (8.9g, 130.8mmol), TBSCl (15.7g, 104.6mmol) and dichloromethane (100mL) were added to the reaction flask and stirred at room temperature for 2 hours. The solid in the system was filtered off, and the filtrate was spin-dried and purified by flash silica gel column chromatography (PE: EA=7:1; Rf=0.6) to obtain a colorless oil 9397A2 (16g, 80%).

Second step: 4-((tert-butyldimethylsilyl)oxo)-1-((trimethylsilyl)oxo)cyclohexanecarbonitrile

Under ice-water bath, 9397A2 (4.4 g, 19.2 mmol) was dissolved in dichloromethane (15 mL), and TMSCN (2.8 mL, 31.1 mmol) and zinc iodide (300 mg, 5 mol%) were added sequentially and stirred for 1 hour. The system was filtered, and the filtrate was spin-dried. The crude product obtained was directly used in the next step.

The third step: 1,4-dihydroxycyclohexanecarboxylic acid

9397A3 (15 g) and concentrated hydrochloric acid (100 mL) were mixed and stirred at 100 degrees for 3 hours. The water of the system was spun off and purified by flash silica gel column chromatography (MeOH: EA=1:6; Rf=0.3) to obtain a crude 9397A4 (8g) as a colorless oil.

Step 4: Methyl 1,4-dihydroxycyclohexanecarboxylate

The obtained 9397A4 crude product was dissolved in methanol (100 mL) and toluene (10 mL) under an ice water bath, and slowly dropped into TMSCHN ₂ (60 mL, 1 M in hexane) and stirred for 15 min. After the reaction, the solvent of the system was unscrewed to obtain 9397A5 crude product, and the next step was directly carried out.

The fifth step: 4-((tert-butyldimethylsilyl)oxo)-1-hydroxycyclohexanecarboxylic acid methyl ester

The obtained crude product was dissolved in dichloromethane (100 mL), and TBSCl (9.3 g, 62 mmol) and imidazole (5.1 g, 75 mmol) were added sequentially and stirred at room temperature for 2 hours. After the reaction was completed, the solid was filtered off, and the obtained filtrate was spin-dried and purified by flash silica gel column chromatography (PE: EA=7:1; Rf=0.6) to obtain 9397A6 (11 g, 83%) as a colorless oil.

Step 6: 1-(allyloxy)-4-((tert-butyldimethylsilyl)oxo)cyclohexanecarboxylic acid methyl ester

Dissolve 9397A6 (10g, 34.7mmol) in DMF (100mL) under ice-water bath, and add sodium hydride (2.7g, 69.4mmol) to the system. After stirring at room temperature for 15min, add allyl bromide (6.2g, 52.1mmol) And stir for 2 hours. After the reaction, 100 mL of water and 100 mL of ethyl acetate were added to the system. The organic phase was spin-dried and purified by flash silica gel column chromatography (PE: EA=7:1; Rf=0.7) to obtain 9397A7 as a colorless oil (9 g, 79%) ).

Step 7: 4-((tert-butyldimethylsilyl)oxo)-1-(2-carbonylethoxy)cyclohexanecarboxylic acid methyl ester

Under ice-water bath, 9397A7 (8g, 24.5mmol) was dissolved in acetonitrile (100mL) and water (70mL), sodium periodate (15.6g, 73.2mmol) and ruthenium trichloride (100mg) were added sequentially and stirred for 1 hour. 100 mL of water and 100 mL of ethyl acetate were added to the system, and the organic phase was spin-dried to obtain a crude colorless oil.

Step 8: (S)-methyl 4-((tert-butyldimethylsilyl)oxo)-1-(2-((1-(6-(4-fluoro-1H-pyrazole- 1-yl)pyridin-3-yl)ethyl)amino)ethoxy)cyclohexyl carboxylate

The resulting 9397A8 crude product was dissolved in dichloroethane (100 mL), 9399A4 (4.5 g) and sodium triacetylborohydride (6.8 g) were added sequentially, and stirred at room temperature overnight. 100 mL of water and 100 mL of ethyl acetate were added to the system, the organic phase was spin-dried and purified by flash silica gel column chromatography (PE: EA = 1:1; Rf = 0.7) to obtain 9397A9 (2 g, 15%) as a colorless oil. LCMS: [M+H] ⁺ 521.16

Step 9: (S)-9-((tert-butyldimethylsilyl)oxo)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridine- 3-yl)ethyl)-1-oxa-4-azaspiro[5.5]undecane-5-one

9397A9 (2g, 3.7mmol) was dissolved in anhydrous methanol (10mL), a methanol solution of sodium methoxide (2mL, 5.4M) was added and stirred at 100 degrees overnight. After the reaction was completed, the solvent was removed and purified by flash silica gel column chromatography (PE: EA=4:1; Rf=0.6) to obtain 9397A10 as a white solid (1 g, 47%). LCMS: [M+H] ⁺ 489.30

Step 10: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-9-hydroxy-1-oxa-4 -Azaspiro[5.5] undecane-5-one

9397A10 (1 g, 2.1 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), TBAF (6 mL, 1 M in THF) was added and stirred at room temperature overnight. After the reaction was completed, the solvent was removed and purified by flash silica gel column chromatography (PE: EA=1:1; Rf=0.3) to obtain 9397A11 (600 mg, 78%) as a white solid. LCMS: [M+H] ⁺ 375.21

Eleventh step: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxa-4-aza Spiro[5.5]undecane-5,9-dione

9397A11 (600 mg, 1.5 mmol) was dissolved in anhydrous dichloromethane (10 mL), PCC (483 mg, 2.3 mmol) was added and stirred at room temperature for 2 hours. After the reaction was completed, the solvent was removed and purified by flash silica gel column chromatography (PE: EA = 1:1; Rf = 0.4) to obtain a white solid 9397A12 2 (100 mg, 34%). LCMS: [M+H] ⁺ 373.22

Step 12: 4-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-5-carbonyl-1-oxa- 4-azaspiro[5.5]undecane-8-en-9-yl trifluoromethanesulfonate

9397A12 (200mg, 0.5mmol) was dissolved in anhydrous tetrahydrofuran (5mL), cooled to -70 degrees, LiHMDS (0.6mL, 1M in THF) was dropped into the system under argon and stirred for 1 hour, then N-benzene Bis(trifluoromethanesulfonimide) (300 mg, 0.8 mmol) was added and slowly warmed to room temperature and stirred for 30 min. After the reaction was completed, saturated ammonium chloride (10 mL) and ethyl acetate (10 mL) were added to the system, and the organic phase was spin-dried and the next step was directly performed. LCMS:[M+H]+505.15

Step 13: 4-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-9-(4,4,5, 5-tetramethyl-1,3,2-dioxaborol-2-yl)-1-oxa-4-azaspiro[5.5]undecane-8-en-5-one

9397A13 was dissolved in anhydrous 1,4-dioxane (10 mL), and pinacol diborate (130 mg, 0.5 mmol), potassium acetate (140 mg, 1.4 mmol) and Pd (dppf) were added in sequence under the protection of argon. Cl ₂ .DCM (40 mg) and stirred at 80 degrees for 3 hours. After the reaction was completed, the solvent was removed and purified by flash silica gel column chromatography (PE:EA=2:1; Rf=0.2) to obtain 9397A14 (100 mg, 42%) as a white solid. LCMS:[M+H] ⁺ 483.19

Step 14: 4-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-9-(4-methyl-6 -((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1-oxa-4-azaspiro[5.5]undecane-8-en-5-one

Under the protection of argon, 9397A14 (100mg, 0.2mmol), 9399A8 (45mg, 0.2mmol), potassium carbonate (69mg, 0.5mol) and tetratriphenylphosphine (25mg, 5mol%) were dissolved in anhydrous 1,4-bis The reaction was conducted in a microwave at 125 degrees for 2 hours in oxane (10 mL). After the reaction was completed, the solvent was removed and purified by flash silica gel column chromatography (EA 100%; Rf = 0.2) to obtain 9397A15 (50 mg, 31%) as a white solid. LCMS:[M+H] ⁺ 544.11

Step 15: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-9-(4-methyl-6 -((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1-oxa-4-azaspiro[5.5]undecane-5-one

9397A15 (50 mg, 0.09 mmol) was dissolved in methanol, ammonium formate (70 mg) and palladium hydroxide (70 mg) were added and stirred at 90 degrees for 3 hours. After the reaction was completed, the crude product of the filtrate was directly purified by high-pressure reversed-phase column chromatography (ACN-0.1% ammonium bicarbonate aqueous solution) and lyophilized to obtain two isomers SZ-9397A (2.6 mg) and SZ-9397B (3.6 mg). LCMS: [M+H] ⁺ 546.22.

SZ-9397A: HPLC t _R =6.43 min. ¹ H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 9.49 (s, 1H), 8.70 (d, J=4.4 Hz, 1H), 8.35 (s, 1H), 7.89-7.95 (m , 3H), 5.74(q, J=6.8Hz, 1H), 3.80-3.85(m, 2H), 2.93-2.96(m, 3H), 2.35-2.39(m, 2H), 2.28(s, 3H), 2.21 (s, 3H), 1.97-2.01 (m, 2H), 1.85-1.87 (m, 2H), 1.59-1.66 (m, 2H), 1.53 (d, J = 6.8Hz, 3H).

SZ-9397B: HPLC t _R =5.95 min. ¹ H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 9.51 (s, 1H), 8.71 (d, J=4.4 Hz, 1H), 8.38 (s, 1H), 7.92-8.05 (m , 3H), 5.82(q, J=6.8Hz, 1H), 3.80-3.85(m, 2H), 2.61-2.93(m, 3H), 2.30-2.39(m, 2H), 2.26(s, 3H), 2.22 (s, 3H), 1.74-2.05 (m, 6H), 1.56 (d, J = 6.8 Hz, 3H).

The HPLC analysis methods of SZ-9397A and SZ-9397B are as follows:

Example 28 SZ-013044: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-9-(4-methyl -6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1-(2,2,2-trifluoroethyl)-1,4,9-tri Azaspiro[5.5]undecane-2,5-dione

Step 1: tert-butyl-(S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2,5-dicarbonyl -1-(2,2,2-trifluoroethyl)-1,4,9-triazaspiro[5.5]undecane-9-carboxylate

013002A4 (1.2g, 2.5mmol) and THF (20mL) were added to the reaction flask, and cooled to 0°C under stirring, and then LiHMDS (1M in THF, 5mL, 5mmol) was slowly added, and the temperature was raised to room temperature and stirred for 20 minutes. Finally, 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.3g, 10mmol) was added, and the temperature was raised to 60°C to react for 12 hours. The reaction solution was quenched with saturated ammonium chloride solution, and then water (100 mL) was added, extracted with EA (50 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography Method (EA/PE 0-50%) purification to obtain 013044A1 (500 mg, 40%, white solid). LCMS: [M+H] ⁺ 455.13 (de-Boc).

Step 2: ((S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-(2,2,2- Trifluoroethyl)-1,4,9-triazaspiro[5.5]undecane-2,5-dione

Compound 013044A1 (500 mg, 1.0 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, stirred at room temperature for 2 hours, and concentrated to remove the solvent to obtain crude product 013044A2, which was directly reacted without purification. LCMS: [M+H] ⁺ 455.27.

Step 3: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-9-(4-methyl-6- ((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1-(2,2,2-trifluoroethyl)-1,4,9-triazaspiro [5.5] Undecane-2,5-dione

Compound 013044A2 (400 mg, 1.0 mol), intermediate 2 (223 mg, 1.0 mmol) and potassium carbonate (500 mg, 4.0 mmol) were added to DMSO (10 mL), and stirred at 110° C. for 16 hours. 50mL of water was added to the system, and extracted with ethyl acetate (20mL) three times. The organic phase was spin-dried under reduced pressure to obtain a crude product. The product was then subjected to reversed-phase column chromatography with acetonitrile/0.1% formic acid water and lyophilized to obtain SZ-013044 (60mg, 9.3%, white solid). LCMS: [M+H] ⁺ 642.31. ¹ H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 9.24 (s, 1H), 8.73 (d, J=4.5 Hz, 1H), 8.42 (d, J=1.6 Hz, 1H), 8.00-7.91(m, 3H), 6.35-6.05(m, 2H), 5.79(q, J=7.1Hz, 1H), 4.70(d, J=12.4Hz, 2H), 4.39-4.29(m, 3H) , 3.93 (d, J = 18.4 Hz, 1H), 3.43-3.38 (m, 1H), 3.30-3.21 (m, 1H), 2.22 (s, 3H), 2.21-2.18 (m, 1H), 2.15 (s , 3H), 2.13-2.06 (m, 1H), 1.93-1.80 (s, 2H), 1.62 (d, J=7.1Hz, 3H).

Example 29 SZ-013034: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-9-(4-methyl -6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,4,9-triazaspiro[5.5]undecane-5-one

Step 1: tert-butyl(S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-5-carbonyl-1,4 ,9-Triazaspiro[5.5]undecane-9-carboxylate

A solution of borane in tetrahydrofuran (9 mL, 9 mmol, 1 M) was added portionwise to a solution of compound 013034A0 (330 mg, 0.698 mmol) in THF (9 mL) at 16 degrees Celsius. The resulting reaction mixture was heated to 31 degrees Celsius and stirring was continued for 3 hours. The resulting reaction mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride solution (10 mL), and then diluted with water (30 mL). Solid sodium carbonate was added to the resulting solution until saturated, and extracted with ethyl acetate (30 mL*3). After combining the organic phases, add anhydrous magnesium sulfate to dry, filter and spin-dry the organic solvent. The obtained crude product was subjected to column purification to obtain the product 013034A1 (130 mg) as a pale yellow oil. LCMS: [M+H+] 459.21@3.609min.

Step 2: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1,4,9-triazaspiro [5.5] Undecane-5-one; trifluoroacetate

Trifluoroacetic acid (3 mL) was added portionwise to the methylene chloride solution (3 mL) of compound 013034A1 (100 mg, 0.21 mmol) at 16 degrees Celsius. The resulting reaction mixture was continued to stir at 16 degrees Celsius for one hour. The resulting reaction mixture was then spin-dried, and then pumped for 3 minutes using an oil pump to obtain the product 013034A2 (100 mg) as a yellow oil, which was directly used in the next reaction. LCMS: [M+H]+359.18@2.603min.

Step 3: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-9-(4-methyl-6- ((5-methyl-1H-pyrazol-3-yl)-12-azaaza)pyrimidin-2-yl)-1,4,9-triazaspiro[5.5]undecane-5- ketone

The suspension of compound 013034A2 (100 mg, 0.21 mmol), compound 1 (63 mg, 0.276 mmol), potassium carbonate (0.3 g, 2.16 mmol) and DMSO (3 mL) was heated to 169 degrees Celsius and stirring was continued for 3 hours. The resulting reaction mixture was cooled to 16 degrees Celsius and then diluted with water (10 mL) and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine (10 mL*3), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. It was then purified using high-pressure preparative chromatography to obtain the white solid compound SZ-013034 (21 mg, 18.6%). LCMS: [M+H+] 546.21@2.986min. ¹ H NMR (400 MHz, CD3OD) δ 8.52 (d, J=4.0 Hz, 1H), 8.39 (s, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.88 (dd, J ₁ = 8.0 Hz , J ₂ = 2.0 Hz, 1H), 7.71 (d, J = 4.0 Hz, 1H), 6.23 (br, 1H), 6.10 (br, 1H), 5.98 (q, J = 8.0 Hz, 1H), 4.61 4.39 (m, 2H), 3.39-3.33 (m, 1H), 3.33-3.26 (m, 2H), 3.16-2.86 (m, 3H), 2.28 (s, 3H) 2.23 (s, 3H), 2.21-2.16 (m, 2H), 1.76 (t, J = 8.0 Hz, 2H), 1.61 (d, J = 8.0 Hz, 3H).

Example 30 SZ-013035: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methyl-9- (4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,4,9-triazaspiro[5.5]undecane -5-one

A solution of borane in tetrahydrofuran (31 mL, 31 mmol, 1 M) was added to the solution of compound 013049A0 (1.1 g, 2.33 mmol) in THF (30 mL) in batches at 16 degrees Celsius with a syringe. The resulting reaction mixture was stirred at 16 degrees Celsius for 3 hours, then heated to 69 degrees Celsius and stirring was continued for 30 minutes. The resulting reaction mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride solution (30 mL), and then diluted with water (30 mL). Solid sodium carbonate was added to the resulting solution until saturated, and extracted with ethyl acetate (60 mL*3). After combining the organic phases, add anhydrous magnesium sulfate to dry, filter and spin-dry the organic solvent. The obtained crude product was subjected to column purification to obtain the product 013034A1 (260 mg) as a pale yellow oil. LCMS: [M+H+] 459.21@3.609min.

Step 2: tert-butyl(S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-5-carbonyl-1,4 ,9-Triazaspiro[5.5]undecane-9-carboxylate

NaH (160 mg, 3.9 mmol) was added portionwise to a solution of compound 013034A1 (180 mg, 0.39 mmol) in tetrahydrofuran (6 mL) at 16 degrees Celsius. The resulting reaction mixture was further stirred at 16 degrees Celsius for 6 minutes. Then, methyl iodide (260 mg, 3.9 mmol) was added dropwise to the above off-white suspension with a syringe. The resulting reaction mixture was sealed with a sealed tube and heated to 69 degrees Celsius and stirring was continued for half a 16 hour. After cooling the resulting reaction mixture to room temperature, saturated aqueous ammonium chloride solution was added to quench (10 mL), followed by dilution with water (10 mL). The resulting solution was extracted with ethyl acetate (30 mL*3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the organic solvent was spin-dried. The residue was purified by column to give the product 013035A1 (90 mg) as a yellow oil. LCMS: [M+H]+473.19@3.169min.

Step 3: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methyl-1,4,9 -Triazaspiro[5.5]undecane-5-one; trifluoroacetate

Trifluoroacetic acid (3 mL) was added portionwise at 16 degrees Celsius to a solution of compound 013035A1 (90 mg, 0.19 mmol) in dichloromethane (3 mL). The resulting reaction mixture was continued to stir at 16 degrees Celsius for one hour. The resulting reaction mixture was spin-dried and the solvent was pumped for three minutes to obtain the product 013035A2 (80 mg) as a yellow oil, which was used directly in the next reaction. LCMS: [M+H]+373.16@2.65min.

Step 4: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methyl-9-(4- Methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,4,9-triazaspiro[5.5]undecane-5- ketone

The suspension of compound 013035A2 (69 mg, 0.139 mmol), compound 1 (63 mg, 0.269 mmol), potassium carbonate (0.31 g, 2.16 mmol) and DMSO (3 mL) was heated to 169 degrees Celsius and stirring was continued for one hour. The resulting reaction mixture was cooled to 16 degrees Celsius and then diluted with water (13 mL) and extracted with ethyl acetate (30 mL*3). The organic phases were combined, washed with saturated brine (10 mL*3), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. It was then purified using high-pressure preparative chromatography to obtain the white solid compound SZ-013035 (18 mg, 23%). LCMS: [M+H+] 560.37@2.789min. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.42 (d, J=4.0 Hz, 1H), 8.29 (d, J=2.0 Hz, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.80 ( dd, J ₁ = 8.0 Hz, J ₂ = 2.0 Hz, 1H), 7.61 (d, J = 4.0 Hz, 1H), 6.12 (br, 1H), 5.98 (br, 1H), 5.90 (q, J = 8.0 Hz, 1H), 4.22 (dd, J ₁ = 12.0 Hz, J ₂ = 8.0 Hz, 1H), 3.43-3.33 (m, 3H), 3.09 (t, J = 8.0 Hz, 2H), 2.90 (m, 1H ), 2.36 (s, 3H) 2.18 (s, 3H), 2.11 (s, 3H), 1.98-1.89 (m, 4H), 1.53 (d, J = 8.0Hz, 3H).

Example 31 SZ-013031 (SZ-013031A and SZ-013031B): (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl )-1-methyl-9-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,4-diazaspiro [5.5] Undecane-2,5-dione

Step 1: 8-(((benzyloxy)carbonyl)amino)-1,4-dioxaspiro[4.5]decane-8-carboxylic acid (013031A1)

Compound 9305A4 (3.63g, 10mmol) and lithium hydroxide monohydrate (2.1g, 50mmol) were dissolved in methanol (20ml) and water (20ml). The system was heated to 60 degrees and stirred for 3 hours. After the reaction was completed, it was cooled down with 1N Hydrochloric acid adjusted the system pH=3, extracted with EA (30mlX3), the organic phase was dried over sodium sulfate and concentrated to obtain 013031A1 (3.63g, colorless oil) without further purification.

Step 2: Benzyl (S)-(8-((1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)carbamoyl)-1 ,4-dioxaspiro[4.5]decane-8-yl)carbamate (013031A2)

013031A1 (3.35g, 10mmol) and (S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethylamine (2.06g, 10mmol) were dissolved in DMF (20ml ), HATU (4.56g, 12mmol) was added and stirred at room temperature for 3 hours. Water (100ml) was added followed by extraction with ethyl acetate (30mlX3). After the organic phase was dried over sodium sulfate, flash silica gel column chromatography was used to obtain 013031A2 (4.5 g, 86% in two steps, white solid). LCMS: [M+H] ⁺ 524.4.

Step 3: (S)-8-amino-N-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1,4-diox Heterospiro[4.5]decane-8-formamide (013031A3)

013031A2 (4.5g, 8.6mmol) was dissolved in methanol (50mL), ammonium formate (5.42g, 86mmol) and palladium hydroxide/C (500mg) were added, stirred at 60°C for 3 hours, filtered, and the organic phase was depressurized Spin dry without further purification to obtain 013031A3 (3.5 g, white solid). LCMS:[M+H]+390.4

Step 4: (S)-8-(2-chloroacetamido)-N-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)- 1,4-dioxaspiro[4.5]decane-8-carboxamide (013031A4)

013031A3 (3.35 g, 8.6 mmol) was dissolved in DCM (50 ml), DIPEA (3.32 g, 25.8 mmol) was added, chloroacetyl chloride (1.16 g, 10.3 mmol) was added dropwise at room temperature and stirred at this temperature for 6 hours. After completion of the reaction, 013031A4 (3.2 g, Y=80%, white solid) was obtained by flash silica gel column chromatography. LCMS: [M+H] ⁺ 466.9.

Step 5: (S)-12-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1,4-dioxa-9, 12-Diazabispiro[4.2.58.25]Pentadecane-10,13-dione (013031A5)

013031A4 (3g, 6.45mmol) was dissolved in anhydrous tetrahydrofuran (50ml), and NaH (516mg, 12.9mmol) was added in portions at 0°C. After 0.5 hours of reaction, the temperature was raised to 65°C for 5 hours. Purification by flash silica gel column chromatography gave 013031A5 (700 mg, Y=25%, white solid). LCMS: [M+H] ⁺ 430.4

Step 6: (S)-12-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-9-methyl-1,4-di Oxa-9,12-diazabispiro[4.2.58.25]pentadecane-10,13-dione (013031A6)

013031A5 (700mg, 1.63mmol) was dissolved in anhydrous tetrahydrofuran (10ml), NaH (130mg, 3.3mmol) was added in portions at 0°C. After 0.5 hours of reaction, methyl iodide (463mg, 3.3mmol) was added to react at room temperature 3 Hours, after the reaction was completed, it was purified by flash silica gel column chromatography to obtain 013031A6 (360 mg, Y=51%, white solid). LCMS: [M+H] ⁺ 444.5

Step 7: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methyl-1,4-di Azaspiro[5.5]undecane-2,5,9-trione (013031A7)

013031A6 (360mg, 0.81mmol) was dissolved in Dioxane (5ml), 4N hydrochloric acid (4mL) was added, stirred at 60°C for 3 hours, then water (50mL) was added, followed by extraction with ethyl acetate (10*3mL), organic The phase was dried over sodium sulfate and spin-dried to obtain the crude product, which was obtained by flash silica gel column chromatography to 013031A7 (300 mg, 91%, white solid). LCMS: [M+H] ⁺ 372.12

Step 8: 4-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methyl-2,5-di Carbonyl-1,4-diazaspiro[5.5]undec-8-en-9-yl trifluoromethanesulfonate (013031A8)

013031A7 (300mg, 0.75mmol) was dissolved in anhydrous tetrahydrofuran (10mL), the system was cooled to -70°C under the protection of argon and LiHMDS (1mL, 1mol/L) was slowly dropped, and then stirred at this temperature for 1 hour Then, phenylbis(trifluoromethanesulfonyl)imide (277 mg, 0.75 mmol) in tetrahydrofuran (3 mL) was quickly added to the system and the temperature was raised to 0°C and stirred for 2 hours. After the reaction was completed, 30 mL of saturated ammonium chloride was added to quench and extracted with 50 mL of ethyl acetate. The organic phase was dried over sodium sulfate, spin-dried and purified by flash silica gel column chromatography to obtain 013031A8 (80 mg, Y=20%, white solid). LCMS: [M+H] ⁺ 532.4.

Step 9: 4-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methyl-9-(4, 4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,4-diazaspiro[5.5]undec-8-ene-2,5- Diketone (013031A9)

013031A8 pinacol (230g, 0.9mmol) (0.48g, 0.9mmol) and the United boronic _{_{acid, Pd (dppf) 2 Cl 2}} · DCM (37mg, 5%), potassium acetate (0.265g, 2.7mmol) under argon protection Mix in dioxane (10 mL) and heat to 80 degrees and stir for 4 hours. After the reaction was completed, the solvent was cooled and removed, and purified by flash silica gel column chromatography to obtain 013031A9 (450 mg, Y=95%, white solid). LCMS: [M+H] ⁺ 510.4.

Step 10: 4-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methyl-9-(4- Methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,4-diazaspiro[5.5]undec-8-ene-2 , 5-dione (013031A10)

013011A09 (0.45g, 0.88mmol), and 9305A8 (200mg, 0.88mmol), Pd (PPh 3) 4 (51mg, 5%), potassium carbonate (364mg, 2.64mmol) were mixed in dioxane under argon protection ( 6 mL) and water (2 mL), stirred under microwave at 125° C. for 5 hours, the resulting reaction solution was spin-dried and purified by flash silica gel column chromatography to obtain 013031A10 (320 mg, Y=63%, white solid). LCMS: [M+H] ⁺ 571.7.

Eleventh step: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methyl-9-(4 -Methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,4-diazaspiro[5.5]undecane-2,5- Dione

013031A10 (320mg, 0.56mmol) was dissolved in methanol (10mL), ammonium formate (352mg, 5.6mmol) and palladium hydroxide/C (30mg) were added, stirred at 60°C for 3 hours, filtered, and the organic phase was decompressed The crude product was obtained by spin-drying, which was purified by medium-pressure reversed-phase column chromatography (ACN-0.1% HCO ₂ H aqueous solution) and lyophilized to obtain SZ-013031A (100 mg, white solid) and SZ-013031B (37 mg, white solid).

LCMS: [M+H] ⁺ 573.32, HPLC: t _R =5.574 min. SZ-013031A: ¹ H NMR (400 MHz, DMSO) δ 11.95 (s, 1H), 9.57 (s, 1H), 8.73 (d, J=4.5 Hz, 1H), 8.40 (s, 1H), 7.95 (m , 3H), 6.82 (s, 1H), 6.20 (s, 1H), 5.80 (q, J = 7.0 Hz, 1H), 4.13 (dd, J = 17.6, 8.6 Hz, 1H), 3.67 (dd, J = 17.7, 9.3Hz, 1H), 3.02(s, 3H), 2.83(s, 1H), 2.27(s, 3H), 2.22(s, 3H), 2.21--1.96(m, 8H), 1.58(d, J = 7.2Hz, 3H).

LCMS: [M+H] ⁺ 573.32, HPLC: t _R =5.363 min. SZ-013031B: ¹ H NMR (400 MHz, DMSO) δ 11.91 (s, 1H), 9.56 (s, 1H), 8.72 (d, J=4.5 Hz, 1H), 8.39 (s, 1H), 8.06–7.82 (m, 3H), 5.84 (q, J = 7.1 Hz, 1H), 4.11 (d, J = 17.8 Hz, 1H), 3.66 (d, J = 17.7 Hz, 1H), 2.94 (s, 3H), 2.72 (dd, J = 23.8, 11.4 Hz, 1H), 2.46-1.80 (m, 14H), 1.59 (d, J = 7.2 Hz, 3H).

HPLC test conditions: instrument: Waters Acquity ARC (UHPLC); chromatography column: XSelect CSH ^TM C18 3.5 μm, 4.6*150 mm Column XP; mobile phase A: 0.1% aqueous ammonia solution; mobile phase B: acetonitrile; flow rate: 1 ml/min Wavelength: 282nm; column temperature: 30°C; blank solvent: methanol; sample solution: dissolve the appropriate amount of analyte with methanol, and filter with 0.22μm filter; gradient elution:

Example 32 SZ-013045: (S)-1-cyclopropyl-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-9 -(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,4,9-triazaspiro[5.5]undecane -2,5-dione

Step 1: tert-Butyl(S)-1-cyclopropyl-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)- 2,5-dicarbonyl-1,4,9-triazaspiro[5.5]undecane-9-carboxylate

To the reaction flask, add compound 013002A4 (230mg, 0.5mmol), cyclopropaneboronic acid (86mg, 1.0mmol), DMAP (183mg, 1.5mmol), anhydrous copper acetate (10mg, 0.05mmol) and THF (10ml), add with stirring LiHMDS (1M, 0.5mL, 0.5mmol), heated to 60 °C for 12 hours. The reaction solution was added with water (100ml), extracted with EA (50ml*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography (EA/PE 0-20%) Purification gave 013045A1 (130 mg, 50%, white solid). LCMS: [M+H] ⁺ 513.26.

Step 2: (S)-1-cyclopropyl-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1,4, 9-Triazaspiro[5.5]undecane-2,5-dione

Compound 013045A1 (130mg, 0.25mmol) was dissolved in dichloromethane (5mL), trifluoroacetic acid (1mL) was added, stirred at room temperature for 1 hour, concentrated to remove the solvent to obtain crude product 013045A2, the next step was carried out without purification. LCMS: [M+H] ⁺ 413.24.

Step 3: (S)-1-Cyclopropyl-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-9-(4 -Methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,4,9-triazaspiro[5.5]undecane-2, 5-dione

Compound 013045A2 (100 mg, 0.25 mmol), intermediate 2 (56 mg, 0.25 mmol) and potassium carbonate (138 mg, 1.0 mmol) were added to DMSO (5 mL) and stirred at 110° C. for 16 hours. 50mL of water was added to the system, and extracted three times with ethyl acetate (20ml). The organic phase was spin-dried under reduced pressure to obtain a crude product. The product was then subjected to reversed-phase column chromatography with acetonitrile/0.1% formic acid water and lyophilized to obtain SZ-013045 (15mg , 10%, white solid). LCMS: [M+H] ⁺ 600.36.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.88 (s, 1H), 9.23 (s, 1H), 8.72 (d, J=4.6 Hz, 1H), 8.40 (s, 1H), 7.96 (d, J = 4.3 Hz, 1H), 7.96-7.92 (m, 2H), 6.34-6.03 (m, 2H), 5.74 (q, J = 7.3 Hz, 1H), 4.60 (d, J = 12.1 Hz, 2H), 4.14 (d, J = 18.7 Hz, 1H), 3.70 (d, J = 18.4 Hz, 1H), 3.46-3.37 (m, 1H), 3.33-3.27 (m, 1H), 2.30-2.25 (m, 1H) , 2.23(s, 3H), 2.21-2.16(m, 2H), 2.15(s, 3H), 2.13-2.07(m, 2H), 1.58(d, J=7.1Hz, 3H), 0.87-0.81(m , 2H), 0.64-0.52 (m, 2H).

Example 33 SZ-013052: (S)-1-(cyclopropylmethyl)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethane Radical)-9-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,4,9-triazaspiro[5.5 ]Undecane-2,5-dione

Step 1: tert-Butyl(S)-4-((cyclopropylmethyl)amino)-4-((1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridine- 3-yl)ethyl)carbamoyl)piperidine-1-carboxylate

In the reaction bottle, add compound 013002A2 (2.1g, 5mmol), cyclopropyl formaldehyde (0.7g, 10mmol) and dichloroethane (20ml), add sodium borohydride acetate (3.1g, 15mmol) with stirring, and react at 20℃4 hour. The reaction solution was added with water (100ml), extracted with DCM (50ml*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by flash silica gel column chromatography (EA/PE 20-50%) Purification gave 013052A1 (2.0 g, 81%, white solid). LCMS: [M+H] ⁺ 487.47.

Step 2: tert-Butyl(S)-4-(2-chloro-N-(cyclopropylmethyl)acetamido)-4-((1-(6-(4-fluoro-1H-pyrazole -1-yl)pyridin-3-yl)ethyl)carbamoyl)piperidine-1-carboxylate

Compound 013052A1 (1.0g, 2.0mmol) was dissolved in anhydrous THF (20ml), stirred, then added triethylamine (600mg, 6.0mmol), cooled to 0 ℃, dropwise added chloroacetyl chloride (280mg, 2.5mmol), drop The temperature was raised to 20°C for 12 hours. The reaction solution was added with water (40ml), extracted with EA (10ml*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography (EA/PE 50-100%) Purification gave 013052A2 (610 mg, 53%, white solid). LCMS: [M+H] ⁺ 563.27.

Step 3: tert-Butyl(S)-1-(cyclopropylmethyl)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl) Ethyl)-2,5-dicarbonyl-1,4,9-triazaspiro[5.5]undecane-9-carboxylate

Add 013052A2 (610mg, 1.1mmol), potassium iodide (180mg, 1.1mmol) and anhydrous THF (10ml) to the reaction flask, stir and cool to 0°C, then add sodium hydride (60% adsorbed to mineral oil, 88mg, 2.2mmol) ), slowly raise the temperature to 60 ℃ and stir the reaction for 2h. After the reaction was completed, it was cooled to room temperature and quenched with saturated ammonium chloride solution. The reaction solution was added with water (50ml), extracted with EA (30ml*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography (EA/PE 50-100%) Purification gave 013052A3 (450 mg, 78%, white solid). LCMS: [M+H] ⁺ 527.25.

Step 4: (S)-1-(cyclopropylmethyl)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)- 1,4,9-Triazaspiro[5.5]undecane-2,5-dione

Compound 013052A3 (200 mg, 0.38 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, stirred at room temperature for 2 hours, and concentrated to remove the solvent to obtain crude product 013052A4, which was directly reacted without purification. LCMS: [M+H] ⁺ 427.28.

Step 5: (S)-1-(cyclopropylmethyl)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)- 9-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,4,9-triazaspiro[5.5]11 Alkane-2,5-dione

Compound 013052A4 (162 mg, 0.38 mmol), intermediate 2 (85 mg, 0.38 mmol) and potassium carbonate (210 mg, 1.5 mmol) were added to DMSO (5 mL), and stirred at 110° C. for 16 hours. 50mL of water was added to the system, and extracted three times with ethyl acetate (20ml). The organic phase was spin-dried under reduced pressure to obtain a crude product. The product was then subjected to reversed-phase column chromatography with acetonitrile/0.1% formic acid water and lyophilized to obtain SZ-013052 (85mg , 36%, white solid). LCMS: [M+H] ⁺ 614.38.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.98 (s, 1H), 9.27 (s, 1H), 8.72 (d, J=4.5 Hz, 1H), 8.43 (d, J=2.1 Hz, 1H) , 8.22 (s, 0.4H) (HCOOH), 8.00-7.92 (m, 3H), 6.33-6.07 (m, 2H), 5.78 (q, J = 7.1Hz, 1H), 4.64 (d, J = 12.3Hz , 2H), 4.20 (d, J = 18.1 Hz, 1H), 3.76 (d, J = 18.1 Hz, 1H), 3.48-3.40 (m, 1H), 3.35-3.21 (m, 3H), 2.22 (s, 3H), 2.15(s, 3H), 2.13-2.05(m, 1H), 2.03-1.93(m, 2H), 1.61(d, J=7.1Hz, 3H), 0.88-0.76(m, 1H), 0.40 -0.30(m, 2H), 0.23-0.12(m, 2H).

Example 34 SZ-013046: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-9-(4-methyl -6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,4,9-triazaspiro[5.5]undecane-2-one

Step 1: tert-butyl(S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-carbonyl-1,4 ,9-Triazaspiro[5.5]undecane-9-carboxylate

Lithium aluminum hydride powder (1 g, 26.3 mmol) was added portionwise to a solution of compound 013046A0 (1 g, 2.11 mmol) in anhydrous tetrahydrofuran (30 mL) at 26 degrees Celsius. The resulting reaction mixture was continued to stir at 26 degrees Celsius for 1 hour. The resulting reaction mixture was diluted with anhydrous tetrahydrofuran (30 mL), and then water (1 g), aqueous sodium hydroxide solution (1 g, 15 wt%) and water (3 g) were slowly added dropwise. The white suspension was stirred vigorously for ten minutes and then filtered. After combining the filtrates, the solvent was dried. The residue was purified by column to give the product 013046A1 (300 mg) as a light yellow solid. LCMS: [M+H+] 459.23@3.641min. ¹ H NMR (400 MHz, DMSO-D6) 8.68 (d, J = 4.0 Hz, 1H), 8.41 (d, J = 2.0 Hz, 1H), 7.96 (dd, J ₁ = 8.0 Hz, J ₂ = 2.0 Hz, 1H), 7.93-7.83(m, 3H), 3.71(q, J=8.0Hz, 1H), 3.58-3.5(m, 2H), 3.10(d, J=16.0Hz, 1H), 2.97(br, 2H ), 2.84 (d, J = 16.0 Hz, 1H), 2.58 (d, J = 12.0 Hz, 1H) 2.31 (d, J = 12.0 Hz, 1H), 1.66-1.6 (m, 1H), 1.6-1.46 ( m, 3H) 1.36 (s, 9H).

Step 2: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1,4,9-triazaspiro [5.5] Undecane-2-one; trifluoroacetate

Trifluoroacetic acid (3 mL) was added portionwise to the dichloromethane solution (3 mL) of compound 013046A1 (190 mg, 0.41 mmol) at 31 degrees Celsius. The resulting reaction mixture was further stirred at 31 degrees Celsius for one hour. The resulting reaction mixture was spinned to dryness, and then pumped for 3 minutes using an oil pump to obtain the product 013046A2 (190 mg) as a pale yellow oil, which was directly used in the next reaction. LCMS: [M+H]+359.21@2.669min.

Step 3: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-9-(4-methyl-6- ((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,4,9-triazaspiro[5.5]undecane-2-one

The suspension of compound 013046A2 (190 mg, 0.41 mmol), compound 1 (136 mg, 0.6 mmol), potassium carbonate (0.3 g, 2.16 mmol) and DMSO (3 mL) was heated to 169 degrees Celsius and stirring was continued for one hour. The resulting reaction mixture was cooled to 31 degrees Celsius and then diluted with water (10 mL) and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine (10 mL*3), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. It was then purified using high-pressure preparative chromatography to obtain the white solid compound SZ-013046 (36 mg, 16%). LCMS: [M+H+] 546.31@3.069min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.82 (s, 1H), 9.13 (s, 1H), 8.68 (d, J=4.0 Hz, 1H), 8.43 (d, J=4.0 Hz, 1H) , 8.00 (dd, J ₁ = 12.0 Hz, J ₂ = 4.0 Hz, 1H), 7.91 (s, 1H), 7.90 (d, J = 4.0 Hz, 1H), 7.87 (s, 1H), 6.18 (br, 1H), 6.05 (s, 1H), 4.09 (d, J = 16.0 Hz, 2H) 3.74 (q, J = 8.0 Hz, 1H), 3.28-3.16 (m, 2H), 3.12 (d, J = 16.0 Hz , 1H), 2.87(d, J=16.0Hz, 1H), 2.65(d, J=12.0Hz, 1H) 2.39(d, J=12.0Hz, 1H), 2.19(s, 3H), 2.08(s, 3H), 1.73-1.66 (m, 1H), 1.63-1.53 (m, 3H) 1.39 (d, J = 8.0 Hz, 3H).

Example 35 SZ-013053 (SZ-013053A and SZ-013053B): (S)-1-ethyl-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridine-3 -Yl)ethyl)-9-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,4-diazaspiro [5.5] Undecane-2,5-dione

Step 1: (S)-8-(ethylamino)-N-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1, 4-dioxaspiro[4.5]decane-8-carboxamide (013053A1)

013031A3 (7.8g, 20mmol) was dissolved in DCE (50ml), a solution of acetaldehyde in tetrahydrofuran (22mL, 1Mol/L) was added, and sodium cyanoborohydride (3.74g, 60mmol) was added in portions at room temperature at this temperature Stir for 6 hours. After completion of the reaction, 013053A1 (4.2 g, Y=50%, white solid) was obtained by flash silica gel column chromatography. LCMS: [M+H] ⁺ 418.4.

Step 2: (S)-8-(2-chloro-N-ethylacetamido)-N-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl )Ethyl)-1,4-dioxaspiro[4.5]decane-8-carboxamide (013053A2)

013053A1 (4.2g, 10mmol) was dissolved in DCM (50ml), DIPEA (3.3g, 25mmol) was added, chloroacetyl chloride (1.36g, 12mmol) was added dropwise at room temperature and stirred at this temperature for 6 hours. After completion of the reaction, 013053A2 (3.7 g, Y=75%, white solid) was obtained by flash silica gel column chromatography. LCMS: [M+H] ⁺ 494.8.

Step 3: (S)-9-ethyl-12-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1,4-di Oxa-9,12-diazabispiro[4.2.58.25]pentadecane-10,13-dione (013053A3)

013053A2 (3.7g, 7.5mmol) was dissolved in anhydrous tetrahydrofuran (50ml), and NaH (600mg, 15mmol) was added in portions at 0°C. After 0.5 hours of reaction, the temperature was raised to 65°C for 5 hours. Purification by flash silica gel column chromatography gave 013053A3 (2.3g, Y=67%, white solid). LCMS: [M+H] ⁺ 456.4

Step 4: (S)-1-ethyl-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1,4-di Azaspiro[5.5]undecane-2,5,9-trione (013053A4)

013053A3 (2.3g, 5mmol) was dissolved in Dioxane (50ml), 4N hydrochloric acid (40mL) was added, stirred at 60°C for 6 hours, then water (500mL) was added, followed by extraction with ethyl acetate (100*3mL), organic The phase was dried over sodium sulfate and spin-dried to obtain the crude product, which was obtained by flash silica gel column chromatography to obtain 013353A4 (1.65 g, Y=80%, white solid). LCMS: [M+H] ⁺ 414.4

Step 5: 1-ethyl-4-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2,5-di Carbonyl-1,4-diazaspiro[5.5]undec-8-en-9-yl trifluoromethanesulfonate (013053A5)

013053A4 (1100mg, 2.7mmol) was dissolved in anhydrous tetrahydrofuran (30mL), the system was cooled to -70°C under the protection of argon and LiHMDS (3mL, 1mol/L) was slowly dropped, and then stirred at this temperature for 1 hour Then, phenylbis(trifluoromethanesulfonyl)imide (964 mg, 0.75 mmol) in tetrahydrofuran (8 mL) was quickly added to the system and the temperature was raised to 0° C. and stirred for 2 hours. After the reaction was completed, 50 mL of saturated ammonium chloride was added to quench and extracted with 50 mL of ethyl acetate. The organic phase was dried over sodium sulfate, spin-dried and purified by flash silica gel column chromatography to obtain 013053A5 (700 mg, Y=48%, white solid). LCMS: [M+H] ⁺ 546.4.

Step 6: 1-ethyl-4-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-9-(4, 4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,4-diazaspiro[5.5]undec-8-ene-2,5- Diketone (013053A6)

013053A5 (700 mg, 1.28 mmol) and biboronic acid pinacol (326 mg, 1.28 mmol), Pd(dppf) ₂ Cl ₂ ·DCM (52 mg, 5%), potassium acetate (0.376 g, 3.84 mmol) under the protection of argon Mix in dioxane (10 mL) and heat to 80 degrees and stir for 4 hours. After the reaction was completed, the solvent was cooled and removed, and purified by flash silica gel column chromatography to obtain 013053A6 (480 mg, Y=72%, white solid). LCMS: [M+H] ⁺ 524.3.

Step 7: 1-ethyl-4-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-9-(4- Methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,4-diazaspiro[5.5]undec-8-ene-2 ,5-dione (013053A7)

013053A6 (0.48g, 0.91mmol), and 9305A8 (208mg, 0.91mmol), Pd (PPh 3) 4 (53mg, 5%), potassium carbonate (376mg, 2.73mmol) were mixed in dioxane under argon protection ( 6mL) and water (2mL), stirred at 125 °C microwave for 5 hours, the resulting reaction solution was spin-dried and purified by flash silica gel column chromatography to obtain 013053A7 (440mg, Y = 75%, white solid). LCMS: [M+H] ⁺ 585.6.

Step 8: (S)-1-ethyl-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-9-(4- Methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,4-diazaspiro[5.5]undecane-2,5-di ketone

013053A7 (400mg, 0.75mmol) was dissolved in methanol (10mL), ammonium formate (472mg, 7.5mmol) and palladium hydroxide/C (40mg) were added, stirred at 60°C for 3 hours, filtered, and the organic phase was depressurized The crude product was obtained by spin-drying, which was purified by medium-pressure reverse phase column chromatography (ACN-0.1% HCO ₂ H aqueous solution) and lyophilized to obtain SZ-013053A (120 mg, white solid) and SZ-013053B (25 mg, white solid).

LCMS: [M+H] ⁺ 587.33, HPLC: t _R =8.737 min. SZ-013053A: ¹ H NMR (400 MHz, DMSO) δ 11.87 (s, 1H), 9.51 (s, 1H), 8.65 (t, J=20.8 Hz, 1H), 8.39 (d, J=26.5 Hz, 1H ), 8.09–7.80 (m, 3H), 6.78 (s, 1H), 6.32 (s, 1H), 5.91–5.69 (m, 1H), 4.08 (d, J=17.7Hz, 1H), 3.62 (d, J = 17.7 Hz, 1H), 3.49 (q, J = 6.8 Hz, 2H), 2.70 (t, J = 11.9 Hz, 1H), 2.42-2.01 (m, 10H), 1.89 (d, J = 10.2 Hz, 4H), 1.56 (d, J = 7.2Hz, 3H), 1.07 (t, J = 7.0Hz, 3H).

LCMS: [M+H] ⁺ 587.33, HPLC: t _R =9.444 min. SZ-013053B: ¹ H NMR (400 MHz, DMSO) δ 11.90 (s, 1H), 9.53 (s, 1H), 8.69 (d, J=4.1 Hz, 1H), 8.37 (s, 1H), 7.96–7.89 (m, 3H), 6.84(s, 1H), 6.14(s, 1H), 5.74(q, J=7.1Hz, 1H), 4.07(d, J=17.7Hz, 1H), 3.61(d, J= 17.6Hz, 1H), 3.41–3.25(m, 2H), 2.91(s, 1H), 2.31–1.82(m, 14H), 1.55(d, J=7.2Hz, 3H), 0.95(t, J=6.9 Hz, 3H).

Example 36 SZ-013054: (S)-1-(2,2-difluoroethyl)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridine-3- Yl)ethyl)-9-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,4,9-triaza Spiro[5.5]undecane-2,5-dione

Step 1: tert-Butyl(S)-1-(2,2-difluoroethyl)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridine-3 -Yl)ethyl)-2,5-dicarbonyl-1,4,9-triazaspiro[5.5]undecane-9-carboxylate

In the reaction flask, compound 013002A4 (1.2g, 2.5mmol) and THF (20mL) were added, LiHMDS (1M, 5mL, 5mmol) was added dropwise, stirred for 10 minutes, and then 2,2-difluoroethyl trifluoromethanesulfonate was added (2.1g, 1.0mmol), react at 20°C for 12 hours. The reaction solution was added with water (100ml), extracted with EA (50ml*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography (EA/PE 0-20%) Purification gave 013054A1 (1.0 g, 74%, white solid). LCMS: [M+H] ⁺ 537.24.

Step 2: (S)-1-(2,2-difluoroethyl)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethane Radical)-1,4,9-triazaspiro[5.5]undecane-2,5-dione

Compound 013054A1 (450mg, 0.84mmol) was dissolved in dichloromethane (5mL), trifluoroacetic acid (1mL) was added, stirred at room temperature for 1 hour, concentrated to remove the solvent to obtain crude product 013054A2, the next step was carried out without purification. LCMS: [M+H] ⁺ 437.22.

Step 3: (S)-1-(2,2-difluoroethyl)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethane Radical)-9-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,4,9-triazaspiro[5.5 ]Undecane-2,5-dione

Compound 013054A2 (360 mg, 0.84 mmol), intermediate 2 (187 mg, 0.84 mmol) and potassium carbonate (460 mg, 3.3 mmol) were added to DMSO (5 mL), and stirred at 110° C. for 16 hours. 50mL of water was added to the system, and extracted three times with ethyl acetate (20ml). The organic phase was spin-dried under reduced pressure to obtain the crude product. The product was then subjected to reversed-phase column chromatography with acetonitrile/0.1% formic acid water and lyophilized to obtain SZ-013054 (105mg , 20%, white solid). LCMS: [M+H] ⁺ 624.36.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.86 (s, 1H), 9.22 (s, 1H), 8.72 (d, J=4.6 Hz, 1H), 8.43 (d, J=1.7 Hz, 1H) , 8.01-7.91 (m, 3H), 6.32-5.91 (m, 3H), 5.78 (q, J = 7.0 Hz, 1H), 4.64 (d, J = 11.7 Hz, 2H), 4.28 (d, J = 17.9 Hz, 1H), 3.92-3.79(m, 3H), 3.47-3.38(m, 1H), 3.33-3.25(m, 1H), 2.22(s, 3H), 2.19-2.06(m, 5H), 1.93- 1.82 (m, 1H), 1.62 (d, J = 7.0 Hz, 3H).

Example 37 SZ-013055: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-9-(4-methyl -6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1-propyl-1,4,9-triazaspiro[5.5]undecane- 2,5-dione

Step 1: tert-Butyl(S)-4-((1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)carbamoyl)-4 -(Propylamino)piperidine-1-carboxylate

To the reaction flask, add compound 013002A2 (2.0g, 4.6mmol), n-propanal (268mg, 4.6mmol) and dichloroethane (20ml), add sodium borohydride acetate (1.46g, 7mmol) with stirring, and react at 20℃4 hour. The reaction solution was added with water (100ml), extracted with DCM (50ml*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by flash silica gel column chromatography (EA/PE 20-50%) Purification gave 013055A1 (2.0 g, 91%, white solid). LCMS: [M+H] ⁺ 475.31.

Step 2: tert-Butyl(S)-4-(2-chloro-N-propylacetamido)-4-((1-(6-(4-fluoro-1H-pyrazol-1-yl) Pyridin-3-yl)ethyl)carbamoyl)piperidine-1-carboxylate

Compound 013055A1 (2.0g, 4.2mmol) was dissolved in anhydrous THF (20ml), stirred, and then added triethylamine (1.5g, 16mmol), cooled to 0 ℃, dropwise added chloroacetyl chloride (600mg, 5.2mmol), drop The temperature was raised to 20°C for 12 hours. The reaction solution was added with water (40ml), extracted with EA (10ml*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography (EA/PE 50-100%) Purification gave 013055A2 (1.5 g, 64%, white solid). LCMS: [M+H] ⁺ 551.27.

Step 3: tert-Butyl(S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2,5-dicarbonyl -1-propyl-1,4,9-triazaspiro[5.5]undecane-9-carboxylate

Add 013055A2 (1.5g, 2.7mmol), potassium iodide (452mg, 2.7mmol) and anhydrous THF (20ml) to the reaction flask, stir and cool to 0°C, then add sodium hydride (60% adsorbed to mineral oil, 216mg, 5.4) mmol), slowly warm up to 80 °C and stir the reaction for 2 h. After the reaction was completed, it was cooled to room temperature and quenched with saturated ammonium chloride solution. The reaction solution was added with water (50ml), extracted with EA (30ml*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography (EA/PE 50-100%) Purification gave 013055A3 (610 mg, 44%, white solid). LCMS: [M+H] ⁺ 515.30.

Step 4: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-propyl-1,4,9 -Triazaspiro[5.5]undecane-2,5-dione

Compound 013055A3 (610 mg, 1.19 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, stirred at room temperature for 2 hours, and concentrated to remove the solvent to obtain crude product 013055A4, which was directly reacted without purification. LCMS: [M+H] ⁺ 415.28.

Step 5: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-9-(4-methyl-6- ((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1-propyl-1,4,9-triazaspiro[5.5]undecane-2,5 -Diketone

Compound 013055A4 (490 mg, 1.2 mmol), intermediate 2 (265 mg, 1.2 mmol) and potassium carbonate (657 mg, 4.8 mmol) were added to DMSO (10 mL) and stirred at 110° C. for 16 hours. 50mL of water was added to the system, and extracted three times with ethyl acetate (20ml). The organic phase was spin-dried under reduced pressure to obtain the crude product. The product was then subjected to reverse phase column chromatography with acetonitrile/0.1% formic acid water and lyophilized to obtain SZ-013055 (190mg , 26%, white solid). LCMS: [M+H] ⁺ 602.37.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.02 (s, 1H), 9.23 (s, 1H), 8.71 (d, J=4.4 Hz, 1H), 8.42 (d, J=1.6 Hz, 1H) , 8.17 (s, 0.3H) (HCOOH), 8.00-7.91 (m, 3H), 6.31-6.06 (m, 2H), 5.78 (q, J = 7.1Hz, 1H), 4.61 (d, J = 12.4Hz , 2H), 4.16 (d, J = 18.0Hz, 1H), 3.72 (d, J = 18.0Hz, 1H), 3.51-3.40 (m, 2H), 3.35-3.17 (m, 2H), 2.22 (s, 3H), 2.21-2.17(m,1H), 2.15(s,3H),2.12-2.06(m,1H),1.94-1.79(m,2H),1.61(d,J=7.1Hz,3H),1.46 -1.35(m, 2H), 0.82-0.75(m, 3H).

Example 38 SZ-013056: (S)-1-butyl-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-9- (4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,4,9-triazaspiro[5.5]undecane- 2,5-dione

Step 1: (S)-tert-butyl 4-(butylamino)-4-((1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl )Carbamoyl)piperidine-1-carboxylate

SZ-013056A1 (1.5g, 3.47mmol), butyraldehyde (0.25g, 3.47mmol) and dichloroethane (10mL) were added to the reaction flask, two drops of acetic acid were added dropwise and sodium triacetoxyborohydride was added in portions ( 0.8g, 3.81mmol) and stirred at room temperature for 2 hours. The solid in the system was filtered off, the filtrate was spin-dried and purified by flash silica gel column chromatography (PE: EA=2:1; Rf=0.6) to obtain a colorless oil SZ-013056A2 (500 mg, 31%). [M+H] ⁺ 489.30

Step 2: (S)-tert-butyl 4-(N-butyl-2-chloroacetamido)-4-((1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridine -3-yl)ethyl)carbamoyl)piperidine-1-carboxylate

Dissolve SZ-013056A2 (500mg, 1.02mmol) in dichloromethane (10mL) under ice-water bath, add triethylamine (0.2mL, 1.53mmol) slowly drop chloroacetyl chloride (137mg, 1.25mmol) and stir for 1 hour. 10mL of water and 10mL of dichloromethane were added to the system. The organic phase was dried with sodium sulfate and spin-dried. The crude product was directly used in the next step. [M+H] ⁺ 567.11

The third step: (S)-tert-butyl 1-butyl-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2, 5-Dicarbonyl-1,4,9-triazaspiro[5.5]undecane-9-carboxylate

SZ-013056A3 (15 g) was dissolved in anhydrous tetrahydrofuran (10 mL), sodium hydride (100 mg, 2.3 mmol) was added to the system and stirred for 30 minutes, and finally potassium iodide (169 mg, 1.02 mmol) was added and stirred at 100 degrees overnight. 5 mL of water and 10 mL of ethyl acetate were added to the system, the organic phase was spin-dried and purified by flash silica gel column chromatography (PE: EA = 1:1; Rf = 0.3) to obtain a colorless oil SZ-013056A4 (120 mg). [M+H] ⁺ 529.16

The fourth step: (S)-1-butyl-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-9-(4- Methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,4,9-triazaspiro[5.5]undecane-2,5 -Diketone

SZ-013056A4 was dissolved in dichloromethane (5mL), trifluoroacetic acid (2mL) was added and stirred at room temperature for 2 hours. After the reaction was completed, the next step was directly spin-dried. [M+H] ⁺ 429.34

Step 5: (S)-9-(4-((1H-pyrazol-5-yl)amino)-6-methylpyrimidin-2-yl)-1-butyl-4-(1-(6 -(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1,4-diazaspiro[5.5]undecane-2,5-dione

The resulting crude SZ-013056A5 was dissolved in DMSO (5 mL), potassium carbonate (160 mg, 1.15 mmol) and pyrimidine chloride intermediate (50 mg, 0.23 mmol) were added sequentially and stirred at 110 degrees overnight. After the reaction, the crude product was directly purified by high-pressure reversed-phase column chromatography (ACN-0.1% ammonium carbonate aqueous solution) and lyophilized to obtain SZ-013056. LCMS:[M+H] ⁺ 616.21

SZ-013056: HPLC t _R = 7.08 min. ¹ H NMR (400 MHz, d ₆ -DMSO) δ 9.24 (s, 1H), 8.72 (d, J=4.4 Hz, 1H), 8.43 (d, J=2.0 Hz, 1H), 7.93-7.99 (m, 3H), 6.14-6.25 (m, 2H), 5.74 (q, J = 6.8Hz, 1H), 4.59 (d, J = 12.8Hz, 2H), 4.16 (d, J = 17.6Hz, 1H), 3.69- 3.79 (m, 1H), 3.42-3.48 (m, 1H), 3.24-3.31 (m, 2H), 2.07-2.33 (.m, 9H), 1.83-1.94 (m, 2H), 1.60 (d, J = 3.2Hz, 3H), 1.33-1.41 (m, 2H), 1.17-1.25 (m, 2H), 0.82 (t, J = 7.2Hz, 3H).

Example 39 SZ-013057: (S)-7-ethyl-11-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-3- (4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-3,7,11-triazaspiro[5.6]dodecyl- 9-ene-8,12-dione

The first step: (S)-tert-butyl 4-(N-ethylacryloylamino)-4-((1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridine-3 -Yl)ethyl)carbamoyl)piperidine-1-carboxylate

Add SZ-013057A1 (1.0g, 2.18mmol), triethylamine (0.5mL, 3.27mmol) and dichloroethane (10mL) to the reaction flask, slowly add chloropropionyl chloride (300mg, 2.18mmol) and at room temperature Stir for 2 hours. The filtrate was spin-dried and purified by flash silica gel column chromatography (PE: EA=2:1; Rf=0.2) to give a colorless oil SZ-013057A2 (1.1 g). [M+H] ⁺ 515.20

The second step: (S)-tert-butyl 7-ethyl-11-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-8, 12-Dicarbonyl-3,7,11-triazaspiro[5.6]dodec-9-ene-3-carboxylic acid ester

Under ice-water bath, SZ-013057A2 (1.1 g, 2.14 mmol) was dissolved in tetrahydrofuran (10 mL), sodium hydride (0.4 g, 10 mmol) was added, and the mixture was refluxed and stirred for 4 hours. After cooling, 10 mL of water and 10 mL of ethyl acetate were added to the system. The organic phase was dried over sodium sulfate, spin-dried and purified by flash silica gel column chromatography (PE: EA = 1:1; Rf = 0.4) to obtain a colorless oil SZ -013057A3 (120mg). [M+H] ⁺ 513.54

The third step: (S)-7-ethyl-11-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-3,7,11 -Triazaspiro[5.6]dodec-9-ene-8,12-dione

SZ-013056A3 was dissolved in dichloromethane (2mL), trifluoroacetic acid (2mL) was added and stirred at room temperature for 2 hours. After the reaction was completed, the next step was directly spin-dried. [M+H] ⁺ 412.59

Step 5: (S)-7-ethyl-11-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-3-(4- Methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-3,7,11-triazaspiro[5.6]dodec-9-ene -8,12-dione

The resulting crude SZ-013056A4 was dissolved in DMSO (5 mL), potassium carbonate (160 mg, 1.15 mmol) and pyrimidine chloride intermediate (50 mg, 0.23 mmol) were added sequentially and stirred at 110 degrees overnight. After the reaction is completed, the crude product is directly purified by high-pressure reversed-phase column chromatography (ACN-0.1% ammonium carbonate aqueous solution) and lyophilized to obtain SZ-013057. LCMS: [M+H] ⁺ 560.12

SZ-013057: HPLC t _R = 7.01 min. ¹ H NMR (400 MHz, d ₆ -DMSO) δ 11.86 (s, 1H), 9.22 (s, 1H), 8.70 (d, J=4.4 Hz, 1H), 8.39 (s, 1H), 7.90-7.95 ( m, 3H), 6.11-6.24 (m, 2H), 5.87 (q, J = 6.8Hz, 1H), 5.65 (s, 1H), 5.14 (s, 1H), 4.61 (t, J = 15.6Hz, 2H ), 4.16 (d, J = 17.6 Hz, 1H), 3.44-3.49 (m, 2H), 3.13-3.33 (m, 2H), 2.22 (s, 3H), 2.13 (s, 3H), 2.06-2.09 ( m, 2H), 1.92-1.83 (m, 2H), 1.89 (d, J = 7.2Hz, 3H), 1.07 (t, J = 6.8Hz, 3H).

Example 40 SZ-013058 (SZ-013058A and SZ-013058B): (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl )-9-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,4-diazaspiro[5.5]dec 1-alkan-2-one

Step 1: 8-(2-chloroacetamido)-1,4-dioxaspiro[4,5]decane-8-carboxylic acid

Compound 1 (8.1g, 71.8mmol) was added dropwise to compound 013058A0 (23.9g, 121.9mmol), sodium carbonate (15.3g, 143.6mmol), acetonitrile (160mL) and water (160mL) at 1-3 degrees Celsius with a syringe In suspension. The resulting reaction mixture was continuously stirred at 1-3 degrees Celsius for 1.6 hours, and then diluted with water (160 mL). (The pH of the system was found to be 8-9 after detection.) Then, the resulting reaction mixture was spin-dried all solvents, and then the residual solvent was removed under reduced pressure by an oil pump to obtain crude compound 013058A1 (31 g, crude product). This compound was directly used in the next reaction. LCMS: [M+H+] 277.98@2.411min.

Step 2: (S)-8-(2-chloroacetamido)-N-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl) -1,4,-dioxaspiro[4,5]decane-8-carboxylic acid amide

After installing the mechanical stirring device, the T3P/ethyl acetate solution (198 mL) was added dropwise to the compound 013058A1 (31 g, crude product), compound 2 (31 g, 128 mmol) and triethylamine (110 mL) in DMF (1.3 L) at 21 degrees Celsius. In the suspension, the resulting reaction mixture was further stirred for 16 hours at 16-23 degrees Celsius. The resulting white suspension was quenched with water (1.6 L), and then extracted with ethyl acetate (600 mL*3). The organic phases were combined and washed with saturated brine (300 mL*3), dried over anhydrous magnesium sulfate, filtered, and the organic solvent was spin-dried and purified by column to obtain compound 013058A2 (8 g) as a yellow viscous oil. LCMS: [M+H]+466.16@3.627min.

Step 3: (S)-12-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1,4-dioxo-9,12 -Diazaspiro[4.2.58.25]Pentadecane-10,13-dione

Solid powdered NaH (1.56 g, 39 mmol) was added portionwise at 21 degrees Celsius to a suspension of compound 013058A2 (1.9 g, 4.06 mmol) and potassium iodide (1.6 g, 9.63 mmol) in tetrahydrofuran (36 mL). The resulting reaction mixture was further stirred at 21 degrees Celsius for 30 minutes. Then, saturated aqueous ammonium chloride solution (30 mL) was added to quench, followed by dilution with water (30 mL), and extraction with ethyl acetate (60 mL*3). The combined organic phases are dried over anhydrous magnesium sulfate, filtered, and the organic solvent is spin-dried. It was then pumped with an oil pump for three minutes to obtain crude compound 013058A3 (1.9 g), which was directly used in the next reaction. LCMS: [M+H+] 430.26@3.167min.

Step 4: (S)-12-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1,4-dioxo-9,12 -Diazaspiro[4.2.58.25]Pentadecane-10-one

Solid lithium aluminum hydride powder (1.3 g, 34.3 mmol) was added portionwise at 23 degrees Celsius to a solution (39 mL) of compound 013058A3 (1.63 g, 3.9 mmol) in tetrahydrofuran. The resulting reaction mixture was continued to stir at 23 degrees Celsius for 1 hour. It was then diluted with tetrahydrofuran (30 mL), followed by water (1.3 g), aqueous sodium hydroxide solution (1.3 g, 15 wt%) and water (3.9 g) in order to quench. The resulting reaction suspension was stirred vigorously at 23 degrees Celsius for half an hour, and then filtered under reduced pressure. After combining the filtrates, all solvents were vortexed. The residue was purified by column to obtain white solid compound 013058A4 (1 g, 61.3%) LCMS: [M+H+]416.21@3.36min.

Step 5: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1,4,-diazaspiro[ 5.5] Undecane-2,9-dione

Dilute hydrochloric acid (13 mL, 78 mmol, 6M) was added in portions to a solution of compound 013058A4 (760 mg, 1.8 mmol) in 1,4-dioxane (13 mL) at 23 degrees Celsius. The resulting reaction mixture was heated to 69 degrees Celsius and stirring continued for 1 hour. Next, the obtained reaction mixture was added with solid sodium carbonate and water to adjust the pH value of the system to 8-9, and the solid sodium carbonate was continued to be added until it was saturated and extracted with ethyl acetate (30 mL*3). After combining the organic phases, dry with anhydrous MgSO ₄ , filter, and spin-dry the organic solvent. It was then pumped with an oil pump for three minutes to obtain the product 013058A5 as a white solid (610 mg, 91%). LCMS: [M+H+] 372.17@3.167min.

Step 6: 4-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-carbonyl-1,4,-di Azaspiro[5.5]undecane-8-ene-9-yl trifluoromethanesulfonate

LiHMDS (1.9 mL, 1.9 mmol) was added portionwise to a solution of compound 013058A5 (610 mg, 1.6 mmol) in tetrahydrofuran (16 mL) at -78 degrees Celsius with a syringe. The resulting reaction mixture was further stirred at -78 degrees Celsius for 1 hour. Then, a solution (3 mL) of PhNTf2 (680 mg, 1.9 mmol) in tetrahydrofuran was added dropwise to the above reaction solution at -78 degrees Celsius. The resulting reaction mixture was stirred at -78-23 degrees Celsius for 16 hours. Then, a saturated aqueous ammonium chloride solution (30 mL) was added to the system to quench the reaction and extracted with ethyl acetate (30 ml*3). The organic phases are combined and dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Next, purification using column chromatography gave compound 013058A6 as a white solid (399 mg, 49%). LCMS: [M+H+] 504.14@3.771min.

Step 7: 4-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-9-(4,4,5,5 -Tetramethyl-1,3,2-6-((5-methyl-1H-pyrazol-3-yl)-12-azaalkyl)pyrimidin-2-yl)-1,4,9- Triazaspiro[5.5]undecane

At 33 degrees Celsius, put 013058A6 (399mg, 0.8mmol), double-linked pinacol borate (253mg, 1mmol), potassium acetate (0.26g, 2.6mmol), 1,4-dioxane (9mL) and PdCl ₂ (dppf). The suspension of DCM (80 mg) was replaced with nitrogen three times with stirring, then heated to 90 degrees Celsius under nitrogen protection and stirring was continued for 3 hours. The resulting reaction mixture was cooled to 33 degrees Celsius, and then quenched by adding water (16 mL). This was followed by ethyl acetate extraction (30 mL*3). After combining the organic phases, add anhydrous MgSO4 to dry, filter and spin-dry the organic solvent. The crude product was purified by flash column chromatography to give the product 013058A7 as a white solid (330 mg, 84.6%). LCMS: [M+H+]482.31@3.905min. LCMS: [M+H+] 532.35@2.513min.

Step 8: 4-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-9-(4-methyl-6- ((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl-1,4,-diazaspiro[5.5]undecane-8-en-2-one

Pd(PPh ₃ ) ₄ (69 mg) was added to compound 013058A7 (330 mg, 1.6 mmol), compound 3 (390 mg, 1.6 mmol), potassium carbonate (690 g, 5.3 mmol), 1,4-bis at 26 degrees Celsius in portions. Oxygen hexacyclic (6mL) and water (1.6mL) suspension. Nitrogen was replaced three times, and the resulting reaction mixture was reacted in a Biotage microwave reactor: 130 degrees Celsius for one hour. The resulting red-yellow solution was cooled to room temperature, quenched with water (30 mL), and extracted with ethyl acetate (30 mL*3). After combining the organic phases, dry with anhydrous MgSO ₄ , filter, and spin-dry the organic solvent. The crude product was purified by flash silica gel column chromatography to give white solid product 013058A8 (130 mg, 46.19%). LCMS: [M+H+] 543.28@3.683min.

Step 9: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-9-(4-methyl-6- ((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl-1,4,-diazaspiro[5.5]undecane-2-one

Compound 013058A8 (130 mg, 0.239 mmol) was added to a black suspension of wet Pd(OH) ₂ /C (300 mg) in methanol (33 mL) at 26 degrees Celsius, followed by solid ammonium formate (3 g). The resulting reaction mixture was heated to 69 degrees Celsius and stirring continued for one hour. After the resulting black suspension was cooled to room temperature, it was filtered through celite and washed with methanol (10 mL*3). After combining the filtrates, the solvent was vortexed and then dissolved with water (30 mL). This solution was basified by adding solid Na ₂ CO ₃ until saturated. Then extract with ethyl acetate (30 mL*3), combine the organic phases, dry with anhydrous MgSO ₄ , filter, and spin-dry the organic solvent. This crude product was purified by high-pressure preparative liquid chromatography to obtain two diastereomers:

SZ-013058A (13 mg, 10%, white solid). LCMS: [M+H+] 545.26@2.821min. HPLC t _R = 5.21 min. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.41 (d, J=2.0 Hz, 1H), 8.37 (d, J=4.0 Hz, 1H), 7.96 (dd, J1=8.0 Hz, J2=2.0 Hz, 1H), 7.87 (d, J = 8.0Hz, 1H), 7.60 (d, J = 4.0Hz, 1H), 6.63 (br, 1H), 6.11 (br, 1H), 3.73 (q, J = 4.0Hz, 1H), 3.33 (d, J = 4.0 Hz, 1H), 3.04 (d, J = 16.0 Hz, 1H), 2.82 (d, J = 8.0 Hz, 1H), 2.68-2.53 (m, 2H), 2.31 ( s, 3H), 2.26 (s, 3H), 2.18-2.11 (m, 2H), 2.03-1.98 (m, 1H), 1.83-1.73 (m, 2H), 1.66-1.53 (m, 4H), 1.49 ( d, J = 8.0 Hz, 3H).

SZ-013058B (3.9 mg, 3%, white solid). LCMS: [M+H+] 545.21@2.916min. HPLC t _R = 6.066 min. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.56 (d, J = 4.0 Hz, 1H), 8.46 (s, 1H), 8.02 (dd, J ₁ = 8.0 Hz, J ₂ = 2.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 6.78 (br, 1H), 6.21 (br, 1H), 3.71 (q, J = 4.0 Hz, 1H), 3.43-3.41 (m, 1H), 3.09-3.07 (m, 1H), 2.73-2.71 (br, 1H), 2.56 (d, J = 8.0Hz, 1H), 2.51 (d, J = 8.0Hz, 1H), 2.36 (s, 3H), 2.33 (s, 3H), 2.23(t, J=4.0Hz, 2H), 2.16-1.91(m, 3H), 1.89-1.81(m, 1H), 1.69-1.58(m, 2H), 1.49(d, J=4.0Hz , 3H).

HPLC test conditions: instrument: Waters Acquity ARC (UHPLC); chromatographic column: XSelect CSH ^™ C183.5μm, 4.6*150mm Column XP; mobile phase A: 0.1% aqueous ammonia solution; mobile phase B: acetonitrile; flow rate: 1ml/min; Wavelength: 282nm; column temperature: 30°C; blank solvent: methanol; sample solution: dissolve the appropriate amount of analyte with methanol, and filter with 0.22μm filter; gradient elution:

Example 41 SZ-013059: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-3,3-dimethyl -9-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,4,9-triazaspiro[5.5]dec Monoxane-2,5-dione

Step 1: tert-Butyl(S)-4-(2-bromo-2-methylpropionylamino)-4-((1-(6-(4-fluoro-1H-pyrazol-1-yl )Pyridin-3-yl)ethyl)carbamoyl)piperidine-1-carboxylate

To the reaction flask, add compound 013002A2 (1.0g, 2.3mmol), anhydrous THF (20ml), stir, then add triethylamine (690mg, 6.9mmol), cool to 0°C, and add bromoacetyl bromide (634mg, 2.8mmol) dropwise ), and the temperature was raised to 20°C for 12 hours after dropping. The reaction solution was added with water (40ml), extracted with EA (10ml*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography (EA/PE 50-100%) Purification gave 013059A1 (1.0 g, 75%, white solid). LCMS: [M+H] ⁺ 581.22, 583.23.

Step 2: tert-Butyl(S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-3,3-dimethyl -2,5-dicarbonyl-1,4,9-triazaspiro[5.5]undecane-9-carboxylate

Add 013059A1 (1.0g, 1.7mmol), potassium iodide (285mg, 1.7mmol) and anhydrous THF (20ml) to the reaction flask, stir and cool to 0°C, then add LiHMDS (1M in THF, 3.4mL, 3.4mmol), The reaction was stirred at 20°C for 6h. After the reaction was completed, it was cooled to room temperature and quenched with saturated ammonium chloride solution. The reaction solution was added with water (50ml), extracted with EA (30ml*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography (EA/PE 50-100%) Purification gave 013059A2 (150 mg, 18%, white solid). LCMS: [M+H] ⁺ 501.27.

Step 3: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-3,3-dimethyl-1, 4,9-Triazaspiro[5.5]undecane-2,5-dione

Compound 013059A2 (150mg, 0.3mmol) was dissolved in dichloromethane (5mL), trifluoroacetic acid (1mL) was added, stirred at room temperature for 1 hour, concentrated to remove the solvent to obtain crude product 013059A3, the next step was carried out without purification. LCMS: [M+H] ⁺ 401.21.

Step 4: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-3,3-dimethyl-9- (4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,4,9-triazaspiro[5.5]undecane- 2,5-dione

Compound 013059A3 (120 mg, 0.3 mmol), intermediate 2 (67 mg, 0.3 mmol) and potassium carbonate (165 mg, 1.2 mmol) were added to DMSO (5 mL), and stirred at 110° C. for 16 hours. Add 50 mL of water to the system and extract three times with ethyl acetate (20 ml). The organic phase was spin-dried under reduced pressure to obtain the crude product. The product was then subjected to reverse phase column chromatography with acetonitrile/0.1% formic acid water and lyophilized to obtain SZ-013059 (25 mg , 14%, white solid). LCMS: [M+H] ⁺ 588.32.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.86 (s, 1H), 9.21 (s, 1H), 8.68 (d, J=4.4 Hz, 1H), 8.36 (d, J=1.2 Hz, 1H) , 7.94 (d, J = 4.4 Hz, 1H), 7.91-7.88 (m, 2H), 6.29-6.05 (m, 2H), 5.91 (q, J = 7.1 Hz, 1H), 4.38-4.26 (m, 2H ), 3.45-3.36 (m, 2H), 2.97 (s, 1H), 2.21 (s, 3H), 2.13 (s, 3H), 1.89-1.76 (m, 2H), 1.76-1.68 (m, 5H), 1.37(s, 3H), 1.31(s, 3H).

Example 42 SZ-013061: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-9-(4-methyl -6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)-1,4,9-triazaspiro[5.5]undecane-2,5-di ketone

Step 1: (S)-9-(6-Bromo-4-methylpyridin-2-yl)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridine- 3-yl)ethyl)-1,4,9-triazaspiro[5.5]undecane-2,5-dione

The reaction flask was added with compound 013002A5 (600mg, 1.6mmol), 2-bromo-6-fluoro-4-methylpyridine (334mg, 1.76mmol), DIPEA (624mg, 4.8mmol) and isopropanol (20ml), and the temperature was raised to Reaction at 100°C for 12 hours. The reaction solution was added with water (50ml), extracted with EA (30ml*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography (EA/PE 50-100%) Purification gave 013061A1 (360 mg, 42%, white solid). LCMS: [M+H] ⁺ 542.14, 544.16.

Step 2: (S)-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-9-(4-methyl-6- ((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)-1,4,9-triazaspiro[5.5]undecane-2,5-dione

In a 20 mL microwave tube, add 013061A1 (360 mg, 0.66 mmol), 5-methyl-1H-pyrazol-3-amine (65 mg, 0.66 mmol), Pd ₂ (dba) ₃ (36 mg, 10%), XantPhos (190 mg, 0.33 mmol), Cs ₂ CO ₃ (643 mg, 1.98 mmol) and 1,4-dioxane (8 ml), argon replacement degassing for 10 minutes, and stirring reaction at 100° C. on a microwave reactor for 2 h. After the reaction, it was cooled to room temperature. The reaction solution was added with water (30ml) and extracted with EA (20ml*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The product was then subjected to reverse phase column chromatography with acetonitrile/0.1% formic acid water. Freeze-drying to obtain SZ-013061 (30 mg, 8%, white solid). LCMS: [M+H] ⁺ 559.32.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.64 (s, 1H), 8.71 (d, J=4.6 Hz, 1H), 8.65 (s, 1H), 8.55 (s, 1H), 8.40 (s, 1H), 7.98-7.91 (m, 3H), 6.36 (s, 1H), 6.02 (s, 1H), 5.78 (q, J = 7.3Hz, 1H), 4.08 (d, J = 17.0Hz, 1H), 4.01-3.90(m, 2H), 3.57(d, J=17.0Hz, 1H), 3.51-3.41(m, 2H), 2.20(s, 3H), 2.15(s, 3H), 2.10-2.00(m, 2H), 1.77-1.63 (m, 2H), 1.58 (d, J=7.1Hz, 3H).

Example 43 SZ-013062: (S)-1-ethyl-4-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-9- (4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-1,4,9-triazaspiro[5.5]undecane -5-one

Sodium cyanoborohydride (160 mg, 2.53 mmol) was added portionwise at 33 degrees Celsius to a solution of compound SZ-013034 (16 mg, 29.3 umol) and acetaldehyde/tetrahydrofuran solution (3 mL, 15 mmol, 5M) in methanol (3 mL), Then a drop of acetic acid (13 mg, 21.67 mmol) was added. The resulting reaction mixture was sealed with a sealed tube and heated to 69 degrees Celsius and stirring was continued for 16 hours. After cooling the resulting reaction mixture to room temperature, it was quenched with saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (10 mL*3). The organic phases are combined and dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. It was then purified using high-pressure preparative chromatography to obtain the white solid compound SZ-013062 (2.3 mg, 13.6%). LCMS: [M+H+] 574.26@2.986min. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.56 (d, J=4.0 Hz, 1H), 8.43 (d, J=2.0 Hz, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.93 ( dd, J ₁ = 8.0 Hz, J ₂ = 2.0 Hz, 1H), 7.63 (d, J = 4.0 Hz, 1H), 6.23 (br, 1H), 6.11 (br, 1H), 6.01 (q, J = 4.0 Hz, 1H), 4.26-4.19(m, 1H), 3.73-3.63(m, 1H), 3.49-3.43(m, 1H), 3.29-3.16(m, 3H), 3.03-2.93(m, 2H), 2.78-2.63(m, 2H), 2.31(s, 3H) 2.23(s, 3H), 2.13-2.03(m, 4H), 1.65(d, J=8.0Hz, 3H), 1.14(t, J=8.0 Hz, 3H).

Example 44 SZ-013063: (S)-2-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-8-(4-methyl -6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-1-one

Step 1: (S)-8-(6-Bromo-4-methylpyridin-2-yl)-2-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridine- 3-yl)ethyl)-2,8-diazaspiro[4.5]decane-1-one

The reaction flask was added compound 9386A3 (1.0 g, 3.0 mmol), 2-bromo-6-fluoro-4-methylpyridine (570 mg, 3.0 mmol), Cs ₂ CO ₃ (2.9 g, 9.0 mmol) and isopropanol ( 20ml), heated to 100 ℃ for 12 hours. The reaction solution was added with water (50ml), extracted with EA (30ml*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column chromatography (EA/PE 50-100%) Purification gave 013063A1 (500 mg, 32%, white solid). LCMS: [M+H] ⁺ 513.17, 515.13.

Step 2: (S)-2-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-8-(4-methyl-6- ((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-1-one

In a 20 mL microwave tube, add 013063A1 (500 mg, 1.0 mmol), 5-methyl-1H-pyrazol-3-amine (106 mg, 1.1 mmol), Pd ₂ (dba) ₃ (50 mg, 10%), XantPhos (290 mg, 0.5 mmol), Cs ₂ CO ₃ (1.0 g, 3.0 mmol) and 1,4-dioxane (8 ml), argon replacement degassing for 10 minutes, and stirring reaction at 100° C. on a microwave reactor for 2 h. After the reaction, it was cooled to room temperature. The reaction solution was added with water (30ml) and extracted with EA (20ml*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The product was then reverse-phase column chromatography with acetonitrile/0.1% formic acid water Freeze-dried to obtain SZ-013063 (70 mg, 13%, white solid). LCMS: [M+H] ⁺ 530.32.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.65 (s, 1H), 8.71 (d, J = 4.6 Hz, 1H), 8.55 (s, 1H), 8.38 (s, 1H), 7.96 (d, J = 4.2 Hz, 1H), 7.93 (d, J = 1.2 Hz, 2H), 6.34 (s, 1H), 6.06-5.96 (m, 2H), 5.33 (q, J = 7.0 Hz, 1H), 4.20- 4.08(m, 2H), 3.47-3.38(m, 1H), 3.10-2.93(m, 3H), 2.19(s, 3H), 2.14(s, 3H), 2.09-1.95(m, 2H), 1.79- 1.64(m, 2H), 1.57(d, J=7.3Hz, 3H), 1.49-1.31(m, 2H).

Effect Example 1 RET activity inhibition test

Test purpose: Staurosporine and BLU-667 were used as positive control compounds. Mobility shift assay using the method of test compound IC ₅₀ values in the RET kinase.

Test conditions:

Enzyme concentration: 2.5nM

ATPKm: 16uM

Pre-incubation: 10min

Reaction time: 60min

The initial concentration of the compound was 1 μM, 3-fold dilution, 10 concentrations, and double-well detection.

experiment method:

1. Compound preparation: Dissolve the compound powder in 100% DMSO to prepare a 10 mM stock solution.

2. Kinase reaction process

(1) Prepare 1×Kinase buffer.

(2) Preparation of compound concentration gradient: The test concentration of the compound is 1 μM, diluted in 384 plates to a 100-fold final concentration of 100% DMSO solution, then the compound is diluted 3-fold, 10 concentrations. Use a dispenser to transfer 250nL of the compound to a final concentration of 100 times.

(3) Prepare a 2.5-fold final concentration of kinase solution with 1×Kinase buffer.

(4) Add 10 μL of 2.5-fold final concentration kinase solution to the compound well and positive control well; add 10 μL of 1×Kinase buffer to the negative control well.

(5) Centrifuge at 1000 rpm for 30 seconds, shake and mix the reaction plate, and incubate at room temperature for 10 minutes.

(6) Use 1×Kinase buffer to prepare 5/3 times the final concentration of ATP and Kinase 2 mixed solution.

(7) Add 15 μL of a 5/3-fold final concentration of ATP and substrate mixed solution to start the reaction.

(8) Centrifuge the 384-well plate at 1000 rpm for 30 seconds, shake and mix, and incubate at room temperature for 60 minutes.

(9) Add 30 μL of termination detection solution to stop the kinase reaction, centrifuge at 1000 rpm for 30 seconds, and mix by shaking.

(10) Use CaliperEZReader to read the conversion rate.

3. Data analysis

Calculation formula: %Inhibition=(Conversion%_max-Conversion%_sample)/(Conversion%_max-Conversion%_min)×100%

Among them: Conversion%_sample is the sample conversion rate reading;

Conversion%_min: the average value of the negative control wells, which represents the conversion rate reading of the enzyme-free wells;

Conversion%_max: The mean value of the positive control well ratio, which represents the conversion reading of the well without compound inhibition.

Fitting the dose-effect curve: taking the log value of concentration as the X-axis and the percentage inhibition rate on the Y-axis, the analysis software GraphPad Prism 5 was used to fit the dose-effect curve to obtain the IC ₅₀ value of each compound for enzyme activity. The test results are shown in Table 1:

Table 1

Effect Example 2 Compound inhibition cell growth test

Test purpose: To detect the inhibitory effect of compounds on cell growth on MTC-TT and LC-2/AD cell lines.

experiment method:

1. Source of cell line and culture conditions

细胞系Cell line	特性characteristic	来源source	培养基Culture medium
LC-2/ADLC-2/AD	贴壁Adhere	CASCAS	F12K+10％FBSF12K+10%FBS
MTC-TTMTC-TT	贴壁Adhere	南京科柏Nanjing Coper	RPMI-1640+10％FBSRPMI-1640+10% FBS

2. Day 0: Inoculation of cells

(1) After cell digestion, prepare a cell suspension and calculate the cell density with an automatic cell counter.

(2) Dilute the cell suspension to the appropriate density according to the plating density

(3) Inoculate 150uL cells into a 96-well plate and add growth medium. Blank medium was used as background control (Min).

(4) 37°C, 5% CO ₂ culture overnight.

3. Day 1: Compound incubation

(1) Preparation of 200* compound mother liquor with DMSO

(2) Dilute the compound with growth medium to a final concentration of 21 times, that is, add 21uL 200* compound to 179uL growth medium.

(3) Add 7.5uL of the diluted compound to the cells and incubate at 37°C, 5% CO _{2 for} 72 hours.

4. Day 4: Testing

(1) Equilibrate the well plate to room temperature before testing.

(2) Add 40uL CellTiter-Glo reagent to each well.

(3) Shake the cell for 2 minutes with a horizontal shaker.

(4) Incubate at room temperature for 10 minutes to stabilize the fluorescent signal.

(5) EnVision multi-label microplate detector detects fluorescence signal.

5. Data analysis

(1) Use GraphPadPrism5 to analyze the data.

(2)%Inh=(Maxsignal-Compoundsignal)/(Maxsignal-Minsignal)×100.

(3) Maximum signal: only add the fluorescence reading of DMSO well.

(4) Minimum signal: the fluorescence reading of the medium-only well.

6. Test results:

Table 2

Although the specific embodiments of the present invention have been described above, those skilled in the art should understand that these are only examples, and various changes or modifications may be made to these embodiments without departing from the principle and essence of the present invention. modify. Therefore, the protection scope of the present invention is defined by the appended claims.

Claims

A heterocyclic compound represented by formula I-0, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof or a crystal form thereof, characterized by:

Wherein R 1 is hydrogen, fluorine, difluoromethyl, methoxy, cyclopropyl or C 1 ～C 4 alkyl;

Y 1 is N or CH;

Y 2 is N, CH, C(F), C(Cl) or C(CN);

R 9 is hydrogen, methyl or difluoromethyl;

middle
Is a single or double bond; when
When it is a single bond, X 1 is N, CH, C(OH), C(F) or C(OCH 3 ); when
When it is a double bond, X 1 is C;

s is 0 or 1; t is 0 or 1;

middle
Is a single or double bond; when
When it is a single bond, X 3 is N, X 2 is CH 2 or C (=O); when
When it is a double bond, X 3 is C and X 2 is N;

X 4 is

A 1 is N;

A 2 is N or CR 3; R 3 is hydrogen, cyano, amino, C 1 ~ C 4 alkyl, fluoro-substituted C 1 ~ C 4 alkyl, substituted C 3 ~ C 6 cycloalkyl, or fluoro C 3 ～C 6 cycloalkyl;

A 3 is C(═O), NR 4 , CH 2 , O or S; R 4 is hydrogen, C 1 ～C 4 alkyl, fluorine substituted C 1 ～C 4 alkyl, C 3 ～C 6 cycloalkane C 1 -C 4 alkyl group substituted by C 1 group, C 3 -C 6 cycloalkyl group, or C 3 -C 6 cycloalkyl group substituted by fluorine

A 4 is NR 5 , C(═O), C(═S) or CH 2 ; R 5 is hydrogen, C 1 ～C 4 alkyl, fluorine substituted C 1 ～C 4 alkyl, C 3 ～C 6 Cycloalkyl, or C 3 ～C 6 cycloalkyl substituted with fluorine;

n is 0 or 1;

A 5 is NR 10 , CH 2 , O or S; R 10 is hydrogen, C 1 ～C 4 alkyl, fluorine substituted C 1 ～C 4 alkyl, C 3 ～C 6 cycloalkyl substituted C 1 ～ C 4 alkyl, C 3 -C 6 cycloalkyl, or C 3 -C 6 cycloalkyl substituted with fluorine;

A 6 is C (=O) or CH 2 ;

A 7 is
Or CR 11 R 12 ; R 11 and R 12 are independently hydrogen or C 1 ˜C 4 alkyl, but R 11 and R 12 are not hydrogen at the same time;

X 6 is C (=O) or CHR 2 ;

R 2 is hydrogen or C 1 ～C 4 alkyl;

X 5 is N or CH;

R 6 is hydrogen, halogen, cyclopropyl, or, unsubstituted or halogen-substituted C 1 ～C 4 alkyl;

R 7 is hydrogen or halogen;

R 8 is hydrogen, halogen, cyclopropyl, or unsubstituted or halogen-substituted C 1 to C 4 alkyl.
The heterocyclic compound represented by formula I-0 according to claim 1, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof, characterized by R 1 is C 1 ～C 4 alkyl;

And/or, Y 1 is CH;

And/or, Y 2 is N or CH;

And/or, R 9 is hydrogen or methyl;

and / or,
middle
Is a single or double bond; when
When it is a single bond, X 1 is N or CH; when
When it is a double bond, X 1 is C;

And/or, s is 1; t is 1;

And/or, X 4 is

And/or when X 4 is
When, A 2 is CR 3 ; R 3 is hydrogen, amino or C 1 ～C 4 alkyl;

And/or when X 4 is
, A 3 is NR 4 , CH 2 , O or S; R 4 is hydrogen, C 1 ～C 4 alkyl, fluorine substituted C 1 ～C 4 alkyl, C 3 ～C 6 cycloalkyl substituted C 1 to C 4 alkyl, C 3 to C 6 cycloalkyl, or fluorine-substituted C 3 to C 6 cycloalkyl;

And/or when X 4 is
, A 4 is C (=O), C (=S) or CH 2 ;

And/or when X 4 is
, A 5 is NR 10 , CH 2 , O or S; R 10 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH 2 CF 3 , cyclopropane, -CH 2 -Cyclopropane;

And/or, n is 1;

And/or, X 6 is CHR 2 ;

And/or, R 2 is C 1 ˜C 4 alkyl;

And/or, X 5 is CH;

And/or R 6 is hydrogen;

And/or R 7 is halogen;

And/or, R 8 is hydrogen.
The heterocyclic compound represented by the formula I-0 according to claim 2, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof, characterized by Lies in that R 1 is methyl;

And/or Y 2 is N;

And/or R 9 is methyl;

and / or,
middle
Is a single key; when
When it is a single bond, X 1 is N or CH;

And/or when X 4 is
, A 2 is CR 3 ; R 3 is amino or C 1 ～C 4 alkyl;

And/or when X 4 is
, A 3 is NR 4 , CH 2 , O or S; R 4 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH 2 CF 3 , cyclopropane, -CH 2 -Cyclopropane;

And/or when X 4 is
, A 4 is C (=O) or CH 2 ;

And/or, R 2 is methyl;

And/or, R 7 is F.
The heterocyclic compound represented by formula I-0 according to claim 3, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof, characterized by Lies in that when X 4 is
, A 2 is CR 3 ; R 3 is amino, methyl or isopropyl;

And/or when X 4 is
, A 4 is C (=O).
The heterocyclic compound represented by formula I-0 according to claim 1, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof, characterized by The definition of the heterocyclic compound as shown in Formula I-0 is as follows:

plan 1:

R 1 is C 1 ～C 4 alkyl;

Y 1 is CH;

Y 2 is N or CH;

R 9 is hydrogen or methyl;

middle
Is a single or double bond; when
When it is a single bond, X 1 is N or CH; when
When it is a double bond, X 1 is C;

s is 0 or 1; t is 0 or 1;

middle
Is a single or double bond; when
When it is a single bond, X 3 is N, X 2 is CH 2 or C (=O); when
When it is a double bond, X 3 is C and X 2 is N;

X 4 is

A 1 is N;

A 2 is CR 3 ; R 3 is hydrogen, amino or C 1 ～C 4 alkyl;

A 3 is C(═O), NR 4 , CH 2 , O or S; R 4 is hydrogen, C 1 ～C 4 alkyl, fluorine substituted C 1 ～C 4 alkyl, C 3 ～C 6 cycloalkane C 1 -C 4 alkyl group substituted by C 1 group, C 3 -C 6 cycloalkyl group, or C 3 -C 6 cycloalkyl group substituted by fluorine

A 4 is C (=O), C (=S) or CH 2 ;

n is 0 or 1;

A 5 is NR 10 , CH 2 , O or S; R 10 is hydrogen, C 1 ～C 4 alkyl, fluorine substituted C 1 ～C 4 alkyl, C 3 ～C 6 cycloalkyl substituted C 1 ～ C 4 alkyl, C 3 -C 6 cycloalkyl, or C 3 -C 6 cycloalkyl substituted with fluorine;

A 6 is C (=O) or CH 2 ;

A 7 is
Or CR 11 R 12 ; R 11 and R 12 are independently hydrogen or C 1 ˜C 4 alkyl, but R 11 and R 12 are not hydrogen at the same time;

X 6 is C (=O) or CHR 2 ;

R 2 is hydrogen or C 1 ～C 4 alkyl;

X 5 is CH;

R 6 is hydrogen;

R 7 is halogen;

R 8 is hydrogen;

Scenario 2:

R 1 is C 1 ～C 4 alkyl;

Y 1 is CH;

Y 2 is N or CH;

R 9 is hydrogen or methyl;

middle
Is a single or double bond; when
When it is a single bond, X 1 is N or CH; when
When it is a double bond, X 1 is C;

s is 0 or 1; t is 0 or 1;

middle
Is a single or double bond; when
When it is a single bond, X 3 is N, X 2 is CH 2 or C (=O); when
When it is a double bond, X 3 is C and X 2 is N;

X 4 is

A 1 is N;

A 2 is CR 3 ; R 3 is amino or C 1 ～C 4 alkyl;

A 3 is NR 4 , CH 2 , O or S; R 4 is hydrogen, C 1 ～C 4 alkyl, fluorine substituted C 1 ～C 4 alkyl, C 3 ～C 6 cycloalkyl substituted C 1 ～ C 4 alkyl, C 3 -C 6 cycloalkyl, or C 3 -C 6 cycloalkyl substituted with fluorine;

A 4 is C (=O) or CH 2 ;

n is 0 or 1;

A 5 is NR 10 , CH 2 , O or S; R 10 is hydrogen, C 1 ～C 4 alkyl, fluorine substituted C 1 ～C 4 alkyl, C 3 ～C 6 cycloalkyl substituted C 1 ～ C 4 alkyl, C 3 -C 6 cycloalkyl, or C 3 -C 6 cycloalkyl substituted with fluorine;

A 6 is C (=O) or CH 2 ;

A 7 is
Or CR 11 R 12 ; R 11 and R 12 are independently hydrogen or C 1 ˜C 4 alkyl, but R 11 and R 12 are not hydrogen at the same time;

X 6 is C (=O) or CHR 2 ;

R 2 is hydrogen or C 1 ～C 4 alkyl;

X 5 is CH;

R 6 is hydrogen;

R 7 is halogen;

R 8 is hydrogen;

Option 3:

R 1 is methyl;

Y 1 is CH;

Y 2 is N or CH;

R 9 is hydrogen or methyl;

middle
Is a single or double bond; when
When it is a single bond, X 1 is N or CH; when
When it is a double bond, X 1 is C;

s is 0 or 1; t is 0 or 1;

middle
Is a single or double bond; when
When it is a single bond, X 3 is N, X 2 is CH 2 or C (=O); when
When it is a double bond, X 3 is C and X 2 is N;

X 4 is

A 1 is N;

A 2 is CR 3 ; R 3 is amino, methyl or isopropyl;

A 3 is NR 4 , CH 2 , O or S; R 4 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH 2 CF 3 , cyclopropane, -CH 2 -ring Propane

A 4 is C (=O) or CH 2 ;

n is 0 or 1;

A 5 is NR 10 , CH 2 , O or S; R 10 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH 2 CF 3 , cyclopropane, -CH 2 -ring Propane

A 6 is C (=O) or CH 2 ;

A 7 is
Or CR 11 R 12 ; R 11 and R 12 are independently hydrogen or methyl, but R 11 and R 12 are not hydrogen at the same time;

X 6 is C (=O) or CHR 2 ;

R 2 is hydrogen or methyl;

X 5 is CH;

R 6 is hydrogen;

R 7 is F;

R 8 is hydrogen;

Option 4:

R 1 is methyl;

Y 1 is CH;

Y 2 is N;

R 9 is methyl;

middle
Is a single key; when
When it is a single bond, X 1 is N or CH;

s is 1; t is 1;

middle
Is a single key; when
When it is a single bond, X 3 is N and X 2 is C (=O);

X 4 is

A 3 is NR 4 , CH 2 , O or S; R 4 is hydrogen, C 1 ～C 4 alkyl, fluorine substituted C 1 ～C 4 alkyl, C 3 ～C 6 cycloalkyl substituted C 1 ～ C 4 alkyl, C 3 -C 6 cycloalkyl, or C 3 -C 6 cycloalkyl substituted with fluorine;

A 4 is C (=O);

n is 1;

X 6 is CHR 2 ;

R 2 is C 1 ～C 4 alkyl;

X 5 is CH;

R 6 is hydrogen;

R 7 is halogen;

R 8 is hydrogen;

Option 5:

R 1 is hydrogen, fluorine, difluoromethyl, methoxy, cyclopropyl or C 1 ～C 4 alkyl;

Y 1 is N or CH;

Y 2 is N, CH, C(F), C(Cl) or C(CN);

R 9 is hydrogen, methyl or difluoromethyl;

middle
Is a single or double bond; when
When it is a single bond, X 1 is N, CH, C(OH), C(F) or C(OCH 3 ); when
When it is a double bond, X 1 is C;

s is 0 or 1; t is 0 or 1;

middle
Is a single or double bond; when
When it is a single bond, X 3 is N, X 2 is CH 2 or C (=O); when
When it is a double bond, X 3 is C and X 2 is N;

X 4 is

A 5 is NR 10 , CH 2 , O or S; R 10 is hydrogen, C 1 ～C 4 alkyl, fluorine substituted C 1 ～C 4 alkyl, C 3 ～C 6 cycloalkyl substituted C 1 ～ C 4 alkyl, C 3 -C 6 cycloalkyl, or C 3 -C 6 cycloalkyl substituted with fluorine;

A 6 is C (=O) or CH 2 ;

A 7 is
Or CR 11 R 12 ; R 11 and R 12 are independently hydrogen or C 1 ˜C 4 alkyl, but R 11 and R 12 are not hydrogen at the same time;

X 6 is C (=O) or CHR 2 ;

R 2 is hydrogen or C 1 ～C 4 alkyl;

X 5 is N or CH;

R 6 is hydrogen, halogen, cyclopropyl, or, unsubstituted or halogen-substituted C 1 ～C 4 alkyl;

R 7 is hydrogen or halogen;

R 8 is hydrogen, halogen, cyclopropyl, or unsubstituted or halogen-substituted C 1 to C 4 alkyl.
The heterocyclic compound represented by formula I-0 according to claim 1, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof, characterized by R 1 is hydrogen, fluorine, difluoromethyl, methoxy, cyclopropyl or C 1 ～C 4 alkyl;

Y 1 is N or CH;

Y 2 is N, CH, C(F), C(Cl) or C(CN);

R 9 is hydrogen, methyl or difluoromethyl;

middle
Is a single or double bond; when
When it is a single bond, X 1 is N, CH, C(OH), C(F) or C(OCH 3 ); when
When it is a double bond, X 1 is C;

s is 0 or 1; t is 0 or 1;

middle
Is a single or double bond; when
When it is a single bond, X 3 is N, X 2 is CH 2 or C (=O); when
When it is a double bond, X 3 is C and X 2 is N;

X 4 is
{Wherein, b with ends X 3 X 4} connector

A 1 is N;

A 2 is N or CR 3; R 3 is hydrogen, cyano, amino, C 1 ~ C 4 alkyl, fluoro-substituted C 1 ~ C 4 alkyl, substituted C 3 ~ C 6 cycloalkyl, or fluoro C 3 ～C 6 cycloalkyl;

A 3 is C(═O), NR 4 , CH 2 , O or S; R 4 is hydrogen, C 1 ～C 4 alkyl, fluorine substituted C 1 ～C 4 alkyl, C 3 ～C 6 cycloalkane C 1 -C 4 alkyl group substituted by C 1 group, C 3 -C 6 cycloalkyl group, or C 3 -C 6 cycloalkyl group substituted by fluorine

A 4 is NR 5 , C(═O) or CH 2 ; R 5 is hydrogen, C 1 -C 4 alkyl, fluorine-substituted C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or, Fluorine-substituted C 3 ～C 6 cycloalkyl;

n is 0 or 1;

X 6 is C (=O) or CHR 2 ;

R 2 is hydrogen or C 1 ～C 4 alkyl;

X 5 is N or CH;

R 6 is hydrogen, halogen, cyclopropyl, or, unsubstituted or halogen-substituted C 1 ～C 4 alkyl;

R 7 is hydrogen or halogen;

R 8 is hydrogen, halogen, cyclopropyl, or unsubstituted or halogen-substituted C 1 to C 4 alkyl.
The heterocyclic compound represented by formula I-0 according to claim 6, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof, characterized by The definition of the heterocyclic compound as shown in Formula I-0 is as follows:

plan 1:

Wherein R 1 is hydrogen, fluorine, difluoromethyl, methoxy, cyclopropyl or C 1 ～C 4 alkyl;

Y 1 is N or CH;

Y 2 is N, CH, C(F), C(Cl) or C(CN);

R 9 is hydrogen, methyl or difluoromethyl;

middle
Is a single or double bond; when
When it is a single bond, X 1 is N, CH, C(OH), C(F) or C(OCH 3 ); when
When it is a double bond, X 1 is C;

s is 0 or 1; t is 0 or 1;

middle
Is a single or double bond; when
When it is a single bond, X 3 is N, X 2 is CH 2 or C (=O); when
When it is a double bond, X 3 is C and X 2 is N;

X 4 is

A 1 is N;

A 2 is N or CR 3; R 3 is hydrogen, cyano, amino, C 1 ~ C 4 alkyl, fluoro-substituted C 1 ~ C 4 alkyl, substituted C 3 ~ C 6 cycloalkyl, or fluoro C 3 ～C 6 cycloalkyl;

A 3 is C(═O), NR 4 , CH 2 , O or S; R 4 is hydrogen, C 1 ～C 4 alkyl, fluorine substituted C 1 ～C 4 alkyl, C 3 ～C 6 cycloalkane C 1 -C 4 alkyl group substituted by C 1 group, C 3 -C 6 cycloalkyl group, or C 3 -C 6 cycloalkyl group substituted by fluorine

A 4 is NR 5 , C(═O) or CH 2 ; R 5 is hydrogen, C 1 -C 4 alkyl, fluorine-substituted C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or, Fluorine-substituted C 3 ～C 6 cycloalkyl;

n is 0 or 1;

X 6 is C (=O) or CHR 2 ;

R 2 is hydrogen or C 1 ～C 4 alkyl;

X 5 is N or CH;

R 6 is hydrogen, halogen, cyclopropyl, or, unsubstituted or halogen-substituted C 1 ～C 4 alkyl;

R 7 is hydrogen or halogen;

R 8 is hydrogen or halogen;

Scenario 2:

R 1 is C 1 ～C 4 alkyl;

Y 1 is CH; Y 2 is N; R 9 is methyl or difluoromethyl;

middle
Is a single or double bond; when
When it is a single bond, X 1 is N or CH; when
When it is a double bond, X 1 is C;

s is 0 or 1; t is 0 or 1;

middle
Is a single or double bond; when
When it is a single bond, X 3 is N, X 2 is CH 2 or C (=O); when
When it is a double bond, X 3 is C and X 2 is N;

X 4 is

A 1 is N;

A 2 is CR 3 ; R 3 is amino or C 1 ～C 4 alkyl;

A 3 is NR 4 , CH 2 , O or S; R 4 is hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 alkyl substituted with fluorine;

A 4 is C (=O) or CH 2 ;

n is 0 or 1;

X 6 is C (=O) or CHR 2 ;

R 2 is hydrogen or C 1 ～C 4 alkyl;

X 5 is CH;

R 6 is hydrogen; R 7 is halogen; R 8 is hydrogen;

Option 3:

R 1 is C 1 ～C 4 alkyl;

Y 1 is CH; Y 2 is N; R 9 is methyl or difluoromethyl;

middle
Is a single or double bond; when
When it is a single bond, X 1 is N or CH; when
When it is a double bond, X 1 is C;

s is 0 or 1; t is 0 or 1;

middle
Is a single or double bond; when
When it is a single bond, X 3 is N, X 2 is CH 2 or C (=O); when
When it is a double bond, X 3 is C and X 2 is N;

X 4 is

A 1 is N;

A 2 is CR 3 ; R 3 is amino or C 1 ～C 4 alkyl;

A 3 is NR 4 , CH 2 , O or S; R 4 is hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 alkyl substituted with fluorine;

When A 3 is NR 4 , A 4 is C (=O) or CH 2 ; when A 3 is CH 2 , O or S, A 4 is CH 2 ;

n is 0 or 1;

X 6 is C (=O) or CHR 2 ;

R 2 is hydrogen or C 1 ～C 4 alkyl;

X 5 is CH;

R 6 is hydrogen; R 7 is halogen; R 8 is hydrogen;

Option 4:

R 1 is C 1 ～C 4 alkyl;

Y 1 is CH; Y 2 is N; R 9 is methyl or difluoromethyl;

middle
Is a single or double bond; when
When it is a single bond, X 1 is N or CH; when
When it is a double bond, X 1 is C;

s is 1; t is 1;

middle
Is a single bond; X 3 is N, X 2 is CH 2 or C (=O);

X 4 is

A 3 is NR 4 , CH 2 , O or S; R 4 is hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 alkyl substituted with fluorine;

A 4 is C (=O) or CH 2 ;

n is 1;

X 6 is CHR 2 ;

R 2 is hydrogen or C 1 ～C 4 alkyl;

X 5 is CH;

R 6 is hydrogen; R 7 is halogen; R 8 is hydrogen;

Option 5:

R 1 is C 1 ～C 4 alkyl;

Y 1 is CH; Y 2 is N; R 9 is methyl or difluoromethyl;

middle
Is a single or double bond; when
When it is a single bond, X 1 is N or CH; when
When it is a double bond, X 1 is C;

s is 1; t is 1;

middle
Is a single bond; X 3 is N, X 2 is CH 2 or C (=O);

X 4 is

A 3 is NR 4 , CH 2 , O or S; R 4 is hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 alkyl substituted with fluorine;

When A 3 is NR 4 , A 4 is C (=O) or CH 2 ; when A 3 is CH 2 , O or S, A 4 is CH 2 ;

n is 1;

X 6 is CHR 2 ;

R 2 is hydrogen or C 1 ～C 4 alkyl;

X 5 is CH;

R 6 is hydrogen; R 7 is halogen; R 8 is hydrogen;

Option 6:

R 1 is C 1 ～C 4 alkyl;

Y 1 is CH; Y 2 is N; R 9 is methyl or difluoromethyl;

middle
Is a single or double bond; when
When it is a single bond, X 1 is N or CH; when
When it is a double bond, X 1 is C;

s is 1; t is 1;

middle
Is a single bond; X 3 is N, X 2 is CH 2 or C (=O);

X 4 is

When X 2 is CH 2 , A 3 is NR 4 and A 4 is C (=O);

When X 2 is C (=O), A 3 is NR 4 , A 4 is C (= O) or CH 2 , or, when A 3 is CH 2 , O or S, A 4 is CH 2 ;

n is 1;

X 6 is CHR 2 ;

R 2 is hydrogen or C 1 ～C 4 alkyl;

X 5 is CH;

R 6 is hydrogen; R 7 is halogen; R 8 is hydrogen.
The heterocyclic compound represented by Formula I-0, its pharmaceutically acceptable salt, its solvate, or its pharmaceutically acceptable salt solvate according to at least one of claims 1-7 Its crystalline form is characterized in that, when R 1 is C 1 -C 4 alkyl, the C 1 -C 4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, Sec-butyl, iso-butyl or tert-butyl;

And/or when
When it is a double bond,
for

And/or when
When it is a single bond and X 1 is CH, C(OH), C(F) or C(OCH 3 ),
for

And/or, when R 3 is a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, Isobutyl or tert-butyl;

And/or, when R 3 is a C 1 ˜C 4 alkyl substituted with fluorine, the number of the fluorine is one or more;

And/or when R 3 is a fluorine-substituted C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary Butyl, isobutyl or tert-butyl;

And/or, when R 3 is C 3 -C 6 cycloalkyl, the C 3 -C 6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

And/or, when R 3 is a C 3 -C 6 cycloalkyl substituted with fluorine, the number of the fluorine is one or more;

And/or, when R 3 is fluorine-substituted C 3 -C 6 cycloalkyl, the C 3 -C 6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

And/or, when R 4 is C 1 ˜C 4 alkyl, the C 1 ˜C 4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, Isobutyl or tert-butyl;

And/or, when R 4 is C 1 ˜C 4 alkyl substituted with fluorine, the number of said fluorine is one or more;

And/or, when R 4 is fluorine-substituted C 1 -C 4 alkyl, the C 1 -C 4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary Butyl, isobutyl or tert-butyl;

And / or, when R 4 is a C 3 ~ C 6 cycloalkyl substituted with C 1 ~ C 4 alkyl, said C 3 ~ C 6 cycloalkyl group number is 1;

And / or, when R 4 is a C 3 ~ C 6 cycloalkyl substituted with C 1 ~ C 4 alkyl, said C 3 ~ C 6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl Or cyclohexyl;

And/or, when R 4 is C 1 -C 4 alkyl substituted with C 3 -C 6 cycloalkyl, the C 1 -C 4 alkyl is methyl, ethyl, n-propyl, isopropyl Group, n-butyl, sec-butyl, isobutyl or tert-butyl;

And/or, when R 4 is C 3 -C 6 cycloalkyl, the C 3 -C 6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

And/or, when R 4 is a C 3 -C 6 cycloalkyl substituted with fluorine, the number of the fluorine is one or more;

And/or, when R 4 is a C 3 -C 6 cycloalkyl substituted with fluorine, the C 3 -C 6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

And/or, when R 5 is C 1 -C 4 alkyl, the C 1 -C 4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, Isobutyl or tert-butyl;

And/or, when R 5 is a C 1 ˜C 4 alkyl substituted with fluorine, the number of the fluorine is one or more;

And/or, when R 5 is fluorine-substituted C 1 -C 4 alkyl, the C 1 -C 4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary Butyl, isobutyl or tert-butyl;

And/or, when R 5 is C 3 -C 6 cycloalkyl, the C 3 -C 6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

And/or, when R 5 is fluorine-substituted C 3 ˜C 6 cycloalkyl, the number of the fluorine is one or more;

And/or, when R 5 is fluorine-substituted C 3 ˜C 6 cycloalkyl, the C 3 ˜C 6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

And/or, when R 10 is C 1 -C 4 alkyl, the C 1 -C 4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, Isobutyl or tert-butyl;

And/or, when R 10 is a C 1 ˜C 4 alkyl substituted with fluorine, the number of the fluorine is one or more;

And/or when R 10 is a fluorine-substituted C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary Butyl, isobutyl or tert-butyl;

And / or, when R 10 is C 3 ~ C 6 cycloalkyl substituted with C 1 ~ C 4 alkyl, said C 3 ~ C 6 cycloalkyl group number is 1;

And / or, when R 10 is C 3 ~ C 6 cycloalkyl substituted with C 1 ~ C 4 alkyl, said C 3 ~ C 6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl Or cyclohexyl;

And/or, when R 10 is a C 1 -C 4 alkyl substituted with a C 3 -C 6 cycloalkyl, the C 1 -C 4 alkyl is methyl, ethyl, n-propyl, isopropyl Group, n-butyl, sec-butyl, isobutyl or tert-butyl;

And/or, when R 10 is C 3 -C 6 cycloalkyl, the C 3 -C 6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

And/or, when R 10 is a C 3 -C 6 cycloalkyl substituted with fluorine, the number of the fluorine is one or more;

And/or, when R 10 is a fluorine-substituted C 3 -C 6 cycloalkyl, the C 3 -C 6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

And/or, when R 11 is C 1 -C 4 alkyl, the C 1 -C 4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, Isobutyl or tert-butyl;

And/or, when R 12 is C 1 ˜C 4 alkyl, the C 1 ˜C 4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, Isobutyl or tert-butyl;

And/or, when X 6 is CHR 2 ,
for

And/or, when R 2 is C 1 -C 4 alkyl, the C 1 -C 4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, Isobutyl or tert-butyl;

And/or, when R 6 is halogen, the halogen is fluorine, chlorine, bromine or iodine;

And/or, when R 6 is halogen substituted C 1 ˜C 4 alkyl, the number of the “halogen” is one or more, and when there are multiple “halogens”, the “halogen” Same or different;

And/or, when R 6 is halogen substituted C 1 ˜C 4 alkyl, the “halogen” is independently fluorine, chlorine, bromine or iodine;

And/or, when R 6 is unsubstituted or halogen-substituted C 1 -C 4 alkyl, the C 1 -C 4 alkyl is independently methyl, ethyl, n-propyl, isopropyl, N-butyl, sec-butyl, isobutyl or tert-butyl;

And/or, when R 7 is halogen, the halogen is fluorine, chlorine, bromine or iodine;

And/or, when R 8 is halogen, the halogen is fluorine, chlorine, bromine or iodine;

And/or, when R 8 is halogen substituted C 1 ˜C 4 alkyl, the number of the “halogen” is one or more, and when there are multiple “halogens”, the “halogen” Same or different;

And/or, when R 8 is halogen substituted C 1 ˜C 4 alkyl, the “halogen” is independently fluorine, chlorine, bromine or iodine;

And/or, when R 8 is unsubstituted or halogen-substituted C 1 -C 4 alkyl, the C 1 -C 4 alkyl is independently methyl, ethyl, n-propyl, isopropyl, N-butyl, sec-butyl, isobutyl or tert-butyl;

And/or, except for the part whose stereo configuration has been determined, the rest of the heterocyclic compound I-0 is a mixture of various stereo configurations;

And/or, all atoms in the heterocyclic compound I-0 are atoms with abundance of natural isotopes.
The heterocyclic compound represented by formula I-0 according to claim 8, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof, characterized by That is, when R 1 is C 1 -C 4 alkyl, the C 1 -C 4 alkyl is methyl;

And/or, when R 3 is C 1 -C 4 alkyl, the C 1 -C 4 alkyl is methyl or isopropyl;

And/or, when R 3 is a C 1 ˜C 4 alkyl substituted with fluorine, the number of the fluorine is 1, 2, or 3;

And/or, when R 3 is fluorine-substituted C 1 -C 4 alkyl, the C 1 -C 4 alkyl is methyl;

And/or, when R 3 is a C 3 ˜C 6 cycloalkyl substituted with fluorine, the number of the fluorine is 1, 2, or 3;

And/or, when R 4 is C 1 -C 4 alkyl, the C 1 -C 4 alkyl is methyl, ethyl, n-propyl or n-butyl;

And/or, when R 4 is a C 1 ˜C 4 alkyl substituted with fluorine, the number of the fluorine is 1, 2, or 3;

And / or, when R 4 is a C 3 ~ C 6 cycloalkyl substituted with C 1 ~ C 4 alkyl, said C 3 ~ C 6 cycloalkyl substituted with C 1 ~ C 4 alkyl is cyclopropylmethyl Base methyl

And/or, when R 4 is C 3 -C 6 cycloalkyl, the C 3 -C 6 cycloalkyl is cyclopropyl;

And/or, when R 4 is fluorine-substituted C 3 ˜C 6 cycloalkyl, the number of the fluorine is 1, 2, or 3;

And/or, when R 5 is C 1 ˜C 4 alkyl, the C 1 ˜C 4 alkyl is methyl;

And/or, when R 5 is C 1 ˜C 4 alkyl substituted with fluorine, the number of the fluorine is 1, 2, or 3;

And/or, when R 5 is a C 3 ˜C 6 cycloalkyl substituted with fluorine, the number of the fluorine is 1, 2, or 3;

And/or, when R 10 is C 1 -C 4 alkyl, the C 1 -C 4 alkyl is C 1 -C 4 alkyl is methyl, ethyl, n-propyl or n-butyl;

And/or, when R 10 is a fluorine-substituted C 1 -C 4 alkyl group, the number of the fluorine is 1, 2, or 3;

And / or, when R 10 is C 3 ~ C 6 cycloalkyl substituted with C 1 ~ C 4 alkyl, said C 3 ~ C 6 cycloalkyl substituted with C 1 ~ C 4 alkyl is cyclopropylmethyl Base methyl

And/or, when R 10 is C 3 -C 6 cycloalkyl, the C 3 -C 6 cycloalkyl is cyclopropyl;

And/or, when R 10 is a C 3 to C 6 cycloalkyl substituted with fluorine, the number of the fluorine is 1, 2, or 3;

And/or, when R 11 is C 1 ˜C 4 alkyl, the C 1 ˜C 4 alkyl is methyl, ethyl, n-propyl or n-butyl;

And/or, when R 12 is C 1 -C 4 alkyl, the C 1 -C 4 alkyl is methyl, ethyl, n-propyl, or n-butyl; and/or, when X 6 is CHR 2 ,
When it is a double bond,
for

One or more of

And/or when X 6 is CHR 2 ,
When it is a single bond and X 1 is CH, C(OH), C(F) or C(OCH 3 ),
for

One or more of

And/or when X 6 is CHR 2 ,
When it is a single bond and X 1 is N,
for

And/or, when R 2 is C 1 ˜C 4 alkyl, the C 1 ˜C 4 alkyl is methyl;

And/or, when R 6 is halogen, the halogen is fluorine;

And/or, when R 6 is halogen-substituted C 1 ˜C 4 alkyl, the number of the “halogen” is 1, 2, or 3;

And/or, when R 6 is halogen substituted C 1 ˜C 4 alkyl, the “halogen” is independently fluorine;

And/or, when R 6 is unsubstituted or halogen-substituted C 1 ˜C 4 alkyl, the C 1 ˜C 4 alkyl is independently methyl;

And/or, when R 7 is halogen, the halogen is fluorine;

And/or, when R 8 is halogen, the halogen is fluorine;

And/or, when R 8 is halogen substituted C 1 ˜C 4 alkyl, the number of the “halogen” is 1, 2, or 3;

And/or, when R 8 is halogen substituted C 1 ˜C 4 alkyl, the “halogen” is independently fluorine;

And/or, when R 8 is an unsubstituted or halogen-substituted C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is independently a methyl group.
The heterocyclic compound represented by formula I-0 according to claim 9, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof, characterized by That is, when R 3 is a fluorine-substituted C 1 -C 4 alkyl group, the fluorine-substituted C 1 -C 4 alkyl group is trifluoromethyl;

And/or, when R 4 is a fluorine-substituted C 1 -C 4 alkyl, the fluorine-substituted C 1 -C 4 alkyl is 2,2,2-trifluoroethyl or 2,2-di Fluoroethyl

And/or, when R 5 is fluorine-substituted C 1 -C 4 alkyl, the fluorine-substituted C 1 -C 4 alkyl is trifluoromethyl;

And/or, when R 10 is a fluorine-substituted C 1 -C 4 alkyl group, the fluorine-substituted C 1 -C 4 alkyl group is 2,2,2-trifluoroethyl or 2,2-difluoro Fluoroethyl

And/or, when R 6 is halogen-substituted C 1 ˜C 4 alkyl, the number of the “halogen” is 1, 2, or 3;

And/or, when R 6 is halogen-substituted C 1 ˜C 4 alkyl, the halogen-substituted C 1 ˜C 4 alkyl is difluoromethyl;

And/or, when R 8 is halogen-substituted C 1 -C 4 alkyl, the halogen-substituted C 1 -C 4 alkyl is difluoromethyl.
The heterocyclic compound represented by formula I-0 according to claim 1, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof, characterized by Lies in

R 1 is hydrogen, fluorine, difluoromethyl, methoxy, cyclopropyl or C 1 ～C 4 alkyl;

Y 1 is N or CH;

Y 2 is N, CH, C(F), C(Cl) or C(CN);

middle
Is a single or double bond; when
When it is a single bond, X 1 is N, CH, C(OH), C(F) or C(OCH 3 ); when
When it is a double bond, X 1 is C;

middle
Is a single or double bond; when
When it is a single bond, X 3 is N, X 2 is CH 2 or C (=O); when
When it is a double bond, X 3 is C and X 2 is N;

X 4 is

A 1 is N;

A 2 is N or CR 3; R 3 is hydrogen, cyano, amino, C 1 ~ C 4 alkyl, fluoro-substituted C 1 ~ C 4 alkyl, substituted C 3 ~ C 6 cycloalkyl, or fluoro C 3 ～C 6 cycloalkyl;

A 3 is C(═O), NR 4 , CH 2 , O or S; R 4 is hydrogen, C 1 ～C 4 alkyl, fluorine substituted C 1 ～C 4 alkyl, C 3 ～C 6 cycloalkane C 3 ～C 6 cycloalkyl substituted by fluoro, or

A 4 is NR 5 , C(═O) or CH 2 ; R 5 is hydrogen, C 1 -C 4 alkyl, fluorine-substituted C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or, Fluorine-substituted C 3 ～C 6 cycloalkyl;

n is 0 or 1;

R 2 is hydrogen or C 1 ～C 4 alkyl;

X 5 is N or CH;

R 6 is hydrogen, halogen, cyclopropyl, or, unsubstituted or halogen-substituted C 1 ～C 4 alkyl;

R 7 is hydrogen or halogen;

R 8 is hydrogen, halogen, cyclopropyl, or, unsubstituted or halogen-substituted C 1 ～C 4 alkyl;

R 9 is hydrogen, methyl or difluoromethyl.
The heterocyclic compound represented by formula I-0 according to claim 11, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof, characterized by Wherein, when R 1 is C 1 -C 4 alkyl, the C 1 -C 4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl Base or tert-butyl;

And/or, when R 3 is a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, Isobutyl or tert-butyl;

And/or when R 3 is a fluorine-substituted C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary Butyl, isobutyl or tert-butyl;

And/or, when R 3 is a C 1 ˜C 4 alkyl substituted with fluorine, the number of the fluorine is one or more;

And/or, when R 3 is C 3 -C 6 cycloalkyl, the C 3 -C 6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

And/or, when R 3 is fluorine-substituted C 3 -C 6 cycloalkyl, the C 3 -C 6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

And/or, when R 3 is a C 3 -C 6 cycloalkyl substituted with fluorine, the number of the fluorine is one or more;

And/or, when R 4 is C 1 ˜C 4 alkyl, the C 1 ˜C 4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, Isobutyl or tert-butyl;

And/or, when R 4 is fluorine-substituted C 1 -C 4 alkyl, the C 1 -C 4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary Butyl, isobutyl or tert-butyl;

And/or, when R 4 is C 1 ˜C 4 alkyl substituted with fluorine, the number of said fluorine is one or more;

And/or, when R 4 is C 3 -C 6 cycloalkyl, the C 3 -C 6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

And/or, when R 4 is a C 3 -C 6 cycloalkyl substituted with fluorine, the C 3 -C 6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

And/or, when R 4 is a C 3 -C 6 cycloalkyl substituted with fluorine, the number of the fluorine is one or more;

And/or, when R 5 is C 1 -C 4 alkyl, the C 1 -C 4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, Isobutyl or tert-butyl;

And/or, when R 5 is fluorine-substituted C 1 -C 4 alkyl, the C 1 -C 4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary Butyl, isobutyl or tert-butyl;

And/or, when R 5 is a C 1 ˜C 4 alkyl substituted with fluorine, the number of the fluorine is one or more;

And/or, when R 5 is C 3 -C 6 cycloalkyl, the C 3 -C 6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

And/or, when R 5 is fluorine-substituted C 3 ˜C 6 cycloalkyl, the C 3 ˜C 6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

And/or, when R 5 is fluorine-substituted C 3 ˜C 6 cycloalkyl, the number of the fluorine is one or more;

And/or, when R 2 is C 1 -C 4 alkyl, the C 1 -C 4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, Isobutyl or tert-butyl;

And/or, when R 6 is halogen, the halogen is fluorine, chlorine, bromine or iodine;

And/or, when R 6 is unsubstituted or halogen-substituted C 1 -C 4 alkyl, the C 1 -C 4 alkyl is independently methyl, ethyl, n-propyl, isopropyl, N-butyl, sec-butyl, isobutyl or tert-butyl;

And/or, when R 6 is halogen substituted C 1 ˜C 4 alkyl, the number of the “halogen” is one or more, and when there are multiple “halogens”, the “halogen” Same or different;

And/or, when R 6 is halogen substituted C 1 ˜C 4 alkyl, the “halogen” is independently fluorine, chlorine, bromine or iodine;

And/or, when R 7 is halogen, the halogen is fluorine, chlorine, bromine or iodine;

And/or, when R 8 is halogen, the halogen is fluorine, chlorine, bromine or iodine;

And/or, when R 8 is unsubstituted or halogen-substituted C 1 -C 4 alkyl, the C 1 -C 4 alkyl is independently methyl, ethyl, n-propyl, isopropyl, N-butyl, sec-butyl, isobutyl or tert-butyl;

And/or, when R 8 is halogen substituted C 1 ˜C 4 alkyl, the number of the “halogen” is one or more, and when there are multiple “halogens”, the “halogen” Same or different;

And/or, when R 8 is halogen substituted C 1 ˜C 4 alkyl, the “halogen” is independently fluorine, chlorine, bromine or iodine;

and / or,
for

And/or when
middle
Is a single bond, when X 1 is CH, C(OH), C(F) or C(OCH 3 );
for

And/or when "
middle
Is a double bond, when X 1 is C;
for
The heterocyclic compound represented by formula I-0 according to claim 12, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof, characterized by Lies in that when X 4 is
Time,
for

And/or when X 4 is
Time,
for

And/or, when R 6 is halogen-substituted C 1 ˜C 4 alkyl, the halogen-substituted C 1 ˜C 4 alkyl is difluoromethyl;

And/or, when R 8 is halogen-substituted C 1 -C 4 alkyl, the halogen-substituted C 1 -C 4 alkyl is difluoromethyl.
The heterocyclic compound represented by formula I-0 according to claim 11, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof, characterized by R 1 is C 1 ～C 4 alkyl;

Y 1 is CH;

Y 2 is N;

middle
Is a single or double bond; when
When it is a single bond, X 1 is N or CH; when
When it is a double bond, X 1 is C;

middle
Is a single key; when
When it is a single bond, X 3 is N and X 2 is C (=O);

X 4 is

A 1 is N;

A 2 is CR 3 ; R 3 is amino or C 1 ～C 4 alkyl;

A 3 is NR 4 , CH 2 , O or S; R 4 is hydrogen or C 1 ～C 4 alkyl;

A 4 is C (=O) or CH 2 ;

n is 0;

R 2 is C 1 ～C 4 alkyl;

X 5 is N or CH;

R 6 is hydrogen;

R 7 is halogen;

R 8 is hydrogen;

R 9 is methyl.
The heterocyclic compound represented by formula I-0 according to claim 1, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof, characterized by The said heterocyclic compound I-0 is any of the following compounds:
The heterocyclic compound represented by formula I-0 according to claim 1, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof, characterized by The said heterocyclic compound I is any of the following compounds:
A solvate of a heterocyclic compound represented by formula I-0, a pharmaceutically acceptable salt thereof, a solvate thereof, a pharmaceutically acceptable salt thereof according to at least one of claims 1-16 The use of substances or their crystal forms in the preparation of RET inhibitors or drugs;

The drugs can be used to prevent and/or treat diseases mediated by abnormal expression of RET;

The "diseases mediated by abnormal expression of RET" such as cancer, but also for example papillary thyroid carcinoma, medullary thyroid carcinoma, pheochromocytoma, pancreatic ductal adenocarcinoma, multiple endocrine tumors (also for example MEN2A or MEN2B), Breast cancer (also for example metastatic breast cancer), testicular cancer, small cell lung cancer, non-small cell lung cancer, chronic myelomonocytic leukemia, colon cancer, rectal cancer, ovarian cancer or salivary gland cancer.
A solvate of a heterocyclic compound represented by formula I-0, a pharmaceutically acceptable salt thereof, a solvate thereof, a pharmaceutically acceptable salt thereof according to at least one of claims 1-16 Application of the substance or its crystal form in the preparation of a medicament, which is used to prevent and/or treat cancer;

Such cancers as papillary thyroid carcinoma, medullary thyroid carcinoma, pheochromocytoma, pancreatic ductal adenocarcinoma, multiple endocrine tumors (also for example MEN2A or MEN2B), breast cancer (also for example metastatic breast cancer), testicular cancer , Small cell lung cancer, non-small cell lung cancer, chronic bone marrow mononuclear leukemia, colon cancer, rectal cancer, ovarian cancer or salivary gland cancer.
A method for inhibiting RET, which comprises administering to a patient a therapeutically effective amount of the heterocyclic compound represented by formula I-0 according to at least one of claims 1 to 16, a pharmaceutically acceptable salt thereof, Solvates, solvates of pharmaceutically acceptable salts thereof, or crystalline forms thereof.
A method for treating or preventing a RET-mediated disease, which comprises administering to a patient a therapeutically effective amount of the heterocyclic compound represented by Formula I-0 according to at least one of claims 1 to 16, and a pharmaceutical An acceptable salt, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystal form thereof;

The "diseases mediated by abnormal expression of RET" such as cancer, but also for example papillary thyroid carcinoma, medullary thyroid carcinoma, pheochromocytoma, pancreatic ductal adenocarcinoma, multiple endocrine tumors (also for example MEN2A or MEN2B), Breast cancer (also for example metastatic breast cancer), testicular cancer, small cell lung cancer, non-small cell lung cancer, chronic bone marrow mononuclear leukemia, colon cancer, rectal cancer, ovarian cancer or salivary gland cancer.
A method for treating or preventing cancer, which comprises administering to a patient a therapeutically effective amount of the heterocyclic compound represented by formula I-0 according to at least one of claims 1 to 16, and a pharmaceutically acceptable salt thereof , Solvates thereof, solvates of pharmaceutically acceptable salts or crystalline forms thereof;

Such cancers as papillary thyroid carcinoma, medullary thyroid carcinoma, pheochromocytoma, pancreatic ductal adenocarcinoma, multiple endocrine tumors (also for example MEN2A or MEN2B), breast cancer (also for example metastatic breast cancer), testicular cancer , Small cell lung cancer, non-small cell lung cancer, chronic bone marrow mononuclear leukemia, colon cancer, rectal cancer, ovarian cancer or salivary gland cancer.
A pharmaceutical composition comprising the heterocyclic compound represented by Formula I-0, its pharmaceutically acceptable salt, its solvate, and its pharmaceutically acceptable according to at least one of claims 1-16 Accepted salt solvates or their crystal forms, and pharmaceutical excipients.