CN111285875B

CN111285875B - Heterocyclic compound, application thereof and pharmaceutical composition containing same

Info

Publication number: CN111285875B
Application number: CN201911238227.9A
Authority: CN
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: Suzhou Sinoway Pharmaceutical Technology Co ltd
Current assignee: Suzhou Sinoway Pharmaceutical Technology Co ltd
Priority date: 2018-12-06
Filing date: 2019-12-06
Publication date: 2023-02-03
Anticipated expiration: 2039-12-06
Also published as: CN111285875A; WO2020114474A1

Abstract

The invention discloses a heterocyclic compound, application thereof and a pharmaceutical composition containing the same. The structure of the compound is shown as a formula I-0, and the compound has a good effect of inhibiting RET kinase.

Description

Heterocyclic compound, application thereof and pharmaceutical composition containing same

Technical Field

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

Background

The RET gene was found in mouse NTH3T3 cells in transformation culture by Takahashi et al (Takahashi M, ritz J, cooper GM. Activation of a novel human transformation gene, RET, by DNA rearrargement. Cell,1985,42 (2): 581-588), and was named RET gene. The RET gene is a protooncogene (10q11.2) located on the long arm of chromosome 10, and the encoded RET protein is a tyrosine kinase receptor, consists of three parts, namely a cysteine-rich cadherin-like extracellular region, a transmembrane region and an intracellular region with tyrosine kinase activity, and has 37 percent of amino acids identical to an ALK kinase region. RET proteins stimulate receptor dimerization through ligand binding to the receptor, and intracellular domain autophosphorylation and intracellular substrate phosphorylation activate downstream signals, playing an important role in the processes of proliferation, migration and differentiation of cells.

RET is involved in renal development and development of the gastrointestinal nervous system under normal physiological conditions, however, mutation of the RET gene results in abnormal activation of ligand-independent, constitutive RET kinases, leading to tumorigenesis. There are two major mechanisms for activation of RET kinase: RET gene point mutation; RET gene rearrangement. Missense mutations in RET may occur in extracellular Cys residues (e.g., C620R, C634R/W), causing aberrant kinase activation. Mutations may also occur in the intracellular kinase active domain (e.g., V804L/M, M918T), which would promote ligand-independent RET kinase activation (Romei C, ciampi R, elisei R.A. complex overview of the roll of the RET proto-oncogene in tyrosine kinase. Nat Rev Endocrinol 2016 12. Point mutations of RET in Medullary Thyroid Carcinoma (MTC) are very common, occurring in approximately 50% of sporadic MTC and almost all familial MTC. RET gene is recombined in a mode of self-breaking and jointing with other genes to form a new fusion gene, so that the activation of RET tyrosine kinase escapes the regulation and control of ligand and is further autophosphorylated, thereby enhancing the signal transduction function, promoting the activation of kinase and initiating the generation of tumor. RET fusions are present in 10-20% of Papillary Thyroid Cancers (PTCs), 1-2% of non-small cell lung cancers (NSCLCs) and many other cancers, such as colon and breast cancers. The above results show that: dysregulation of the RET signaling pathway is an important driver of many neoplastic diseases.

No specific inhibitors against RET are currently on the market, but several multi-targeted tyrosine kinase inhibitors have been used in clinical studies of patients with RET gene mutations, such as: vandetanib, cabozantinib and lenvatinib, and the like. The current multi-target tyrosine kinase inhibitor treatment for RET fusion NSCLC patients is inferior to other NSCLC driving genes in efficiency and survival data. In addition, patients are exposed to RET TKIs for a long time, and the incidence of grade 3-4 toxicity is high due to the inhibition effect on VEGFR kinase. Therefore, the RET specific inhibitor with higher selectivity and stronger activity is developed, the curative effect is improved, the toxicity is limited, and the RET specific inhibitor is expected to become a new means for treating various malignant tumors such as thyroid cancer, NSCLC and the like.

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

Blueprint Medicines patent WO2018017983 discloses another class of compounds, compound 218 having the structure:

disclosure of Invention

The invention aims to solve the technical problem that the existing compound has a single structure, and therefore, the invention provides a heterocyclic compound, application thereof and a pharmaceutical composition containing the heterocyclic compound. The compound has better inhibitory effect on RET kinase.

The invention provides a heterocyclic compound shown as a formula I-0 or a pharmaceutically acceptable salt thereof;

wherein R is ¹ Is hydrogen, fluorine, difluoromethyl, methoxy, cyclopropyl or C ₁ ～C ₄ An alkyl group;

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;

in

Is a single bond or a double bond; when in use

When it is a single bond, X ¹ Is N, CH, C (OH), C (F) Or C (OCH) ₃ ) (ii) a When in use

When it is a double bond, X ¹ Is C;

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

in (1)

Is a single bond or a double bond; when the temperature is higher than the set temperature

When it is a single bond, X ³ Is N, X ² Is CH ₂ Or C (= O); when in use

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

X ⁴ is composed of

{ wherein, X ⁴ B terminal of (A) and X ³ Connection }

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 radical, C ₃ ～C ₆ Cycloalkyl, or, fluoro substituted C ₃ ～C ₆ A cycloalkyl group;

A ³ is C (= O), NR ⁴ 、CH ₂ O or S; r ⁴ Is hydrogen, C ₁ ～C ₄ Alkyl, fluoro substituted C ₁ ～C ₄ Alkyl radical, C ₃ ～C ₆ Cycloalkyl-substituted C ₁ ～C ₄ Alkyl radical, C ₃ ～C ₆ Cycloalkyl, or, fluoro substituted C ₃ ～C ₆ A cycloalkyl group;

A ⁴ is NR ⁵ 、C(＝O)、C(= S) or CH ₂ ；R ⁵ Is hydrogen, C ₁ ～C ₄ Alkyl, fluoro substituted C ₁ ～C ₄ Alkyl radical, C ₃ ～C ₆ Cycloalkyl, or, fluoro substituted C ₃ ～C ₆ A cycloalkyl group;

n is 0 or 1;

A ⁵ is NR ¹⁰ 、CH ₂ O or S; r is ¹⁰ Is hydrogen, C ₁ ～C ₄ Alkyl, fluoro substituted C ₁ ～C ₄ Alkyl radical, C ₃ ～C ₆ Cycloalkyl-substituted C ₁ ～C ₄ Alkyl radical, C ₃ ～C ₆ Cycloalkyl, or, fluoro substituted C ₃ ～C ₆ A cycloalkyl group;

A ⁶ is C (= O) or CH ₂ ；

A ⁷ Is composed of

Or CR ¹¹ R ¹² ；R ¹¹ And R ¹² Independently hydrogen or C ₁ ～C ₄ Alkyl, but R ¹¹ And R ¹² Not hydrogen at the same time;

X ⁶ is C (= O) or CHR ² ；

R ² Is hydrogen or C ₁ ～C ₄ An alkyl group;

X ⁵ is N or CH;

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

R ⁷ is hydrogen or halogen;

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

In one embodiment, the definition of some groups in the heterocyclic compound I-0 or the pharmaceutically acceptable salt thereof can be as follows, and the definition of the groups that are not indicated are as described in any of the above (hereinafter referred to as "in one embodiment"): r ¹ Is C ₁ ～C ₄ An alkyl group.

In a certain technical scheme: r ¹ Is a methyl group.

In a certain technical solution: y is ¹ Is CH.

In a certain technical scheme: y is ² Is N or CH.

In a certain technical scheme: y is ² Is N.

In a certain technical scheme: r ⁹ Is hydrogen or methyl.

In a certain technical scheme: r ⁹ Is methyl.

In a certain technical solution:

in (1)

Is a single or double bond; when in use

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

When it is a double bond, X ¹ Is C.

In a certain technical scheme:

in

Is a single bond; when in use

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

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

In a certain technical scheme: x ⁴ Is composed of

In a certain technical scheme: x ⁴ Is composed of

In a certain technical scheme: when X is present ⁴ Is composed of

When, A ² Is CR ³ ；R ³ Is hydrogen, amino or C ₁ ～C ₄ An alkyl group.

In a certain technical scheme: when X is present ⁴ Is composed of

When, A ² Is CR ³ ；R ³ Is amino or C ₁ ～C ₄ An alkyl group.

In a certain technical scheme: when X is present ⁴ Is composed of

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

In a certain technical scheme: when X is present ⁴ Is composed of

When, 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 radical, C ₃ ～C ₆ Cycloalkyl-substituted C ₁ ～C ₄ Alkyl radical, C ₃ ～C ₆ Cycloalkyl, or, fluoro substituted C ₃ ～C ₆ A cycloalkyl group.

In a certain technical scheme: when X is ⁴ Is composed of

When, A ³ Is NR ⁴ 、CH ₂ O or S; r ⁴ Is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butylradical-CH ₂ CF ₃ Cyclopropane, -CH ₂ -cyclopropane.

In a certain technical scheme: when X is present ⁴ Is composed of

When, A ⁴ Is C (= O), C (= S) or CH ₂ 。

In a certain technical solution: when X is present ⁴ Is composed of

When, A ⁴ Is C (= O) or CH ₂ 。

In a certain technical solution: when X is ⁴ Is composed of

When, A ⁴ Is C (= O).

In a certain technical solution: when X is present ⁴ Is composed of

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

In a certain technical scheme: n is 1.

In a certain technical scheme: x ⁶ Is CHR ² 。

In a certain technical scheme: r is ² Is C ₁ ～C ₄ An alkyl group.

In a certain technical scheme: r is ² Is hydrogen or methyl.

In a certain technical scheme: x ⁵ Is CH.

In a certain technical solution: r ⁶ Is hydrogen.

In a certain technical solution: r ⁷ Is halogen.

In a certain technical scheme: r ⁷ Is F.

In a certain technical solution: r ⁸ Is hydrogen.

In a certain technical solution: r is ¹ Is C ₁ ～C ₄ An alkyl group;

Y ¹ is CH;

Y ² is N or CH;

R ⁹ is hydrogen or methyl;

in (1)

Is a single or double bond; when the temperature is higher than the set temperature

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

When it is a double bond, X ¹ Is C;

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

in (1)

Is a single or double bond; when in use

When it is a single bond, X ³ Is N, X ² Is CH ₂ Or C (= O); when in use

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

X ⁴ is composed of

{ therein, X ⁴ B terminal of (A) and X ³ Connection }

A ¹ Is N;

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

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 composed of

X ⁶ is C (= O) or CHR ² ；

R ² Is hydrogen or C ₁ ～C ₄ An alkyl group;

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 An alkyl group;

Y ¹ is CH;

Y ² is N or CH;

R ⁹ is hydrogen or methyl;

in (1)

Is a single bond or a double bond; when in use

When it is a single bond, X ¹ Is N or CH; when the temperature is higher than the set temperature

When it is a double bond, X ¹ Is C;

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

in

Is a single or double bond; when in use

When it is a single bond, X ³ Is N, X ² Is CH ₂ Or C (= O); when in use

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

X ⁴ is composed of

{ wherein, X ⁴ B terminal and X ³ Connection }

A ¹ Is N;

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

A ³ is NR ⁴ 、CH ₂ O or S; r is ⁴ Is hydrogen, C ₁ ～C ₄ Alkyl, fluoro substituted C ₁ ～C ₄ Alkyl radical, C ₃ ～C ₆ Cycloalkyl-substituted C ₁ ～C ₄ Alkyl radical, C ₃ ～C ₆ Cycloalkyl, or, fluoro substituted C ₃ ～C ₆ A cycloalkyl group;

A ⁴ is C (= O) or CH ₂ ；

n is 0 or 1;

A ⁶ is C (= O) or CH ₂ ；

A ⁷ Is composed of

Or CR ¹¹ R ¹² ；R ¹¹ And R ¹² Independently is hydrogen or C ₁ ～C ₄ Alkyl, but R ¹¹ And R ¹² Is not hydrogen at the same time;

X ⁶ is C (= O) or CHR ² ；

R ² Is hydrogen or C ₁ ～C ₄ An alkyl group;

X ⁵ is CH;

R ⁶ is hydrogen;

R ⁷ is halogen;

R ⁸ is hydrogen.

In a certain technical scheme: r ¹ Is methyl;

Y ¹ is CH;

Y ² is N or CH;

R ⁹ is hydrogen or methyl;

in (1)

When it is a double bond, X ¹ Is C;

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

in (1)

Is a single bond or a double bond; when in use

When it is a single bond, X ³ Is N, X ² Is CH ₂ Or C (= O); when in use

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

X ⁴ is composed of

{ therein, X ⁴ B terminal of (A) and X ³ Connection }

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 is ⁴ Is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH ₂ CF ₃ Cyclopropane, -CH ₂ -cyclopropane;

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 -a cyclopropane;

A ⁶ is C (= O) or CH ₂ ；

A ⁷ Is composed of

Or CR ¹¹ R ¹² ；R ¹¹ And R ¹² Independently is hydrogen or methyl, except that R ¹¹ And R ¹² 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 certain technical scheme: r is ¹ Is methyl;

Y ¹ is CH;

Y ² is N;

R ⁹ is methyl;

in (1)

Is a single bond; when in use

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

s is 1; t is 1;

in (1)

Is a single bond; when in use

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

X ⁴ is composed of

{ therein, X ⁴ B terminal and X ³ Connection }

A ⁴ is C (= O);

n is 1;

X ⁶ is CHR ² ；

R ² Is C ₁ ～C ₄ An alkyl group;

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 An alkyl group;

Y ¹ is N or CH;

Y ² is N, CH, C (F), C (Cl) or C (C)N)；

R ⁹ Is hydrogen, methyl or difluoromethyl;

in

When it is a single bond, X ¹ Is N, CH, C (OH), C (F) Or C (OCH) ₃ ) (ii) a When the temperature is higher than the set temperature

When it is a double bond, X ¹ Is C;

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

in (1)

Is a single bond or a double bond; when in use

When it is a single bond, X ³ Is N, X ² Is CH ₂ Or C (= O); when in use

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

X ⁴ is composed of

{ wherein, X ⁴ B terminal and X ³ Connection }

A ⁵ Is NR ¹⁰ 、CH ₂ O or S; r is ¹⁰ Is hydrogen, C ₁ ～C ₄ Alkyl, fluoro substituted C ₁ ～C ₄ Alkyl radical、C ₃ ～C ₆ Cycloalkyl-substituted C ₁ ～C ₄ Alkyl radical, C ₃ ～C ₆ Cycloalkyl, or, fluoro substituted C ₃ ～C ₆ A cycloalkyl group;

A ⁶ is C (= O) or CH ₂ ；

A ⁷ Is composed of

X ⁶ is C (= O) or CHR ² ；

R ² Is hydrogen or C ₁ ～C ₄ An alkyl group;

X ⁵ is N or CH;

R ⁷ is hydrogen or halogen;

In a certain technical scheme: when R is ¹ Is C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

In a certain technical scheme: when R is ¹ Is C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ The alkyl group is a methyl group.

In a certain technical scheme: when the temperature is higher than the set temperature

In the case of a double bond, the double bond,

is composed of

And/or

In a certain technical scheme: when in use

Is a single bond, X ¹ Is CH, C (OH), C (F) Or C (OCH) ₃ ) When the temperature of the water is higher than the set temperature,

is composed of

And/or

In a certain technical solution: when R is ³ Is C ₁ ～C ₄ When alkyl, said 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 is ³ Is C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ Alkyl is methyl or isopropyl.

In a certain technical scheme: when R is ³ Is fluorine substituted C ₁ ～C ₄ In the case of an alkyl group, the number of fluorine atoms is one or more.

In a certain technical scheme: when R is ³ Is fluorine substituted C ₁ ～C ₄ In the case of an alkyl group, the number of fluorine atoms is 1,2 or 3.

In a certain technical scheme: when R is ³ Is fluorine substituted C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

At a certain pointIn one technical scheme: when R is ³ Is fluorine substituted C ₁ ～C ₄ When alkyl, said fluorine substituted C ₁ ～C ₄ The alkyl group is trifluoromethyl.

In a certain technical scheme: when R is ³ Is C ₃ ～C ₆ When there is a cycloalkyl group, said C ₃ ～C ₆ Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In a certain technical scheme: when R is ³ Is fluorine substituted C ₃ ～C ₆ In the case of cycloalkyl, the number of fluorine atoms is one or more.

In a certain technical solution: when R is ³ Is fluorine substituted C ₃ ～C ₆ In the case of cycloalkyl, the number of fluorine atoms is 1,2 or 3.

In a certain technical solution: when R is ³ Is fluorine substituted C ₃ ～C ₆ When there is a cycloalkyl group, said C ₃ ～C ₆ Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In a certain technical scheme: when R is ⁴ Is C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

In a certain technical scheme: when R is ⁴ Is C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ Alkyl is methyl, ethyl, n-propyl or n-butyl.

In a certain technical scheme: when R is ⁴ Is fluorine substituted C ₁ ～C ₄ In the case of an alkyl group, the number of fluorine atoms is one or more.

In a certain technical scheme: when R is ⁴ Is fluorine substituted C ₁ ～C ₄ In the case of an alkyl group, the number of fluorine atoms is 1,2 or 3.

In a certain technical solution: when R is ⁴ Is fluorine substituted C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ The alkyl is methyl, ethyl, n-propyl, isopropyl or n-butylAlkyl, sec-butyl, isobutyl or tert-butyl.

In a certain technical scheme: when R is ⁴ Is fluorine substituted C ₁ ～C ₄ When alkyl, said fluorine substituted C ₁ ～C ₄ The alkyl group is a2, 2-trifluoroethyl group or a2, 2-difluoroethyl group.

In a certain technical scheme: when R is ⁴ Is C ₃ ～C ₆ Cycloalkyl-substituted C ₁ ～C ₄ When alkyl, said C ₃ ～C ₆ The number of cycloalkyl groups is 1.

In a certain technical scheme: when R is ⁴ Is C ₃ ～C ₆ Cycloalkyl-substituted C ₁ ～C ₄ When alkyl, said C ₃ ～C ₆ Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In a certain technical scheme: when R is ⁴ Is C ₃ ～C ₆ Cycloalkyl-substituted C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

In a certain technical scheme: when R is ⁴ Is C ₃ ～C ₆ Cycloalkyl-substituted C ₁ ～C ₄ When alkyl, said C ₃ ～C ₆ Cycloalkyl-substituted C ₁ ～C ₄ Alkyl is cyclopropylmethyl.

In a certain technical scheme: when R is ⁴ Is C ₃ ～C ₆ When there is a cycloalkyl group, said C ₃ ～C ₆ Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In a certain technical scheme: when R is ⁴ Is C ₃ ～C ₆ When there is a cycloalkyl group, said C ₃ ～C ₆ Cycloalkyl is cyclopropyl.

In a certain technical scheme: when R is ⁴ Is fluorine substituted C ₃ ～C ₆ In the case of cycloalkyl, the number of fluorine atoms is one or more.

In a certain technical scheme: when R is ⁴ For taking fluorineSubstituted C ₃ ～C ₆ In the case of cycloalkyl, the number of fluorine atoms is 1,2 or 3.

In a certain technical solution: when R is ⁴ Is fluorine substituted C ₃ ～C ₆ When there is a cycloalkyl group, said C ₃ ～C ₆ Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In a certain technical scheme: when R is ⁵ Is C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

In a certain technical scheme: when R is ⁵ Is C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ The alkyl group is a methyl group.

In a certain technical scheme: when R is ⁵ Is fluorine substituted C ₁ ～C ₄ In the case of an alkyl group, the number of fluorine atoms is one or more.

In a certain technical scheme: when R is ⁵ Is fluorine substituted C ₁ ～C ₄ In the case of an alkyl group, the number of fluorine atoms is 1,2 or 3.

In a certain technical solution: when R is ⁵ Is fluorine substituted C ₁ ～C ₄ When alkyl, said 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 is ⁵ Is fluorine substituted C ₁ ～C ₄ When alkyl, said fluorine substituted C ₁ ～C ₄ The alkyl group is trifluoromethyl.

In a certain technical solution: when R is ⁵ Is C ₃ ～C ₆ When a cycloalkyl group is said to be C ₃ ～C ₆ Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

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

In a certain technical scheme: when R is ⁵ Is fluorine substituted C ₃ ～C ₆ In the case of cycloalkyl, the number of fluorine atoms is 1,2 or 3.

In a certain technical scheme: when R is ⁵ Is fluorine substituted C ₃ ～C ₆ When a cycloalkyl group is said to be C ₃ ～C ₆ Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In a certain technical solution: when R is ¹⁰ Is C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

In a certain technical scheme: when R is ¹⁰ Is C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ Alkyl is methyl, ethyl, n-propyl or n-butyl.

In a certain technical scheme: when R is ¹⁰ Is fluorine substituted C ₁ ～C ₄ In the case of an alkyl group, the number of fluorine atoms is one or more.

In a certain technical scheme: when R is ¹⁰ Is fluorine substituted C ₁ ～C ₄ In the case of an alkyl group, the number of fluorine atoms is 1,2 or 3.

In a certain technical scheme: when R is ¹⁰ Is fluorine substituted C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

In a certain technical scheme: when R is ¹⁰ Is fluorine substituted C ₁ ～C ₄ When alkyl, said fluorine substituted C ₁ ～C ₄ The alkyl group is a2, 2-trifluoroethyl group or a2, 2-difluoroethyl group.

In a certain technical scheme: when R is ¹⁰ Is C ₃ ～C ₆ Cycloalkyl-substituted C ₁ ～C ₄ When alkyl, said C ₃ ～C ₆ The number of cycloalkyl groups is 1.

In a certain technical scheme: when R is ¹⁰ Is C ₃ ～C ₆ Cycloalkyl-substituted C ₁ ～C ₄ When alkyl, said C ₃ ～C ₆ Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In a certain technical scheme: when R is ¹⁰ Is C ₃ ～C ₆ Cycloalkyl-substituted C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

In a certain technical scheme: when R is ¹⁰ Is C ₃ ～C ₆ Cycloalkyl-substituted C ₁ ～C ₄ When alkyl, said C ₃ ～C ₆ Cycloalkyl-substituted C ₁ ～C ₄ The alkyl group is cyclopropylmethyl.

In a certain technical scheme: when R is ¹⁰ Is C ₃ ～C ₆ When a cycloalkyl group is said to be C ₃ ～C ₆ Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In a certain technical scheme: when R is ¹⁰ Is C ₃ ～C ₆ When there is a cycloalkyl group, said C ₃ ～C ₆ Cycloalkyl is cyclopropyl.

In a certain technical scheme: when R is ¹⁰ Is fluorine substituted C ₃ ～C ₆ In the case of cycloalkyl, the number of fluorine atoms is one or more.

In a certain technical scheme: when R is ¹⁰ Is fluorine substituted C ₃ ～C ₆ In the case of cycloalkyl, the number of fluorine atoms is 1,2 or 3.

In a certain technical solution: when R is ¹⁰ Is fluorine substituted C ₃ ～C ₆ When there is a cycloalkyl group, said C ₃ ～C ₆ Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In a certain technical solution: when R is ¹¹ Is C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl。

In a certain technical scheme: when R is ¹¹ Is C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ Alkyl is methyl, ethyl, n-propyl or n-butyl.

In a certain technical scheme: when R is ¹² Is C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

In a certain technical scheme: when R is ¹² Is C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ Alkyl is methyl, ethyl, n-propyl or n-butyl.

In a certain technical scheme: when X is present ⁶ Is CHR ² When the temperature of the water is higher than the set temperature,

is composed of

And/or

In a certain technical scheme: when X is present ⁶ Is CHR ² 、

In the case of a double bond, the double bond,

is composed of

And

one or more of (a).

In a certain technical solution: when X is ⁶ Is CHR ² 、

is composed of

And

one or more of (a).

In a certain technical solution: when X is present ⁶ Is CHR ² 、

Is a single bond, X ¹ In the case of N, the compound is,

is composed of

And/or

In a certain technical scheme: when R is ² Is C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

In a certain technical scheme: when R is ² Is C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ Alkyl is methyl.

In a certain technical scheme: when R is ⁶ When it is halogen, theHalogen of (a) is fluorine, chlorine, bromine or iodine.

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

In a certain technical solution: when R is ⁶ Is halogen substituted C ₁ ～C ₄ When the alkyl group is used, the number of the "halogen" is one or more.

In a certain technical solution: when R is ⁶ Is halogen-substituted C ₁ ～C ₄ In the case of alkyl, the number of the "halogen" is 1,2 or 3.

In a certain technical scheme: when R is ⁶ Is halogen substituted C ₁ ～C ₄ When alkyl, the "halogen" is independently fluorine, chlorine, bromine or iodine.

In a certain technical scheme: when R is ⁶ Is halogen substituted C ₁ ～C ₄ When alkyl, the "halogen" is fluorine.

In a certain technical scheme: when R is ⁶ Is unsubstituted or halogen-substituted C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

In a certain technical scheme: when R is ⁶ Is unsubstituted or halogen-substituted C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ The alkyl group is a methyl group.

In a certain technical scheme: when R is ⁶ Is halogen-substituted C ₁ ～C ₄ When alkyl, said halogen substituted C ₁ ～C ₄ The alkyl group is difluoromethyl.

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

In a certain technical scheme: when R is ⁷ When halogen is used, the halogen is fluorine.

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

In a certain technical fieldIn the scheme: when R is ⁸ When halogen is used, the halogen is fluorine.

In a certain technical scheme: when R is ⁸ Is halogen substituted C ₁ ～C ₄ When the alkyl group is used, the number of the "halogen" is one or more.

In a certain technical scheme: when R is ⁸ Is halogen substituted C ₁ ～C ₄ In the case of alkyl, the number of the "halogen" is 1,2 or 3.

In a certain technical solution: when R is ⁸ Is halogen substituted C ₁ ～C ₄ When alkyl, the "halogen" is independently fluorine, chlorine, bromine or iodine.

In a certain technical scheme: when R is ⁸ Is halogen-substituted C ₁ ～C ₄ When alkyl, the "halogen" is fluorine.

In a certain technical scheme: when R is ⁸ Is unsubstituted or halogen-substituted C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

In a certain technical scheme: when R is ⁸ Is unsubstituted or halogen-substituted C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ Alkyl is methyl.

In a certain technical solution: when R is ⁸ Is halogen substituted C ₁ ～C ₄ When alkyl, said halogen being substituted by C ₁ ～C ₄ The alkyl group is difluoromethyl.

In a certain technical scheme: except the part with determined spatial configuration, the rest part of the heterocyclic compound I-0 is the mixture of the respective spatial configuration.

In a certain technical scheme: all atoms in the heterocyclic compound I-0 are atoms with natural isotopic abundance.

In a certain technical scheme: r ¹ Is hydrogen, fluorine, difluoromethyl, methoxy, cyclopropyl or C ₁ ～C ₄ An alkyl group;

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;

in (1)

When it is a double bond, X ¹ Is C;

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

in (1)

Is a single bond or a double bond; when in use

When it is a single bond, X ³ Is N, X ² Is CH ₂ Or C (= O); when in use

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

X ⁴ is composed of

{ therein, X ⁴ B terminal of (A) and X ³ Connection }

A ¹ Is N;

A ² is N orCR ³ ；R ³ Is hydrogen, cyano, amino, C ₁ ～C ₄ Alkyl, fluoro substituted C ₁ ～C ₄ Alkyl radical, C ₃ ～C ₆ Cycloalkyl, or, fluoro substituted C ₃ ～C ₆ A cycloalkyl group;

A ⁴ is NR ⁵ C (= O) or CH ₂ ；R ⁵ Is hydrogen, C ₁ ～C ₄ Alkyl, fluoro substituted C ₁ ～C ₄ Alkyl radical, C ₃ ～C ₆ Cycloalkyl, or, fluoro substituted C ₃ ～C ₆ A cycloalkyl group;

n is 0 or 1;

X ⁶ is C (= O) or CHR ² ；

R ² Is hydrogen or C ₁ ～C ₄ An alkyl group;

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;

in (1)

Is a single bond or a double bond; when in use

When it is a double bond, X ¹ Is C;

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

in (1)

Is a single bond or a double bond; when in use

When it is a single bond, X ³ Is N, X ² Is CH ₂ Or C (= O); when in use

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

X ⁴ is composed of

{ wherein, X ⁴ B terminal and X ³ Connection }

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 An alkyl group;

X ⁵ is N or CH;

R ⁷ is hydrogen or halogen;

R ⁸ hydrogen and halogen.

In a certain technical solution: when R is ¹ Is C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ The alkyl group is a methyl group.

In the case of a double bond, the double bond,

is composed of

And/or

is composed of

And/or

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

In a certain technical scheme: when R is ³ Is fluorine substituted C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ The alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or isobutylOr a tert-butyl group.

In a certain technical solution: when R is ³ Is fluorine substituted C ₁ ～C ₄ When alkyl, said fluorine substituted C ₁ ～C ₄ The alkyl group is trifluoromethyl.

In a certain technical scheme: when R is ³ Is C ₃ ～C ₆ When a cycloalkyl group is said to be C ₃ ～C ₆ Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In a certain technical solution: when R is ³ Is fluorine substituted C ₃ ～C ₆ In the case of cycloalkyl, the number of fluorine atoms is one or more.

In a certain technical scheme: when R is ³ Is fluorine substituted C ₃ ～C ₆ In the case of cycloalkyl, the number of fluorine atoms is 1,2 or 3.

In a certain technical solution: when R is ³ Is fluorine substituted C ₃ ～C ₆ When a cycloalkyl group is said to be C ₃ ～C ₆ Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In a certain technical scheme: when R is ⁴ Is C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ Alkyl is methyl or ethyl.

In a certain technical solution: when R is ⁴ Is fluorine substituted C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ The alkyl is methyl or ethylN-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

In a certain technical solution: when R is ⁴ Is fluorine substituted C ₁ ～C ₄ When alkyl, said fluorine substituted C ₁ ～C ₄ The alkyl group is 2, 2-trifluoroethyl.

In a certain technical solution: when R is ⁴ Is C ₃ ～C ₆ Cycloalkyl-substituted C ₁ ～C ₄ When alkyl, said C ₃ ～C ₆ Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In a certain technical scheme: when R is ⁴ Is C ₃ ～C ₆ Cycloalkyl-substituted C ₁ ～C ₄ When alkyl, said C ₃ ～C ₆ Cycloalkyl-substituted C ₁ ～C ₄ The alkyl group is cyclopropylmethyl.

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

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

In a certain technical scheme: when R is ⁴ Is fluorine substituted C ₃ ～C ₆ When there is a cycloalkyl group, said C ₃ ～C ₆ Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In a certain technical solution: when R is ⁵ Is fluorine substituted C ₁ ～C ₄ In the case of an alkyl group, the number of fluorine atoms is 1,2 or 3.

In a certain technical scheme: when R is ⁵ Is fluorine substituted C ₁ ～C ₄ When alkyl, said 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 is ⁵ Is C ₃ ～C ₆ When there is a cycloalkyl group, said C ₃ ～C ₆ Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In a certain technical solution: when R is ⁵ Is fluorine substituted C ₃ ～C ₆ When a cycloalkyl group is said to be C ₃ ～C ₆ Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

is composed of

And/or

In a certain technical solution: when R is ² Is C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ The alkyl group is a methyl group.

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

In a certain technical scheme: when R is ⁶ When halogen is used, the halogen is fluorine.

In a certain technical scheme: when R is ⁶ Is halogen-substituted C ₁ ～C ₄ When the alkyl is a group, the number of the "halogen" is one or more.

In a certain technical solution: when R is ⁶ Is halogen substituted C ₁ ～C ₄ In the case of alkyl, the number of the "halogen" is 1,2 or 3.

In a certain technical fieldIn the scheme: when R is ⁶ Is halogen substituted C ₁ ～C ₄ When alkyl, the "halogen" is fluorine.

In a certain technical scheme: when R is ⁶ Is halogen substituted C ₁ ～C ₄ When alkyl, said halogen substituted C ₁ ～C ₄ The alkyl group is difluoromethyl.

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

In a certain technical scheme: when R is ⁸ When halogen is used, the halogen is fluorine.

In a certain technical scheme: when R is ⁸ Is halogen substituted C ₁ ～C ₄ When the alkyl is a group, the number of the "halogen" is one or more.

In a certain technical solution: when R is ⁸ Is halogen substituted C ₁ ～C ₄ In the case of alkyl, the number of the "halogen" is 1,2 or 3.

In a certain technical scheme: when R is ⁸ Is halogen substituted C ₁ ～C ₄ When alkyl, the "halogen" is independently fluorine, chlorine, bromine or iodine.

In a certain technical scheme: when R is ⁸ Is halogen-substituted C ₁ ～C ₄ When alkyl is present, theThe "halogen" of (a) is fluorine.

In a certain technical solution: when R is ⁸ Is unsubstituted or halogen-substituted C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ The alkyl group is a methyl group.

In a certain technical solution: when R is ⁸ Is halogen-substituted C ₁ ～C ₄ When alkyl, said halogen being substituted by C ₁ ～C ₄ The alkyl group is difluoromethyl.

In a certain technical scheme: r ¹ Is C ₁ ～C ₄ An alkyl group.

In a certain technical scheme: y is ¹ Is CH.

In a certain technical scheme: y is ² Is N.

In a certain technical scheme: r ⁹ Is methyl or difluoromethyl.

In a certain technical scheme: when in use

In (1)

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

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

In a certain technical scheme:

in (1)

Is a single bond.

In a certain technical scheme: x ⁴ Is composed of

{ wherein, X ⁴ B terminal and X ³ Connect }.

In a certain technical solution: a. The ² Is CR ³ ；R ³ Is amino or C ₁ ～C ₄ An alkyl group.

In a certain technical scheme: a. The ³ Is NR ⁴ 、CH ₂ O or S; r is ⁴ Is hydrogen, C ₁ ～C ₄ Alkyl, or, fluoro substituted C ₁ ～C ₄ An alkyl group;

A ⁴ is C (= O) or CH ₂ 。

In a certain technical scheme: a. The ³ Is NR ⁴ 、CH ₂ O or S; r ⁴ Is hydrogen, C ₁ ～C ₄ Alkyl, or, fluoro substituted C ₁ ～C ₄ An alkyl group;

when A is ³ Is NR ⁴ When, A ⁴ Is C (= O) or CH ₂ (ii) a When A is ³ Is CH ₂ O or S, A ⁴ Is CH ₂ 。

In a certain technical scheme:

in

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

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

when X is present ² When is C (= O), A ³ Is NR ⁴ ，A ⁴ Is C (= O) or CH ₂ Or, A ³ Is CH ₂ When, O or S is, A ⁴ Is CH ₂ 。

In a certain technical scheme: n is 1.

In a certain technical solution: x ⁶ Is CHR ² 。

In a certain technical schemeThe method comprises the following steps: x ⁵ Is CH.

In a certain technical scheme: r is ⁶ Is hydrogen; r is ⁷ Is halogen; r is ⁸ Is hydrogen.

In a certain technical scheme: r ¹ Is C ₁ ～C ₄ An alkyl group;

Y ¹ is CH; y is ² Is N; r ⁹ Is methyl or difluoromethyl;

in

Is a single bond or a double bond; when in use

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

When it is a double bond, X ¹ Is C;

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

in (1)

When it is a single bond, X ³ Is N, X ² Is CH ₂ Or C (= O); when in use

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

X ⁴ is composed of

{ wherein, X ⁴ B terminal and X ³ Connection }

A ¹ Is N;

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

A ³ is NR ⁴ 、CH ₂ O or S; r ⁴ Is hydrogen, C ₁ ～C ₄ Alkyl, or, fluoro substituted C ₁ ～C ₄ An alkyl group;

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 An alkyl group;

X ⁵ is CH;

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

In a certain technical solution: r ¹ Is C ₁ ～C ₄ An alkyl group;

Y ¹ is CH; y is ² Is N; r ⁹ Is methyl or difluoromethyl;

in

Is a single bond or a double bond; when in use

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

When it is a double bond, X ¹ Is C;

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

in (1)

Is a single or double bond; when in use

When it is a single bond, X ³ Is N, X ² Is CH ₂ Or C (= O); when in use

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

X ⁴ is composed of

{ wherein, X ⁴ B terminal and X ³ Connection }

A ¹ Is N;

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

A ³ is NR ⁴ 、CH ₂ O or S; r is ⁴ Is hydrogen, C ₁ ～C ₄ Alkyl, or, fluoro substituted C ₁ ～C ₄ An alkyl group;

when A is ³ Is NR ⁴ When, A ⁴ Is C (= O) or CH ₂ (ii) a When A is 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 An alkyl group;

X ⁵ is CH;

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

In a certain technical solution: r ¹ Is C ₁ ～C ₄ An alkyl group;

Y ¹ is CH; y is ² Is N; r ⁹ Is methyl or difluoromethyl；

In

Is a single bond or a double bond; when in use

When it is a double bond, X ¹ Is C;

s is 1; t is 1;

in (1)

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

X ⁴ is composed of

{ therein, X ⁴ B terminal and X ³ Connection }

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 An alkyl group;

X ⁵ is CH;

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

In a certain technical solution: r ¹ Is C ₁ ～C ₄ An alkyl group;

Y ¹ is CH; y is ² Is N; r ⁹ Is methyl or difluoromethyl;

in (1)

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

When it is a double bond, X ¹ Is C;

s is 1; t is 1;

in (1)

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

X ⁴ is composed of

{ wherein, X ⁴ B terminal of (A) and X ³ Connection }

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

n is 1;

X ⁶ is CHR ² ；

R ² Is hydrogen or C ₁ ～C ₄ An alkyl group;

X ⁵ is CH;

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

In a certain technical solution: r is ¹ Is C ₁ ～C ₄ An alkyl group;

Y ¹ is CH; y is ² Is N; r ⁹ Is methyl or difluoromethyl;

in (1)

Is a single or double bond; when in use

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

When it is a double bond, X ¹ Is C;

s is 1; t is 1;

in (1)

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

X ⁴ is composed of

{ wherein, X ⁴ B terminal of (A) and X ³ Connection }

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

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

n is 1;

X ⁶ is CHR ² ；

R ² Is hydrogen or C ₁ ～C ₄ An alkyl group;

X ⁵ is CH;

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

In a certain technical scheme, the heterocyclic compound I-0 is:

wherein R is ¹ Is hydrogen, fluorine, difluoromethyl, methoxy, cyclopropyl or C ₁ ～C ₄ Alkyl { such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, and also for example methyl };

Y ¹ is N or CH;

Y ² is N, CH, C (F), C (Cl) or C (CN);

in (1)

Is a single bond or a double bond; when in use

When it is a double bond, X ¹ Is C;

in (1)

Is a single bond or a double bond; when in use

When it is a single bond, X ³ Is N, X ² Is CH ₂ Or C (= O); when in use

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

X ⁴ is composed of

{ wherein, X ⁴ B terminal and X ³ Connection }

A ¹ Is N;

A ² is N or CR ³ ；R ³ Is hydrogen, cyano, amino, C ₁ ～C ₄ Alkyl { such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl }, for example methyl or isopropyl }, fluoro-substituted C ₁ ～C ₄ Alkyl { the number of fluorine is one or more [ e.g. 2 or 3 ]](ii) a Said "C ₁ ～C ₄ Alkyl radicals "such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl }, C ₃ ～C ₆ Cycloalkyl { e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl }, or, fluoro-substituted C ₃ ～C ₆ Cycloalkyl { said fluorine number is one or more [ e.g. 2 or 3 ]](ii) a Said "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 is ⁴ Is hydrogen, C ₁ ～C ₄ Alkyl radicals { e.g. methyl, ethyl, n-propyl, isoPropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, and also, for example, methyl }, fluorine-substituted C ₁ ～C ₄ Alkyl { the number of said fluorine is one or more [ e.g. 2 or 3 ]](ii) a Said "C ₁ ～C ₄ Alkyl "for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl }, C ₃ ～C ₆ Cycloalkyl { e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl }, or, fluoro-substituted C ₃ ～C ₆ Cycloalkyl { said fluorine number is one or more [ e.g. 2 or 3 ]](ii) a Said "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 { e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, also e.g. methyl }, fluoro-substituted C ₁ ～C ₄ Alkyl { the number of said fluorine is one or more [ e.g. 2 or 3 ]](ii) a Said "C ₁ ～C ₄ Alkyl "for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl }, C ₃ ～C ₆ Cycloalkyl { e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl }, or, fluoro-substituted C ₃ ～C ₆ Cycloalkyl { the number of fluorine is one or more [ e.g. 2 or 3 ]](ii) a Said "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 { such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, and also for example methyl };

X ⁵ is N or CH;

R ⁶ is hydrogen, halogen { e.g. fluorine, chlorine, bromine or iodine, and further e.g. fluorine }, cyclopropyl, or C, unsubstituted or halogen-substituted ₁ ～C ₄ Alkyl { the number of the "halogen" is one orPlural [ said "plural", e.g. 2 or 3]When a plurality of "halogen" s are present, the "halogen" s may be the same or different. The halogen can be fluorine, chlorine, bromine or iodine independently, and can also be fluorine. Said "C ₁ ～C ₄ Alkyl "is for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, and is further for example methyl. Said "halogen-substituted C ₁ ～C ₄ Alkyl "such as difluoromethyl };

R ⁷ hydrogen or halogen { e.g. fluorine, chlorine, bromine or iodine, and further e.g. fluorine };

R ⁸ is hydrogen, halogen { e.g. fluorine, chlorine, bromine or iodine, and further e.g. fluorine }, cyclopropyl, or C, unsubstituted or halogen-substituted ₁ ～C ₄ Alkyl { the "halogen" number is one or more [ the "multiple" such as 2 or 3]When a plurality of "halogen" s are present, the "halogen" s may be the same or different. The halogen can be fluorine, chlorine, bromine or iodine independently, and can also be fluorine. Said "C ₁ ～C ₄ Alkyl "is for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, and also for example methyl. Said "halogen-substituted C ₁ ～C ₄ Alkyl "such as difluoromethyl };

R ⁹ is hydrogen, methyl or difluoromethyl.

In one embodiment, the definition of certain groups in the heterocyclic compound I or a pharmaceutically acceptable salt thereof can be as follows (the definition of the groups is not indicated in any of the above schemes):

is composed of

And/or

when the temperature is higher than the set temperature

In

Is a single bond, X ¹ Is CH, C (OH), C (F) Or C (OCH) ₃ ) When the current is over;

is composed of

And/or

In one embodiment, the definition of certain groups in the heterocyclic compound I or the pharmaceutically acceptable salt thereof can be as follows (the definition of the groups is as described in any of the preceding schemes):

when the temperature is higher than the set temperature

In (1)

Is a double bond, X ¹ When is C;

is composed of

And/or

is composed of

is composed of

is composed of

R ¹ is C ₁ ～C ₄ An alkyl group;

Y ¹ is CH;

Y ² is N;

in

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

When it is a double bond, X ¹ Is C;

in (1)

Is a single bond; when in use

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

X ⁴ is composed of

A ¹ Is N;

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

A ³ is NR ⁴ 、CH ₂ O or S; r is ⁴ Is hydrogen or C ₁ ～C ₄ An alkyl group;

A ⁴ is C (= O) or CH ₂ ；

n is 0;

R ² is C ₁ ～C ₄ An alkyl group;

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 An alkyl group;

Y ¹ is CH;

Y ² is N, CH, C (F), C (Cl) or C (CN).

In (1)

When it is a double bond, X ¹ Is C;

in (1)

Is a single bond; when the temperature is higher than the set temperature

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

X ⁴ is composed of

A ¹ Is N;

A ² is CR ³ ；R ³ Is amino, C ₁ ～C ₄ Alkyl, fluoro substituted C ₁ ～C ₄ Alkyl radical, C ₃ ～C ₆ Cycloalkyl, or, fluoro substituted C ₃ ～C ₆ A cycloalkyl group;

A ³ is NR ⁴ 、CH ₂ O or S; r is ⁴ Is hydrogen, C ₁ ～C ₄ Alkyl, fluoro substituted C ₁ ～C ₄ Alkyl radical, C ₃ ～C ₆ Cycloalkyl, or, fluoro substituted C ₃ ～C ₆ A cycloalkyl group;

n is 0;

R ² is C ₁ ～C ₄ An alkyl group;

X ⁵ is N or CH;

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

R ⁷ is halogen;

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

R ⁹ is hydrogen, methyl or difluoromethyl.

R ¹ is fluorine, difluoromethyl, methoxy, cyclopropyl or C ₁ ～C ₄ An alkyl group.

R ¹ is C ₁ ～C ₄ An alkyl group.

Y ¹ is CH.

Y ² is N.

in (1)

Is a single bond; when the temperature is higher than the set temperature

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

X ⁴ b terminal and X ³ And (4) connecting.

A ² is CR ³ ；R ³ Is amino, C ₁ ～C ₄ Alkyl, fluoro substituted C ₁ ～C ₄ Alkyl radical, C ₃ ～C ₆ Cycloalkyl, orFluorine substituted C ₃ ～C ₆ A cycloalkyl group.

A ² is CR ³ ；R ³ Is amino or C ₁ ～C ₄ An alkyl group.

A ³ is NR ⁴ 、CH ₂ O or S; r is ⁴ Is hydrogen, C ₁ ～C ₄ Alkyl, fluoro substituted C ₁ ～C ₄ Alkyl radical, C ₃ ～C ₆ Cycloalkyl, or, fluoro substituted C ₃ ～C ₆ A cycloalkyl group.

A ³ is NR ⁴ 、CH ₂ O or S; r ⁴ Is hydrogen or C ₁ ～C ₄ An alkyl group.

A ⁴ is C (= O) or CH ₂ 。

n is 0.

R ² is C ₁ ～C ₄ An alkyl group.

X ⁵ is N or CH.

R ⁶ is hydrogen, cyclopropyl, or C, unsubstituted or substituted by halogen ₁ ～C ₄ An alkyl group.

R ⁶ is hydrogen.

R ⁷ is a halogen.

R ⁸ is hydrogen, cyclopropyl, or C, unsubstituted or substituted by halogen ₁ ～C ₄ An alkyl group.

R ⁸ is hydrogen.

R ⁹ is methyl.

In a certain embodiment, in the heterocyclic compound I-0 or a pharmaceutically acceptable salt thereof, the heterocyclic compound I-0 may be any one of the following compounds:

in a certain embodiment, in the heterocyclic compound I-0 or the pharmaceutically acceptable salt thereof, the heterocyclic compound I-0 may be any of the following compounds:

with a retention time of 5.79min under the following HPLC conditions

Instrument Waters Acquity ARC (UHPLC); a chromatographic column: XSelect CSH ^TM C18 2.5 μm, 4.6 × 150mm Column XP; mobile phase A is 0.1% ammonia water solution; the mobile phase B is acetonitrile; flow rate: 1ml/min; wavelength: 282nm; column temperature: 30 ℃; the blank solvent is methanol;dissolving a proper amount of a substance to be detected in methanol, and filtering the solution by using a 0.22 mu m filter membrane; gradient elution:

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

Retention time of 6.24min under HPLC conditions described below

Instrument Waters Acquity ARC (UHPLC); a chromatographic column: XSelect CSH ^TM C18 2.5 μm, 4.6 × 150mm Column XP; mobile phase A is 0.1% ammonia water solution; the mobile phase B is acetonitrile; flow rate: 1ml/min; wavelength: 282nm; column temperature: 30 ℃; the blank solvent is methanol; dissolving a proper amount of a substance to be detected in methanol, and filtering the solution by using a 0.22 mu m filter membrane; gradient elution:

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

With a retention time of 6.07min under the following HPLC conditions

Instrument Waters Acquity ARC (UHPLC); and (3) chromatographic column: XSelect CSH ^TM C18 2.5 μm, 4.6 × 150mm Column XP; mobile phase A is 0.1% formic acid water solution; the mobile phase B is acetonitrile; flow rate: 1ml/min; wavelength: 290nm; column temperature: 30 ℃; the blank solvent is methanol; dissolving a proper amount of a substance to be detected in methanol, and filtering the solution by using a 0.22 mu m filter membrane; gradient elution:

time (min)	A(％)	B(％)
			0	75	25
10	55	45
			13	20	80
13.1	75	25
			18	75	25

With a retention time of 6.35min under the following HPLC conditions

Instrument Waters Acquity ARC (UHPLC); a chromatographic column: xselect CSH ^TM C18 2.5 μm, 4.6 × 150mm Column XP; mobile phase A is 0.1% formic acid water solution; the mobile phase B is acetonitrile; flow rate: 1ml/min; wavelength: 290nm; column temperature: 30 ℃; the blank solvent is methanol; dissolving a proper amount of a substance to be detected in methanol, and filtering the solution by using a 0.22 mu m filter membrane; gradient elution:

with a retention time of 6.49min under the following HPLC conditions

Instrument Waters Acquity ARC (UHPLC); a chromatographic column: XSelect CSH ^TM C ₁₈ 2.5um4.6 x 150mm Column XP; mobile phase A is 0.1% ammonia water solution; the mobile phase B is acetonitrile; flow rate: 1ml/min; wavelength: 254nm; column temperature: 30 ℃; the blank solvent is methanol; dissolving a proper amount of a substance to be detected in methanol, and filtering the solution by using a 0.22 mu m filter membrane; gradient elution:

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

With a retention time of 5.68min under the following HPLC conditions

Instrument Waters Acquity ARC (UHPLC); and (3) chromatographic column: XSelect CSH ^TM C ₁₈ 2.5um4.6 x 150mm Column XP; mobile phase A is 0.1% ammonia water solution; the mobile phase B is acetonitrile; flow rate: 1ml/min; wavelength: 254nm; column temperature: 30 ℃; the blank solvent is methanol; dissolving a proper amount of a substance to be detected in methanol, and filtering the solution by using a 0.22 mu m filter membrane; gradient elution:

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

With a retention time of 6.32min under the following HPLC conditions

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

With a retention time of 7.53min under the following HPLC conditions

Instrument Waters Acquity ARC (UHPLC); a chromatographic column: XSelect CSH ^TM C ₁₈ 3.5um 4.6 x 150mm Column XP; mobile phase A is 0.1% ammonia water solution; the mobile phase B is acetonitrile; flow rate: 1.0ml/min; wavelength: 287nm; column temperature: 30 ℃; the blank solvent is methanol; dissolving a proper amount of a substance to be detected in methanol, filtering the solution by using a 0.22um filter membrane, and performing gradient elution:

time (min)	A(％)	B(％)
			0	75	25
10	37.5	62.5
			15	20	80
15.1	75	25
			18	75	25

With a retention time of 8.45min under the following HPLC conditions

Instrument Waters Acquity ARC (UHPLC); and (3) chromatographic column: XSelect CSH ^TM C ₁₈ 3.5um 4.6 x 150mm Column XP; mobile phase A is 0.1% ammonia water solution; the mobile phase B is acetonitrile; flow rate: 1.0ml/min; wavelength: 287nm; column temperature: 30 ℃; the blank solvent is methanol; dissolving a proper amount of a substance to be detected in methanol, filtering the solution by using a 0.22um filter membrane, and performing gradient elution:

with a retention time of 5.95min under the following HPLC conditions

Instrument Waters Acquity ARC (UHPLC); and (3) chromatographic column: XSelect CSH ^TM C ₁₈ 2.5um4.6 x 150mm Column XP; mobile phase A is 0.1% ammonia water solution; the mobile phase B is acetonitrile; flow rate: 1.0ml/min; wavelength: PDA full wavelength, 254nm,220nm; column temperature: 30 ℃; the blank solvent is methanol; dissolving a proper amount of a substance to be detected in methanol, filtering the solution by using a 0.22um filter membrane, and performing gradient elution:

with a retention time of 6.43min under the following HPLC conditions

with a retention time of 5.574min under the following HPLC conditions

Instrument Waters Acquity ARC (UHPLC); a chromatographic column: XSelect CSH ^TM C183.5 μm, 4.6 × 150mm Column XP; mobile phase A is 0.1% ammonia water solution; the mobile phase B is acetonitrile; flow rate: 1ml/min; wavelength: 282nm; column temperature: 30 ℃; the blank solvent is methanol; dissolving a proper amount of a substance to be detected in methanol, and filtering the solution by using a 0.22 mu m filter membrane; gradient elution:

with a retention time of 5.363min under the following HPLC conditions

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

Having a retention time of 8.737min under the following HPLC conditions

time (min)	A(％)	B(％)
			0	75	25
15	20	80
			18	20	80
18.1	75	25
			23	75	25

With a retention time of 9.444min under the following HPLC conditions

Instrument Waters Acquity ARC (UHPLC); and (3) chromatographic column: XSelect CSH ^TM C183.5 μm, 4.6 × 150mm Column XP; mobile phase A is 0.1% ammonia water solution; the mobile phase B is acetonitrile; flow rate: 1ml/min; wavelength: 282nm; column temperature: 30 ℃; the blank solvent is methanol; dissolving a proper amount of a substance to be detected in methanol, and filtering the solution by using a 0.22 mu m filter membrane; gradient elution:

time (min)	A(％)	B(％)
			0	75	25
15	20	80
			18	20	80
18.1	75	25
			23	75	25

With a retention time of 5.21min under the following HPLC conditions

Instrument Waters Acquity ARC (UHPLC); chromatographic column：XSelect CSH ^TM C183.5 μm, 4.6 × 150mm Column XP; mobile phase A is 0.1% ammonia water solution; the mobile phase B is acetonitrile; flow rate: 1ml/min; wavelength: 282nm; column temperature: 30 ℃; the blank solvent is methanol; dissolving a proper amount of a substance to be detected in methanol, and filtering the solution by using a 0.22 mu m filter membrane; gradient elution:

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

With a retention time of 6.066min under the following HPLC conditions

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

The invention also provides application of the heterocyclic compound I-0 or pharmaceutically acceptable salt thereof in preparing RET inhibitors.

The present invention also provides the use of the above-mentioned heterocyclic compound I-0 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention and/or treatment of a disease mediated by abnormal expression of RET.

The "disease mediated by aberrant expression of RET" is, for example, cancer, in turn, papillary Thyroid Carcinoma (PTC), medullary Thyroid Carcinoma (MTC), pheochromocytoma (PC), ductal pancreatic adenocarcinoma, multiple endocrine tumors (MEN 2A or MEN 2B), 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.

The invention also provides application of the heterocyclic compound I-0 or the pharmaceutically acceptable salt thereof in preparing a medicament for preventing and/or treating cancer.

Such "cancers" are for example Papillary Thyroid Carcinoma (PTC), medullary Thyroid Carcinoma (MTC), pheochromocytoma (PC), ductal pancreatic adenocarcinoma, multiple endocrine tumors (MEN 2A or MEN 2B), 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.

The invention also provides a pharmaceutical composition, which comprises the heterocyclic compound I-0 or the pharmaceutically acceptable salt thereof and pharmaceutic adjuvants.

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

the term "alkyl" refers to a straight or branched chain alkyl group having the indicated number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

The term "cycloalkyl" refers to a ring having the indicated number of ring atoms (e.g., C) ₃ -C ₆ Cycloalkyl) and fully saturated hydrocarbon rings. "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 salts of the compounds of the present invention prepared with pharmaceutically acceptable, relatively non-toxic acids or bases.

When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting a prototype of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Salts derived with pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines including substituted amines, cyclic amines, naturally occurring amines, and analogs thereof, such as arginine, betaine, caffeine, choline, N' -benzhydrylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and analogs thereof.

When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting a prototype of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. The acid may be an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, and the like. 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, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like.

Certain compounds of the present invention have chiral carbon atoms, double bonds, carbocyclic rings or heterocyclic rings, and thus each configurational isomer { optical isomers (e.g., enantiomers, diastereomers, etc.), cis-trans isomers, etc. } and mixtures thereof (e.g., racemates) are within the scope of the present invention. When certain compounds of the present invention indicate a particular configuration, it is meant that the configurational isomer is present and substantially free of other isomers.

The atoms in the compounds of the invention may be naturally isotopically abundant atoms or non-naturally isotopically abundant atoms. That is, one or more atoms in the compounds of the invention may be non-naturally isotopically abundant atoms. The isotopic variations thus produced are within the scope of the present invention. The amount of any isotope in the atoms of unnatural isotopic abundance can be between 0% and 100%. Taking hydrogen (H) as an example, it may be a natural isotopically abundant hydrogen atom (99.985% ¹ H+0.015％ ² H + is less than 0.001% ³ H) Or may be non-naturally isotopically abundant atoms (e.g. greater than 95%) ² H)。

When any variable (e.g., halogen) occurs multiple times within a definition of a compound, the definition of the occurrence of that variable at each position is independent of the definition of the occurrence of the remaining positions, and their meanings are independent of each other and do not affect each other. Thus, 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 one position is independent of the definition of halogen at the remaining positions. In addition, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The term "inhibitor" refers to a molecule that is reducing, blocking, preventing, delaying activation, inactivating, desensitizing, or down-regulating, for example, a gene, protein, ligand, receptor, or cell.

The term "aberrant expression of RET" means an increase in RET activity caused by signaling through RET.

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

The term "treating" any disease or disorder refers in one embodiment to ameliorating the disease or disorder (i.e., arresting the disease, or, reducing the degree or severity of presenting with its clinical symptoms). In another embodiment, "treating" refers to improving at least one physical parameter, which may not be perceptible by the subject. In another embodiment, "treating" or "treatment" refers to modulating a disease or disorder, or both, physically (e.g., stabilizing distinguishable symptoms), physiologically (e.g., stabilizing physical parameters). In another embodiment, "treating" or "treatment" refers to slowing the progression of the disease.

The term "cancer" refers to a malignant or benign growth of cells in the 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, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, prostate cancer, and uterine leiomyosarcoma). <xnotran> , "" , , , , , , / (atypical teratoid/rhabdoid tumor), , , , ( ), , , , , , , , , , , , (craniopharyngioma), T- , , , (ependymoblastoma), , , , , , , () , , (GIST), , , , , , () , , (hypopharyngeal cancer), , ( ), , , , , , , , , , , , , , , T- , , , , </xnotran> Waldenstrom macroglobulinemia, medulloblastoma (medulloblastoma), medullocellular epithelioma (medullohepilioma), melanoma, mesothelioma, oral cancer, chronic myelogenous leukemia, myeloid leukemia, multiple myeloma, nasopharyngeal cancer (aspephalygeal cancer), neuroblastoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, epithelial ovarian epithelioma, ovarian germ cell tumor, ovarian low-grade potential malignancy, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, intermediate differentiated pinealoma (pineal carcinoma of ovarian differentiation), pinealoblastoma, and supratentorial primary neuroblastoma (epithelial neoplasia) pituitary tumors, plasma cell tumors/multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, tumor ewing's sarcoma family, sarcoma, kaposi's disease, sezary syndrome, skin cancer, small cell lung cancer, small bowel cancer, soft tissue sarcoma, squamous cell cancer, stomach (stomach) cancer, supratentorial primordial extrablastoma, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma (thymoma) and thymus cancer, thyroid cancer, urinary tract cancer, uterine sarcoma, vaginal cancer, vulval cancer, waldenstrom macroglobulinemia, and Wilms tumor.

The term "pharmaceutical excipient" refers to excipients and additives used in the manufacture of pharmaceutical products and in the formulation of pharmaceutical formulations; is a substance that has been reasonably evaluated in terms of safety and is included in pharmaceutical preparations, in addition to an active ingredient or a precursor.

The above preferred conditions may be combined arbitrarily to obtain preferred embodiments of the present invention without departing from the general knowledge in the art.

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

The positive progress effects of the invention are as follows: the compound has better inhibitory effect on RET kinase.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

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

and (3) chromatographic column: CORTECS C ₁₈ 2.7μm、4.6*50mm Column；

Mobile phase A is 0.1% formic acid water solution;

the mobile phase B is 0.1 percent of formic acid acetonitrile solution;

time (min)	A(％)	B(％)
			0	90	10
0.7	90	10
			2.5	10	90
4	10	90
			4.1	90	10
6.5	90	10

Flow rate: 1ml/min;

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

column temperature: 30 ℃;

sample pan: temperature is not controlled;

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

Example 1SZ-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:

the reaction flask was charged with compound 1 (17g, 69.6 mmol) and anhydrous dichloromethane (500 ml), stirred, further added with N, N-isopropylamine (22.5g, 174mmol), stirred at room temperature for 30 minutes, slowly added dropwise with trimethylchlorosilane (15.1g, 140mmol), and then heated to reflux for 3 hours during which argon was bubbled for 30 seconds every 30 minutes to remove hydrogen chloride gas generated by the reaction. The reaction was cooled to-10 ℃ and Fmoc-Cl (16.7 g,64.6 mmol), EDCI. HCl (21.1g, 0.11mol) were added and stirring was continued for 3h during which argon was bubbled for 30 seconds every 30 minutes to remove the hydrogen chloride gas produced by the reaction. Adding 2.5% of Na into the reaction solution ₂ CO ₃ Aqueous solution (1000 ml) was extracted with ether (100ml x 2), aqueous phase adjusted to pH 2 with 2N hydrochloric acid, extracted with ethyl acetate (300ml x 3), organic phase dried over anhydrous sodium sulfate, filtered, filtrate concentrated under reduced pressure to give compound 9307A1 (24.4g, 85%, white foamy solid) which was not purified directly to the next reaction. LCMS: [ M + H] ⁺ 367.08(De-Boc)。

Step 2:

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

And 3, step 3:

9307A2 (4.5g, 7.9mmol) and methanol (30 ml) were added to a reaction flask, followed by stirring, followed by addition of ethylenediamine (30 ml), and reaction at 20 ℃ for 2And (4) hours. The reaction solution was concentrated under reduced pressure to give a crude product, which was purified by flash silica gel column chromatography (EA/PE 50-100%) to give 9307A3 (2.5g, 91%, colorless oily liquid). LCMS: [ M + H] ⁺ 348.12。

And 4, step 4:

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

And 5, step 5:

the compound 9307A4 (1g, 2.8mmol) was dissolved in dichloromethane (5 ml), and trifluoroacetic acid (1 ml) was added to stir at room temperature for 2 hours, and the solvent was removed by concentration to give a crude 9307A5, which was reacted in the next step without purification. LCMS: [ M + H] ⁺ 258.07。

And 6, step 6:

compound 9307A5 (178mg, 0.5mol), compound 2 (112mg, 0.5mmol) and potassium carbonate (276mg, 2mmol) were added to DMSO (5 ml), and stirred at 110 ℃ for 16 hours. Water (50 mL) was added to the system, extracted with ethyl acetate (10mL. Times.3), and the organic phase was concentrated under reduced pressure to give a crude product, which was purified by medium-pressure reverse phase column chromatography (ACN-0.1% HCO) ₂ Aqueous H) and lyophilized to give SZ-9312 (18.6 mg,9%, white solid). LCMS: [ M + H] ⁺ 445.14。 ¹ H NMR(400MHz,DMSO-d6)δ9.21(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＝13.2Hz,1H),1.29(d,J＝13.4Hz,1H).

Example 2SZ-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:

9307A1 (932mg, 1mmol) and DMF (5 ml) were added to a reaction flask and stirred, followed by addition of (S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethylamine (prepared according to WO 2017079140) (412mg, 1mmol), DIPEA (516mg, 2mmol) and finally HATU (912mg, 2mmol) and reaction at 20 ℃ for 1 hour. Water (40 ml) was added to the reaction mixture, extracted with EA (10ml X3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by flash silica gel column chromatography (EA/PE 0-50%) to give 9315A0 (900mg, 69%, white foam). LCMS: [ M + H] ⁺ 654.20。

Step 2:

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

And 3, 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-carboxylic acid ester (9315A 2)

Compound 9315A1 (330mg, 0.76mmol) was dissolved in acetic acid (3 ml) and triethyl orthoacetate (6 ml) and stirred at 100 ℃ 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%) to give compound 9315A2 (230mg, 66%, colorless oily liquid). LCMS: [ M + H ]] ⁺ 457.12@3.60min。

And 4, 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 (9315A 3)

The compound 9315A2 (230mg, 0.50mmol) was dissolved in dichloromethane (5 ml), trifluoroacetic acid (1 ml) was added, stirred at room temperature for 2 hours, and the solvent was removed by concentration to give a crude 9315A3, which was reacted in the next step without purification. LCMS: [ M + H] ⁺ 357.08@2.70min。

And 5, 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-en-4-one (SZ-9315)

Compound 9315A3 (170mg, 0.50mol), compound 3 (110mg, 0.50mmol) (prepared according to WO 2017079140) and potassium carbonate (207mg, 1.50mmol) were added to DMSO (5 ml) and stirred at 110 ℃ for 16 hours. Water (50 ml) was added to the system, extracted with ethyl acetate (20 ml x 3), the organic phase was concentrated under reduced pressure to give the crude product, purified by flash column chromatography on silica gel (DCM/EA 50% -100%), dissolved in acetonitrile and water, lyophilized to give SZ-9315 (160mg, 58%, pale yellow solid). LCMS: [ M + H] ⁺ 544.16@3.03min。 ¹ H NMR(400MHz,DMSO-d6)δ11.84(s,1H),9.21(s,1H),8.68(d,J＝4.5Hz,1H),8.43(d,J＝2.1Hz,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＝7.0Hz,3H),1.73-1.58(m,2H),1.44-1.30(m,2H)。

Example 3SZ-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-carboxylic acid ester (9316A 1)

Compound 9315A1 (330mg, 0.76mmol) was dissolved in acetic acid (3 ml) and triethyl isobutyrate (6 ml) and stirred at 100 degrees under microwave for 1 hour, the solvent was removed by concentration, and the residue was purified by flash silica gel column chromatography (PE/EA 50% -100%) to give compound 9316A1 (240mg, 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 (9316A 2)

The compound 9316A1 (240mg, 0.50mmol) was dissolved in dichloromethane (5 ml), trifluoroacetic acid (1 ml) was added, stirred at room temperature for 2 hours, and the solvent was removed by concentration to give a crude 9316A2, which was reacted in the next step without purification. LCMS: [ M + H] ⁺ 385.13@2.82min。

And 3, 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-en-4-one (SZ-9316)

Compound 9316A2 (190mg, 0.50mol), compound 3 (110mg, 0.50mmol) and potassium carbonate (207mg, 1.50mmol) were added to DMSO (5 ml), and stirred at 110 ℃ for 16 hours. Water (50 ml) was added to the system, extracted with ethyl acetate (20ml. Times.3), and the organic phase was concentrated under reduced pressure to give a crude product, which was purified by flash silica gel column chromatography (DCM/EA 50% -100%), dissolved in acetonitrile and water, and lyophilized to give SZ-9316 (160mg, 58%, pale yellow solid). LCMS: [ M + H ]] ⁺ 572.18@3.40min。 ¹ H NMR(400MHz,DMSO-d6)δ11.83(s,1H),9.22(s,1H),8.68(d,J＝4.4Hz,1H),8.40(d,J＝1.6Hz,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＝6.7Hz,3H),1.13(d,J＝6.7Hz,3H)。

Example 4SZ-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 (9305A 12); 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

Step 1: diethyl 1, 4-dioxaspiro [4.5] decane-8, 8-dicarboxylate (9305A 2)

Compound 9305A1 (50g, 0.2mol) was dissolved in anhydrous toluene (400 ml), ethylene glycol (13.6 ml) and p-toluenesulfonic acid monohydrate (400mg, 2mmol) were added sequentially, then the water was partitioned in a reflux trap 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 give 9305A2 (70 g, colorless oil).

Step 2: 8- (Ethylestero < ethoxycarbonyl >) -1, 4-dioxaspiro [4.5] decane-8-carboxylic acid (9305A 3)

9305A2 (70g, 0.2mol) was dissolved in methanol (400 ml), 1N sodium hydroxide (250 ml) was added 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 extraction with ethyl acetate (300 ml), and the organic phase was dried over sodium sulfate and concentrated to give 9305A3 (50 g, two steps 94%, colorless oil). ¹ H NMR(400MHz,CDCl ₃ )δ4.22(q,J＝8.5Hz,2H),3.94(s,4H),2.18-2.22(m,4H),1.68-1.73(m,4H),1.27(t,J＝8.5Hz,3H)。

And 3, step 3: ethyl 8- (((benzyloxy) carbonyl) amino) -1, 4-dioxaspiro [4.5] decane-8-carboxylic acid ester (9305A 4)

9305A3 (45g, 0.17mol) was dissolved in toluene (200 ml), triethylamine (52g, 0.51mol) and DPPA (0.17 mol) were added, the reaction temperature was controlled not to exceed 30 degrees and stirred for 1 hour, followed by stirring at 100 degrees for 2 hours, and finally benzyl alcohol (17.6 g, 0.17mol) was added and stirred at this temperature overnight. The reaction was cooled and purified by flash column chromatography on silica gel (PE/EA 20% -30%) to give 9305A4 (19g, 53%, colorless oil). ¹ H NMR(400MHz,CDCl ₃ )δ7.26-7.35(m,5H),5.08(s,2H),4.97(s,1H),4.14(q,J＝5.5Hz,2H),3.94(s,4H),2.11-2.19(m,4H),1.69-1.72(m,4H),1.20(t,J＝5.5Hz,3H)。

And 4, step 4: ethyl 1- (((benzyloxy) carbonyl) amino) -4-carbonyl cyclohexanecarboxylate (9305A 5)

9305A4 (19g, 62.9mmol) was dissolved in dioxane (200 ml), and 6N hydrochloric acid (100 ml) was added at room temperature and stirred at this temperature for 16 hours. After the reaction was complete, ethyl acetate (300 ml) was added and extracted, and the organic phase was dried over sodium sulfate and concentrated to give 9305A5 (169g, 97% as a colorless oil).

And 5, step 5: ethyl 1- (((benzyloxy) carbonyl) amino) -4- (((trifluoromethyl) sulfonyl) oxo) cyclohex-3-enecarboxylate (9305A 6)

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

And 6, a step of: ethyl 1- (((benzyloxy) carbonyl) amino) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohex-3-enecarboxylate (9305A 7)

9305A6 (1.6g, 3.5mmol) and Biboronic acid pinacol (0.9, 3.5mmol), pd (dppf) ₂ Cl _2. DCM (144mg, 5%), potassium acetate (1.0 g,10.6 mmol) were mixed in dioxane (30 ml) under argon and heated to 80 ℃ with stirring 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。

And 7, step 7: ethyl 1- (((benzyloxy) carbonyl) amino) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) cyclohex-3-enecarboxylate (9305A 9)

9305A7 (0.5g, 1.2mmol), 3 (259mg, 1.2mmol), pd (PPh) ₃ ) ₄ (100mg, 5%), potassium carbonate (400mg, 3.0 mmol) were mixed in dioxane (6 ml) and water (2 ml) under argon protection at 125 deg.CStirring under microwave for 5 hr, concentrating the obtained reaction solution, and purifying with flash silica gel column chromatography (PE/EA 50% -70%) to obtain 9305A9 (500mg, 85%, colorless oily substance). LCMS: [ M + H] ⁺ 491.10。

And 8, step 8: 1- (((benzyloxy) carbonyl) amino) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) cyclohex-3-enecarboxylic acid (9305A 10)

9305A9 (0.5g, 1.0 mmol) and lithium hydroxide monohydrate (125mg, 3.1mmol) were dissolved in tetrahydrofuran (2 ml), methanol (2 ml) and water (2 ml), and the system was heated to 60 ℃ and stirred for 3 hours, after completion of the reaction, cooled and concentrated to give 9305A10 without further purification. 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 (270mg, 0.97mmol), HATU (555mg, 1.46mmol), DIPEA (0.46ml, 2.91mmol) were mixed in DMF (4 ml) and stirred at room temperature for 16 hours. After completion of the reaction, DMF was removed by concentration under reduced pressure, followed by purification by flash silica gel column chromatography (EA) to give 9305A12 (SZ-9367) (60 mg, white solid). LCMS: [ M + H ]] ⁺ 543.10，HPLC:t _R ＝6.49min。 ¹ H NMR(400MHz,DMSO-d6)δ11.90(s,1H),9.54(s,1H),8.72(s,1H),8.68(d,J＝5.5Hz,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＝9.0Hz,3H)。

SZ-9367HPLC analytical method

Instrument-Waters Acquity ARC (UHPLC)

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

Mobile phase A0.1% ammonia water solution

Mobile phase B of acetonitrile

Gradient elution:

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

Flow rate: 1ml/min

Wavelength: 254nm

Column temperature: 30 deg.C

Blank solvent methanol

Sample solution, which is obtained by dissolving a proper amount of SZ-9367 in methanol, filtering with a 0.22um filter membrane, and performing liquid chromatography 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-9336A and SZ-9336B)

9305A12 (20 mg) was suspended in ethanol (2 ml), dissolved by dropping 2 drops of acetic acid, and stirred overnight at 60 ℃ under a hydrogen atmosphere. After the reaction, the system pH =9 was adjusted with saturated sodium carbonate, extracted with dichloromethane, the organic phase was concentrated and separated and purified with preparative plates to give two isomers SZ-9336A (6 mg) and SZ-9336B (1.2 mg).

SZ-9336A:LCMS:[M+H] ⁺ 545.10，HPLC t _R ＝5.79min。 ¹ H NMR(400MHz,CD ₃ OD)δ8.40(dd.J ₁ ＝0.5Hz,J ₂ ＝5.0Hz,1H),8.36(d,J＝2.5Hz,1H),7.93(d,J＝10.0Hz,1H),7.82(d,J＝10.5Hz,1H),7.56(d,J＝5.0Hz,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＝9.0Hz,3H),1.58-1.66(m,2H)。

SZ-9336B:LCMS:[M+H] ⁺ 545.10，HPLC：t _R ＝6.24min. ¹ H NMR(400MHz,CD ₃ OD)δ8.40(d,J＝5.0Hz,1H),8.35(d,J＝3.0Hz,1H),7.92(dd,J ₁ ＝3.5Hz,J ₂ ＝10.5Hz,1H),7.81(d,J＝10.5Hz,1H),7.58(d,J＝5.5Hz,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＝9.0Hz,1H),1.57-1.65(m,2H)。

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

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

Example 5SZ-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-sulfanyl-1, 3, 8-triazaspiro [4.5] decan-4-one

Step 1:

the compound 9315A1 (1g, 2.3mmol) was dissolved in THF (20 ml), and triethylamine (1g, 10mmol) and thiocarbonyldiimidazole (1.78g, 10mmol) were added thereto and the mixture was stirred at 60 ℃ for 16 hours. Water (50 ml) was added to the system, extracted with ethyl acetate (50mlx 2), the organic phase was concentrated under reduced pressure, and the resulting residue was isolated and purified using preparative plates (DCM: CH) ₃ OH =20, 1) to give compound 9384A1 (200mg, 18%, yellow solid). LCMS: [ M + H] ⁺ 475.03。

Step 2:

the compound 9384A1 (100mg, 0.21mmol) was dissolved in dichloromethane (2 ml), trifluoroacetic acid (0.5 ml) was added thereto, and the mixture was stirred at room temperature for 2 hours, and the solvent was removed by concentration to obtain 9384A2, which was reacted in the next step without purification. LCMS: [ M + H] ⁺ 375.05。

And 3, step 3:

compound 9384A2 (100mg, 0.27mol), compound 3 (60mg, 0.27mmol), and potassium carbonate (186mg, 1.35mmol) were added to DMSO (5 ml), and stirred at 110 ℃ for 16 hours. Adding water (50 ml), extracting with ethyl acetate (20ml × 3), concentrating under reduced pressure to obtain crude product, and performing high pressure reverse phase column chromatography (ACN-0.1% ₂ Aqueous H) and lyophilized to afford SZ-9384 (23.5 mg,16%, white solid). LCMS: [ M + H ]] ⁺ 562.08。 ¹ H NMR(400MHz,CD ₃ OD)δ8.53–8.49(m,2H),8.05(dd,J＝8.6,2.3Hz,1H),7.92(d,J＝8.6Hz,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 6SZ-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-en-4-one

Step 1:

compound SZ-9384 (50mg, 0.089mmol) was dissolved in methanol (3 ml), and 7M ammonia methanol solution (0.1 ml) and 70% t-butyl hydroperoxide (0.1 ml) were added. Water (10 ml) was added to the system, extracted with ethyl acetate (10ml. Times.3), and the organic phase was concentrated under reduced pressure to obtain a crude product, which was subjected to high-pressure reverse phase column chromatography (ACN-0.1% HCO) ₂ Aqueous H) and lyophilized to give SZ-9333 (3.2mg, 6%, white solid). LCMS: [ M + H] ⁺ 545.12。 ¹ H NMR(400MHz,CD ₃ OD)δ8.54(d,J＝4.4Hz,1H),8.50(d,J＝2.3Hz,1H),8.04(dd,J＝8.6,2.3Hz,1H),7.98(d,J＝8.6Hz,1H),7.73(d,J＝4.4Hz,1H),6.15(d,J＝12.9Hz,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 7SZ-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] decane-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 WO 2017079140) (0.3g, 2.13mmol) and DIPEA (0.9ml, 4.26mmol) were added to the reaction flask and stirred to dissolve. HATU (0.91g, 1.1 mmol) was added and reacted at 23-26 ℃ for 16 hours. The reaction solution was extracted with water (30 ml), EA (30ml × 3), the organic phases were combined and washed with saturated brine (30 ml × 3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by flash silica gel column chromatography (PE: EA =3, 1 to EA, DCM: meOH =10, rf = 0.3) to give 9334A0 (860mg, 61.9%, an off-white solid). LCMS: [ M + H] ⁺ 655.19@4.19min。

Step 2:

9334A0 (730mg, 1.11mmol) and methanol (6 ml) were added to the reaction flask and stirred to dissolve them. Then diethylamine (6 ml) was added in portions and reacted at 26 ℃ for 3 hours. The reaction was concentrated under reduced pressure to give a crude product, which was purified by flash silica gel column chromatography (PE: EA =1 to EA, DCM: meOH =10 1, rf = 0.3) to give 9334A1 (0.426 g,53.3%, light yellow oil left overnight to become solid). LCMS De-Boc [ M + H] ⁺ 333.08@2.85min。

And 3, 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] decane-8-carboxylic acid ester (9334A 2)

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

And 4, step 4: (S) -3- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-methyl-1, 3, 8-triazaspiro [4.5] decane-2, 4-dione; trifluoroacetate (9334A 3)

Compound 9334A2 (91mg, 0.19mmol) is dissolved in dichloromethane (3 ml), trifluoroacetic acid (3 ml) is added, stirring is carried out at 23 ℃ for 1 hour, and the solvent is removed by concentration under reduced pressure to obtain crude 9334A3, which is directly used for the next reaction. LCMS: [ M + H] ⁺ 359.06@2.72min。

And 5, 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] decane-2, 4-dione (SZ-9334)

Compound 9334A3 (91mg, 0.19mol), compound 3 (133mg, 0.60mmol) (prepared according to WO 2017079140) and potassium carbonate (0.26g, 1.8mmol) were added to DMSO (6 ml) and stirred at 110 deg.CAnd 39 hours. Water (30 ml) was added to the system, followed by extraction with ethyl acetate (30 ml. Times.3). The combined organic phases were washed with saturated brine (30 ml x 3), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product SZ-9334 (0.1 g) was purified by preparative thin layer chromatography (EA; rf = 0.5). Then purified using column chromatography [ (PE: EA =3, 1 to EA, DCM: meOH = 10)]Crude SZ-9334 (30 mg) was obtained. Followed by purification using high pressure preparative chromatography gave SZ-9334 (14mg, 14.29%, white solid). LCMS: [ M + H] ⁺ 546.10@3.16min。 ¹ H NMR(400MHz,CD ₃ OD)δ8.51(s,1H),8.50(s,1H),8.46(d,J＝4.0Hz,1H),8.04-8.01(dd,J1＝8.0Hz,J2＝4.0Hz,1H),7.93-7.91(d,J＝8.0Hz,1H),7.69-7.68(d,J＝4.0Hz,1H),5.43-5.36(q,J＝8.0Hz,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 8SZ-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] decane-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] decane-8-carboxylate (9335A 1)

NaH (0.16g, 60Wt%) was added portionwise to a solution of compound 9334A2 (190mg, 0.39mmol) in DMF at 23 deg.C and the reaction mixture was stirred for an additional 1h at 23 deg.C. Methyl iodide (0.6 g) was then added dropwise to the reaction solution. The resulting reaction mixture was stirred for another half hour. The reaction was then quenched by dropwise addition of saturated aqueous ammonium chloride (3 ml), followed by dilution with water (30 ml) and extraction with ethyl acetate (30 ml x 3). The organic phases are combined and dried over anhydrous magnesium sulfateFiltered and concentrated to remove the organic solvent, and the crude product was purified by preparative thin layer chromatography (PE: EA = 1. 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] decane-2, 4-dione; trifluoroacetate (9335A 2)

Compound 9335A1 (119mg, 26umol) was dissolved in dichloromethane (3.3 ml), trifluoroacetic acid (3.6 ml) was added, stirring was performed at 23 degrees celsius for 1 hour, the solvent was removed by water pump concentration, and then pumping was performed for three minutes using an oil pump. The crude product (9335A 2) was used directly in the next reaction. LCMS: [ M + H] ⁺ 373.08@2.73min。

And 3, 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] decane-2, 4-dione (SZ-9335)

Compound 9335A2 (136mg, 0.29mol), compound 3 (130mg, 0.60mmol) and potassium carbonate (0.39g, 0.3mmol) were added to DMSO (6 ml) and stirred at 180 ℃ for 1.5 hours. After the resulting reaction mixture was cooled to room temperature, water (30 ml) was added to the system, followed by extraction with ethyl acetate (30 ml. Times.3). The combined organic phases were washed with saturated brine (30 ml x 3), dried over anhydrous magnesium sulfate and filtered. The organic phase was concentrated under reduced pressure to give crude which was isolated once by medium pressure preparative chromatography and then purified by high pressure preparative chromatography to give SZ-9335 (2.1mg, 1.3%, white solid). LCMS: [ M + H ]] ⁺ 560.1 0@3.33min。 ¹ H NMR(400MHz,CD ₃ OD)δ8.51-8.50(d,J＝4.0Hz 1H),8.47-8.46(d,J＝4.0Hz 1H),8.05-8.02(dd,J1＝8.0Hz,J2＝4.0Hz,1H),7.93-7.91(d,J＝8.0Hz,1H),7.69-7.68(d,4.0Hz 1H),6.12-6.10(d,J＝8.0Hz,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 9SZ-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:

a reaction bottle is filled with a compound 9306A0 (8g, 40mmol), naOH (3.2g, 80mmol), THF (100 ml) and water (100 ml) to be stirred, then di-tert-butyl dicarbonate (13g, 60mmol) is added to be stirred at room temperature overnight, the reaction liquid is adjusted to pH 2 with 1N hydrochloric acid, ethyl acetate (300ml x 3) is used for extraction, an organic phase is dried by anhydrous sodium sulfate, filtration is carried out, a filtrate is decompressed and concentrated to obtain a compound 9306A1 (10.8g, 85 percent, white foamy solid), and the next reaction is carried out directly after impurity. 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 WO 2017079140) (6.18g, 30mmol) and DIPEA (10ml, 60mmol) were charged into a reaction flask and stirred to dissolve. HATU (13.68g, 36mmol) was added and reacted at 23-26 ℃ for 16 hours. The reaction mixture was extracted with EA (100 ml) in water (300 ml), the organic phases were combined and washed with saturated brine (100 ml 3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product which was purified by flash silica gel column chromatography to give 9306A2 (12g, 81%, white foamy solid). LCMS: [ M + H] ⁺ 490.07

And 3, step 3:

9306A2 (9.78g, 20mmol), naOH (4.8g, 120mmol) and DMF (100 ml) were charged in a reaction flask, and the reaction mixture was heated to 60 ℃ and stirred for 3 hours. Water (300 ml) was added to the reaction mixture and filtered to give crude 9306A3 (7g, 84% as a white powdery solid). LCMS: [ M + H] ⁺ 416.02

And 4, step 4:

9306A3 (4.15g, 10mmol) and DMF (30 ml) were added to a reaction flask, naH (480mg, 20mmol) was added in portions at 0 ℃ and stirred for 1 hour, and methyl iodide (2) was further added dropwise82g, 20mmol) was stirred at 26 ℃ and reacted overnight. Water (300 ml) was added to the reaction mixture and filtered to give crude 9306A4 (3.9g, 90%, white powdery solid). LCMS M + H] ⁺ 430.04

And 5, step 5:

9306A4 (3.5g, 8.16mmol) and Dioxane (100 ml) were added to a reaction flask, 6N hydrochloric acid (100 ml) was added at 0 ℃, stirred overnight at 26 ℃, the reaction solution was adjusted to pH with saturated sodium carbonate solution, =9, extracted with EA (100 mlx 3), the organic phases were combined and washed with saturated saline (100 mlx 3), dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated under reduced pressure to give a crude product, which was purified by flash silica gel column chromatography to give 9306A5 (2.9g, 92%, white foamy solid). LCMS De-Boc [ M + H] ⁺ 386.01

And 6, a step of:

9306A5 (2.9g, 7.53mol) was dissolved in anhydrous tetrahydrofuran (50 ml), the system was cooled to-70 ℃ under argon protection and LiHMDS (15ml, 15mol/L) was slowly added dropwise, then stirring was carried out at temperature again for 1 hour, and then phenylbis (trifluoromethanesulfonyl) imide (5.4g, 15mmol) in tetrahydrofuran (30 ml) was quickly added to the system and stirred at elevated temperature to 0 ℃ for 3 hours. After the reaction was complete, 20ml of saturated ammonium chloride was added and quenched, extracted with 50ml of ethyl acetate, and the organic phase was dried over sodium sulfate, concentrated and purified by flash column chromatography to afford 9305A6 as a colorless oil (2.9 g,75%, white foamy solid). LCMS De-Boc [ M + H] ⁺ 517.94

And 7, step 7:

9306A6 (2.9g, 5.6mmol) and Biboronic acid pinacol (1.7g, 36.72mmol), pd (dppf) ₂ Cl _2. DCM (228mg, 5%), potassium acetate (1.65g, 16.8mmol) were mixed in dioxane (50 ml) under argon and heated to 80 ℃ with stirring for 4 h. After the reaction was completed, the solvent was removed by cooling, and the reaction mixture was purified by flash silica gel column chromatography to give 9305A7 (2.0 g,72%, white foamy solid) as a colorless oil. LCMS: [ M + H] ⁺ 496.06。

And 8, step 8:

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

Step 9:

9306A8 (330 mg) was suspended in ethanol (10 ml), dissolved by dropping acetic acid (5 ml), and stirred at 60 ℃ overnight under a hydrogen atmosphere. After the reaction, adjusting the pH of the system to about =9 with saturated sodium carbonate, extracting with EA, concentrating the organic phase under reduced pressure to obtain a crude product, purifying with high pressure reverse phase column chromatography (ACN-0.1% ammonium carbonate aqueous solution), and freeze-drying to obtain two isomers SZ-9306A (60 mg) and SZ-9306B (12 mg). LCMS: [ M + H] ⁺ 559.04

SZ-9306A：HPLC t _R ＝6.07min。 ¹ H NMR(400MHz,DMSO-d6)δ11.87(s,1H),9.55(s,1H),8.68(d,J＝4.4Hz,1H),8.43(d,J＝1.9Hz,1H),7.95(ddd,J＝18.9,11.7,5.4Hz,3H),6.67(s,2H),5.34(q,J＝7.1Hz,1H),2.81(s,3H),2.64(t,J＝12.3Hz,1H),2.38–2.26(m,2H),2.21(d,J＝22.5Hz,6H),1.95(dd,J＝18.0,8.8Hz,2H),1.89–1.64(m,7H)。

SZ-9306B：HPLC t _R ＝6.35min。 ¹ H NMR(400MHz,DMSO-d6)δ11.93(s,1H),9.55(s,1H),8.68(d,J＝4.4Hz,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).

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

Instrument-Waters Acquity ARC (UHPLC)

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

Mobile phase A0.1% aqueous formic acid solution

Mobile phase B acetonitrile

Time (min)	A(％)	B(％)
			0	75	25
10	55	45
			13	20	80
13.1	75	25
			18	75	25

Flow rate: 1ml/min

Wavelength: 290nm of

Column temperature: 30 deg.C

Blank solvent methanol

Dissolving a proper amount of SZ-9306A or SZ-9306B in methanol, filtering with a 0.22um filter membrane, and analyzing by liquid chromatography.

Example 10SZ-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] decan-1-one

Step 1:

LiHMDS (69ml, 69mmol) was added dropwise to a solution of compound 1 (11g, 42.6 mmol) in THF (160 ml) at-78 deg.C. The resulting reaction mixture was stirred at-78-23 ℃ for an additional half an hour. Then, it was cooled to-78 ℃ and allyl bromide (6.9 g, 60mmol) was added dropwise to the above reaction solution. The resulting reaction mixture was stirred at-78-23 ℃ for an additional 16 hours. Adding saturated NH to the obtained reaction mixture ₄ Aqueous Cl (160 ml) was quenched and diluted with water (30 ml). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (0.1Lx3). The combined organic phases were dried over anhydrous MgSO4, filtered, and concentrated to remove the organic solvent. The resulting crude product was purified by flash silica gel column chromatography (PE: EA =10, 1, rf = 0.1) to give the product 9386A0 (11g, 87.3%) as a yellow liquid.

Step 2:

9334A0 (6.3 g, 21mmol) was added to a mixed solution of water (80 ml) and acetonitrile (80 ml) at 23 ℃ followed by the addition of NaIO4 (14.6 g) and RuCl3 solid (0.13 g) in that order. The resulting reaction mixture was stirred at 23 ℃ for an additional 3 hours. The resulting dark brown suspension was diluted with water (110 ml) and extracted with ethyl acetate (0.3 Lx3). The combined organic phases were dried over anhydrous MgSO4, filtered, and concentrated to remove the organic solvent. The resulting crude product was purified by flash silica gel column chromatography (PE: EA =10, 1 to 1, rf = 0.3) to afford 9386A1 (1.8g, 28.6%, light yellow liquid).

And 3, 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] decane-8-carboxylic acid ester (9386A 2)

NaBH (OAc) 3 (3.9 g) was added portionwise to a solution of compound 9386A1 (1.8g, 0.59mmol) and compound 2 in 1, 2-dichloroethane at 23 deg.C and the resulting reaction mixture was stirred for an additional 16 hours at 16-23 deg.C. The resulting reaction mixture was then heated to 110 degrees celsius and stirring was continued for 1 hour. The resulting reaction mixture was concentrated to remove the organic solvent, and the residue was quenched with saturated aqueous NH4Cl (30 ml), followed by extraction with ethyl acetate (30 mx 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated to remove the solvent, and the residue was purified by flash silica gel column chromatography (PE: EA =3,off-white solid compound 9386A2 (1.6 g, 67.8%) was obtained. LCMS: [ M + Na] ⁺ 466.01@3.79min。

And 4, step 4: (S) -2- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2, 8-triazaspiro [4.5] decan-1-one; trifluoroacetate salt (9386A 3)

The compound 9386A2 (0.6 g, 1.39mmol) was dissolved in dichloromethane (3 ml), trifluoroacetic acid (3 ml) was added, stirring was performed at 21 ℃ for 1 hour, the solvent was removed by water pump concentration, and then pumping was performed for three minutes using an oil pump. The crude 9386A3 (0.6 g) was reacted directly in the next step. LCMS: [ M + H] ⁺ 344.06@2.683min。

And 5, 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] decan-1-one (SZ-9386)

Compound 9386A3 (0.6g, 1.39mol), compound 3 (0.58g, 2.58mmol) and potassium carbonate (1.1g, 7.8mmol) were sequentially added to DMSO (6 ml), and stirred at 110 ℃ for 3 hours. Water (30 ml) was added to the system, followed by extraction with ethyl acetate (30 ml. Times.3). The combined organic phases were washed with saturated brine (30 ml x 3), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the crude product. Followed by purification using high pressure preparative chromatography gave SZ-9386 (110mg, 14.9%, white solid). LCMS: [ M + H] ⁺ 531.10@3.103min。 ¹ H NMR(400MHz,CD ₃ OD)δ8.51(d,J＝4.0Hz,1H),8.35(s,1H),7.93(d,J＝8.0Hz,1H),7.87(d,J＝8.0Hz,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＝4.0Hz,3H),1.5(d,J＝12.0Hz,1H)，1.41(d,J＝12.0Hz,1H)。

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

Step 1: tert-butyl (S) -2- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2, 8-diazaspiro [4.5] decane-8-carboxylic acid ester (013004A 1)

LAH (0.16g, 4.19mmol) was added portionwise to a solution of the compound 9386A2 (0.3g, 0.67mmol) in THF at 23 deg.C, then THF (3 ml) was added to dilute the reaction. The resulting reaction mixture was stirred at 23 ℃ for an additional 30 minutes. The resulting reaction mixture was cooled to 1-3 deg.C and THF (13 ml) was added to dilute the reaction. Then, water (0.16 ml), an aqueous NaOH solution (0.16ml, 16Wt%) and water (0.5 ml) were added in this order to quench the reaction system. The resulting reaction mixture was stirred for another half hour. The solid was then filtered and washed with THF (6 mlx 3). The filtrates were combined and concentrated under reduced pressure to give the crude product which was purified by preparative thin layer chromatography (PE: EA = 1. 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 (013004A 2)

Compound 013004A1 (30mg, 69.8umol) was dissolved in methylene chloride (3 ml), and trifluoroacetic acid (3 ml) was added thereto, followed by stirring at 21 ℃ for 1 hour, concentration by a water pump to remove the solvent, and pumping with an oil pump for three minutes. The crude 013004A2 (31mg, 98%) was reacted directly in the next step. LCMS: [ M + H] ⁺ 330.07@0.873min。

And 3, step 3: (S) -2- (2- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2, 8-diazaspiro [4.5] decan-8-yl) -6-methyl-N- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-4-amine (SZ-013004)

Compound 013004A2 (31mg, 69umol), compound 3 (31mg, 0.13mmol) and potassium carbonate (0.126g, 0.9mmol) were added to DMSO (3 ml), and stirred at 110 ℃ for 16 hours. After the resulting reaction mixture was cooled to room temperature, water (30 ml) was added to the system, followed by extraction with ethyl acetate (30 ml. Times.3). The combined organic phases were washed with saturated brine (30 ml x 3), dried over anhydrous magnesium sulfate and filtered. The organic phase was concentrated under reduced pressure to give a crude product which was purified by preparative high pressure chromatography to give SZ-013004 (6.3mg, 18%, white solid). LCMS: [ M + H ]] ⁺ 517.10@2.23min。 ¹ H NMR(400MHz,CD ₃ OD)δ8.49(d,J＝4.0Hz 1H),8.37(d,J＝4.0Hz 1H),7.95(dd,J1＝16.0Hz,J2＝8.0Hz,1H),7.91(d,J＝16.0Hz,1H),7.68(d,J＝4.0Hz,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＝4.0Hz,3H)。

Example 12SZ-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

013002A4 (560mg, 1.2mmol) and THF (20 ml) were charged to a reaction flask, cooled to 0 ℃ with stirring, and NaH (95mg, 2.4 mmol) was slowly added thereto, and the mixture was warmed to room temperature and stirred for 20 minutes. Finally, meI (185mg, 1.3 mmol) was added and reacted at 20 ℃ for 12 hours. The reaction was quenched with saturated ammonium chloride solution, then water (100 ml) was added, extracted with EA (50ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to give crude product, which was purified by flash silica gel column chromatography (EA/PE 0-50%) to give 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

The compound 9391A1 (270mg, 0.55mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, stirred at room temperature for 2 hours, and the solvent was removed by concentration to give the crude 9391A2, which was reacted in the next step without purification.

And 3, 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-dione

Compound 9391A2 (214mg, 0.55mol), intermediate 2 (122mg, 0.55mmol) and potassium carbonate (303mg, 2.2mmol) were added to DMSO (5 mL) and stirred at 110 ℃ for 16h. 50mL of water was added to the system, extracted with ethyl acetate (20 mL) three times, the organic phase was vacuum-spin-dried to give a crude product, which was then subjected to reversed-phase column chromatography with acetonitrile/0.1% formic acid water and freeze-dried to give SZ-9391 (100mg, 32%, white solid). LCMS: [ M + H ]] ⁺ 574.5。

¹ H NMR(400MHz,DMSO-d6)δ9.25(s,1H),8.70(d,J＝4.5Hz,1H),8.40(s,1H),7.99-7.89(m,3H),6.29-6.01(m,2H),5.77(q,J＝7.0Hz,1H),4.55-4.45(m,2H),4.14(d,J＝17.8Hz,1H),3.69(d,J＝17.8Hz,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＝7.0Hz,3H)。

Example 13SZ-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] decan-2-one

Step 1: tert-butyl-4- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -4-formylpiperidine-1-carboxylic acid ester

The reaction flask was charged with compound 9380A0 (1.4g, 3.1mmol), PCC (1.34g, 6.2mmol) and DCM (40 ml) and stirred at 25 deg.C for 12 hours, filtered through celite, and the filtrate was concentrated under reduced pressure to give 9380A1 (1.1g, 79%, white foamy solid) which was purified by flash silica gel column chromatography. LCMS De-Boc [ M + H] ⁺ 451.48。

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

9380A1 (1.1g, 2.4mmol), (S) -1- (6- (4) was added to the reaction flask-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethylamine (prepared according to WO 2017079140) (0.5g, 2.4 mmol) and acetic acid (0.1 mL), DCM (20 mL) were dissolved with stirring. Finally, sodium triacetoxyborohydride (1.56g, 7.3mmol) was added and reacted at 23-26 ℃ for 6 hours. The reaction solution was added with saturated ammonium chloride solution (100 ml), extracted with EA (30ml × 3), the organic phases were combined and washed with saturated brine (30ml × 3), dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated under reduced pressure to give crude product, which was purified by flash silica gel column chromatography to give 9380A2 (800mg, 52%, white foamy solid). LCMS: [ M + H ]] ⁺ 641.28。

And 3, step 3: tert-butyl- (S) -4-amino-4- (((1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) amino) methyl) piperidine-1-carboxylic acid ester

The reaction flask was charged with 9380A2 (0.8g, 1.25mmol), diethylamine (5 mL) and methanol (20 mL), and the reaction was stirred at 25 ℃ for 3 hours. The reaction was concentrated under reduced pressure to give a crude product, which was purified by flash silica gel column chromatography to give 9380A3 (400mg, 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 (0.4 g, 1.15mmol), di-tert-butyl dicarbonate (0.3g, 1.38mmol) and DCM (20 mL) were charged into a reaction flask, stirred at 25 ℃ for 1 hour, the reaction solution was added with a saturated ammonium chloride solution (50 mL), extracted with EA (15mL. Multidot.3), the organic phases were combined, washed with a saturated saline solution (15mL. Multidot.3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by flash silica gel column chromatography to give 9380A4 (460mg, 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-carboxylic acid ester

9380A4 (460mg, 0.89mmol), naOH (213mg, 5.32mmol) and DMF (5 mL) were added to a reaction flask, the mixture was stirred at 60 ℃ for 3 hours, water (60 mL) was added to the reaction mixture, EA (15mL. Times.3) was used for extraction, the organic phases were combined, washed with saturated brine (15mL. Times.3), and dried over anhydrous magnesium sulfateFiltration and concentration of the filtrate under reduced pressure gave the crude product which was purified by flash silica gel column chromatography to give 9380A5 (330mg, 84%, white foamy solid). LCMS: [ M + H] ⁺ 445.16。

And a sixth step: (S) -3- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1,3, 8-triazaspiro [4.5] decan-2-one

9380A5 (330mg, 0.74mmol) was added to the reaction flask, dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was slowly added dropwise, stirred at 25 ℃ for 2 hours, and the solvent was dried without purification to afford 9380A6 (360 mg, crude) which was directly used in the next step. LCMS: [ M + H] ⁺ 345.23。

The seventh step: (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] decan-2-one

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

¹ H NMR(400MHz,DMSO-d6)δ11.83(s,1H),9.19(s,1H),8.69(dd,J＝4.6,0.7Hz,1H),8.39(s,1H),8.02–7.78(m,3H),7.04(s,1H),6.13(d,J＝43.1Hz,2H),5.10(q,J＝7.1Hz,1H),3.91–3.74(m,2H),3.74–3.55(m,2H),3.28(d,J＝9.0Hz,1H),2.89(d,J＝9.0Hz,1H),2.18(s,3H),2.09(s,3H),1.59(dd,J＝11.0,6.5Hz,2H),1.51(d,J＝7.2Hz,5H)。

Example 14SZ-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] decan-2-one

Step 1: methyl-8-amino-1, 4-dioxaspiro [4.5] decane-8-carboxylic acid ester

After compound 013011A0 (18g, 90mmol) was dissolved in methanol hydrochloride solution (400 mL), the mixture was reacted under reflux for 6 hours, the system was cooled to room temperature, and the reaction mixture was dried under reduced pressure to give crude 013011A1 (25 g, colorless oily substance) which was used in the next reaction without purification. LCMS: [ M + H] ⁺ 216.08。

Step 2: methyl-8- ((tert-butoxycarbonyl) amino) -1, 4-dioxaspiro [4.5] decane-8-carboxylic acid ester

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

And 3, step 3: tert-butyl (8-hydroxymethyl) -1, 4-dioxaspiro [4.5] decan-8-yl) carbamate

013011A2 (8g, 0.025mol) was dissolved in THF (100 ml), and LiAlH was added in portions ₄ (1g, 0.025mol), stirring for 1 hour with the reaction temperature controlled not to exceed 25 ℃, TLC monitoring disappearance of the starting material, quenching by addition of saturated ammonium chloride, followed by extraction with ethyl acetate (300 mL), drying of the organic phase over sodium sulfate and spin-drying to give a crude product, which was subjected to flash silica gel column chromatography to give 013011A3 (3.3g, 46%, colorless oily liquid). LCMS: [ M + H] ⁺ 288.08。

And 4, step 4: tert-butyl (8-formyl-1, 4-dioxa-si [4.5] dec-8-yl) carbamate

013011A3 (2.87g, 0.01mol) was dissolved in DCM (30 ml), PCC (6.46g, 0.03mol) was added thereto, the mixture was stirred at 25 ℃ for 4 hours, and the reaction mixture was stirred with silica gel to obtain 013011A4 (2g, 70%, white solid) by flash silica gel column chromatography. LCMS: [ M + H] ⁺ 285.99。

And 5, step 5: tert-butyl- (8- (((6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) methyl) amino) methyl) -1, 4-dioxaspiro [4.5] decan-8-yl) carbamate

013011A4 (2g, 7 mmol) was dissolved in DCE (30 mL), and glacial acetic acid (1 mL) and sodium triacetoxyborohydride (4.45g, 21mmol), 25 deg.C were addedAfter stirring for 4 hours under the conditions, the reaction mixture was stirred with silica gel and subjected to flash silica gel column chromatography to give 013011A5 (2.3g, 70%, white solid). LCMS: [ M + H] ⁺ 476.12。

And 6, step 6: (S) -3- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -9, 12-dioxa-1, 3-diazaspiro [4.2.4 ⁸ .2 ⁵ ]Tetradecan-2-one

013011A5 (2.3g, 4.84mmol) was dissolved in DMF (30 mL), sodium hydroxide (1.16g, 29mmol) was added, stirring was carried out at 60 ℃ for 4 hours, then water (100 mL) was added, followed by extraction with ethyl acetate (30X 3mL), the organic phase was dried over sodium sulfate and spun dry to give 013011A6 (1.6 g,82%, white solid) by flash silica gel column chromatography. LCMS: [ M + H] ⁺ 402.07。

And 7, step 7: (S) -3- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1-methyl-9, 12-dioxa-1, 3-diazaspiro [4.2.4 ⁸ .2 ⁵ ]Tetradecan-2-one

013011A6 (1.6g, 4mmol) was dissolved in DMF (20 mL), sodium hydride (0.16g, 4mmol) was added and stirred at 0 ℃ for 1 hour, then iodomethane (0.85g, 6mmol) was added and stirred at 40 ℃ for 4 hours, then water (100 mL) was added followed by extraction with ethyl acetate (30 x 3mL), the organic phase was dried over sodium sulfate and spun dry to give a crude product, which was chromatographed on flash silica gel to give 013011A7 (1.45g, 87%, white solid). LCMS: [ M + H ]] ⁺ 416.10。

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

013011A7 (1.45g, 3.5 mmol) was dissolved in Dioxane (30 mL), 4N hydrochloric acid (9 mL) was added, stirring was carried out at 40 ℃ for 6 hours, then water (100 mL) was added, followed by extraction with ethyl acetate (30X 3 mL), the organic phase was dried over sodium sulfate and then spun to give crude product, which was subjected to flash silica gel column chromatography to give 013011A8 (1g, 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 (20 mL), the system was cooled to-70 ℃ under the protection of argon and LiHMDS (3mL, 1mol/L) was slowly dropped in, and then stirred at this temperature for 1 hour, and then phenylbis (trifluoromethanesulfonyl) imide (1g, 2.7mmol) in tetrahydrofuran (10 mL) was rapidly added to the system and stirred at 0 ℃ for 3 hours. After the reaction was complete, 100mL of saturated ammonium chloride was added and quenched, extracted with 50mL of ethyl acetate, and the organic phase was dried over sodium sulfate, spun dry and purified by flash silica gel column chromatography to give 013011A9 (0.8g, 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, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3-diazaspiro [4.5] dec-7-en-2-one

013011A9 (0.8g, 1.6mmol) and Biboronic acid pinacol (0.4g, 1.6mmol), pd (dppf) ₂ Cl _2. DCM (65mg, 5%), potassium acetate (0.47g, 4.8mmol) were mixed in dioxane (30 mL) under argon and heated to 80 ℃ with stirring for 4 hours. After the reaction, the solvent was removed by cooling, and the reaction mixture was purified by flash silica gel column chromatography to obtain 013011A10 (0.6g, 78%, white solid). LCMS: [ M + H] ⁺ 482.16。

And 11, 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%) and potassium carbonate (518mg, 3.75mmol) were mixed with dioxane (6 mL) and water (2 mL) under an argon atmosphere, and stirred at 125 ℃ for 5 hours under a microwave, and the resulting reaction mixture was spin-dried and purified by flash silica gel column chromatography to give 013011A11 (600mg, 89%, white solid). LCMS: [ M + H ]] ⁺ 542.16。

And (12) step: (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] decan-2-one

013011A11 (0.6 g, 1.1mmol) was dissolved in methanol (10 mL), and ammonium formate (0.7 g, 11mmol) and ammonium formate (0.6g, 11mmol) were addedPalladium hydroxide/C (100 mg), stirring at 60 deg.C for 3 hr, filtering, spin-drying the organic phase under reduced pressure to give crude product, and subjecting to medium pressure reverse phase column chromatography (ACN-0.1% HCO) ₂ Aqueous H) and lyophilized to give SZ-013011A (150 mg, white solid) and SZ-013011B (50 mg, white solid). LCMS: [ M + H] ⁺ 545.7。

SZ-013011A:LCMS t _R ＝2.059min，HPLC t _R ＝5.68min， ¹ H NMR(400MHz,DMSO-d6)δ11.89(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＝28.4,13.2Hz,4H),1.71–1.48(m,6H),1.40(d,J＝12.1Hz,1H)。

SZ-013011B:LCMS t _R ＝2.100min，HPLC t _R ＝6.32min， ¹ H NMR(400MHz,DMSO-d6)δ11.92(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＝7.1Hz,1H),5.11(q,J＝7.1Hz,1H),3.31(d,J＝9.0Hz,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＝12.4Hz,1H)。

The HPLC analysis method of SZ-013011A and SZ-013011B is as follows:

instrument Waters Acquity ARC (UHPLC); a chromatographic column: xsselect CSHTMC 18.5 um4.6 x 150mm Column XP; mobile phase A is 0.1% ammonia water solution; the mobile phase B is acetonitrile; flow rate: 1ml/min; wavelength: PDA full wavelength, 254nm,220nm; column temperature: 30 ℃; the blank solvent is methanol; dissolving a proper amount of a substance to be detected in methanol, and filtering the solution by using a 0.22 mu m filter membrane; gradient elution:

example 15SZ-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-dione

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

9307A1 (2.3g, 5 mmol) and DMF (20 ml) were added to a reaction flask, stirred, added with (S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethylamine (prepared according to WO 2017079140) (1.0g, 5 mmol), DIPEA (1.9g, 15mmol), and finally HATU (2.3g, 6 mmol), and reacted at 20 ℃ for 1 hour. Water (100 ml) was added to the reaction mixture, extracted with EA (50 ml. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by flash silica gel column chromatography (EA/PE 0-50%) to give 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) carbamoyl) piperidine-1-carboxylate (013002 A2)

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

And 3, step 3: tert-butyl (S) -4- (2-chloroacetylamino) -4- ((1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) carbamoyl) piperidine-1-carboxylate (013002A 3)

013002A2 (1.1g, 2.5mmol) and anhydrous THF (20 ml) were added to a reaction flask, stirred, added triethylamine (500mg, 5mmol), cooled to 0 ℃, dropwise added chloroacetyl chloride (316mg, 2.8mmol), and reacted for 12 hours after dropping to 20 ℃. Water (40 ml) was added to the reaction solution, and EA (10 ml. Times.3) was used for extraction to obtain an organic solutionThe phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by flash silica gel column chromatography (EA/PE 50-100%) to give 013002A3 (500mg, 39%, white solid). LCMS: [ M + H] ⁺ 509.04。

And 4, 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 (013002A 4)

013002A3 (500mg, 1.0 mmol) and anhydrous THF (10 ml) were added to a reaction flask, stirred, cooled to 0 deg.C, added sodium hydride (60% adsorbed in mineral oil, 80mg,2.0 mmol), slowly warmed to 60 deg.C and stirred for reaction for 20 minutes. After completion of the reaction, the reaction mixture was cooled to room temperature and quenched with 2ml of water. The reaction was extracted with water (40 ml) and EA (10 ml x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product which was purified by flash silica gel column chromatography (EA/PE 50-100%) to give 013002A4 (400mg, 85%, white solid). LCMS: [ M + H] ⁺ 473.01。

And 5, 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 (013002A 5)

After compound 013002A4 (200mg, 0.42mmol) was dissolved in dichloromethane (5 ml), trifluoroacetic acid (1 ml) was added thereto, and the mixture was stirred at room temperature for 2 hours, and the solvent was removed by concentration to obtain crude 013002A5, which was reacted in the next step without purification. LCMS: [ M + H ]] ⁺ 373.06。

And 6, 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 (157mg, 0.42mol), intermediate 2 (93mg, 0.42mmol) and potassium carbonate (231mg, 1.68mmol) were added to DMSO (5 ml) and stirred at 110 ℃ for 16 hours. To the system was added 50ml of water, extracted with ethyl acetate (20 ml x 3), concentrated under reduced pressure to give the crude product, purified by flash column chromatography on silica gel (DCM/EA 50%), dissolved in acetonitrile/water and lyophilized to give SZ-013002 (110mg, 47%, white solid). LCMS: [ M + H] ⁺ 560.15； ¹ H NMR(400MHz,DMSO-d6)δ11.87(s,1H),9.25(s,1H),8.70(d,J＝4.4Hz,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＝17Hz,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＝7.1Hz,3H)。

Example 16SZ-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] decan-3-one

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

A tetrahydrofuran solution of TBAF (15mL, 15mmol, 1M) was added in portions to a THF (3 mL) solution of compound 1 (1.29g, 5mmol) and nitromethane (0.8mL, 15mmol) at 23 deg.C. The resulting reaction mixture was heated to 86 degrees celsius and stirring was continued for 16 hours. The reaction mixture was cooled to room temperature and saturated NH was added ₄ Aqueous Cl (30 mL) was quenched and extracted with ethyl acetate (30ml × 3). The organic phases are combined and then anhydrous Mg is added ₂ Drying with SO4, filtering, and spin-drying the organic solvent. The resulting crude product was purified by silica gel column chromatography (PE: EA =30>10; rf = 0.3) to give 013005A0 (1.1 g, crude) as a colorless oil.

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

A solution of KOH (0.126g, 1.1mmol) in methanol (3.6 mL) was added dropwise to a solution of 013005A0 (0.6 g, 1.8mmol) in methanol (6 mL) at 1-3 deg.C. The resulting reaction mixture was stirred at 1-3 ℃ for an additional 30 minutes. Then adding Mg ₂ A solution of SO4 (0.19g, 1.36mmol) and potassium permanganate (0.216g, 1.36mmol) in water (30 mL) was added dropwise to the above reaction solution. The resulting reaction mixture was stirred at 1-3 ℃ for an additional 1 hour. Diatom for the resulting suspensionThe mixture was filtered through a filter, and the filtrate was combined with spin-dried solvent, and then further concentrated under reduced pressure using an oil pump to give 013005A1 (0.29 g, crude) as a pale yellow oil which was used directly in the next reaction.

And 3, 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-carboxylic acid ester

NaBH (OAc) ₃ (0.63g, 3mmol) was added portionwise at 23 ℃ to a suspension of compound 013005A1 (0.29g, 1mmol) and compound 2 (0.23g, 1mmol) in 1, 2-dichloroethane (6 mL) and the reaction mixture was stirred for a further 16h at 16-23 ℃. The resulting reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) and extracted with dichloromethane (30ml × 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated to remove the solvent, and the residue was purified by flash silica gel column chromatography (PE: EA =10>3:1->1:1->EA->EA: meOH = 10; rf = 0.3) to yield 013005A2 as an off-white solid (0.3g, 67%). LCMS: [ M + H ]] ⁺ 444.04@3.686min。

And 4, step 4: (S) -2- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2, 8-diazaspiro [4.5] decan-3-one; trifluoroacetic acid salt

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

And 5, 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] decan-3-one

A suspension of compound 013005A3 (0.23g, 0.67mmol), compound 3 (0.16g, 0.73mmol), potassium carbonate (0.56g, 3.9mmol) and DMSO (6 mL) was heated to 180 deg.C and stirring was continued for 1 hour. The resulting reaction mixture was cooled to 21 ℃ and then diluted with water (30 mL) and extracted with ethyl acetate (30ml × 3). The combined organic phases were washed with saturated brine (30mL. Multidot.3) and washed with brineDried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. Followed by purification using column chromatography (PE: EA =10>3:1->1:1->EA->MeOH =10 in DCM (3V/V% concentrated ammonia was added to aid elution), rf =0.1 to give impure compound SZ-013005 (50 mg). Followed by purification using HPLC to give SZ-013005 as a white solid (3.6 mg, 46.9%). LCMS: [ M + H] ⁺ 531.13@3.001min。1H NMR(400MHz,CD ₃ OD)δ8.54(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 17SZ-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] decan-1-one

Step 1: ethyl-1, 4-dioxaspiro [4,5] decane-8-carboxylic acid ester

LiHMDS (51mL, 51mmol) was added dropwise to a solution of Compound 1 (6.5g, 30mmol) in THF (60 mL) at-78 deg.C. The resulting reaction mixture was stirred for an additional one hour at-78 to 16 ℃. Then cooled to-78 deg.C and allyl bromide (3.39mL, 39mmol) was added dropwise to the reaction solution. The resulting reaction mixture was stirred at-78 to 16 degrees celsius for an additional 16 hours. Adding saturated NH to the obtained reaction mixture ₄ Aqueous Cl (90 mL) was quenched and diluted with water (30 mL). After separation of the organic phase, the aqueous phase was extracted with ethyl acetate (0.1l × 3). The organic phases were combined and dried over anhydrous MgSO4, filtered and the organic solvent was spin-dried. Oil pump was then used for three minutes to give product 9387A0 as a yellow liquid (8 g, crude).

Step 2: ethyl 8-allyl-1, 4-dioxyspiro [4,5] decane-8-carboxylic acid ester

9387A0 (5.18g, 21mmol) was added at 13 deg.CInto a mixed solution of water (93 mL) and acetonitrile (96 mL), followed by addition of NaIO4 (13.9 g) and RuCl in this order in portions ₃ Solid (0.129 g). The resulting reaction mixture was stirred at 13 ℃ for an additional 1.6 hours. The resulting off-white suspension was diluted with water (390 mL) and extracted with ethyl acetate (0.3 l x 3). The organic phases were combined, dried over anhydrous MgSO4, filtered and the organic solvent was spin-dried. Oil pump was then used for three minutes to give 9387A1 as a pale yellow oil (3.9 g, crude).

And 3, step 3: (S) -10- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1, 4-dioxo-10-azaspiro [4.2.4 ⁸ .2 ⁵ ]Tetradecyl-9-ones

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

And 4, step 4: (S) -2- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-azaspiro [4.5] decane-1, 8-dione

The compound 9387A2 (2.6 g, 6.48mmol) was dissolved in 1, 4-dioxane (29 mL), hydrochloric acid (30mL, 6M) was added to the reaction batch at 13 degrees Celsius, heated to 69 degrees Celsius and stirring was continued for 16 hours. The resulting reaction mixture was cooled to 13 degrees Celsius and solid Na was used ₂ CO ₃ Adjusting the pH of the system>9 (if a large amount of insoluble solid appears, it is dissolved in water, but the carrier is Na ₂ CO ₃ Saturation). The mixture was extracted with ethyl acetate (60ml x 3), the organic phases were combined and anhydrous MgSO was used ₄ Drying, filtration and spin-drying of the organic solvent gave the product 9387A3 (1.96g, 86%) as a white solid which was used directly in the next stepAnd (4) reacting. LCMS: [ M + H] ⁺ 357.19@3.280min。

And 5, step 5: 2- ((S) 1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1-carbonyl-2-azaspiro [4.5] dec-7-en-8-yl trifluoromethanesulfonate

LiHMDS (16.5mL, 16.5mmol) was added portionwise with a syringe to a solution of compound 9387A3 (1.96g, 5.5 mol) in tetrahydrofuran at-78 ℃. The resulting reaction mixture was stirred at-78 ℃ for an additional 1 hour. Then a solution of PhNTf2 (2.16g, 6.1mmol) in tetrahydrofuran (13 mL) was added slowly at-78 degrees celsius. The resulting reaction mixture was warmed to 13 ℃ at-78 and stirred for an additional 16 hours. Then adding saturated NH into the system ₄ The reaction was quenched with aqueous Cl (100 mL) and extracted with ethyl acetate (60ml × 3). The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a crude product. Followed by purification using column chromatography (PE: EA =10>3:1->1, rf = 0.3) to obtain a white solid compound 9387A4 (1.26g, 46.9%). LCMS: [ M + H ⁺ ]489.16@3.987mi。

And 6, step 6: 2- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2-azaspiro [4.5] dec-7-en-1-one

9387A4 (1.26g, 2.58mmol), bispcould Na borate (0.8g, 3.1mmol), potassium acetate (0.8g, 8mmol), 1, 4-dioxane (26 mL) and PdCl at 18 deg.C ₂ A suspension of (dppf) DCM (68 mg) was replaced with nitrogen three times with stirring, then heated to 90 degrees celsius under nitrogen blanket and stirring continued for 3 hours. The resulting reaction mixture was cooled to 19 degrees Celsius and then quenched by addition of water (60 mL). Extraction with ethyl acetate (60ml × 3). The organic phases were combined and anhydrous MgSO was added ₄ Drying, filtering and spin-drying the organic solvent. The crude product was purified by flash column chromatography (PE: EA =10>3:1->1:1->1:3->EA; rf = 0.3) yielded the product 9387A5 as a white solid (1.01g, 83.7%). LCMS: [ M + H ⁺ ]467.30@4.101min。

And 7, 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

At 16 degree centigradePd (PPh) ₃ ) ₄ (69 mg) was added portionwise to a suspension of the compound 9387A5 (0.8g, 1.6mmol), the compound 3 (0.39g, 1.6mmol), potassium carbonate (0.69g, 5.3mmol), 1, 4-dioxane (13 mL) and water (3 mL). Nitrogen was replaced three times and the resulting reaction mixture was in a Biotage microwave reactor: the reaction was carried out at 130 ℃ for one hour. The resulting red-yellow solution was cooled to room temperature, quenched with water (60 mL), and extracted with ethyl acetate (60ml × 3). The organic phases were combined and anhydrous MgSO was added ₄ Drying, filtering and spin-drying the organic solvent. The crude product was purified by flash silica gel column chromatography (PE: EA =3>1:1->1:3->EA->EA:MeOH＝30:1->16; rf = 0.1) yielded the product 9387A6 as a white solid (0.39g, 46.19%). LCMS: [ M + H ⁺ ]528.32@3.208min。

And 8, 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] decan-1-one.

The compound 9387A6 (300mg, 0.568mmol) was added to Pd (OH) at 16 deg.C ₂ To a black suspension of/C (300 mg) in methanol (60 mL) was added ammonium formate solids (16 g). The resulting reaction mixture was heated to 69 degrees celsius and stirring was continued for one hour. After cooling to room temperature, it was filtered through celite and washed with methanol (30ml × 3). The filtrates were combined, the solvent was spun dry and then dissolved in water (60 mL), and the solution was dissolved by adding solid Na ₂ CO ₃ Basification until saturation. Then extracted with ethyl acetate (60mL. Multidot.3), the organic phases were combined and anhydrous MgSO was added ₄ Drying, filtering and spin-drying the organic solvent. This crude product was purified by high pressure preparative liquid chromatography to give two diastereomers:

SZ-9387A (86mg, 28%, white solid). LCMS: [ M + H ] ⁺ ]530.32@3.217min。HPLC t _R ＝7.53min。 ¹ H NMR(400MHz,CD ₃ OD)δ8.42(d,J＝4.0Hz,1H),8.28(d,J＝4.0Hz,1H),7.85(d,J＝8.0Hz,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 (110mg, 37%, white solid). LCMS: [ M + H +]530.32@3.349min。HPLC t _R ＝8.45min。 ¹ H NMR(400MHz,CD ₃ OD)δ8.53(dd,J1＝4.0Hz,J2＝2.0Hz,1H),8.40(s,1H),7.96(d,J＝8.0Hz,1H),7.91(dd,J1＝4.0Hz,J2＝2.0Hz,1H),7.71(d,J＝4.0Hz,1H),6.75(br,1H),6.44(br,1H),5.44(q,J＝4.0Hz,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)。

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

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

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

wavelength: 287nm; column temperature: 30 ℃; the blank solvent is methanol;

the sample solution is prepared by dissolving appropriate amount of SZ-9387 in methanol, filtering with 0.22um filter membrane, and analyzing with liquid chromatography.

Time (min)	A(％)	B(％)
			0	75	25
10	37.5	62.5
			15	20	80
15.1	75	25
			18	75	25

Example 18SZ-9329:2- (2- ((6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) methyl) -3-methyl-1, 4, 8-triazaspiro [4.5] decan-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] decan-8-yl) pyrimidin-4-amine

4-piperidone ethylene glycol (470mg, 3.2mol), intermediate 2 (670mg, 3.0mmol) and potassium carbonate (1.2g, 9.0mmol) were added to DMSO (5 mL), and stirred at 110 ℃ for 16 hours. To the system was added 50mL of water, extracted with ethyl acetate (20mL × 3), and the organic phase was pressure-dried to give a crude product, which was subjected to flash silica gel column chromatography (MeOH/EA 10%) to give 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), and 6N concentrated hydrochloric acid (5 mL, 30mmol) was added with stirring and reacted at 20 ℃ for 2 hours. Neutralizing the reaction solution with saturated sodium bicarbonate, extracting with ethyl acetate (20ml × 3), vacuum drying to obtain crude product, and purifying with flash silica gel column chromatography (EA/PE 0-10%)Conversion afforded 9329A2 (700mg, 81%, white solid). LCMS: [ M + H] ⁺ 287.08。

And 3, step 3: 2- (2- ((6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) methyl) -3-methyl-1, 4, 8-triazaspiro [4.5] decan-1, 3-dien-8-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine

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

¹ H NMR(400MHz,DMSO-d ₆ )δ11.86(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 19SZ-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] decan-1, 3-dien-2-yl) methanone

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

2-chloro-5-hydroxymethylpyridine (4.3g, 30mmol), 4-fluoro-1H-pyrazole (2.6g, 20mmol), cesium carbonate (9.6g, 30mmol) and DMSO (100 ml) were charged in a reaction flask, heated to 140 ℃ and stirred for 16 hours. The reaction mixture was extracted with water (200 ml) and EA (150ml. Multidot.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product which was purified by flash silica gel column chromatography (EA/PE 0-50%) to give 013037A1 (5.0 g,87%, white solid). LCMS: [ M + H] ⁺ 194.03。

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

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

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

013037A2 (3.6g, 19mmol), potassium iodide (2.8g, 19mmol), lithium hydroxide monohydrate (1.8g, 42mmol) and DMF (20 ml) were charged into a reaction flask, stirred, acetylacetone (19g, 190mmol) was added thereto, and the mixture was allowed to rise to 75 ℃ completely for 3 hours. The reaction mixture was stirred with water (200 ml) and filtered to give 013037A3 (3.2g, 61%, white solid). LCMS: [ M + H ]] ⁺ 276.10。

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

013037A3 (3.2g, 11.6 mmol) and anhydrous THF (20 ml) were charged into a reaction flask, cooled to 0 ℃ with stirring, added with sodium hydride (500mg, 12.8mmol), and then raised to 20 ℃ for reaction for 20 minutes. The system was cooled to-78 deg.C and nitrosobenzene (1.5g, 12.8mmol, in 15mL THF) was added slowly. After the addition, the temperature was raised to 20 ℃ for 1 hour. The reaction was quenched with saturated ammonium chloride. The reaction mixture was extracted with water (40 ml) and EA (10ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by flash silica gel column chromatography (EA/PE 50-100%) to give 013037A4 (1g, 35%, white solid).

And 5, step 5: tert-butyl 2- ((6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) methyl) -3-methyl-1, 4, 8-triazaspiro [4.5] decane-1, 3-diene-8-carboxylate

After the compound 013037A4 (1g, 4.0mmol) was dissolved in toluene (20 mL), N-Boc piperidone (800mg, 4.0mmol) and ammonium acetate (1.5g, 20mmol) were added thereto, and the mixture was refluxed for 12 hours with stirring, the solvent was dried by spinning to obtain a crude product after the reaction was completed, which was purified by flash silica gel column chromatography (EA/PE 50-100%) to obtain 013037A5 (600mg, 35%, white solid). LCMS:[M+H] ⁺ 427.25。

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

Compound 013037A5 (600mg, 1.4 mol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, stirred at room temperature for 2 hours, and the solvent was removed by concentration to give crude 013037A6, which was reacted in the next step without purification. LCMS: [ M + H ]] ⁺ 327.19。

And 7, 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] decan-1, 3-dien-2-yl) methanone

Compound 013037A6 (460mg, 1.4 mol), intermediate 2 (310mg, 1.4 mmol) and potassium carbonate (770mg, 5.6 mmol) were added to DMSO (5 mL) and stirred at 110 ℃ for 16 hours. To the system was added 50mL of water, extracted three times with ethyl acetate (20 mL), the organic phase was vacuum-dried to give the crude product, purified by flash silica gel column chromatography (MeOH/EA 10%), and the product was purified by reverse phase column chromatography with acetonitrile/0.1% formic acid water, lyophilized to give SZ-013037 (60mg, 8%, white solid). LCMS: [ M + H] ⁺ 528.30。

¹ H NMR(400MHz,DMSO-d ₆ )δ11.87(s,1H),9.27(s,1H),9.19-9.17(m,1H),8.84(d,J＝4.4Hz,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 20SZ-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] undecan-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] is added into a reaction bottle]Undecane-9-carboxylic acid tert-butyl ester (270mg, 1.0mmol)Potassium iodide (166mg, 1.0 mmol) and THF (10 ml) were cooled to 0 ℃ with stirring, then sodium hydride (80mg, 2.0 mmol) was added, and after stirring for 20 minutes, 013037A2 (211mg, 1.0 mmol) was added, and the mixture was allowed to rise to 20 ℃ to react for 3 hours. The reaction was quenched with saturated ammonium chloride solution, water (20 ml) was added, 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 give a crude product which was purified by flash silica gel column chromatography (EA/PE 0-50%) to give 013038A1 (360mg, 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] undecan-1-one

After compound 013038A1 (360mg, 0.81mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 2 hours, and the solvent was removed by concentration to obtain crude 013038A2, which was reacted in the next step without purification. LCMS: [ M + H ]] ⁺ 344.21。

And 3, 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] undecan-1-one

Compound 013038A2 (278mg, 0.81mol), intermediate 2 (180mg, 0.81mmol) and potassium carbonate (447mg, 3.24mmol) were added to DMSO (5 mL) and stirred at 110 ℃ for 16 hours. To the system was added 50mL of water, extracted with ethyl acetate (20mL of 3), and the organic phase was pressure-dried to give a crude product, which was purified by flash silica gel column chromatography (MeOH/EA 10%), and the product was further subjected to reversed phase column chromatography with acetonitrile/0.1% formic acid water, and freeze-dried to give SZ-013038 (180mg, 42%, white solid). LCMS: [ M + H ]] ⁺ 531.32。

¹ H NMR(400MHz,DMSO-d ₆ )δ11.85(s,1H),9.21(s,1H),8.69(d,J＝4.6Hz,1H),8.32(d,J＝1.9Hz,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 21SZ-013039:2- (2- ((6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) methyl) -2, 9-diazaspiro [5.5] undecan-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] undecane-9-carboxylate

013037A2 (211mg, 1.0 mmol) and 2, 9-diazaspiro [5.5] were added to the reaction flask]Tert-butyl undecane-2-carboxylate (250mg, 1.0 mmol), potassium iodide (166mg, 1.0 mmol), DIPEA (380mg, 3.0 mmol) and acetonitrile (10 ml), and they were heated to 80 ℃ with stirring for 2 hours. Water (20 ml) was added, extracted with EA (15ml × 3), the organic phases combined, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure to give a crude product which was purified by flash silica gel column chromatography (EA/PE 0-50%) to give 013039A1 (400mg, 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 (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 2 hours, and the solvent was removed by concentration to give crude 013039A2, which was reacted in the next step without purification. LCMS: [ M + H] ⁺ 330.22。

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

Compound 013039A2 (300mg, 0.93mol), intermediate 2 (210mg, 0.93mmol) and potassium carbonate (510mg, 3.72mmol) were added to DMSO (5 mL) and stirred at 110 deg.C for 16h. To the system was added 50mL of water, extracted with ethyl acetate (20mL of 3), and the organic phase was pressure-dried to give a crude product, which was purified by flash silica gel column chromatography (MeOH/EA 10%), and the product was further subjected to reverse phase column chromatography with acetonitrile/0.1% formic acid water, and freeze-dried to give SZ-013039 (140mg, 29%, white solid). LCMS: [ M + H ]] ⁺ 517.29。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.16(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 22SZ-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] undecan-5-one

Step 1: 1-tert-butyl-4-methyl-4- (allyloxy) piperidine-1, 4-dicarboxylic acid ester (9399A 2)

9399A1 (4.8g, 18.4mmol) was dissolved in DMF (50 mL), and sodium hydride (1.6 g,60% in oil, 27.1mmol) was added in portions, with stirring continued for 10min after addition. Allyl bromide (3.2g, 26.6 mmol) was added in one portion and stirred at room temperature for 1 hour, water (50 ml) was added to the reaction solution, extracted with EA (50 mLx 2), the organic phase was dried and purified by flash silica gel column chromatography (EA: PE = 1) to give 9399A2 as a colorless oil (3.7g, 61%). LCMS (liquid Crystal display Module) (M-100)] ⁺ 199.13。

Step 2: 1-tert-butyl-4-methyl-4- (2-carbonylethoxy) piperidine-1, 4-dicarboxylate (9399A 3)

9399A2 (1g, 5 mmol) was dissolved in 15mL of acetonitrile and 15mL of water, and sodium periodate (2.1g, 9.8mmol) and a catalytic amount of ruthenium trichloride (1%) were added in this order, and after the reaction mixture was stirred at room temperature for 2 hours, water (50 mL) was added, followed by extraction with EA (50 mL), and the organic phase was dried by spin drying to obtain 1g of crude 9399A 3. LCMS: [ M + H] ⁺ 301.21。

And 3, 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 (9399A 5)

9399A3 (500 mg crude) and 9399A4 (460mg, 1.65mmol) were suspended in dichloroethane (15 mL), sodium triacetoxyborohydride (690mg, 3.3mmol) was added to the system, the reaction was gradually clarified, sodium carbonate was added after 3 hours to adjust the pH of the system to about 8, DCM (50 mL) was extracted, the organic phase was dried and purified by flash column chromatography on silica gel (EA: meOH)= 10). LCMS: [ M + H] ⁺ 491.11。

And 4, 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 (9399A 6)

9399A5 (400mg, 0.81mmol) was dissolved in 10mL of anhydrous methanol, 0.4mL of a methanol saturated solution of sodium methoxide was added in one portion, the reaction solution was stirred at 50 ℃ for 20 hours, and after removing the solvent by rotary chromatography on flash silica gel column (EA: PE = 1), 9399A6 (220 mg) was obtained as a colorless oil. LCMS: [ M + H] ⁺ 459.03。

And 5, step 5: (S) -4- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1-oxa-4, 9-diazaspiro [5.5] undecan-5-one (9399A 7)

9399A6 (220 mg) was dissolved in DCM (5 mL) and TFA (2 mL) was added, and after 2h the solvent was spun off to give 9399A7, which was reacted directly in the next step. LCMS: [ M + H] ⁺ 359.18。

And 6, a step of: (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] undecan-5-one (SZ-9399)

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 ℃ for 6 hours, after the reaction was complete the crude product was directly purified by high pressure reverse phase column chromatography (ACN-0.1% aqueous ammonium carbonate) and lyophilized to give SZ-9399 (66mg, 28%). LCMS: [ M + H] ⁺ 546.21。HPLC t _R ＝7.25min。 ¹ H NMR(400MHz,DMSO-d6)δ 11.84(s,1H),9.22(s,1H),8.66(dd,J ₁ ＝4.4Hz,J ₂ ＝0.8Hz,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 23SZ-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) ethyl) carbamoyl) piperidine-1-carboxylate

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

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

013043A1 (800mg, 1.7 mmol) and anhydrous THF (20 ml) were added to a reaction flask, stirred, triethylamine (500mg, 5 mmol) was added, cooled to 0 deg.C, chloroacetyl chloride (214mg, 1.9 mmol) was added dropwise, and the reaction was allowed to proceed for 12 hours at 20 deg.C after completion of the dropwise addition. The reaction solution was extracted with water (40 ml) and EA (10ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by flash silica gel column chromatography (EA/PE 50-100%) to give 013043A2 (550mg, 60% as a white solid). LCMS: [ M + H ]] ⁺ 537.26。

And 3, 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-carboxylic acid ester

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

And 4, 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 (5 mL), trifluoroacetic acid (1 mL) was added, stirred at room temperature for 2 hours, and the solvent was removed by concentration to give crude 013043A4, which was reacted in the next step without purification. LCMS: [ M + H] ⁺ 401.24。

And 5, 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-dione

Compound 013043A4 (200mg, 0.44mol), intermediate 2 (110mg, 0.5 mmol) and potassium carbonate (270mg, 2.0 mmol) were added to DMSO (5 mL) and stirred at 110 ℃ for 16 hours. To the system was added 50mL of water, extracted three times with ethyl acetate (20 mL), the organic phase was pressure-spun dried to give the crude product, purified by flash silica gel column chromatography (MeOH/EA 10%), and the product was subjected to reverse phase column chromatography with acetonitrile/0.1% formic acid water, and freeze-dried to give SZ-013043 (70mg, 27%, white solid). LCMS: [ M + H ]] ⁺ 588.34。 ¹ H NMR(400MHz,CDCl ₃ )δ11.87(s,1H),9.24(s,1H),8.72-8.69(m,1H),8.40(d,J＝2.0Hz,1H),7.98-7.90(m,3H),6.29-6.03(m,2H),5.76(q,J＝7.0Hz,1H),4.58(d,J＝12.5Hz,2H),4.14(d,J＝17.5Hz,1H),3.69(d,J＝17.5Hz,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＝7.23Hz,3H),0.99(t,J＝7.10Hz,3H)。

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

Step 1: tert-butyl- (S) -4- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) 1,4, 9-triazaspiro [5.5] undecane-9-carboxylic acid ester

A solution of borane in tetrahydrofuran (21mL, 21mmol, 1M) was added portionwise to a solution of compound 013049A0 (1g, 2.1mmol) in THF (16 mL) at 21 deg.C. The resulting reaction mixture was heated to 69 degrees celsius and stirring was continued for 1.8 hours. The reaction mixture was cooled to room temperature and saturated NH was added ₄ Aqueous Cl (10 mL) was quenched and then diluted with water (30 mL). Adding solid Na into the obtained solution ₂ CO ₃ After saturation, ethyl acetate was extracted (30ml × 3). The organic phases are combined and then anhydrous Mg is added ₂ SO ₄ Drying, filtering and spin-drying the organic solvent. The crude product was purified by silica gel column chromatography (PE: EA =10>3, a step of; rf = 0.3) to give 013005A1 (90 mg) as a light 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; trifluoroacetic acid salt

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

And 3, step 3: : (S) -2- (4- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1,4, 9-triazaspiro [5.5] undecan-9-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine

013049A2 (90mg, 0.19mmol), 1 (60mg, 0.269mmol), potassium carbonate (0.3g, 2.169mmol)And DMSO (3 mL) were heated to 169 degrees celsius and stirring was continued for 90 minutes. The resulting reaction mixture was cooled to 21 ℃ and then diluted with water (10 mL) and extracted with ethyl acetate (10 mL _ 3). The combined organic phases were washed with saturated brine (10mL. Multidot.3), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a crude product. Purification by HPLC then yielded SZ-013049 as a white solid (6 mg, 6%). LCMS: [ M + H] ⁺ 532.35@2.513min。 ¹ H NMR(400MHz,CD ₃ OD)δ8.54(d,J＝4.0Hz,1H),8.46(d,J＝2.0Hz,1H),8.03(dd,J1＝8.0Hz,J ₂ ＝2.0Hz,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＝4.0Hz,3H)。

Example 25SZ-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-allylazetidine-1, 3-dicarboxylate

1- (tert-butyl) 3-methylazetidine-1, 3-dicarboxylate (2.0g, 9.3mmol) and anhydrous THF (20 ml) were charged into a reaction flask, cooled to 0 ℃ and LDA (2M in THF,10mL, 20mmol) was added under stirring, and the reaction was gradually raised to 20 ℃ for 1 hour. Allyl bromide (1.35g, 11mmol) was then added dropwise and the reaction continued for 12h. The reaction was quenched with saturated ammonium chloride, water (100 ml) was added, 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 give a crude product which was purified by flash silica gel column chromatography (EA/PE 0-20%) to give 013048A1 (0.6 g,25%, colorless oily liquid). LCMS: [ M + H ]] ⁺ 256.08。

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

Into a reaction flask was added compound 013048A1 (0.6g, 2.3mmol), ruthenium chloride (5 mg, 0.02mml), acetonitrile (5 mL) and water (3 mL), and sodium periodate (1.5 g,7.0mml in 2mL of water) was added with stirring and reacted at 20 ℃ for 1 hour. The reaction was extracted with EA (50ml × 3) and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give crude 013048A2 (0.5 g,87%, colorless oily liquid) which was used directly in the next step. LCMS: [ M + H] ⁺ 258.04。

And 3, 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

To a reaction flask were added 013048A2 (0.5g, 2.0mmol), (S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethylamine (prepared according to WO 2017079140) (480mg, 2.4 mmol), HOAc (0.5 mL), 1, 2-dichloroethane (10 mL), and finally sodium triacetoxyborohydride (1.2g, 6.0mmol) and reacted at 20 ℃ for 2 hours, followed by heating and refluxing for 12 hours. The reaction was extracted with water (100 mL), EA (50ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product which was purified by flash silica gel column chromatography (EA/PE 0-50%) to give 013048A3 (400mg, 48%, white solid). LCMS: [ M + H] ⁺ 416.2。

And 4, 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 (400mg, 1mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, stirred at room temperature for 2 hours, and the solvent was removed by concentration to give crude 013048A4, which was reacted in the next step without purification. LCMS: [ M + H] ⁺ 316.14。

And 5, 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 (300mg, 1.0 mmol), intermediate 2 (223mg, 1.0 mmol) and potassium carbonate (500mg, 4.0 mmol) were added to DMSO (5 mL) and stirred at 110 ℃ for 16 hours. Adding 50mL of water into the system, extracting with ethyl acetate (20 mL) for three times, vacuum-drying the organic phase to obtain a crude product, purifying by flash silica gel column chromatography (DCM/EA 50%), dissolving the product with acetonitrile/water, and freezingDrying gave SZ-013048 (200mg, 40%, white solid). LCMS: [ M + H] ⁺ 503.40。

¹ H NMR(400MHz,DMSO-d6)δ11.86(s,1H),9.39(s,1H),8.71(dd,J＝4.6,0.7Hz,1H),8.41(d,J＝1.5Hz,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 26SZ-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 (10 mL) were charged into a reaction flask, and Cbz-Cl (0.85g, 5mmol) was added thereto with stirring, followed by reaction at 20 ℃ for 12 hours. The reaction was extracted with EA (50ml × 3) and water (100 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product which was purified by flash silica gel column chromatography (EA/PE 0-20%) to give 013050A1 (1.5g, 99%, white solid). LCMS: [ M + H] ⁺ 379.13。

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

After adding the compound 013050A1 (1.5g, 3.9mmol) and methanol (10 mL) to a reaction flask and stirring with water (3 mL), lithium hydroxide monohydrate (1.6 g, 39mmol) was added and the reaction was carried out at 20 ℃ for 2 hours. The reaction was neutralized with 1M hydrochloric acid, 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 give a crude product, which was purified by flash silica gel column chromatography (EA/PE 0-50%) to give 013050A2 (1.1g, 81%, colorless oily liquid). LCMS: [ M + H] ⁺ 251.05(de-Boc)。

And 3, step 3: tert-butyl (S) -3- (((benzyloxy) carbonyl) amino) -3- ((1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) carbamoyl) azetidine-1-carboxylate

013050A2 (1.1g, 3.1mmol) and DMF (15 ml) were charged to a reaction flask, stirred, and then (S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethylamine (prepared according to WO 2017079140) (0.64g, 3.1mmol), DIPEA (1.5g, 12mmol) and finally HATU (1.2g, 3.1mmol) were added and reacted at 20 ℃ for 1 hour. The reaction was extracted with EA (50ml × 3) and water (100 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product which was purified by flash silica gel column chromatography (EA/PE 0-50%) to give 013050A3 (2.0 g,95%, white solid). LCMS: [ M + H ]] ⁺ 539.21。

And 4, 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 (2.0 g, 3.7mmol), palladium on carbon (10%, 300 mg) and methanol (20 mL) were charged in a reaction flask, and vacuum-hydrogen replacement was performed 3 times with stirring, followed by reaction under a hydrogen atmosphere for 4 hours. The reaction was filtered and the filtrate was concentrated under reduced pressure to give crude 013050A4 (1.5g, 100%, white solid) which was used directly in the next step. LCMS: [ M + H] ⁺ 405.18。

And 5, step 5: tert-butyl (S) -3- (2-chloroacetylamino) -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 (20 ml), stirred, triethylamine (1.1g, 11mmol) was added, cooled to 0 ℃, chloroacetyl chloride (500mg, 4.4mmol) was added dropwise, and the temperature was raised to 20 ℃ after dropping to react for 12 hours. The reaction solution was extracted with EA (10ml × 3) after adding water (40 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by flash silica gel column chromatography (EA/PE 50-100%) to give 013050A5 (1.5g, 84%, white solid). LCMS: [ M + H] ⁺ 481.17。

And 6, 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-carboxylate

013050A5 (1.5g, 3.1mmol) and iodination were added to the reaction flaskPotassium (500mg, 3.1mmol) and anhydrous THF (20 mL) were stirred, cooled to 0 deg.C, added sodium hydride (60% adsorbed to mineral oil, 250mg, 6.2mmol), slowly warmed to 60 deg.C and stirred for reaction for 20 min. After completion of the reaction, the reaction was cooled to room temperature, and quenched with a saturated ammonium chloride solution. The reaction was extracted with EA (30ml × 3) and the organic phases combined, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure to give crude product which was purified by flash silica gel column chromatography (EA/PE 50-100%) to give 013050A6 (1.2g, 87%, white solid). LCMS: [ M + H] ⁺ 445.19。

And 7, 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 (440mg, 1mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, stirring was carried out at room temperature for 2 hours, and the solvent was removed by concentration to obtain crude 013050A7, which was reacted in the next step without purification. LCMS: [ M + H] ⁺ 345.18。

And 8, 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 (320mg, 1.0 mmol), intermediate 2 (223mg, 1.0 mmol) and potassium carbonate (500mg, 4.0 mmol) were added to DMSO (5 mL), and stirred at 110 ℃ for 16 hours. To the system was added 50mL of water, extracted three times with ethyl acetate (20 mL), the organic phase was rotary dried under reduced pressure to give the crude product, purified by flash silica gel column chromatography (DCM/EA 50%), dissolved in acetonitrile/water, and lyophilized to give SZ-013050 (200mg, 37%, white solid). LCMS: [ M + H] ⁺ 532.38。

¹ H NMR(400MHz,DMSO-d6)δ11.87(s,1H),9.42(s,1H),9.22(s,1H),8.72(d,J＝4.5Hz,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＝17.1Hz,1H),2.22(s,3H),2.15(s,3H),1.60(d,J＝7.2Hz,3H)。

Example 27SZ-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] undecan-5-one

The first step is as follows: 4- ((tert-butyldimethylsilyl) oxo) cyclohexanone

A reaction flask was charged with 9397A1 (10g, 87.7mmol), imidazole (8.9g, 130.8mmol), TBSCl (15.7g, 104.6mmol), and dichloromethane (100 mL) and stirred at room temperature for 2 hours. The solid in the system was filtered off, and the filtrate was spun dry and purified by flash silica gel column chromatography (PE: EA =7, 1, rf = 0.6) to give 9397A2 (1lg, 80%) as a colorless oil.

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

9397A2 (4.4g, 19.2mmol) was dissolved in dichloromethane (15 mL) under an ice-water bath, and TMSCN (2.8mL, 31.1mmol) and zinc iodide (300mg, 5 mol%) were added in this order and stirred for 1 hour. Filtering the system, and spin-drying the filtrate to obtain the crude product.

The third step: 1, 4-dihydroxycyclohexanecarboxylic acids

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 give crude 9397A4 as a colorless oil (8 g).

The fourth step: 1, 4-dihydroxycyclohexanecarboxylic acid methyl ester

The resulting crude 9397A4 was dissolved in methanol (100 mL) and toluene (10 mL) in an ice-water bath and TMSCHN was slowly added dropwise ₂ (60mL, 1M in hexane) and stirred for 15min. After the reaction is finished, the solvent of the system is removed by screwing to obtain a 9397A5 crude product which is directly used for the next step.

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

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

And a sixth step: 1- (allyloxy) -4- ((tert-butyldimethylsilyl) oxo) cyclohexanecarboxylic acid methyl ester

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

The seventh step: 4- ((tert-Butyldimethylsilyl) oxo) -1- (2-carbonylethoxy) cyclohexanecarboxylic acid methyl ester

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

Eighth step: (S) -methyl 4- ((tert-butyldimethylsilyl) oxo) -1- (2- ((1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) amino) ethoxy) cyclohexanecarboxylic acid ester

The resulting crude 9397A8 was dissolved in dichloroethane (100 mL), and 9399A4 (4.5 g) and sodium triacetoxyborohydride (6.8 g) were added in that order and stirred at room temperature overnight. To the system was added 100mL of water and 100mL of ethyl acetate, the organic phase was spun dry and purified by flash silica gel column chromatography (PE: EA =1, rf = 0.7) to give 9397A9 (2g, 15%) as a colorless oil. LCMS: [ M + H] ⁺ 521.16

The ninth step: (S) -9- ((tert-butyldimethylsilyl) oxo) -4- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1-oxa-4-azaspiro [5.5] undecan-5-one

9397A9 (2g, 3.7mmol) is dissolved in anhydrous methanol (10 mL) and addedSodium methoxide in methanol (2ml, 5.4m) was added and stirred at 100 deg.c overnight. After completion of the reaction, the solvent was removed by rotation and purified by flash silica gel column chromatography (PE: EA =4, 1 rf = 0.6) to give 9397a10 (1g, 47%) as a white solid. LCMS: [ M + H ]] ⁺ 489.30

The tenth step: (S) -4- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -9-hydroxy-1-oxa-4-azaspiro [5.5] undecan-5-one

9397A10 (1g, 2.1mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), TBAF (6 mL,1M in THF) was added and stirred at room temperature overnight. After completion of the reaction, the solvent was removed by rotary evaporation and purified by flash silica gel column chromatography (PE: EA =1, rf = 0.3) to give 9397a11 (600mg, 78%) as a white solid. LCMS: [ M + H] ⁺ 375.21

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

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

A twelfth step: 4- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -5-carbonyl-1-oxa-4-azaspiro [5.5] undec-8-en-9-yl trifluoromethanesulfonate

9397A12 (200mg, 0.5 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), cooled to-70 deg.C, liHMDS (0.6 mL,1M in THF) was added dropwise to the system under argon and stirred for 1 hour, then N-phenylbis (trifluoromethanesulfonimide) (300mg, 0.8 mmol) was added and slowly warmed to room temperature and stirred for 30min. After the reaction was complete, saturated ammonium chloride (10 mL) and ethyl acetate (10 mL) were added to the system and the organic phase was spun dry and directly taken next. LCMS [ + H ] +505.15

The thirteenth step: 4- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -9- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-oxa-4-azaspiro [5.5] undecan-8-en-5-one

9397A13 dissolved in anhydrous 1, 4-dioxane (10 mL)Adding pinacolato diboron (130mg, 0.5mmol), potassium acetate (140mg, 1.4mmol) and Pd (dppf) Cl into the mixture in turn under the protection of argon ₂ DCM (40 mg) and stir at 80 ℃ for 3 h. After completion of the reaction, the solvent was removed by rotation and purified by flash silica gel column chromatography (PE: EA =2, 1 rf = 0.2) to give 9397a14 (100mg, 42%) as a white solid. LCMS: [ M + H ]] ⁺ 483.19

A fourteenth step of: 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] undecan-8-en-5-one

9397A14 (100mg, 0.2mmol), 9399A8 (45mg, 0.2mmol), potassium carbonate (69mg, 0.5mol), and tetratriphenylphosphine (25mg, 5mol%) were dissolved in anhydrous 1, 4-dioxane (10 mL) under argon protection and reacted with microwaves at 125 ℃ for 2 hours. After completion of the reaction the solvent was spun off and purified by flash silica gel column chromatography (EA 100%; rf = 0.2) to yield 9397a15 (50mg, 31%) as a white solid. LCMS: [ M + H] ⁺ 544.11

The fifteenth step: (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] undecan-5-one

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

SZ-9397A：HPLC t _R ＝6.43min。 ¹ H NMR(400MHz,DMSO-d6)δ11.93(s,1H),9.49(s,1H),8.70(d,J＝4.4Hz,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 ＝5.95min。 ¹ H NMR(400MHz,DMSO-d6)δ11.91(s,1H),9.51(s,1H),8.71(d,J＝4.4Hz,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＝6.8Hz,3H)。

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

instrument Waters Acquity ARC (UHPLC); a chromatographic column: xsselect CSHTMC 18.5um 4.6 × 150mm Column XP; mobile phase A is 0.1% ammonia water solution; the mobile phase B is acetonitrile; flow rate: 1ml/min; wavelength: PDA full wavelength, 254nm,220nm; column temperature: 30 ℃; the blank solvent is methanol; dissolving a proper amount of a substance to be detected in methanol, and filtering the solution by using a 0.22 mu m filter membrane; gradient elution:

example 28SZ-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-trifluoroethyl) -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) -2, 5-dicarbonyl-1- (2, 2-trifluoroethyl) -1,4, 9-triazaspiro [5.5] undecane-9-carboxylic acid ester

013002A4 (1.2g, 2.5 mmol) and THF (20 mL) were charged into a reaction flask, cooled to 0 ℃ with stirring, and LiHMDS (1M in THF,5mL,5 mmol) was slowly added thereto, and the mixture was stirred at room temperature for 20 minutes. Finally, 2-trifluoroethyl trifluoromethanesulfonate (2.3g, 10mmol) was added, and the temperature was raised to 60 ℃ to react for 12 hours. The reaction was quenched with saturated ammonium chloride solution, then water (100 mL) was added, 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 give a crude product which was purified by flash silica gel column chromatography (EA/PE 0-50%) to give 013044A1 (500mg, 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-trifluoroethyl) -1,4, 9-triazaspiro [5.5] undecane-2, 5-dione

Compound 013044A1 (500mg, 1.0 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, stirred at room temperature for 2 hours, and the solvent was removed by concentration to give crude 013044A2, which was reacted in the next step without purification. LCMS: [ M + H] ⁺ 455.27。

And 3, 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-trifluoroethyl) -1,4, 9-triazaspiro [5.5] undecane-2, 5-dione

Compound 013044A2 (400mg, 1.0 mol), intermediate 2 (223mg, 1.0 mmol) and potassium carbonate (500mg, 4.0 mmol) were added to DMSO (10 mL) and stirred at 110 ℃ for 16 hours. 50mL of water is added into the system, ethyl acetate (20 mL) is extracted for three times, the organic phase is decompressed and dried to obtain a crude product, and the product is subjected to reversed phase column chromatography by acetonitrile/0.1% formic acid water and freeze drying to obtain SZ-013044 (60mg, 9.3% of white solid). LCMS: [ M + H] ⁺ 642.31。 ¹ H NMR(400MHz,DMSO-d6)δ11.87(s,1H),9.24(s,1H),8.73(d,J＝4.5Hz,1H),8.42(d,J＝1.6Hz,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＝18.4Hz,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 29SZ-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] undecan-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-carboxylic acid ester

A solution of borane in tetrahydrofuran (9mL, 9mmol, 1M) was added portionwise at 16 deg.C to a solution of compound 013034A0 (330mg, 0.69824 mmol) in THF (9 mL). 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 and quenched with saturated aqueous ammonium chloride (10 mL) and then diluted with water (30 mL). After the resulting solution was saturated with solid sodium carbonate, it was extracted with ethyl acetate (30ml × 3). After the organic phases are combined, anhydrous magnesium sulfate is added for drying, filtering and the organic solvent is dried in a spinning mode. The crude product was column purified to give 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] undecan-5-one; trifluoroacetic acid salt

Trifluoroacetic acid (3 mL) was added portionwise to a solution of 013034A1 (100mg, 0.21mmol) in dichloromethane (3 mL) at 16 ℃. The resulting reaction mixture was stirred at 16 ℃ for an additional hour. The resulting reaction mixture was then solvent-spun dry and then pumped using an oil pump for three minutes to give 013034A2 (100 mg) as a yellow oil which was used directly in the next reaction. LCMS [ M + H ] +359.18@2.603min.

And 3, 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-azaalkyl) pyrimidin-2-yl) -1,4, 9-triazaspiro [5.5] undecan-5-one

A suspension of compound 013034A2 (100mg, 0.21mmol), compound 1 (63mg, 0.276mmol), potassium carbonate (0.3g, 2.16mmol) and DMSO (3 mL) was heated to 169 deg.C and stirring was continued for 3 hours. The resulting reaction mixture was cooled to 16 ℃ and then diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10mL. Multidot.3), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a crude product. Followed by purification using high pressure preparative chromatography gave compound SZ-013034 as a white solid (21mg, 18.6%). LCMS: [ M + H +]546.21@2.986min。 ¹ H NMR(400MHz,CD3OD)δ8.52(d,J＝4.0Hz,1H),8.39(s,1H),7.95(d,J＝8.0Hz,1H),7.88(dd,J ₁ ＝8.0Hz,J ₂ ＝2.0Hz,1H),7.71(d,J＝4.0Hz,1H),6.23(br,1H),6.10(br,1H),5.98(q,J＝8.0Hz,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＝8.0Hz,2H),1.61(d,J＝8.0Hz,3H)。

Example 30SZ-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] undecan-5-one

A solution of borane in tetrahydrofuran (31mL, 31mmol, 1M) was added portionwise to a solution of compound 013049A0 (1.1g, 2.33mmol) in THF (30 mL) at 16 deg.C using 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 and quenched with saturated aqueous ammonium chloride (30 mL) and then diluted with water (30 mL). The resulting solution was added solid sodium carbonate until saturation and extracted with ethyl acetate (60ml x 3). After the organic phases are combined, anhydrous magnesium sulfate is added for drying, filtering and spin-drying the organic solvent. The crude product was column purified to give 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-carboxylic acid ester

NaH (160mg, 3.9mmol) was added portionwise at 16 deg.C to a solution of compound 013034A1 (180mg, 0.39mmol) in tetrahydrofuran (6 mL). The resulting reaction mixture was stirred at 16 ℃ for an additional 6 minutes. Methyl iodide (260mg, 3.9 mmol) was then added dropwise to the above off-white suspension by syringe. The resulting reaction mixture was sealed with a sealed tube, heated to 69 degrees celsius and stirring was continued for half 16 hours. After the resulting reaction mixture was cooled to room temperature, it was quenched by addition of saturated aqueous ammonium chloride (10 mL), followed by dilution with water (10 mL). The resulting solution was extracted with ethyl acetate (30ml × 3), the organic phases combined and dried over anhydrous magnesium sulphate, filtered and the organic solvent was spin dried. The residue was purified by column to give 013035A1 (90 mg) as a yellow oil. LCMS [ + H ] +473.19@ 3.1699 min.

And 3, step 3: (S) -4- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1-methyl-1, 4, 9-triazaspiro [5.5] undecan-5-one; trifluoroacetic acid salt

Trifluoroacetic acid (3 mL) was added portionwise at 16 ℃ to a solution of compound 013035A1 (90mg, 0.19mmol) in dichloromethane (3 mL). The resulting reaction mixture was stirred at 16 ℃ for an additional hour. The resulting reaction mixture was solvent-dried by rotary evaporation, and then pumped using an oil pump for three minutes to give 013035A2 (80 mg) as a yellow oily product which was used directly in the next reaction. LCMS [ M + H ] +373.16@2.65min.

And 4, 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] undecan-5-one

A suspension of compound 013035A2 (69mg, 0.139mmol), compound 1 (63mg, 0.269mmol), potassium carbonate (0.31g, 2.169mmol) and DMSO (3 mL) was heated to 169 deg.C and stirring was continued for one hour. The resulting reaction mixture was cooled to 16 degrees celsius then diluted with water (13 mL) and extracted with ethyl acetate (30ml × 3). The combined organic phases were washed with saturated brine (10mL × 3), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude product. Purification by high pressure preparative chromatography gave SZ-013035 as a white solid (18mg, 23%). LCMS: [ M + H +]560.37@2.789min。 ¹ H NMR(400MHz,CD ₃ OD)δ8.42(d,J＝4.0Hz,1H),8.29(d,J＝2.0Hz,1H),7.84(d,J＝8.0Hz,1H),7.80(dd,J ₁ ＝8.0Hz,J ₂ ＝2.0Hz,1H),7.61(d,J＝4.0Hz,1H),6.12(br,1H),5.98(br,1H),5.90(q,J＝8.0Hz,1H),4.22(dd,J ₁ ＝12.0Hz,J ₂ ＝8.0Hz,1H),3.43-3.33(m,3H),3.09(t,J＝8.0Hz,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 31SZ-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 (013031A 1)

Compound 9305A4 (3.63g, 10mmol) and lithium hydroxide monohydrate (2.1g, 50mmol) were dissolved in methanol (20 ml) and water (20 ml), the system was heated to 60 ℃ and stirred for 3 hours, after the reaction was completed, it was cooled, the system pH was adjusted with 1N hydrochloric acid =3, ea (30 ml x 3) was extracted, and the organic phase was dried over sodium sulfate and concentrated to give 013031A1 (3.63 g, 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] decan-8-yl) carbamate (013031A 2)

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 (20 ml), HATU (4.56g, 12mmol) was added, and after stirring at room temperature for 3 hours, water (100 ml) was added followed by extraction with ethyl acetate (30 ml X3), and the organic phase was dried over sodium persulfate and then subjected to flash silica gel column chromatography to give 013031A2 (4.5 g, two steps 86%, a white solid). LCMS: [ M + H] ⁺ 524.4。

And 3, step 3: (S) -8-amino-N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1, 4-dioxaspiro [4.5] decane-8-carboxamide (013031A 3)

013031A2 (4.5g, 8.6 mmol) was dissolved in methanol (50 mL), ammonium formate (5.42g, 86mmol) and palladium hydroxide/C (500 mg) were added, stirred at 60 ℃ for 3 hours, filtered, and the organic phase was spin-dried under reduced pressure to give 013031A3 (3.5 g, white solid) without further purification. LCMS [ + H ] +390.4

And 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 (013031A 4)

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

And 5, step 5: (S) -12- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1, 4-dioxa-9, 12-diazaspiro [4.2.58.25] pentadecane-10, 13-dione (013031A 5)

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

And 6, a step of: (S) -12- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -9-methyl-1, 4-dioxa-9, 12-diaza-dispiro [4.2.58.25] pentadecane-10, 13-dione (013031A 6)

013031A5 (700mg, 1.63mmol) is dissolved in anhydrous tetrahydrofuran (10 ml), naH (130mg, 3.3mmol) is added in portions at 0 ℃, after 0.5 hour of reaction, iodomethane (463mg, 3.3mmol) is added for reaction at room temperature for 3 hours, and after the reaction is finished, 013031A6 (360mg, Y =51%, white solid) is obtained by purification with flash silica gel column chromatography. LCMS: [ M + H] ⁺ 444.5

And 7, step 7: (S) -4- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1-methyl-1, 4-diazaspiro [5.5] undecane-2, 5, 9-trione (013031A 7)

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

And 8, step 8: 4- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1-methyl-2, 5-dicarbonyl-1, 4-diazaspiro [5.5] undec-8-en-9-yl trifluoromethanesulfonate (013031A 8)

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

And 9, step 9: 4- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1-methyl-9- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 4-diazaspiro [5.5] undec-8-ene-2, 5-dione (013031A 9)

013031A8 (0.48g, 0.9mmol) and Biboronic acid pinacol (230g, 0.9mmol), pd (dppf) ₂ Cl _2. DCM (37mg, 5%), potassium acetate (0.265g, 2.7 mmol) were mixed in dioxane (10 mL) under argon and heated to 80 deg.C and stirred for 4 h. After the reaction, the solvent was removed by cooling, and the reaction mixture was purified by flash silica gel column chromatography to obtain 013031A9 (450mg, 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 (013031 a 10)

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

The 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 (10 mL), ammonium formate (352m g,5.6 mmol) and palladium hydroxide/C (30 mg) were added, stirred at 60 ℃ for 3 hours, filtered, the organic phase was dried under reduced pressure to give a crude product, and the crude product was subjected to medium pressure reverse phase column chromatography (ACN-0.1% HCO) ₂ Aqueous H) and freeze dried to give SZ-013031A (100 mg, white solid) and SZ-013031B (37 mg, white solid).

LCMS:[M+H] ⁺ 573.32，HPLC:t _R ＝5.574min。SZ-013031A： ¹ H NMR(400MHz,DMSO)δ11.95(s,1H),9.57(s,1H),8.73(d,J＝4.5Hz,1H),8.40(s,1H),7.95(m,3H),6.82(s,1H)，6.20(s,1H),5.80(q,J＝7.0Hz,1H),4.13(dd,J＝17.6,8.6Hz,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 ＝5.363min。SZ-013031B： ¹ H NMR(400MHz,DMSO)δ11.91(s,1H),9.56(s,1H),8.72(d,J＝4.5Hz,1H),8.39(s,1H),8.06–7.82(m,3H),5.84(q,J＝7.1Hz,1H),4.11(d,J＝17.8Hz,1H),3.66(d,J＝17.7Hz,1H),2.94(s,3H),2.72(dd,J＝23.8,11.4Hz,1H),2.46–1.80(m,14H),1.59(d,J＝7.2Hz,3H).

HPLC test conditions: instrument Waters Acquity ARC (UHPLC); a chromatographic column: XSelect CSH ^TM C183.5 μm, 4.6 × 150mm Column XP; mobile phase A is 0.1% ammonia water solution; the mobile phase B is acetonitrile; flow rate: 1ml/min; wavelength: 282nm; column temperature: 30 ℃; the blank solvent is methanol; dissolving a proper amount of a substance to be detected in methanol, and filtering the solution by using a 0.22 mu m filter membrane; gradient elution:

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

Example 32SZ-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

Into a reaction flask were charged 013002A4 (230mg, 0.5mmol), cyclopropaneboronic acid (86mg, 1.0 mmol), DMAP (183mg, 1.5mmol), anhydrous copper acetate (10mg, 0.05mmol) and THF (10 ml), and LiHMDS (1M, 0.5mL, 0.5mmol) was added with stirring, and the mixture was heated to 60 ℃ to react for 12 hours. The reaction was extracted with water (100 ml) and EA (50ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product which was purified by flash silica gel column chromatography (EA/PE 0-20%) to give 013045A1 (130mg, 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 (5 mL), trifluoroacetic acid (1 mL) was added, stirred at room temperature for 1 hour, and the solvent was removed by concentration to give crude 013045A2, which was reacted in the next step without purification. LCMS: [ M + H] ⁺ 413.24。

And 3, 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 (100mg, 0.25mmol), intermediate 2 (56mg, 0.25mmol) and potassium carbonate (138mg, 1.0 mmol) were added to DMSO (5 mL) and stirred at 110 ℃ for 16 hours. 50mL of water is added into the system, extraction is carried out for three times by ethyl acetate (20 mL), organic phase is subjected to decompression spin-drying to obtain a crude product, and the product is subjected to reversed phase column chromatography by acetonitrile/0.1% formic acid water and freeze-drying to obtain SZ-013045 (15mg, 10% white solid). LCMS: [ M + H] ⁺ 600.36。

¹ H NMR(400MHz,DMSO-d ₆ )δ11.88(s,1H),9.23(s,1H),8.72(d,J＝4.6Hz,1H),8.40(s,1H),7.96(d,J＝4.3Hz,1H),7.96-7.92(m,2H),6.34-6.03(m,2H),5.74(q,J＝7.3Hz,1H),4.60(d,J＝12.1Hz,2H),4.14(d,J＝18.7Hz,1H),3.70(d,J＝18.4Hz,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 33SZ-013052: (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] undecane-2, 5-dione

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

After adding 013002A2 (2.1g, 5 mmol), cyclopropylformaldehyde (0.7g, 10mmol) and dichloroethane (20 ml) to a reaction flask, sodium borohydride acetate (3.1g, 15mmol) was added thereto with stirring, and the mixture was reacted at 20 ℃ for 4 hours. The reaction was extracted with DCM (50ml × 3) and water (100 ml), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give crude product which was purified by flash silica gel column chromatography (EA/PE 20-50%) to give 013052A1 (2.0g, 81%, white solid). LCMS: [ M + H] ⁺ 487.47。

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

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

And 3, 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-carboxylic acid ester

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

And 4, 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 (200mg, 0.38mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 2 hours, and the solvent was removed by concentration to give crude 013052A4, which was reacted in the next step without purification. LCMS: [ M + H ]] ⁺ 427.28。

And 5, 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] undecane-2, 5-dione

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

¹ H NMR(400MHz,DMSO-d ₆ )δ11.98(s,1H),9.27(s,1H),8.72(d,J＝4.5Hz,1H),8.43(d,J＝2.1Hz,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＝18.1Hz,1H),3.76(d,J＝18.1Hz,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 34SZ-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] undecan-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-carboxylic acid ester

Lithium aluminum hydride powder (1g, 26.3mmol) was added portionwise to a solution of compound 013046A0 (1g, 2.11mmol) in anhydrous tetrahydrofuran (30 mL) at 26 deg.C. The resulting reaction mixture was stirred at 26 ℃ for an additional 1 hour. The resulting reaction mixture was diluted with anhydrous tetrahydrofuran (30 mL), and water (1 g), an aqueous sodium hydroxide solution (1g, 15Wt%) and water (3 g) were added dropwise in this order. The white suspension was stirred vigorously for ten minutes and then filtered. The filtrates were combined and the solvent was spin-dried. The residue was purified by column chromatography to give 013046A1 (300 mg) as a pale yellow solid. LCMS: [ M + H +]459.23@3.641min。 ¹ H NMR(400MHz,DMSO-D6)8.68(d,J＝4.0Hz,1H),8.41(d,J＝2.0Hz,1H),7.96(dd,J ₁ ＝8.0Hz,J ₂ ＝2.0Hz,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＝16.0Hz,1H),2.58(d,J＝12.0Hz,1H)2.31(d,J＝12.0Hz,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] undecan-2-one; trifluoroacetic acid salt

Trifluoroacetic acid (3 mL) was added portionwise to a solution of compound 013046A1 (190mg, 0.41mmol) in dichloromethane (3 mL) at 31 deg.C. The resulting reaction mixture was stirred at 31 ℃ for an additional hour. The resulting reaction mixture was solvent-dried by rotary evaporation, followed by pumping for three minutes using an oil pump to give 013046A2 (190 mg) as a pale yellow oil which was used directly in the next reaction. LCMS [ + H ] +359.21@2.669min.

And 3, 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] undecan-2-one

A suspension of compound 013046A2 (190mg, 0.41mmol), compound 1 (136mg, 0.6 mmol), potassium carbonate (0.3 g, 2.16mmol) 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 ℃ and then diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10mL × 3), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude product. Purification by high pressure preparative chromatography gave SZ-013046 as a white solid (36mg, 16%). LCMS: [ M + H +]546.31@3.069min。 ¹ H NMR(400MHz,DMSO-d ₆ )δ11.82(s,1H),9.13(s,1H),8.68(d,J＝4.0Hz,1H),8.43(d,J＝4.0Hz,1H),8.00(dd,J ₁ ＝12.0Hz,J ₂ ＝4.0Hz,1H),7.91(s,1H),7.90(d,J＝4.0Hz,1H),7.87(s,1H),6.18(br,1H),6.05(s,1H),4.09(d,J＝16.0Hz,2H)3.74(q,J＝8.0Hz,1H),3.28-3.16(m,2H),3.12(d,J＝16.0Hz,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＝8.0Hz,3H)。

Example 35SZ-013053 (SZ-013053A and SZ-013053B): (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-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 (013053A 1)

013031A3 (7.8g, 20mmol) was dissolved in DCE (50 ml), and a solution of acetaldehyde in tetrahydrofuran (22mL, 1Mol/L) was added, and sodium cyanoborohydride (3.74g, 60mmol) was added in portions at room temperature and stirred at that temperature for 6 hours. After completion of the reaction, flash silica gel column chromatography was used to obtain 013053A1 (4.2g, Y =50%, white solid). 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 (013053A 2)

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

And 3, step 3: (S) -9-Ethyl-12- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1, 4-dioxa-9, 12-diaza-dispiro [4.2.58.25] pentadecane-10, 13-dione (013053A 3)

013053A2 (3.7g, 7.5mmol) was dissolved in anhydrous tetrahydrofuran (50 ml), naH (600mg, 15mmol) was added in portions at 0 ℃ to react for 0.5 hour, then the temperature was raised to 65 ℃ to react for 5 hours, and after the reaction was completed, the reaction product was purified by flash silica gel column chromatography to obtain 013053A3 (2.3g, Y =67%, white solid). LCMS: [ M + H] ⁺ 456.4

And 4, step 4: (S) -1-Ethyl-4- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1, 4-diazaspiro [5.5] undecane-2, 5, 9-trione (013053A 4)

013053A3 (2.3 g,5 mmol) was dissolved in Dioxane (50 mL), 4N hydrochloric acid (40 mL) was added, stirring was carried out at 60 ℃ for 6 hours, then water (500 mL) was added, followed by extraction with ethyl acetate (100X 3 mL), the organic phase was dried over sodium sulfate and then dried by spin drying to give 013353A4 (1.65g, Y =80%, white solid) which was chromatographed on silica gel flash. LCMS: [ M + H] ⁺ 414.4

And 5, step 5: 1-Ethyl-4- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2, 5-dicarbonyl-1, 4-diazaspiro [5.5] undec-8-en-9-yl trifluoromethanesulfonate (013053A 5)

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

And 6, a step of: 1-Ethyl-4- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -9- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 4-diazaspiro [5.5] undec-8-ene-2, 5-dione (013053A 6)

013053A5 (700mg, 1.28mmol) and Biboronic acid pinacol (326mg, 1.28mmol), pd (dppf) ₂ Cl _2. DCM (52mg, 5%), potassium acetate (0.376g, 3.84mmol) was mixed in dioxane (10 mL) under argon and heated to 80 deg.C with stirring for 4 h. After the reaction, the solvent was removed by cooling, and the reaction mixture was purified by flash silica gel column chromatography to obtain 013053A6 (480mg, Y =72%, white solid). LCMS: [ M + H] ⁺ 524.3。

And 7, 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 (013053A 7)

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

And 8, 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-dione

013053A7 (400mg, 0.75mmol) was dissolved in methanol (10 mL), ammonium formate (472m g, 7.5mmol) and palladium hydroxide/C (40 mg) were added, stirred at 60 ℃ for 3 hours, filtered, the organic phase was dried under reduced pressure to obtain a crude product, and the crude product was purified by medium pressure reverse phase column chromatography (ACN-0.1 HCO) ₂ Aqueous H) and lyophilized to give SZ-013053A (120 mg, white solid) and SZ-013053B (25 mg, white solid).

LCMS:[M+H] ⁺ 587.33，HPLC:t _R ＝8.737min。SZ-013053A： ¹ H NMR(400MHz,DMSO)δ11.87(s,1H),9.51(s,1H),8.65(t,J＝20.8Hz,1H),8.39(d,J＝26.5Hz,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＝17.7Hz,1H),3.49(q,J＝6.8Hz,2H),2.70(t,J＝11.9Hz,1H),2.42–2.01(m,10H),1.89(d,J＝10.2Hz,4H),1.56(d,J＝7.2Hz,3H),1.07(t,J＝7.0Hz,3H).

LCMS:[M+H] ⁺ 587.33，HPLC:t _R ＝9.444min。SZ-013053B： ¹ H NMR(400MHz,DMSO)δ11.90(s,1H),9.53(s,1H),8.69(d,J＝4.1Hz,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＝6.9Hz,3H).

example 36SZ-013054: (S) -1- (2, 2-difluoroethyl) -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- (2, 2-difluoroethyl) -4- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2, 5-dicarbonyl-1, 4, 9-triazaspiro [5.5] undecane-9-carboxylic acid ester

After adding 013002A4 (1.2 g,2.5 mmol) and THF (20 mL) to a reaction flask, liHMDS (1M, 5mL,5 mmol) was added dropwise and stirred for 10 minutes, 2-difluoroethyl trifluoromethanesulfonate (2.1g, 1.0 mmol) was added and reacted at 20 ℃ for 12 hours. The reaction mixture was extracted with water (100 ml) and EA (50ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product which was purified by flash silica gel column chromatography (EA/PE 0-20%) to give 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) ethyl) -1,4, 9-triazaspiro [5.5] undecane-2, 5-dione

Compound 013054A1 (450mg, 0.84mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hour, and the solvent was removed by concentration to give crude 013054A2, which was reacted in the next step without purification. LCMS: [ M + H ]] ⁺ 437.22。

And 3, step 3: (S) -1- (2, 2-difluoroethyl) -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 013054A2 (360mg, 0.84mmol), intermediate 2 (187mg, 0.84mmol) and potassium carbonate (460mg, 3.3mmol) were added to DMSO (5 mL) and stirred at 110 ℃ for 16h. Adding 50mL of water into the system, extracting with ethyl acetate (20 mL) for three times, performing vacuum spin-drying on the organic phase to obtain a crude product, and performing reverse phase column layer on the product by using acetonitrile/0.1% formic acid waterThe precipitate was separated and lyophilized to give SZ-013054 (105mg, 20%, white solid). LCMS: [ M + H] ⁺ 624.36。

¹ H NMR(400MHz,DMSO-d ₆ )δ11.86(s,1H),9.22(s,1H),8.72(d,J＝4.6Hz,1H),8.43(d,J＝1.7Hz,1H),8.01-7.91(m,3H),6.32-5.91(m,3H),5.78(q,J＝7.0Hz,1H),4.64(d,J＝11.7Hz,2H),4.28(d,J＝17.9Hz,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＝7.0Hz,3H).

Example 37SZ-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

A reaction vessel was charged with 013002A2 (2.0g, 4.6 mmol), n-propanal (268mg, 4.6 mmol) and dichloroethane (20 ml), and then sodium borohydride acetate (1.46g, 7 mmol) was added under stirring to react at 20 ℃ for 4 hours. The reaction was extracted with DCM (50ml × 3) and water (100 ml), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give crude product which was purified by flash silica gel column chromatography (EA/PE 20-50%) to give 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

The compound 013055A1 (2.0g, 4.2mmol) was dissolved in anhydrous THF (20 ml), stirred, added with triethylamine (1.5g, 169mol), cooled to 0 ℃, added with chloroacetyl chloride (600mg, 5.2mmol), and reacted at 20 ℃ for 12 hours after dropping. Adding water (40 ml) into the reaction solution, extracting with EA (10ml × 3), combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain a crude product, and using quick-drying silicaPurification by gel column chromatography (EA/PE 50-100%) gave 013055A2 (1.5g, 64%, white solid). LCMS: [ M + H] ⁺ 551.27。

And 3, 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

013055A2 (1.5g, 2.7mmol), potassium iodide (452mg, 2.7mmol) and anhydrous THF (20 ml) were charged into a reaction flask, stirred, cooled to 0 deg.C, sodium hydride (60% adsorbed in mineral oil, 216mg, 5.4mmol) was added, the temperature was slowly raised to 80 deg.C and the reaction was stirred for 2 hours. After the reaction was completed, it was cooled to room temperature, and the reaction was quenched with a saturated ammonium chloride solution. The reaction was extracted with water (50 ml) and EA (30ml × 3), the organic phases combined, dried over anhydrous sodium sulphate, filtered and the filtrate concentrated under reduced pressure to give a crude product which was purified by flash silica gel column chromatography (EA/PE 50-100%) to give 013055A3 (610mg, 44%, white solid). LCMS: [ M + H ]] ⁺ 515.30。

And 4, 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 (610mg, 1.19mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 2 hours, and the solvent was removed by concentration to give crude 013055A4, which was reacted in the next step without purification. LCMS: [ M + H] ⁺ 415.28。

And 5, 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-dione

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

¹ H NMR(400MHz,DMSO-d ₆ )δ12.02(s,1H),9.23(s,1H),8.71(d,J＝4.4Hz,1H),8.42(d,J＝1.6Hz,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 38SZ-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

The first step is as follows: (S) -tert-butyl 4- (butylamino) -4- ((1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) carbamoyl) piperidine-1-carboxylate

A reaction flask was charged with SZ-013056A1 (1.5g, 3.47mmol), butylaldehyde (0.25g, 3.47mmol) and dichloroethane (10 mL), two drops of acetic acid were added dropwise, sodium triacetoxyborohydride (0.8g, 3.81mmol) was added in portions, and the mixture was 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 =2, 1, rf = 0.6) to give SZ-013056A2 (500mg, 31%) as a colorless oil. [ M + H ]] ⁺ 489.30

The second step is that: (S) -tert-butyl 4- (N-butyl-2-chloroacetamido) -4- ((1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) carbamoyl) piperidine-1-carboxylate

SZ-013056A2 (500mg, 1.02mmol) was dissolved in dichloromethane (10 mL) in an ice-water bath, triethylamine (0.2mL, 1.53mmol) was added thereto, and chloroacetyl chloride (137mg, 1.25mmol) was slowly added dropwise thereto and stirred for 1 hour. 10mL of water and 10mL of dichloromethane were added to the system, and the mixture was dried over sodium sulfate for the organic phase and then spin-dried to obtain a crude product, which 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

Will SZ-013056A3 (15 g) was dissolved in anhydrous tetrahydrofuran (10 mL), sodium hydride (100mg, 2.3 mmol) was added to the system and stirred for 30 minutes, and finally potassium iodide (1699 mg, 1.02mmol) was added and stirred at 100 deg.C overnight. 5mL of water and 10mL 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, rf = 0.3) to give SZ-013056A4 (120 mg) as a colorless oil. [ 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-dione

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

The fifth step: (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), and potassium carbonate (160mg, 1.15mmol) and the pyrimidine chloride intermediate (50mg, 0.23mmol) were added sequentially and stirred at 110 ℃ overnight. After the reaction is finished, the crude product is directly purified by high-pressure reversed-phase column chromatography (ACN-0.1% ammonium carbonate aqueous solution), and is frozen and dried to obtain SZ-013056.LCMS: [ M + H] ⁺ 616.21

SZ-013056：HPLC t _R ＝7.08min。 ¹ H NMR(400MHz,d ₆ -DMSO)δ9.24(s,1H),8.72(d,J＝4.4Hz,1H),8.43(d,J＝2.0Hz,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 39SZ-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] dodec-9-ene-8, 12-dione

The first step is as follows: (S) -tert-butyl 4- (N-ethylacryloylamido) -4- ((1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) carbamoyl) piperidine-1-carboxylate

A reaction flask was charged with SZ-013057A1 (1.0g, 2.18mmol), triethylamine (0.5mL, 3.27mmol) and dichloroethane (10 mL), and chlorinated propionyl chloride (300mg, 2.18mmol) was slowly added and stirred at room temperature for 2 hours. The filtrate was dried and purified by flash silica gel column chromatography (PE: EA = 21. [ M + H ]] ⁺ 515.20

The second step is that: (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-carboxylate

SZ-013057A2 (1.1g, 2.14mmol) was dissolved in tetrahydrofuran (10 mL) in an ice-water bath, and sodium hydride (0.4g, 10mmol) was added thereto, followed by stirring under reflux for 4 hours. After cooling, 10mL of water and 10mL of ethyl acetate were added to the system, and the organic phase was dried over sodium sulfate, dried, and purified by flash silica gel column chromatography (PE: EA =1, rf = 0.4) to give SZ-013057A3 (120 mg) as a colorless oil. [ 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 (2 mL), trifluoroacetic acid (2 mL) was added and stirred at room temperature for 2 hours, and after the reaction was complete the next step was spin dried directly. [ M + H ]] ⁺ 412.59

The fifth step: (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), and potassium carbonate (160mg, 1.15mmol) and the pyrimidine chloride intermediate (50mg, 0.23mmol) were added sequentially and stirred at 110 ℃ overnight. Directly adding the crude product after the reaction is finishedPurifying by high pressure reversed phase column chromatography (ACN-0.1% ammonium carbonate aqueous solution), and lyophilizing to obtain SZ-013057.LCMS: [ M + H] ⁺ 560.12

SZ-013057：HPLC t _R ＝7.01min。 ¹ H NMR(400MHz,d ₆ -DMSO)δ11.86(s,1H),9.22(s,1H),8.70(d,J＝4.4Hz,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＝17.6Hz,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 40SZ-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] undecan-2-one

Step 1: 8- (2-chloroacetamido) -1, 4-dioxaspiro [4,5] decaalkane-8-carboxylic acid

Compound 1 (8.1g, 71.8mmol) was added dropwise to a suspension of compound 013058A0 (23.9g, 121.9mmol), sodium carbonate (15.3g, 143.6mmol), acetonitrile (160 mL) and water (160 mL) at 1-3 ℃ using a syringe. The resulting reaction mixture was stirred at 1-3 deg.C for an additional 1.6 hours, then diluted with water (160 mL). (system pH =8-9 was found after examination) the reaction mixture was then spun dry of all solvents and the residual solvent was removed under reduced pressure from an oil pump to give crude compound 013058A1 (31 g, crude). This compound was used directly 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] decaalkane-8-carboxylic acid amide

After the mechanical stirring device was installed, a solution of T3P/ethyl acetate (198 mL) was added dropwise to a suspension of compound 013058A1 (31 g, crude), compound 2 (31g, 128mmol) and triethylamine (110 mL) in DMF (1.3L) at 21 deg.C, and the resulting reaction mixture was stirred for an additional 16 hours at 16-23 deg.C. The resulting white suspension was quenched with water (1.6L) and extracted with ethyl acetate (600ml × 3). The combined organic phases were washed with saturated brine (300ml × 3), dried over anhydrous magnesium sulfate, filtered, the organic solvent was dried by spinning, and purified by column chromatography to give 013058A2 (8 g) as a yellow viscous oil. LCMS [ M + H ] +466.16@3.627min.

And 3, 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 (1.56g, 39mmol) was added portionwise to a suspension of compound 013058A2 (1.9g, 4.06mmol) and potassium iodide (1.6g, 9.63mmol) in tetrahydrofuran (36 mL) at 21 deg.C. The resulting reaction mixture was stirred at 21 ℃ for an additional 30 minutes. Then quenched with saturated aqueous ammonium chloride (30 mL), diluted with water (30 mL) and extracted with ethyl acetate (60ml x 3). The combined organic phases were dried over anhydrous magnesium sulfate, filtered and the organic solvent was spin dried. Then, pumping with an oil pump for three minutes gave crude compound 013058A3 (1.9 g), which was used directly in the next reaction. LCMS: [ M + H + ]430.26@3.167min.

And 4, 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] pentadecan-10-one

Solid lithium aluminum hydride powder (1.3g, 34.3mmol) was added portionwise to a solution of compound 013058A3 (1.63g, 3.9mmol) in tetrahydrofuran (39 mL) at 23 ℃. The resulting reaction mixture was stirred at 23 ℃ for an additional 1 hour. Then, tetrahydrofuran was added to dilute (30 mL), followed by the sequential addition of water (1.3 g), aqueous sodium hydroxide (1.3 g, 15Wt%) and water (3.9 g) to quench. The resulting reaction suspension was stirred vigorously at 23 ℃ for half an hour and then filtered under reduced pressure. The filtrates were combined and all solvents were spin dried. The residue was column purified to give the white solid compound 013058A4 (1g, 61.3%) LCMS: [ M + H + ]416.21@3.36min.

And 5, 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 (13mL, 78mmol, 6M) was added portionwise at 23 deg.C to a solution of compound 013058A4 (760mg, 1.8mmol) in 1, 4-dioxane (13 mL). The resulting reaction mixture was heated to 69 degrees celsius and stirring was continued for 1 hour. The resulting reaction mixture was then adjusted to pH 8-9 by adding solid sodium carbonate and water and the solid sodium carbonate addition was continued until saturated and extracted with ethyl acetate (30ml x 3). The organic phases were combined and anhydrous MgSO was added ₄ Drying, filtering and spin-drying the organic solvent. Oil pump then gave product 013058A5 as a white solid (610mg, 91%). LCMS: [ M + H +]372.17@3.167min。

And 6, step 6: 4- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-carbonyl-1, 4-diazaspiro [5.5] undec-8-en-9-yl trifluoromethanesulfonate

LiHMDS (1.9mL, 1.9mmol) was added portionwise to a solution of compound 013058A5 (610mg, 1.6mmol) in tetrahydrofuran (16 mL) at-78 deg.C using a syringe. The resulting reaction mixture was stirred at-78 ℃ for an additional 1 hour. Then a solution of PhNTf2 (680 mg, 1.9mmol) in tetrahydrofuran (3 mL) was added dropwise to the above reaction solution at-78 deg.C using a syringe. The resulting reaction mixture was stirred at-78-23 ℃ for an additional 16 hours. The reaction was then quenched by addition of saturated aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (30ml × 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a crude product. This was followed by purification by column chromatography to give 013058A6 as a white solid (399mg, 49%). LCMS [ + H + ]504.14@3.771min.

And 7, step 7: 4- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -9- (4, 5-tetramethyl-1, 3,2-6- ((5-methyl-1H-pyrazol-3-yl) -12-azaalkyl) pyrimidin-2-yl) -1,4, 9-triazaspiro [5.5] undecane

013058A6 (399mg, 0.8mmol), bispyribacloborate (253mg, 1mmol), potassium acetate (0.26g, 2.6 mmol), 1, 4-dioxane (9 mL) and PdCl at 33 deg.C ₂ A suspension of DCM (80 mg) was replaced with nitrogen three times with stirring and then heated to 90 ℃ under nitrogen blanketAnd stirring was continued for 3 hours. The resulting reaction mixture was cooled to 33 degrees Celsius and then quenched by addition of water (16 mL). Followed by extraction with ethyl acetate (30ml × 3). The organic phases were combined and dried over anhydrous MgSO4, filtered and the organic solvent was spin-dried. The crude product was purified by flash column chromatography to give 013058A7 as a white solid (330mg, 84.6%). LCMS: [ M + H +]482.31@3.905min。LCMS:[M+H+]532.35@2.513min。

And 8, 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] undecan-8-en-2-one

Pd (PPh) at 26 deg.C ₃ ) ₄ (69 mg) was added portionwise to a suspension of compound 013058A7 (330mg, 1.6 mmol), compound 3 (390mg, 1.6 mmol), potassium carbonate (690g, 5.3 mmol), 1, 4-dioxane (6 mL) and water (1.6 mL). Nitrogen was replaced three times and the resulting reaction mixture was in a Biotage microwave reactor: the reaction was carried out at 130 ℃ for one hour. The resulting red-yellow solution was cooled to room temperature, quenched with water (30 mL) and extracted with ethyl acetate (30ml × 3). The organic phases were combined and anhydrous MgSO was added ₄ Drying, filtering and spin-drying the organic solvent. The crude product was purified by flash column chromatography on silica gel to give 013058A8 (130mg, 46.19%) as a white solid. 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] undecan-2-one

Compound 013058A8 (130mg, 0.239mmol) was added to wet Pd (OH) at 26 deg.C ₂ To a black suspension of/C (300 mg) in methanol (33 mL) was added ammonium formate solid (3 g). The resulting reaction mixture was heated to 69 degrees celsius and stirring was continued for one hour. The resulting black suspension was cooled to room temperature, filtered through celite and washed with methanol (10ml × 3). The filtrates were combined, the solvent was spun dry and then dissolved in water (30 mL), and the solution was dissolved by adding solid Na ₂ CO ₃ Basification until saturation. Then extracted with ethyl acetate (30mL. Multidot.3), the organic phases combined and anhydrous MgSO added ₄ Drying, filtering and spin-drying the organic solvent. The crude product is subjected to high pressure to prepare a liquid phase colorAfter spectral purification two diastereomers were obtained:

SZ-013058A (13mg, 10%, white solid). LCMS: [ M + H +]545.26@2.821min。HPLC t _R ＝5.21min。 ¹ H NMR(400MHz,CD ₃ OD)δ8.41(d,J＝2.0Hz,1H),8.37(d,J＝4.0Hz,1H),7.96(dd,J1＝8.0Hz,J2＝2.0Hz,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＝4.0Hz,1H),3.04(d,J＝16.0Hz,1H),2.82(d,J＝8.0Hz,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＝8.0Hz,3H)。

SZ-013058B (3.9mg, 3%, white solid). LCMS: [ M + H +]545.21@2.916min。HPLC t _R ＝6.066min。 ¹ H NMR(400MHz,CD ₃ OD)δ8.56(d,J＝4.0Hz,1H),8.46(s,1H),8.02(dd,J ₁ ＝8.0Hz,J ₂ ＝2.0Hz,1H),7.99(d,J＝8.0Hz,1H),6.78(br,1H),6.21(br,1H),3.71(q,J＝4.0Hz,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)。

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

Example 41SZ-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] undecane-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

The reaction flask was charged with 013002A2 (1.0g, 2.3mmol) and anhydrous THF (20 ml), stirred, added with triethylamine (690mg, 6.9mmol), and cooled to room temperatureBromoacetyl bromide (634mg, 2.8mmol) is added dropwise at 0 ℃, and the temperature is raised to 20 ℃ after dropping for 12 hours of reaction. The reaction solution was extracted with water (40 ml) and EA (10ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by flash silica gel column chromatography (EA/PE 50-100%) to give 013059A1 (1.0g, 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

013059A1 (1.0g, 1.7mmol), potassium iodide (285mg, 1.7mmol) and anhydrous THF (20 ml) were put into a reaction flask, stirred, cooled to 0 ℃, added with LiHMDS (1M in THF,3.4mL, 3.4mmol), and stirred at 20 ℃ for 6 hours. After completion of the reaction, the reaction was cooled to room temperature, and quenched with a saturated ammonium chloride solution. The reaction was extracted with water (50 ml) and EA (30ml × 3), the organic phases combined, dried over anhydrous sodium sulphate, filtered and the filtrate concentrated under reduced pressure to give a crude product which was purified by flash silica gel column chromatography (EA/PE 50-100%) to give 013059A2 (150mg, 18%, white solid). LCMS: [ M + H] ⁺ 501.27。

And 3, 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 (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hour, and the solvent was removed by concentration to give crude 013059A3, which was reacted in the next step without purification. LCMS: [ M + H ]] ⁺ 401.21。

And 4, 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 (120mg, 0.3mmol), intermediate 2 (67mg, 0.3mmol) and potassium carbonate (165mg, 1.2mmol) were added to DMSO (5 mL), and stirred at 110 ℃ for 16 hours. Adding 50mL of water into the system, extracting with ethyl acetate (20 mL) for three times, performing vacuum spin-drying on the organic phase to obtain a crude product, performing reversed phase column chromatography on the product with acetonitrile/0.1% formic acid water, and performing freeze-drying to obtain SZ-013059 (25mg, 14%, white solid). LCMS: [ M + H ]] ⁺ 588.32。

¹ H NMR(400MHz,DMSO-d ₆ )δ11.86(s,1H),9.21(s,1H),8.68(d,J＝4.4Hz,1H),8.36(d,J＝1.2Hz,1H),7.94(d,J＝4.4Hz,1H),7.91-7.88(m,2H),6.29-6.05(m,2H),5.91(q,J＝7.1Hz,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 42SZ-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-dione

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

Compound 013002A5 (600mg, 1.6 mmol), 2-bromo-6-fluoro-4-methylpyridine (334mg, 1.76mmol), DIPEA (624mg, 4.8mmol) and isopropanol (20 ml) were charged into a reaction flask, and the temperature was raised to 100 ℃ for 12 hours. The reaction was extracted with water (50 ml) and EA (30ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to give a crude product, which was purified by flash silica gel column chromatography (EA/PE 50-100%) to give 013061A1 (360mg, 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

013061A1 (360mg, 0.66mmol), 5-methyl-1H-pyrazol-3-amine (65mg, 0.66mmol) and Pd are added into a 20mL microwave tube ₂ (dba) ₃ (36mg,10％)，XantPhos(190mg,0.33mmol)，Cs ₂ CO ₃ (643mg, 1.98mmol) and 1, 4-dioxane (8 ml), degassed for 10 minutes under argon, and stirred in a microwave reactor at 100 ℃ for 2 hours. After the reaction was completed, it was cooled to room temperature.The reaction mixture was extracted with EA (20ml × 3) in water (30 ml), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to give a crude product, which was subjected to reverse phase column chromatography with acetonitrile/0.1% formic acid water, and freeze-dried to give SZ-013061 (30mg, 8%, white solid). LCMS: [ M + H] ⁺ 559.32。

¹ H NMR(400MHz,DMSO-d ₆ )δ11.64(s,1H),8.71(d,J＝4.6Hz,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 43SZ-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] undecan-5-one

Sodium cyanoborohydride (160mg, 2.53mmol) was added portionwise at 33 ℃ to a solution of compound SZ-013034 (16mg, 29.3umol) and acetaldehyde/tetrahydrofuran solution (3mL, 15mmol, 5M) in methanol (3 mL), followed by a drop of acetic acid (13mg, 21.67mmol). The resulting reaction mixture was capped with a stopcock, heated to 69 degrees Celsius and stirred for an additional 16 hours. After the resulting reaction mixture was cooled to room temperature, it was quenched by addition of saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (10 mL. Multidot.3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a crude product. Followed by purification using high pressure preparative chromatography gave SZ-013062 as a white solid (2.3mg, 13.6%). LCMS: [ M + H +]574.26@2.986min。 ¹ H NMR(400MHz,CD ₃ OD)δ8.56(d,J＝4.0Hz,1H),8.43(d,J＝2.0Hz,1H),7.98(d,J＝8.0Hz,1H),7.93(dd,J ₁ ＝8.0Hz,J ₂ ＝2.0Hz,1H),7.63(d,J＝4.0Hz,1H),6.23(br,1H),6.11(br,1H),6.01(q,J＝4.0Hz,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＝8.0Hz,3H)。

Example 44SZ-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] decan-1-one

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

A reaction flask was charged with the compound 9386A3 (1.0g, 3.0mmol), 2-bromo-6-fluoro-4-methylpyridine (570mg, 3.0mmol), cs ₂ CO ₃ (2.9g, 9.0mmol) and isopropanol (20 ml), and the reaction was carried out while the temperature was raised to 100 ℃ for 12 hours. The reaction was extracted with water (50 ml) and EA (30ml × 3), the organic phases combined, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure to give a crude product which was purified by flash silica gel column chromatography (EA/PE 50-100%) to give 013063A1 (500mg, 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] decan-1-one

013063A1 (500mg, 1.0 mmol), 5-methyl-1H-pyrazol-3-amine (106mg, 1.1 mmol) and Pd were added to a 20mL microwave tube ₂ (dba) ₃ (50mg,10％)，XantPhos(290mg,0.5mmol)，Cs ₂ CO ₃ (1.0 g,3.0 mmol) and 1, 4-dioxane (8 ml), degassed for 10 minutes with argon displacement, and reacted for 2 hours with stirring at 100 ℃ in a microwave reactor. After the reaction was completed, the reaction mixture was cooled to room temperature. The reaction mixture was extracted with EA (20ml × 3) in water (30 ml), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to give a crude product, which was subjected to reverse phase column chromatography with acetonitrile/0.1% formic acid water, and freeze-dried to give SZ-013063 (70mg, 13%, white solid). LCMS: [ M + H ]] ⁺ 530.32。

¹ H NMR(400MHz,DMSO-d ₆ )δ11.65(s,1H),8.71(d,J＝4.6Hz,1H),8.55(s,1H),8.38(s,1H),7.96(d,J＝4.2Hz,1H),7.93(d,J＝1.2Hz,2H),6.34(s,1H),6.06-5.96(m,2H),5.33(q,J＝7.0Hz,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 1RET Activity inhibition test

The purpose of the test is as follows: staurosporine and BLU-667 were used as positive control compounds. IC of compound on RET kinase is detected by using Mobility shift assay method ₅₀ The value is obtained.

The test conditions are as follows:

enzyme concentration: 2.5nM

ATPKm：16uM

Pre-incubation: for 10min

Reaction time: 60min

Compound starting concentration 1 μ M,3 fold dilution, 10 concentrations, duplicate wells assay.

The test method comprises the following steps:

1. compound preparation A10 mM stock solution was prepared by dissolving compound powder in 100% DMSO.

2. Kinase reaction process

(1) A1 XKinase buffer was prepared.

(2) Preparation of compound concentration gradient: the test concentration of compounds was 1. Mu.M, diluted into 100-fold final concentration of 100-fold DMSO solution in 384 plates, after which the compounds were diluted 3-fold, 10 concentrations. Using a dispenser, 250nL of 100-fold final concentration of compound was transferred to the target plate.

(3) A2.5 fold final concentration of Kinase solution was prepared using a1 XKinase buffer.

(4) Add 10. Mu.L of 2.5 fold final concentration kinase solution to the compound well and positive control well, respectively; mu.L of 1 × Kinase buffer was added to the negative control wells.

(5) Centrifuge at 1000rpm for 30 seconds, shake the plate and incubate at room temperature for 10 minutes.

(6) A5/3 fold final ATP and Kinase substrate 2 mixture was prepared using a1 XKinase buffer.

(7) The reaction was initiated by adding 15. Mu.L of a 5/3 fold final ATP and substrate mixture.

(8) The 384 well plate was centrifuged at 1000rpm for 30 seconds, shaken well and incubated at room temperature for 60 minutes.

(9) Add 30. Mu.L of termination detection solution to stop the kinase reaction, centrifuge at 1000rpm for 30 seconds, shake and mix.

(10) The conversion was read with a Caliper EZ Reader.

3. Data analysis

Calculating the formula: % Inhibition = (Conversion% _ max-Conversion% _ sample)/(Conversion% _ max-Conversion% _ min) × 100%

Wherein: conversion% _ sample is the Conversion reading for the sample;

conversion% _ min: negative control well mean, representing conversion readings without enzyme live wells;

conversion% _ max: positive control wells are averaged for conversion readings in wells without compound inhibition.

Fitting a dose-response curve: the log value of the concentration is taken as an X axis, the percentage inhibition rate is taken as a Y axis, and an analysis software GraphPad Prism 5 is adopted to fit a dose-effect curve, so that the IC of each compound on the enzyme activity is obtained ₅₀ The value is obtained. The test results are shown in table 1:

TABLE 1

Effect example 2 inhibition of cell growth assay by Compounds

The purpose of the test is as follows: the inhibitory effect of compounds on cell growth was examined on MTC-TT and LC-2/AD cell lines.

The test method comprises the following steps:

1. cell line sources and culture conditions

Cell lines	Characteristics of	Source	Culture medium
				LC-2/AD	Wall-attached type	CAS	F12K+10％FBS
MTC-TT	Wall-attached type	Cupressus chingii of Nanjing Kogyu	RPMI-1640+10％FBS

2. Day 0: seeding cells

(1) After cell digestion, a cell suspension was prepared and cell density was calculated using an automatic cell counter.

(2) Diluting the cell suspension to an appropriate density according to the plating density

(3) 150uL of cells were seeded into 96-well plates and growth medium was added. Blank medium was used as background control (Min).

(4)37℃，5％CO ₂ The culture was carried out overnight.

3. Day 1: incubation of Compounds

(1) Preparation of 200 compound mother liquors with DMSO

(2) Compounds were diluted to 21-fold final concentration with growth medium, i.e. 21uL 200 compounds were added to 179uL growth medium.

(3) Adding 7.5uL of the diluted compound to the cells, 37 ℃,5% CO ₂ The culture was carried out for 72 hours.

4. Day 4: detection of

(1) The well plates were equilibrated to room temperature prior to detection.

(2) 40uL CellTiter-Glo reagent was added to each well.

(3) The cells were lysed by shaking with a horizontal shaker for 2 minutes.

(4) The fluorescence signal was stabilized by incubation for 10min at room temperature.

(5) The EnVision multi-label microplate detector detects the fluorescence signal.

5. Data analysis

(1) Data were analyzed using GraphPad Prism 5.

(2)％Inh＝(Max signal-Compound signal)/(Max signal-Min signal)×100。

(3) Maximum signal: fluorescence readings from DMSO wells only.

(4) Minimum signal: fluorescence readings from wells to which medium was added only.

6. And (3) detection results:

TABLE 2

Claims

1. A heterocyclic compound represented by formula I-0, or a pharmaceutically acceptable salt thereof, characterized in that:

wherein R is ¹ Is C ₁ ～C ₄ An alkyl group;

Y ¹ is CH;

Y ² is N or CH;

R ⁹ is methyl;

in (1)

Is a single bond or a double bond; when in use

When it is a double bond, X ¹ Is C;

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

in (1)

Is a single bond or a double bond; when in use

When it is a single bond, X ³ Is N, X ² Is CH ₂ Or C (= O); when in use

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

X ⁴ is composed of

Wherein, X ⁴ B terminal and X ³ Connecting;

A ¹ is N;

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

A ³ is NR ⁴ 、CH ₂ Or O; r ⁴ Is hydrogen, C ₁ ～C ₄ Alkyl, fluoro substituted C ₁ ～C ₄ Alkyl radical, C ₃ ～C ₆ Cycloalkyl-substituted C ₁ ～C ₄ Alkyl radical, C ₃ ～C ₆ Cycloalkyl, or, fluoro substituted C ₃ ～C ₆ A cycloalkyl group;

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

When A is ³ Is CH ₂ When, A ⁴ Is C (= O) or CH ₂ ；

When A is ³ When is O, A ⁴ Is CH ₂ ；

n is 0 or 1;

A ⁵ is NR ¹⁰ ；R ¹⁰ Is C ₁ ～C ₄ An alkyl group;

A ⁶ is C (= O) or CH ₂ ；

A ⁷ Is composed of

X ⁶ is C (= O) or CHR ² ；

R ² Is hydrogen or C ₁ ～C ₄ An alkyl group;

X ⁵ is CH;

R ⁶ is hydrogen;

R ⁷ is halogen;

R ⁸ is hydrogen.

2. The heterocyclic compound of formula I-0, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, where s is 1; t is 1;

and/or, X ⁴ Is composed of

And/or, when X ⁴ Is composed of

When, A ⁵ Is NR ¹⁰ ；R ¹⁰ Is methyl, ethyl, n-propyl, isopropyl or n-butyl;

and/or n is 1;

and/or, X ⁶ Is CHR ² ；

And/or, R ² Is C ₁ ～C ₄ An alkyl group.

3. The heterocyclic compound of formula I-0, or a pharmaceutically acceptable salt thereof, as claimed in claim 2, where R is ¹ Is methyl;

and/or, Y ² Is N;

and/or the presence of a gas in the atmosphere,

in

Is a single bond; when in use

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

and/or when X ⁴ Is composed of

When, A ² Is CR ³ ；R ³ Is amino or C ₁ ～C ₄ An alkyl group;

and/or, when X ⁴ Is composed of

When, A ³ Is NR ⁴ 、CH ₂ Or O; r ⁴ Is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH ₂ CF ₃ Cyclopropane or-CH ₂ -cyclopropane;

and/or, when X ⁴ Is composed of

When, A ⁴ Is C (= O) or CH ₂ ；

And/or, R ² Is methyl;

and/or, R ⁷ Is F.

4. The heterocyclic compound of formula I-0, or a pharmaceutically acceptable salt thereof, as claimed in claim 3, where X is ⁴ Is composed of

When, A ² Is CR ³ ；R ³ Is amino, methyl or isopropyl;

and/or, when X ⁴ Is composed of

When, A ⁴ Is C (= O).

5. The heterocyclic compound of formula I-0, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, where R is ¹ Is C ₁ ～C ₄ An alkyl group;

Y ¹ is CH;

Y ² is N or CH;

R ⁹ is methyl;

in (1)

Is a single bond or a double bond; when in use

When it is a double bond, X ¹ Is C;

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

in (1)

When it is a single bond, X ³ Is N, X ² Is CH ₂ Or C (= O); when in use

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

X ⁴ is composed of

A ¹ Is N;

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

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

When A is ³ Is CH ₂ When, A ⁴ Is C (= O) or CH ₂ ；

When A is ³ When is O, A ⁴ Is CH ₂ ；

n is 0 or 1;

A ⁵ is NR ¹⁰ ；R ¹⁰ Is C ₁ ～C ₄ An alkyl group;

A ⁶ is C (= O) or CH ₂ ；

A ⁷ Is composed of

Or CR ¹¹ R ¹² ；R ¹¹ And R ¹² Independently is hydrogen or C ₁ ～C ₄ Alkyl, but R ¹¹ And R ¹² Not hydrogen at the same time;

X ⁶ is C (= O) or CHR ² ；

R ² Is hydrogen or C ₁ ～C ₄ An alkyl group;

X ⁵ is CH;

R ⁶ is hydrogen;

R ⁷ is halogen;

R ⁸ is hydrogen.

6. The heterocyclic compound of formula I-0, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, where R is ¹ Is methyl;

Y ¹ is CH;

Y ² is N or CH;

R ⁹ is methyl;

in (1)

When it is a double bond, X ¹ Is C;

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

in (1)

When it is a single bond, X ³ Is N, X ² Is CH ₂ Or C (= O); when the temperature is higher than the set temperature

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

X ⁴ is composed of

A ¹ Is N;

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

A ³ is NR ⁴ 、CH ₂ Or O; r ⁴ Is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH ₂ CF ₃ Cyclopropane or-CH ₂ -cyclopropane;

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

When A is ³ Is CH ₂ When, A ⁴ Is C (= O) or CH ₂ ；

When A is ³ When is O, A ⁴ Is CH ₂ ；

n is 0 or 1;

A ⁵ is NR ¹⁰ ；R ¹⁰ Is methyl, ethyl, n-propyl, isopropyl or n-butyl;

A ⁶ is C (= O) or CH ₂ ；

A ⁷ Is composed of

Or CR ¹¹ R ¹² ；R ¹¹ And R ¹² Independently is hydrogen or methyl, but R ¹¹ And R ¹² 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.

7. The heterocyclic compound of formula I-0, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, where R is ¹ Is methyl;

Y ¹ is CH;

Y ² is N;

R ⁹ is methyl;

in (1)

Is a single bond; when in use

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

s is 1; t is 1;

in (1)

Is a single bond; when in use

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

X ⁴ is composed of

A ⁴ is C (= O); n is 1;

X ⁶ is CHR ² ；

R ² Is C ₁ ～C ₄ An alkyl group;

X ⁵ is CH;

R ⁶ is hydrogen;

R ⁷ is halogen;

R ⁸ is hydrogen.

8. The heterocyclic compound of formula I-0, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, where R is ¹ Is C ₁ ～C ₄ An alkyl group;

Y ¹ is CH;

Y ² is N or CH;

R ⁹ is methyl;

in (1)

Is a single bond or a double bond; when in use

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

When it is a double bond, X ¹ Is C;

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

in (1)

Is a single bond or a double bond; when in use

When it is a single bond, X ³ Is N, X ² Is CH ₂ Or C (= O); when in use

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

X ⁴ is composed of

A ⁵ Is NR ¹⁰ ；R ¹⁰ Is C ₁ ～C ₄ An alkyl group;

A ⁶ is C (= O) or CH ₂ ；

A ⁷ Is composed of

X ⁶ is C (= O) or CHR ² ；

R ² Is hydrogen or C ₁ ～C ₄ An alkyl group;

X ⁵ is CH;

R ⁶ is hydrogen;

R ⁷ is halogen;

R ⁸ is hydrogen.

9. The heterocyclic compound of formula I-0, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, where R is ¹ Is C ₁ ～C ₄ An alkyl group;

Y ¹ is CH;

Y ² is N or CH;

R ⁹ is methyl;

in (1)

Is a single bond or a double bond; when in use

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

When it is a double bond, X ¹ Is C;

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

in

When it is a single bond, X ³ Is N, X ² Is CH ₂ Or C (= O); when in use

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

X ⁴ is composed of

{ wherein, X ⁴ B terminal and X ³ Connection }

A ¹ Is N;

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

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

When A is ³ Is CH ₂ When, A ⁴ Is C (= O) or CH ₂ ；

When A is ³ When is O, 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 An alkyl group;

X ⁵ is CH;

R ⁶ is hydrogen;

R ⁷ is halogen;

R ⁸ is hydrogen.

10. The heterocyclic compound of formula I-0, or a pharmaceutically acceptable salt thereof, as claimed in claim 9, where R is ¹ Is C ₁ ～C ₄ An alkyl group;

Y ¹ is CH;

Y ² is N;

R ⁹ is methyl;

in (1)

Is a single bond or a double bond; when in use

When it is a double bond, X ¹ Is C;

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

in (1)

Is a single bond or a double bond; when in use

When it is a single bond, X ³ Is N, X ² Is CH ₂ Or C (= O); when in use

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

X ⁴ is composed of

A ¹ Is N;

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

A ³ is NR ⁴ 、CH ₂ Or O; r ⁴ Is hydrogen, C ₁ ～C ₄ Alkyl, or, fluoro substituted C ₁ ～C ₄ An alkyl group;

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

When A is ³ Is CH ₂ When, A ⁴ Is C (= O) or CH ₂ ；

When A is ³ When is O, 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 An alkyl group;

X ⁵ is CH;

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

11. The heterocyclic compound of formula I-0, or a pharmaceutically acceptable salt thereof, as claimed in claim 9, where R is ¹ Is C ₁ ～C ₄ An alkyl group;

Y ¹ is CH; y is ² Is N; r ⁹ Is methyl;

in (1)

Is a single bond or a double bond; when in use

When it is a double bond, X ¹ Is C;

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

in

Is a single bond or a double bond; when in use

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

X ⁴ is composed of

A ¹ Is N;

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

when A is ³ Is NR ⁴ When, A ⁴ Is C (= O) or CH ₂ (ii) a When A is ³ Is CH ₂ Or O is, 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 An alkyl group;

X ⁵ is CH;

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

12. The heterocyclic compound of formula I-0, or a pharmaceutically acceptable salt thereof, as claimed in claim 9, where R is ¹ Is C ₁ ～C ₄ An alkyl group;

Y ¹ is CH; y is ² Is N; r ⁹ Is methyl;

in (1)

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

When it is a double bond, X ¹ Is C;

s is 1; t is 1;

in

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

X ⁴ is composed of

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

When A is ³ Is CH ₂ When, A ⁴ Is C (= O) or CH ₂ ；

When A is ³ When is O, A ⁴ Is CH ₂ ；

n is 1;

X ⁶ is CHR ² ；

R ² Is hydrogen or C ₁ ～C ₄ An alkyl group;

X ⁵ is CH;

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

13. The heterocyclic compound of formula I-0, or a pharmaceutically acceptable salt thereof, as claimed in claim 9, where R is ¹ Is C ₁ ～C ₄ An alkyl group;

Y ¹ is CH; y is ² Is N; r ⁹ Is methyl;

in (1)

Is a single bondWhen, X ¹ Is N or CH; when in use

When it is a double bond, X ¹ Is C;

s is 1; t is 1;

in (1)

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

X ⁴ is composed of

when A is ³ Is NR ⁴ When, A ⁴ Is C (= O) or CH ₂ (ii) a When A is ³ Is CH ₂ Or when O is present, A ⁴ Is CH ₂ ；

n is 1;

X ⁶ is CHR ² ；

R ² Is hydrogen or C ₁ ～C ₄ An alkyl group;

X ⁵ is CH;

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

14. The heterocyclic compound of formula I-0, or a pharmaceutically acceptable salt thereof, as claimed in claim 9, where R is ¹ Is C ₁ ～C ₄ An alkyl group;

Y ¹ is CH; y is ² Is N; r ⁹ Is methyl;

in

Is a single or double bond; when in use

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

When it is a double bond, X ¹ Is C;

s is 1; t is 1;

in (1)

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

X ⁴ is composed of

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

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

n is 1;

X ⁶ is CHR ² ；

R ² Is hydrogen or C ₁ ～C ₄ An alkyl group;

X ⁵ is CH;

R ⁶ is hydrogen; r ⁷ Is halogen; r is ⁸ Is hydrogen。

15. The heterocyclic compound of formula I-0, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, where R is ¹ Is C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl;

and/or when

In the case of a double bond, the double bond,

is composed of

And/or

And/or when

Is a single bond, X ¹ In the case of the group CH,

is composed of

And/or

And/or when R ³ Is C ₁ ～C ₄ When alkyl, said 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 When alkyl, said 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 When the alkyl is adopted, the number of the fluorine is one or more;

and/or when R ⁴ Is fluorine substituted C ₁ ～C ₄ When alkyl, said 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 ₃ ～C ₆ Cycloalkyl-substituted C ₁ ～C ₄ When alkyl, said C ₃ ～C ₆ The number of cycloalkyl groups is 1;

and/or when R ⁴ Is C ₃ ～C ₆ Cycloalkyl-substituted C ₁ ～C ₄ When alkyl, said C ₃ ～C ₆ Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

and/or when R ⁴ Is C ₃ ～C ₆ Cycloalkyl-substituted C ₁ ～C ₄ When alkyl, said 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 ₃ ～C ₆ When there is a cycloalkyl group, said C ₃ ～C ₆ Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

and/or when R ⁴ Is fluorine substituted C ₃ ～C ₆ When the alkyl is cycloalkyl, the number of fluorine is one or more;

and/or when R ⁴ Is fluorine substituted C ₃ ～C ₆ When a cycloalkyl group is said to be C ₃ ～C ₆ Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

and/or when R ¹⁰ Is C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl;

and/or when R ¹¹ Is C ₁ ～C ₄ When alkyl, said 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 When alkyl, said 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 When the temperature of the water is higher than the set temperature,

is composed of

And/or

And/or when R ² Is C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl;

and/or when R ⁷ When the halogen is fluorine, chlorine, bromine or iodine;

and/or, except the part with determined spatial configuration, the rest part of the heterocyclic compound I-0 is the mixture of all spatial configurations;

and/or all atoms in the heterocyclic compound I-0 are atoms with natural isotopic abundance.

16. The heterocyclic compound of formula I-0, or a pharmaceutically acceptable salt thereof, as claimed in claim 15, where when R is ¹ Is C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ Alkyl is methyl;

and/or when R ³ Is C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ Alkyl is methyl or isopropyl;

and/or when R ⁴ Is C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ Alkyl is methyl, ethyl, n-propyl or n-butyl;

and/or when R ⁴ Is fluorine substituted C ₁ ～C ₄ In the case of alkyl, the number of fluorine is 1,2 or 3;

and/or when R ⁴ Is C ₃ ～C ₆ Cycloalkyl-substituted C ₁ ～C ₄ When alkyl, said C ₃ ～C ₆ Cycloalkyl-substituted C ₁ ～C ₄ Alkyl is cyclopropylmethyl;

and/or when R ⁴ Is C ₃ ～C ₆ When a cycloalkyl group is said to be C ₃ ～C ₆ Cycloalkyl is cyclopropyl;

and/or when R ⁴ Is fluorine substituted C ₃ ～C ₆ In the case of cycloalkyl, the number of fluorine is 1,2 or 3;

and/or when R ¹⁰ Is C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ Alkyl is C ₁ ～C ₄ Alkyl is methyl, ethyl, n-propyl or n-butyl;

and/or when R ¹¹ Is C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ Alkyl is methyl, ethyl, n-propyl or n-butyl;

and/or when R ¹² Is C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ Alkyl is methyl, ethyl, n-propyl or n-butyl;

and/or, when X ⁶ Is CHR ² 、

In the case of a double bond, the double bond,

is composed of

And

one or more of;

and/or, when X ⁶ Is CHR ² 、

Is a single bond, X ¹ In the case of the group CH,

is composed of

And

one or more of (a);

and/or, when X ⁶ Is CHR ² 、

Is a single bond, X ¹ In the case of N, the compound is,

is composed of

And/or

And/or when R ² Is C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ Alkyl is methyl;

and/or when R ⁷ When halogen is used, the halogen is fluorine.

17. The heterocyclic compound of formula I-0, or a pharmaceutically acceptable salt thereof, as claimed in claim 16, where when R is ⁴ Is fluorine substituted C ₁ ～C ₄ When alkyl, said fluorine substituted C ₁ ～C ₄ The alkyl group is a2, 2-trifluoroethyl group or a2, 2-difluoroethyl group.

18. The heterocyclic compound of formula I-0 or a pharmaceutically acceptable salt thereof according to claim 1, which is

R ¹ Is C ₁ ～C ₄ An alkyl group;

Y ¹ is CH;

Y ² is N or CH;

in (1)

Is a single or double bond; when in use

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

When it is a double bond, X ¹ Is C;

in

Is a single or double bond; when in use

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

X ⁴ is composed of

A ¹ Is N;

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

A ³ is NR ⁴ 、CH ₂ Or O; r is ⁴ Is hydrogen, C ₁ ～C ₄ Alkyl, fluoro substituted C ₁ ～C ₄ Alkyl radical, C ₃ ～C ₆ Cycloalkyl, or, fluoro substituted C ₃ ～C ₆ A cycloalkyl group;

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

When A is ³ Is CH ₂ When, A ⁴ Is C (= O) or CH ₂ ；

When A is ³ When is O, A ⁴ Is CH ₂ ；

n is 0 or 1;

R ² is hydrogen or C ₁ ～C ₄ An alkyl group;

X ⁵ is CH;

R ⁶ is hydrogen; r ⁷ Is halogen;

R ⁸ is hydrogen;

R ⁹ is methyl.

19. The heterocyclic compound of formula I-0, or a pharmaceutically acceptable salt thereof, as claimed in claim 18, where when R is ¹ Is C ₁ ～C ₄ When alkyl, said C ₁ ～C ₄ Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl;

and/or when R ⁷ When the halogen is fluorine, chlorine, bromine or iodine;

and/or the presence of a gas in the atmosphere,

is composed of

And/or

And/or when

In (1)

Is a single bond, X ¹ When is CH;

is composed of

And/or

And/or when

In (1)

Is a double bond, X ¹ When is C;

is composed of

And/or

20. The heterocyclic compound of formula I-0, or a pharmaceutically acceptable salt thereof, as claimed in claim 19, where when X is ⁴ Is composed of

When the temperature of the water is higher than the set temperature,

is composed of

And/or when X ⁴ Is composed of

When the utility model is used, the water is discharged,

is composed of

21. The heterocyclic compound of formula I-0, or pharmaceutically acceptable salt thereof, as claimed in claim 18, where R is ¹ Is C ₁ ～C ₄ An alkyl group;

Y ¹ is CH;

Y ² is N;

in (1)

Is a single bond or a double bond; when in use

When it is a double bond, X ¹ Is C;

in (1)

Is a single bond; when in use

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

X ⁴ is composed of

A ¹ Is N;

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

A ³ is NR ⁴ 、CH ₂ Or O; r ⁴ Is hydrogen or C ₁ ～C ₄ An alkyl group;

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

When A is ³ Is CH ₂ When, A ⁴ Is C (= O) or CH ₂ ；

When A is ³ When is O, A ⁴ Is CH ₂ ；

n is 0;

R ² is C ₁ ～C ₄ An alkyl group;

X ⁵ is CH;

R ⁶ is hydrogen;

R ⁷ is halogen;

R ⁸ is hydrogen;

R ⁹ is methyl.

22. The heterocyclic compound of formula I-0, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein the heterocyclic compound I-0 is any one of the following compounds:

23. the heterocyclic compound of formula I-0, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the heterocyclic compound I is any one of the following compounds:

24. use of a heterocyclic compound of formula I-0 according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, for the preparation of a RET inhibitor or a medicament for the prevention and/or treatment of a disease mediated by aberrant expression of RET.

25. Use of a heterocyclic compound of formula I-0, or a pharmaceutically acceptable salt thereof, as defined in claim 24, for the preparation of a RET inhibitor or a medicament, wherein the "disease mediated by aberrant expression of RET" is cancer.

26. Use of a heterocyclic compound of formula I-0 or a pharmaceutically acceptable salt thereof as defined in claim 25 for the preparation of a RET inhibitor or medicament, wherein the cancer is papillary thyroid cancer, medullary thyroid cancer, pheochromocytoma, ductal pancreatic adenocarcinoma, multiple endocrine tumors, 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.

27. Use of a heterocyclic compound of formula I-0 or a pharmaceutically acceptable salt thereof as defined in claim 26 for the preparation of a RET inhibitor or medicament, wherein the multiple endocrine neoplasia is MEN2A or MEN2B; the breast cancer is metastatic breast cancer.

28. Use of a heterocyclic compound of formula I-0 according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention and/or treatment of cancer.

29. Use of a heterocyclic compound as shown in formula I-0 or a pharmaceutically acceptable salt thereof according to claim 28, which is papillary thyroid cancer, medullary thyroid cancer, pheochromocytoma, ductal adenocarcinoma of the pancreas, multiple endocrine tumors, 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, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament.

30. Use of the heterocyclic compound according to formula I-0, or a pharmaceutically acceptable salt thereof, as defined in claim 29, for the manufacture of a medicament, wherein the multiple endocrine tumor is MEN2A or MEN2B; the breast cancer is metastatic breast cancer.

31. A pharmaceutical composition, which comprises the heterocyclic compound shown in formula I-0 or pharmaceutically acceptable salt thereof according to any one of claims 1 to 23, and a pharmaceutical adjuvant.