CN114634512B

CN114634512B - Compounds as inhibitors of bruton's tyrosine kinase, preparation method and medical application thereof

Info

Publication number: CN114634512B
Application number: CN202111534599.3A
Authority: CN
Inventors: 李璞慧; 燕银发; 武和平; 刘建; 杨方龙; 刘�东; 庄凌航; 宋春英; 刘苏星
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2020-12-16
Filing date: 2021-12-15
Publication date: 2023-11-14
Anticipated expiration: 2041-12-15
Also published as: CN114634512A

Abstract

The present disclosure relates to compounds that are inhibitors of bruton's tyrosine kinase, methods for their preparation, and pharmaceutical uses. In particular, the present disclosure relates to compounds of formula (I) as inhibitors of Bruton's Tyrosine Kinase (BTK), pharmaceutical compositions containing these compounds, processes for their preparation, and the use of these compounds as therapeutic agents for the treatment of various diseases associated with excessive BTK activity, including cancer, immune diseases, cardiovascular diseases, viral infections, inflammation, metabolic/endocrine dysfunctions and neurological disorders.

Description

Compounds as inhibitors of bruton's tyrosine kinase, preparation method and medical application thereof

Technical Field

The present disclosure relates to inhibitors of Bruton's Tyrosine Kinase (BTK), including wild-type and mutant BTK, for the treatment of BTK-related diseases or disorders, such as cancer, immune diseases, cardiovascular diseases, viral infections, inflammation, metabolism/endocrine function disorders and neurological disorders.

Background

Bruton's Tyrosine Kinase (BTK) is a cytoplasmic non-receptor tyrosine kinase of the TEC family. The protein structure comprises an N-terminal pleckstrin substrate homology (PH) domain, a TEC Homology (TH) domain, SRC Homology (SH) domains SH2 and SH3, and a kinase domain with enzymatic activity (Hendriks RW et al, nat Rev cancer.2014, 14:219-232). Its PH domain recruits BTK to the cell membrane by interacting with phosphatidylinositol-3, 4, 5-triphosphate (PIP 3) produced by phosphatidylinositol-3 kinase (PI 3K). Transmembrane proteins, such as the B Cell Receptor (BCR) complex, promote phosphorylation of BTK at Y551 by SYK or SRC family kinases, leading to activation of BTK kinase and subsequent autophosphorylation of Y223 in the SH3 domain (Rawlings DJ et al, science 1996, 271:822-825). BTK is expressed in B lymphocytes and is essential at various stages of B lymphocyte development (Burger JA et al, nat Rev cancer.2018, 18:148-167). BTK was initially shown to mutate in human primary immunodeficiency X-linked agaropectinemia (XLA). XLA patients are characterized by a low B Cell count and little antibody in their circulation (Vetrie D, et al, nature.1993,361:226-233; tsukada S et al, cell,1993, 72:279-290). BTK can also be expressed in certain types of myeloid cells, such as macrophages, neutrophils, and mast cells. Among these innate immune cells, BTK has been shown in toll-like receptor (TLR), fc receptor (FCR) and chemokine receptor mediated signaling (Croford et al, expert Rev Clin Immunol,2016, 12:763-773). Activation of BTK stimulates several downstream signaling pathways, such as the nfkb and MAP (mitogen activated protein) kinase pathways. Abnormal expression and/or activation of BTK has been found in a variety of B cell malignancies, which is critical for cancer cell survival and autoimmune disease.

BTK inhibitors have been developed for the purpose of treating cancer and autoimmune diseases, such as Chronic Lymphocytic Leukemia (CLL) and Rheumatoid Arthritis (RA) or lupus. Several covalent BTK inhibitors have been used clinically for B cell malignancies. However, these inhibitors target cysteine residue C481 in the BTK kinase domain to covalently bind to the side chain thiol. Drug resistance has emerged with the treatment of clinical covalent BTK inhibitors in cancer patients. Mutations in the BTK protein have been reported in recurrent cancers, such as C481S, C481Y, C R and C481F, and have been shown to result in the loss of the drug covalent binding site (Liu L et al, future Med Chem,2018, 10:343-356).

Recurrence of cancer such as CLL or Mantle Cell Lymphoma (MCL) following treatment with covalent BTK inhibitors is an increasingly important clinical issue (Wayach JA et al, J Clin Oncol,2017, 35:1437-1443). It is therefore an object of the present disclosure to provide non-covalently bound BTK inhibitors, more particularly as reversible inhibitors. These reversible inhibitors are expected to be comparable to existing BTK inhibitors in the clinic, but are also effective against BTK mutants.

Disclosure of Invention

In order to avoid the limitations of covalently binding to inhibitors of Bruton's Tyrosine Kinase (BTK), the present disclosure provides compounds and methods for inhibiting BTK, and the use of these compounds in the treatment of diseases associated with overactive BTK, including cancer, immune diseases, cardiovascular diseases, viral infections, inflammation, metabolic/endocrine dysfunctions, and neurological disorders.

In one aspect, the present disclosure provides a compound of formula (I) having the structure:

or a pharmaceutically acceptable salt thereof,

wherein:

R ¹ selected from hydrogen, alkyl, -OR ⁵ 、-NR ^6a R ^6b Cyano and-C (O) NR ^6a R ^6b ；

R ² Selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, 3 to 6 membered cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, 3-to 6-membered cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, haloalkyl, -NR ^7a R ^7b 、-OR ⁸ 、-OC(O)R ⁹ 、-C(O)R ⁹ 、-C(O)OR ⁸ 、-NR ^d C(O)R ⁹ 、-C(O)NR ^7a R ^7b 、-NR ^d S(O) _t R ⁹ 、-S(O) _t R ⁹ 、-S(O) _t OR ⁸ 、-S(O) _t NR ^7a R ^7b One or more of cyano, oxo, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, sometimes preferably one to five, sometimes more preferably one to three groups;

ring a is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

r in each occurrence ³ Identical or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, cyano, -NR ^10a R ^10b 、-OR ¹¹ Oxo, -C (O) R ¹² 、-C(O)OR ¹¹ 、-C(O)NR ^10a R ^10b 、-S(O) _t R ¹² 、-S(O) _t OR ¹¹ Cycloalkyl, heterocyclyl, aryl, and heteroaryl;

or two adjacent R ³ Substituents together with ring a may optionally be linked to form cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein each of the cycloalkyl, heterocyclyl, aryl and heteroaryl groups is independently optionally substituted with one or more, sometimes preferably one to five, sometimes more preferably one to three groups selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxy, oxo and hydroxyalkyl;

L ₁ is-CR ^a R ^b -；

L ₂ is-NR ^c -；

Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

r in each occurrence ⁴ Identical or different and are each independently selected from hydrogen, halogen, alkyl, cyano, -NR ^10a R ^10b 、-OR ¹¹ 、-S(O) _t R ¹² Hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted with a member selected from the group consisting of halogen, alkyl, haloalkyl, -NR ^7a R ^7b 、-OR ⁸ One or more of cyano, oxo, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, sometimes preferably one to five, sometimes more preferably one to three groups;

or two adjacent R ⁴ Substituents together with ring B may optionally be linked to form cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groupsEach independently optionally substituted with one or more, sometimes preferably one to five, sometimes more preferably one to three groups selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxy, oxo, and hydroxyalkyl;

R ^a 、R ^b 、R ^c and R is ^d The same or different and are each independently selected from hydrogen, alkyl, haloalkyl and hydroxyalkyl;

R ⁵ 、R ^6a 、R ^6b 、R ^7a 、R ^7b 、R ⁸ 、R ⁹ 、R ^10a 、R ^10b 、R ¹¹ And R is ¹² The same or different and are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted with one or more, sometimes preferably one to five, sometimes more preferably one to three groups selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxy, oxo, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups;

t is 0, 1 or 2;

m is 0, 1, 2, 3, 4, 5 or 6; and is also provided with

n is 0, 1, 2, 3, 4, 5 or 6.

In some embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L ₁ is-CR ^a R ^b -，R ^a And R is ^b Are all hydrogen.

In some embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L ₂ is-NR ^c -，R ^c Is hydrogen.

In some embodiments of the present disclosure, the compound of formula (I) is selected from the group consisting of compounds of formula (II):

or a pharmaceutically acceptable salt thereof,

wherein:

ring a, ring B, R ¹ To R ⁴ M and n are as defined for formula (I).

In some embodiments, the present disclosure provides a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein R ¹ Selected from hydrogen, C _1-6 Alkyl, -OR ⁵ 、-NR ^6a R ^6b Cyano and-C (O) NR ^6a R ^6b The method comprises the steps of carrying out a first treatment on the surface of the Preferably, R ¹ is-NR ^6a R ^6b ；R ⁵ 、R ^6a And R is ^6b As defined by formula (I).

In some embodiments of the present disclosure, the compound of formula (I) or formula (II) is selected from the group consisting of compounds of formula (III):

or a pharmaceutically acceptable salt thereof,

wherein:

ring a, ring B, R ² To R ⁴ M and n are as defined for formula (I).

In some embodiments, the present disclosure provides compounds of formula (I), formula (II) or formula (III), or a pharmaceutically acceptable salt thereof, wherein ring a is selected from the group consisting of 3-to 8-membered cycloalkyl, 3-to 12-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 10-membered heteroaryl; preferably, ring a is selected from 3 to 6 membered cycloalkyl, phenyl and 5 or 6 membered heteroaryl; more preferably, ring A is selected from phenyl, pyridyl, thienyl, thiazolyl and

in some embodiments, the present disclosure provides compounds of formula (I), formula (II) or formula (III), or a pharmaceutically acceptable salt thereof, wherein ring B is selected from the group consisting of 3-to 8-membered cycloalkyl, 3-to 12-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 10-membered heteroaryl; preferably, ring B is phenyl or 5 or 6 membered heteroaryl; more preferably, ring B is selected from phenyl, pyridyl, thienyl and thiazolyl.

In some embodiments, the present disclosure provides compounds of formula (I), formula (II) or formula (III), or a pharmaceutically acceptable salt thereof, wherein R ² Selected from C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, 3 to 6 membered cycloalkyl and 3 to 12 membered heterocyclyl; preferably, R ² Selected from C _1-6 Alkyl, C _1-6 Haloalkyl and 3 to 6 membered heterocyclyl; more preferably, R ² Is C _1-6 Alkyl or C _1-6 A haloalkyl group; most preferably, R ² Is C _1-6 A haloalkyl group.

In some embodiments, the present disclosure provides compounds of formula (I), formula (II) or formula (III), or a pharmaceutically acceptable salt thereof, wherein R ² Selected from isopropyl, 1-trifluoropropan-2-yl, tetrahydrofuranyl and tetrahydropyranyl; preferably, R ² Selected from isopropyl, 1-trifluoropropan-2-yl and tetrahydropyranyl; more preferably, R ² Is isopropyl or 1, 1-trifluoropropan-2-yl; most preferably, R ² Is 1, 1-trifluoropropan-2-yl.

In some embodiments, the present disclosure provides compounds of formula (I), formula (II) or formula (III), or pharmaceutically acceptable salts thereof, wherein each occurrence of R ³ Identical or different and are each independently selected from hydrogen, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, cyano and-OR ¹¹ The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ¹¹ Selected from hydrogen, C _1-6 Alkyl, C _1-6 Haloalkyl, 3-to 8-membered cycloalkyl and 3-to 12-membered heterocyclyl; preferably, R per occurrence ³ Identical OR different and are each independently selected from hydrogen, halogen and-OR ¹¹ The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ¹¹ Selected from C _1-6 Alkyl, C _1-6 Haloalkyl and 3 to 6 membered cycloalkyl; more preferably, R per occurrence ³ The same or different and are each independently selected from hydrogen, fluoro, methoxy, ethoxy and cyclopropyloxy.

In some embodiments, the present disclosure provides compounds of formula (I), formula (II) or formula (III), or pharmaceutically acceptable salts thereof, wherein each occurrence of R ³ Identical or different, and each is independentAt the site selected from hydrogen, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, cyano and-OR ¹¹ The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ¹¹ Selected from hydrogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; preferably, R per occurrence ³ The same or different and are each independently selected from hydrogen, fluoro, methoxy and ethoxy.

In some embodiments, the present disclosure provides compounds of formula (I), formula (II) or formula (III), or pharmaceutically acceptable salts thereof, wherein two adjacent R ³ The substituents together with ring a may optionally be linked to form a 3 to 8 membered cycloalkyl; wherein the 3-to 8-membered cycloalkyl is optionally independently selected from halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy and C _1-6 One or more, sometimes preferably one to five, sometimes more preferably one to three groups of the hydroxyalkyl groups are substituted; preferably, two adjacent R ³ The substituents together with ring a may optionally be linked to form a 3-6 membered cycloalkyl.

In some embodiments, the present disclosure provides compounds of formula (I), formula (II) or formula (III), or pharmaceutically acceptable salts thereof, wherein each occurrence of R ⁴ Identical or different and are each independently selected from hydrogen, halogen, C _1-6 Alkyl, -NR ^10a R ^10b 、-OR ¹¹ 、-S(O) _t R ¹² And C _1-6 A hydroxyalkyl group; wherein R is ^10a 、R ^10b 、R ¹¹ And R is ¹² Identical or different and are each independently selected from hydrogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; t is 2; preferably, R per occurrence ⁴ Identical or different and are each independently selected from hydrogen, fluoro, methoxy, ethoxy, OCF ₃ 、OCHF ₂ 、N(CH ₃ ) ₂ And S (O) ₂ CH ₃ 。

In some embodiments, the present disclosure provides compounds of formula (I), formula (II) or formula (III), or pharmaceutically acceptable salts thereof, wherein two adjacent R ⁴ The substituents together with ring B may optionally be linked to form a 3 to 12 membered heterocyclyl; wherein the 3 to 12 memberedHeterocyclyl is optionally independently selected from halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy and C _1-6 One or more groups in the hydroxyalkyl group are sometimes substituted with preferably one to five, and sometimes more preferably one to three.

In some embodiments, the present disclosure provides compounds of formula (I), formula (II) or formula (III), or pharmaceutically acceptable salts thereof, wherein two adjacent R ⁴ The substituents together with ring B may optionally be linked to form a 5 or 6 membered heterocyclic group containing one to two oxygen atoms; wherein the 5-or 6-membered heterocyclyl is optionally independently selected from halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy and C _1-6 One or more groups in the haloalkoxy group are substituted with one to five groups being sometimes preferred, and one to three groups being sometimes more preferred.

In some embodiments, the present disclosure provides a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2.

In some embodiments, the present disclosure provides a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.

In some embodiments, the present disclosure provides a compound of formula (I), formula (II) or formula (III), or a pharmaceutically acceptable salt thereof, whereinSelected from->

In some embodiments, the present disclosure provides a compound of formula (I), formula (II) or formula (III), or a pharmaceutically acceptable salt thereof, wherein Selected from->

In some embodiments, the present disclosure provides compounds of formula (I), formula (II) or formula (III), or a pharmaceutically acceptable salt thereof, wherein R ² Selected from C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, 3 to 6 membered cycloalkyl and 3 to 12 membered heterocyclyl;selected from-> Selected from->

In some embodiments, the present disclosure provides compounds of formula (I), formula (II) or formula (III), or a pharmaceutically acceptable salt thereof, wherein R ² Selected from C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, 3-6 membered cycloalkyl and 3-12 membered heterocyclyl;selected from-> Selected from->

In some embodiments, the present disclosure provides a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R ² Selected from C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, 3 to 6 membered cycloalkyl and 3 to 12 membered heterocyclyl; ring a is selected from 3 to 8 membered cycloalkyl, 3 to 12 membered heterocyclyl, 6 to 10 membered aryl, and 5 to 10 membered heteroaryl; ring B is selected from 3 to 8 membered cycloalkyl, 3 to 12 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl; r in each occurrence ³ Identical or different and are each independently selected from hydrogen, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, cyano and-OR ¹¹ The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ¹¹ Selected from hydrogen, C _1-6 Alkyl, C _1-6 Haloalkyl, 3-to 8-membered cycloalkylAnd 3 to 12 membered heterocyclyl; or two adjacent R ³ The substituents together with ring a may optionally be linked to form a 3 to 8 membered cycloalkyl; wherein the 3-to 8-membered cycloalkyl is optionally independently selected from halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy and C _1-6 One to three groups in the hydroxyalkyl group are substituted; r in each occurrence ⁴ Identical or different and are each independently selected from hydrogen, halogen, C _1-6 Alkyl, -NR ^10a R ^10b 、-OR ¹¹ 、-S(O) _t R ¹² And C _1-6 A hydroxyalkyl group; wherein R is ^10a 、R ^10b 、R ¹¹ And R is ¹² Identical or different and are each independently selected from hydrogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; t is 2; or two adjacent R ⁴ The substituents together with ring B may optionally be linked to form a 5 or 6 membered heterocyclic group containing one to two oxygen atoms; wherein the 5-or 6-membered heterocyclyl is optionally independently selected from halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy and C _1-6 One to three groups in the haloalkoxy group are substituted; m is 0, 1 or 2; and n is 0, 1 or 2.

In some embodiments, the present disclosure provides a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R ² Selected from C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, 3 to 6 membered cycloalkyl and 3 to 12 membered heterocyclyl; ring a is selected from 3 to 8 membered cycloalkyl, 3 to 12 membered heterocyclyl, 6 to 10 membered aryl, and 5 to 10 membered heteroaryl; ring B is selected from 3 to 8 membered cycloalkyl, 3 to 12 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl; r in each occurrence ³ Identical or different and are each independently selected from hydrogen, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, cyano and-OR ¹¹ The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ¹¹ Selected from hydrogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; or two adjacent R ³ The substituents together with ring a may optionally be linked to form a 3 to 8 membered cycloalkyl; wherein the 3-to 8-membered cycloalkyl is optionally independently selected from halogenElement, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy and C _1-6 One to three groups in the hydroxyalkyl group are substituted; r in each occurrence ⁴ Identical or different and are each independently selected from hydrogen, halogen, C _1-6 Alkyl, -NR ^10a R ^10b 、-OR ¹¹ 、-S(O) _t R ¹² And C _1-6 A hydroxyalkyl group; wherein R is ^10a 、R ^10b 、R ¹¹ And R is ¹² Identical or different and are each independently selected from hydrogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; t is 2; or two adjacent R ⁴ The substituents together with ring B may optionally be linked to form a 5 or 6 membered heterocyclic group containing one to two oxygen atoms; wherein the 5-or 6-membered heterocyclyl is optionally independently selected from halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy and C _1-6 One to three groups in the haloalkoxy group are substituted; m is 0, 1 or 2; and n is 0, 1 or 2.

In some embodiments, the present disclosure provides a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R ² Selected from C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, 3 to 6 membered cycloalkyl and 3 to 12 membered heterocyclyl;selected from the group consisting of Selected from->

In some embodiments, the present disclosure provides a compound of formula (III)Salts, wherein R is ² Selected from C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, 3 to 6 membered cycloalkyl and 3 to 12 membered heterocyclyl;selected from the group consisting of Selected from the group consisting of

In some embodiments, the present disclosure provides a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R ² Selected from isopropyl, 1-trifluoropropan-2-yl and tetrahydropyranyl;selected from-> Selected from->

In some embodiments, the present disclosure provides a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R ² Selected from isopropyl, 1-trifluoropropane-2-yl and tetrahydropyranyl;selected from-> Selected from->

In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein ring a is selected from 3-to 6-membered cycloalkyl, phenyl, and 5-or 6-membered heteroaryl; ring B is phenyl or 5 or 6 membered heteroaryl; r is R ² Selected from C _1-6 Alkyl, C _1-6 Haloalkyl and 3 to 6 membered heterocyclyl; r in each occurrence ³ Identical OR different and are each independently selected from hydrogen, halogen and-OR ¹¹ The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ¹¹ Selected from C _1-6 Alkyl, C _1-6 Haloalkyl and 3 to 6 membered cycloalkyl; or two adjacent R ³ The substituents together with ring a may optionally be linked to form a 3-6 membered cycloalkyl; r in each occurrence ⁴ Identical or different and are each independently selected from hydrogen, halogen, C _1-6 Alkyl, -NR ^10a R ^10b 、-OR ¹¹ 、-S(O) _t R ¹² And C _1-6 A hydroxyalkyl group; wherein R is ^10a 、R ^10b 、R ¹¹ And R is ¹² Identical or different and are each independently selected from hydrogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; t is 2; m is 0, 1 or 2; n is 0, 1 or 2.

Table a exemplary compounds of the present disclosure include, but are not limited to:

/>

in another aspect, the present disclosure provides a compound of formula (IIB):

or a salt thereof,

wherein:

ring A, R ¹ To R ³ And m is as defined for formula (II).

In another aspect, the present disclosure provides a compound of formula (IIIB):

or a salt thereof,

wherein:

ring A, R ² 、R ³ And m is as defined in formula (III).

Table B exemplary compounds of the present disclosure include, but are not limited to:

table C exemplary compounds of the present disclosure include, but are not limited to:

/>

in another aspect, the present disclosure provides a method of preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof, comprising the steps of:

reacting a compound of formula (IA) or a salt thereof with a compound of formula (V) to obtain a compound of formula (I) or a pharmaceutically acceptable salt thereof;

wherein:

x is halogen; preferably, X is iodine;

Y is selected from halogen,

R is hydrogen or alkyl; preferably Y is selected from iodine,And is also provided with

Ring a, ring B, L ₁ 、L ₂ 、R ¹ To R ⁴ M and n are as defined for formula (I).

In another aspect, the present disclosure provides a method of preparing a compound of formula (II), or a pharmaceutically acceptable salt thereof, comprising the steps of:

reacting a compound of formula (IIA) or a salt thereof with a compound of formula (V-1) to obtain a compound of formula (II) or a pharmaceutically acceptable salt thereof;

wherein:

x is halogen; preferably, X is iodine;

y is selected from halogen,/>

Ring a, ring B, R ¹ To R ⁴ M and n are as defined for formula (II).

In another aspect, the present disclosure provides a method of preparing a compound of formula (III), or a pharmaceutically acceptable salt thereof, comprising the steps of:

reacting a compound of formula (IIIA) or a salt thereof with a compound of formula (V-1) to provide a compound of formula (III) or a pharmaceutically acceptable salt thereof;

wherein:

x is halogen; preferably, X is iodine;

y is selected from halogen,

Ring a, ring B, R ² To R ⁴ M and n are as defined in formula (III).

Reacting a compound of formula (IIB) or a salt thereof with a compound of formula (VI) to obtain a compound of formula (II) or a pharmaceutically acceptable salt thereof;

wherein:

R ^t selected from halogen, hydroxy and alkoxy; and is also provided with

Ring a, ring B, R ¹ To R ⁴ M and n are as defined for formula (II).

reacting a compound of formula (IIIB) or a salt thereof with a compound of formula (VI) to obtain a compound of formula (III) or a pharmaceutically acceptable salt thereof;

wherein:

R ^t selected from halogen, hydroxy and alkoxy; and is also provided with

Ring a, ring B, R ² To R ⁴ M and n are as defined in formula (III).

The present disclosure also provides a pharmaceutical composition comprising a compound of formula (I), formula (II), formula (III), or table a, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, and other excipients.

The present disclosure also provides a method of treating a disease or disorder by inhibiting BTK, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

The present disclosure also provides a method of treating a disease or disorder modulated by BTK, wherein the method comprises the step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

In another aspect, the present disclosure also relates to the use of a compound of formula (I), formula (II), formula (III), and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for inhibiting BTK.

In another aspect, the present disclosure also relates to the use of a compound of formula (I), formula (II), formula (III), and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating a disease or disorder modulated by BTK.

In another aspect, the present disclosure also relates to a compound of formula (I), formula (II), formula (III), and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicament.

In another aspect, the present disclosure also relates to compounds of formula (I), formula (II), formula (III), and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in inhibiting BTK.

In another aspect, the present disclosure also relates to compounds of formula (I), formula (II), formula (III), and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating a disease or disorder modulated by BTK.

In some embodiments, a disease or disorder treatable by modulating/inhibiting BTK may be selected from: cancer, immune diseases, cardiovascular diseases, viral infections, inflammation, metabolic/endocrine dysfunctions and neurological disorders; preferably, the condition modulated by BTK is selected from B-cell malignancy, B-cell lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, non-hodgkin's lymphoma (e.g., ABC-DLBCL), mantle cell lymphoma, follicular lymphoma, hairy cell leukemia, B-cell non-hodgkin's lymphoma, waldenstrom's macroglobulinemia, multiple myeloma, bone cancer, bone metastasis, arthritis, multiple sclerosis, osteoporosis, irritable bowel syndrome, inflammatory bowel disease, crohn's disease, sjogren's syndrome, and lupus.

In some embodiments, the present disclosure relates to the use of a compound of formula (I), formula (II), formula (III), and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating a disease or disorder selected from the group consisting of: b cell malignancy, B cell lymphoma, diffuse large B cell lymphoma, chronic lymphocytic leukemia, non-Hodgkin's lymphoma (e.g., ABC-DLBCL), mantle cell lymphoma, follicular lymphoma, hairy cell leukemia, B cell non-Hodgkin's lymphoma, waldensted giant globulinemia, multiple myeloma, bone cancer, bone metastasis, follicular lymphoma, chronic lymphocytic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytomer tumor, extranodal marginal zone B cell lymphoma, lymph node marginal zone B cell lymphoma, mediastinal (thymus) large B cell lymphoma, intravascular large B cell lymphoma, primary exudative lymphoma burkitt lymphoma/leukemia (burkitt lymphoma/leukemia), lymphomatoid granuloma, inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, still's disease, juvenile arthritis, diabetes mellitus, myasthenia gravis, hashimoto's thyroiditis, ord's thyroiditis, graves' disease, sjogren's syndrome, multiple sclerosis, guillain-Barre syndrome, acute disseminated encephalomyelitis, addison's disease, visual cord clonus syndrome (soclonius-myoclonus syndrome), ankylosing spondylitis, antiphospholipid syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, autoimmune hepatitis, autoimmune disease, multiple sclerosis, guillain-Barre syndrome (Guillain-Barre syndrome), goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, lyter's syndrome, high-safety arteritis (Takayasu's arteritis), temporal arteritis, warm autoimmune hemolytic anemia, wegener's granulomatosis, psoriasis, systemic alopecia, behcet's disease, chronic fatigue, familial autonomic nerve abnormalities, endometriosis, interstitial cystitis, neuromyocarditis, scleroderma, vulvodynia, graft versus host disease, transplantation, transfusion, allergy (anaplaxis), allergy (allergy), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, atopic bronchitis, asthma, inflammation, blepharitis, bronchiolitis, asthma, systemic alopecia, behcet's disease, chronic fatigue, familial autonomic nerve abnormalities, endometriosis, interstitial cystitis, neuromyocarditis, scleroderma, graft versus host disease, transplantation, transfusion, allergy (anaplaxis), allergy, type I hypersensitivity, bronchitis, asthma, allergic rhinitis, blepharitis, bronchiolitis, asthma, and the like bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryocystitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, suppurative sweat gland, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, ovaritis, orchitis, osteomyelitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, uveitis, vaginitis, vasculitis, vulvitis, pulmonary fibrosis, idiopathic pulmonary Inflammation (IPF), common interstitial pneumonia (UIP), interstitial lung disease, cryptogenic Fibrositis (CFA), bronchiolitis obliterans, bronchiectasis, fatty liver disease, steatosis (e.g., nonalcoholic steatohepatitis (NASH)), cholestatic liver disease (e.g., primary Biliary Cirrhosis (PBC)), cirrhosis disease, alcohol-induced liver fibrosis, bile duct injury, bile duct fibrosis, cholestasis or cholangiopathy, liver or liver fibrosis (including but not limited to liver fibrosis associated with alcoholism), viral infection (e.g., hepatitis c, b-type or d-type hepatitis), autoimmune hepatitis, nonalcoholic fatty liver disease (NAFLD), progressive massive fibrosis, exposure to toxins or irritants (e.g., alcohol, drugs and environmental toxins), renal fibrosis (e.g., chronic kidney fibrosis), damage/fibrosis-related kidney disease (e.g., diabetes-related chronic kidney disease (e.g., diabetic nephropathy)), lupus, nephrosclerosis, glomerulonephritis, focal segmental glomerulosclerosis, kidney disease, chronic kidney disease-associated with alcoholism d-related renal fibrosis (e.g., chronic kidney cirrhosis of humans, chronic kidney) or radiation renal disease (e.g., 4 d-type d), chronic kidney injury, capillary inflammation, chronic renal inflammation (e.g., chronic kidney injury, capillary inflammation, chronic renal inflammation (e.g., capillary inflammation, chronic renal inflammation) Fibrosis associated with scleroderma; radiation-induced intestinal fibrosis; fibrosis associated with proctitis diseases such as Barrett's esophagus and chronic gastritis, and/or fibrosis associated with proctitis diseases such as Inflammatory Bowel Disease (IBD), ulcerative colitis and crohn's disease, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity and neovascular glaucoma.

In some embodiments, the disclosure relates to a method of treating a disease or disorder selected from the group consisting of: b cell malignancy, B cell lymphoma, diffuse large B cell lymphoma, chronic lymphocytic leukemia, non-Hodgkin's lymphoma (e.g., ABC-DLBCL), mantle cell lymphoma, follicular lymphoma, hairy cell leukemia, B cell non-Hodgkin's lymphoma, waldensted giant globulinemia, multiple myeloma, bone cancer, bone metastasis, follicular lymphoma, chronic lymphocytic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytomer tumor, extranodal marginal zone B cell lymphoma, lymph node marginal zone B cell lymphoma, mediastinal (thymus) large B cell lymphoma, intravascular large B cell lymphoma, primary exudative lymphoma burkitt lymphoma/leukemia (burkitt lymphoma/leukemia), lymphomatoid granuloma, inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, still's disease, juvenile arthritis, diabetes mellitus, myasthenia gravis, hashimoto's thyroiditis (Hashimoto's thrombitis), ord thyroiditis (Ord's sthyridis), graves ' disease (Graves ' disease), sjogren's syndrome, multiple sclerosis, guillain-Barre syndrome (guillailin-Barre syndrome), acute disseminated encephalomyelitis, addison's disease, optic clonus's disease (osclonus-myoclonus syndrome), ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, lyter's syndrome, high-safety arteritis, temporal arteritis, warm autoimmune hemolytic anemia, wegener's granulomatosis, psoriasis, systemic alopecia, behcet's disease, chronic fatigue, familial autonomic nerve abnormality, endometriosis, interstitial cystitis, neuromyocarditis, scleroderma, vulvodynia, graft versus host disease, transplantation, transfusion, allergy (anaplaxis), allergy (allergy), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, atopic bronchitis, asthma, inflammation, blepharitis, bronchiolitis, asthma, systemic alopecia, behcet's disease, chronic fatigue, familial autonomic nerve abnormality, endometriosis, interstitial cystitis, neuromyocarditis, scleroderma, graft versus host disease, transplantation, blood transfusion, allergy (anaplaxis), allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, atopic dermatitis, asthma, blepharitis, bronchiolitis, and inflammatory disease bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryocystitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, suppurative sweat gland, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, ovaritis, orchitis, osteomyelitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, uveitis, vaginitis, vasculitis, vulvitis, pulmonary fibrosis, idiopathic pulmonary Inflammation (IPF), common interstitial pneumonia (UIP), interstitial lung disease, cryptogenic Fibrositis (CFA), bronchiolitis obliterans, bronchiectasis, fatty liver disease, steatosis (e.g., nonalcoholic steatohepatitis (NASH)), cholestatic liver disease (e.g., primary Biliary Cirrhosis (PBC)), cirrhosis disease, alcohol-induced liver fibrosis, bile duct injury, bile duct fibrosis, cholestasis or cholangiopathy, liver or liver fibrosis (including but not limited to liver fibrosis associated with alcoholism), viral infection (e.g., hepatitis c, b-type or d-type hepatitis), autoimmune hepatitis, nonalcoholic fatty liver disease (NAFLD), progressive massive fibrosis, exposure to toxins or irritants (e.g., alcohol, drugs and environmental toxins), renal fibrosis (e.g., chronic kidney fibrosis), damage/fibrosis-related kidney disease (e.g., diabetes-related chronic kidney disease (e.g., diabetic nephropathy)), lupus, nephrosclerosis, glomerulonephritis, focal segmental glomerulosclerosis, kidney disease, chronic kidney disease-associated with alcoholism d-related renal fibrosis (e.g., chronic kidney cirrhosis of humans, chronic kidney) or radiation renal disease (e.g., 4 d-type d), chronic kidney injury, capillary inflammation, chronic renal inflammation (e.g., chronic kidney injury, capillary inflammation, chronic renal inflammation (e.g., capillary inflammation, chronic renal inflammation) Fibrosis associated with scleroderma; radiation-induced intestinal fibrosis; fibrosis associated with proctitis diseases such as Barrett's esophagus and chronic gastritis, and/or fibrosis associated with proctitis diseases such as Inflammatory Bowel Disease (IBD), ulcerative colitis and crohn's disease, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity and neovascular glaucoma, wherein the method comprises the step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (III) and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

The compositions of the present disclosure may be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure may be formulated in various dosage forms for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular, or subcutaneous), rectal, inhaled, or insufflation administration.

The compounds of the present disclosure may also be formulated in sustained release dosage forms.

Common formulations include tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. The oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions. Such compositions may comprise one or more additives selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives to provide a pleasant and palatable pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, and lubricating agents. The tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or delay disintegration and absorption of the drug in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, water-soluble taste masking materials may be used.

Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water soluble carrier.

The aqueous suspension contains the active substance and excipients suitable for the preparation of aqueous suspensions for mixing. Such excipients are suspending, dispersing or wetting agents and may be naturally occurring phospholipids. The aqueous suspension may also contain one or more preservatives, one or more colorants, one or more flavoring agents, and one or more sweeteners.

The oil suspensions may be formulated by suspending the active ingredient in a vegetable or mineral oil. The oil suspension may contain a thickener. The above-described sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.

The active ingredient and the dispersing or wetting agent, suspending agent or one or more preservatives may be prepared by adding water as dispersible powders or granules suitable for the preparation of an aqueous suspension. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Other excipients, for example sweetening, flavoring and coloring agents, may also be added. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

The pharmaceutical compositions of the present disclosure may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, or a mineral oil, or a mixture thereof. Suitable emulsifying agents may be naturally occurring phosphatides. Sweeteners may also be used. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase. The injection or microemulsion may be injected into the blood stream of the individual by local bolus injection. Alternatively, the solution or microemulsion may be advantageously applied in a manner that maintains a constant circulating concentration of the compounds of the present disclosure. To maintain this constant concentration, a continuous intravenous delivery device may be used. An example of such a device is a Deltec CADD-PLUS. TM.5400 model intravenous pump.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspension may be formulated according to known techniques with suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, nontoxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium, and fatty acids can be employed in the preparation of injectables.

The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

For buccal administration, the compositions may be formulated in conventional manner as tablets or lozenges.

For intranasal administration or administration by inhalation, the active compounds of the present disclosure are conveniently delivered in the form of a solution or suspension that is released from a pump spray container squeezed or pumped by the patient, or in the form of a spray from a pressurized container or nebulizer, using a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of pressurized aerosols, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules or cartridges (e.g., made of gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of the present disclosure and a suitable powder base such as lactose or starch.

As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including, but not limited to, the following: the activity of the particular compound employed, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, and the like. In addition, the optimal mode of treatment, e.g., mode of treatment, daily dose, or type of pharmaceutically acceptable salt thereof, can be verified according to conventional treatment protocols.

Description of the terms

Unless otherwise indicated, terms used in the specification and claims have the following meanings.

"alkyl" means containing C ₁ -C ₁₂ A linear or branched saturated aliphatic hydrocarbon group. In some embodiments, it is sometimes preferred that the alkyl group is an alkyl group (i.e., C) having 1 to 8 carbon atoms (e.g., 1,2, 3, 4, 5, 6, 7, or 8 carbon atoms) _1-8 Alkyl), sometimes more preferably, alkyl is an alkyl having 1 to 6 carbon atoms (i.e., C _1-6 Alkyl). Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl 4, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and branched isomers thereof. In some embodiments, alkyl groups are sometimes more preferably lower alkyl groups having 1 to 6 carbon atoms (i.e., C _1-6 Lower alkyl), sometimes more preferably havingLower alkyl having 1 to 4 carbon atoms (i.e. C _1-4 Lower alkyl). Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. Alkyl groups may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. Preferably, the substituents are one or more, sometimes preferably 1 to 5, sometimes more preferably 1 to 3, independently selected from the group consisting of halogen, alkoxy, alkenyl, alkynyl, alkylsulfonyl, alkylamino, mercapto, hydroxy, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycle, cycloalkylthio, heterocycloalkylthio and oxo.

"alkenyl" means an alkyl group as defined above having at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like, preferably C _2-12 Alkenyl groups, sometimes more preferably C _2-8 Alkenyl groups, sometimes more preferably C _2-6 Alkenyl groups, sometimes even more preferably C _2-4 Alkenyl groups. Alkenyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, independently selected from the group consisting of halogen, alkoxy, alkynyl, alkylsulfonyl, alkylamino, mercapto, hydroxy, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocyclyl, cycloalkylthio, heterocycloalkylthio, and oxo.

"alkynyl" means an alkyl group as defined above having at least two carbon atoms and at least one carbon-carbon triple bond, e.g., ethynyl, 1-propynyl, 2-propynyl, 1-, 2-or 3-butynyl, and the like, preferably C _2-12 Alkynyl, sometimes more preferably C _2-8 Alkynyl radicals havingMore preferably C _2-6 Alkynyl, sometimes even more preferably C _2-4 Alkynyl groups. Alkynyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, preferably 1 to 5, and sometimes more preferably 1 to 3, independently selected from alkenyl, alkoxy, alkylsulfonyl, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.

The term "alkylene" refers to a saturated, straight or branched, divalent aliphatic hydrocarbon group, derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane. Straight or branched chain groups (i.e. C) containing 1 to 12 carbon atoms (e.g. 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 carbon atoms) _1-12 An alkylene group). Alkylene groups having 1 to 8 carbon atoms (i.e. C _1-8 Alkylene groups), more preferably alkylene groups of 1 to 6 carbon atoms (i.e. C _1-6 Alkylene groups) are sometimes more preferably alkylene groups of 1 to 4 carbon atoms (i.e., C _1-4 An alkylene group). Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH) ₂ (-), 1-ethylene (-CH (CH) ₃ ) (-), 1, 2-ethylene (-CH) ₂ CH ₂ ) -, 1-propylene (-CH (CH) ₂ CH ₃ ) (-), 1, 2-propylene (-CH) ₂ CH(CH ₃ ) (-), 1, 3-propylene (-CH) ₂ CH ₂ CH ₂ (-), 1, 4-butylene (-CH) ₂ CH ₂ CH ₂ CH ₂ (-), etc. The alkylene group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, independently selected from alkenyl, alkynyl, alkoxy, alkylsulfonyl, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.

"alkenylene" means an alkylene group as defined above having at least two carbon atoms and at least one carbon-carbon double bond, preferably C _2-12 Alkenylene, sometimes more preferably C _2-8 Alkenylene groupC is sometimes more preferable _2-6 Alkenylene radicals, sometimes even more preferably C _2-4 Alkenylene radicals. Non-limiting examples of alkenylenes include, but are not limited to, -ch=ch-, -ch=chch ₂ -、-CH＝CHCH ₂ CH ₂ -、-CH ₂ CH＝CHCH ₂ -and the like. Alkenylene groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, independently selected from alkynyl, alkoxy, alkylsulfonyl, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.

"cycloalkyl" refers to a saturated and/or partially unsaturated monocyclic or polycyclic hydrocarbon group having 3 to 20 carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms) (i.e., a 3 to 20 membered cycloalkyl group), sometimes more preferably 3 to 8 carbon atoms (i.e., a 3 to 8 membered cycloalkyl group), sometimes even more preferably 3 to 6 carbon atoms (i.e., a 3 to 6 membered cycloalkyl group). Representative examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like. Polycyclic cycloalkyl includes cycloalkyl groups having spiro rings, fused ring cycloalkyl groups, or bridged ring cycloalkyl groups.

"spirocycloalkyl" means a 5-to 20-membered polycyclic group attached between the rings through a common carbon atom, known as a spiro atom, wherein one or more of the rings may contain one or more, preferably one to three, double bonds, which may be aryl and heteroaryl. Preferably, the spirocycloalkyl group is 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). Depending on the number of common spiro atoms, spirocycloalkyl groups may be classified as mono-or poly-spirocycloalkyl (e.g., double spirocycloalkyl), preferably mono-or double spirocycloalkyl, more preferably 3/5, 3/6, 4/4, 4/5, 4/6, 5/5, 5/6, 6/6. Representative examples of spirocycloalkyl groups include, but are not limited to, the following groups:

"fused ring alkyl" refers to a polycyclic group which is a cycloalkyl group attached together in a fused manner to one or more, preferably one to five, and sometimes more preferably one to three groups independently selected from cycloalkyl, heterocyclyl, aryl and heteroaryl. Wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are as defined in the disclosure. The condensed ring alkyl group may be classified into a polycyclic condensed ring alkyl group such as a bicyclic ring, a tricyclic ring, a tetracyclic ring, etc., according to the number of member rings, and preferably refers to a bicyclic or tricyclic condensed ring alkyl group, more preferably refers to an aryl-condensed C group _5-8 Cycloalkyl, heteroaryl fused C _5-8 Cycloalkyl, 4 membered heterocyclyl-fused C _5-8 Cycloalkyl, 5 membered heterocyclyl-fused C _5-8 Cycloalkyl, C ₆ Cycloalkyl-fused C _5-8 Cycloalkyl or C ₅ Cycloalkyl-fused C _5-8 Cycloalkyl groups. Representative examples of fused ring alkyl groups include, but are not limited to, the following groups:

"bridged cycloalkyl" means a 5 to 20 membered polycyclic hydrocarbon group wherein every two rings in the system share two atoms which are not directly attached. Wherein the ring may have one or more, preferably one to three double bonds. Preferably, the bridged cycloalkyl groups are 6 to 14 membered, more preferably 7 to 10 membered (e.g., 7, 8, 9 and 10 membered). Bridged cycloalkyl groups may be classified into polycyclic bridged cycloalkyl groups such as bicyclic, tricyclic, tetracyclic and the like, depending on the number of member rings, and preferably refers to bicyclic, tricyclic or tetracyclic bridged cycloalkyl groups, more preferably bicyclic or tricyclic bridged cycloalkyl groups. Representative examples of bridged cycloalkyl groups include, but are not limited to, the following groups:

cycloalkyl groups may be fused to the ring of aryl, heteroaryl or heterocycloalkyl groups, which may beThe ring attached to the parent structure is cycloalkyl. Representative examples include, but are not limited to, indanyl (e.g) Tetrahydronaphthyl (e.g.)>) Benzocycloheptyl radicals (e.g.)>) Etc. Cycloalkyl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, independently selected from the group consisting of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfonyl, alkylamino, mercapto, hydroxy, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocyclyl, cycloalkylthio, heterocycloalkylthio, and oxo.

"heterocyclyl" means a 3 to 20 membered saturated or partially unsaturated monocyclic or polycyclic group having one or more, preferably one to five, and sometimes more preferably one to three heteroatoms selected from N, O and S, optionally oxo (i.e., forming S (O) and S (O)) as ring atoms ₂ ) But does not contain-O-; -O-S-and-S-S-, and the remaining ring atoms are C. Preferably, the heterocyclyl is a 3 to 12 membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 membered) heterocyclyl (i.e., a 3 to 12 membered heterocyclyl) having 1 to 4 heteroatoms (e.g., 1, 2, 3, and 4 heteroatoms); more preferably 3 to 8 membered (e.g., 3, 4, 5, 6, 7 and 8 membered) heterocyclyl (i.e., 3 to 8 membered heterocyclyl) having 1 to 3 heteroatoms (e.g., 1, 2 and 3 heteroatoms); even more preferably 3 to 6 membered (e.g., 3, 4, 5, and 6 membered) heterocyclyl (i.e., 3 to 6 membered heterocyclyl) having 1 to 3 heteroatoms (e.g., 1, 2, and 3 heteroatoms); most preferred are 5-or 6-membered heterocyclyl (i.e., 5-or 6-membered heterocyclyl) groups having 1 to 3 heteroatoms (e.g., 1, 2, and 3 heteroatoms). Representative examples of monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, sulfomorpholinyl, homopiperazinyl, and the like. Polycyclic impurities The cyclic group includes heterocyclic groups having spiro, fused or bridged rings.

"spiroheterocyclyl" means a 5-to 20-membered polycyclic heterocyclic group attached between the rings through a common carbon atom (referred to as the spiro atom), wherein the rings have one or more heteroatoms selected from N, O and S as ring atoms, and the S may optionally be oxo (i.e., form S (O) and S (O)) ₂ ) And the remaining ring atoms are C, wherein one or more rings may contain one or more double bonds. Preferably, the spiroheterocyclyl is 6 to 14 membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 membered), more preferably 7 to 10 membered. Depending on the number of common spiro atoms, the spiro heterocyclyl group may be classified as a mono-or multi-spiro heterocyclyl group (e.g., a double spiro heterocyclyl group), preferably a mono-or double spiro heterocyclyl group, more preferably a 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered mono-spiro heterocyclyl group. Representative examples of spiroheterocyclyl groups include, but are not limited to, the following groups:

"fused heterocyclyl" refers to a polycyclic group which is a heterocyclic group attached together in a fused manner to one or more, preferably one to three, groups independently selected from cycloalkyl, heterocyclyl, aryl and heteroaryl. Wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are as defined in the disclosure. The fused heterocyclic group may be classified into a polycyclic fused heterocyclic group such as a bicyclic, tricyclic, tetracyclic and the like, depending on the number of member rings, preferably refers to a bicyclic or tricyclic fused heterocyclic group, more preferably refers to an aryl-fused 5-to 8-membered heterocyclic group, a heteroaryl-fused 5-to 8-membered heterocyclic group, C _5-8 Cycloalkyl-fused 4-membered heterocyclyl, C _5-8 Cycloalkyl-fused 5-membered heterocyclyl, C _5-8 Cycloalkyl-fused 6-membered heterocyclyl.

Representative examples of fused heterocyclyl groups include, but are not limited to, the following groups:

"bridged heterocyclyl" means a 5-to 14-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14-membered) polycyclic heterocycloalkyl wherein every two rings in the system share two atoms that are not directly attached, wherein the rings may have one or more, preferably one to three double bonds, and the rings have one or more, preferably one to five, and sometimes more preferably one to three heteroatoms independently selected from N, O and S as ring atoms, which S may optionally be oxo (i.e., form S (O) and S (O) ₂ ) And the remaining ring atoms are C. Preferably, the bridged heterocyclyl is 6 to 14 membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13, and 14 membered), more preferably 7 to 10 membered bridged heterocyclyl. The bridged heterocyclic group may be classified into a polycyclic bridged heterocyclic group such as a bicyclic, tricyclic, tetracyclic group, etc., according to the number of member rings, and preferably refers to a bicyclic, tricyclic, or tetracyclic bridged heterocyclic group, more preferably a bicyclic or tricyclic bridged heterocyclic group. Representative examples of bridged heterocyclyl groups include, but are not limited to, the following groups:

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the ring of the heterocyclyl may be fused to a ring of an aryl, heteroaryl or cycloalkyl group, wherein the ring attached to the parent structure is heterocyclyl. Representative examples include, but are not limited to, the following groups:

Etc.

The heterocyclyl is optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably 1 to 5 (e.g., 1, 2, 3, 4, and 5), and sometimes more preferably 1 to 3, are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.

"aryl" refers to a 6 to 14 membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13, and 14 membered) all-carbon monocyclic or fused multicyclic (fused ring systems refer to each ring in the system sharing a pair of contiguous carbon atoms with the other ring in the system) group having a fully conjugated pi-electron system. Preferably, aryl is 6 to 10 membered (e.g., 6, 7, 8, 9 and 10 membered), such as phenyl and naphthyl, most preferably phenyl. The aryl group may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl group. Representative examples include, but are not limited to, the following groups:

aryl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxy.

"heteroaryl" refers to an aryl system having 5 to 14 ring atoms (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14) with 1 to 4 heteroatoms (e.g., 1, 2, 3, and 4 heteroatoms) selected from O, S and N as ring atoms. Preferably, heteroaryl is 5 to 10 membered (e.g., 5, 6, 7, 8, 9, and 10 membered), more preferably 5 or 6 membered, such as thiadiazole, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, thiazolyl, furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. Heteroaryl groups may be fused to a ring of aryl, heterocyclyl or cycloalkyl groups, wherein the ring attached to the parent structure is heteroaryl. Representative examples include, but are not limited to, the following groups:

heteroaryl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably 1 to 5 (e.g., 1, 2, 3, 4, and 5), and sometimes more preferably 1 to 3, are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.

"alkoxy" refers to an-O- (alkyl) group wherein alkyl is as defined above. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and the like. Alkoxy groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably 1 to 5 (e.g., 1, 2, 3, 4, and 5), and sometimes more preferably 1 to 3, are independently selected from alkenyl, alkynyl, alkoxy, alkylsulfonyl, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.

"amino protecting group" refers to a derivative of a group that is commonly used to block or protect an amino group when reacting with other functional groups on a compound. Examples of such protecting groups include carbamates, amides, alkyl and aryl groups and imines, as well as many N-heteroatom derivatives, which can be removed to regenerate the desired amino group. Non-limiting examples include (trimethylsilyl) ethoxymethyl (SEM), tetrahydropyranyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), (9-fluorenylmethyloxycarbonyl) (Fmoc), acetyl, benzyl, allyl, p-methoxybenzyl (Pmb), and the like.

"hydroxy protecting group" refers to a derivative of a hydroxy group that is typically used to block or protect the hydroxy group when reacting with other functional groups on a compound. Examples of such protecting groups include triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl, and the like; or C _1-10 Alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C _1-6 Alkoxy substituted C _1-6 Alkyl-or phenyl-substituted C _1-6 Alkyl, most preferably C _1-4 Alkoxy substituted C _1-4 Alkyl groups such as: methyl, t-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-Tetrahydropyranyl (THP), and the like; or (C) _1-10 Alkyl or aryl) acyl, such as formyl, acetyl, benzoyl, p-nitrobenzoyl and the like; or (C) _1-6 Alkyl or C _6-10 Aryl) sulfonyl; or (C) _1-6 Alkoxy or C _6-10 Aryloxy) carbonyl.

"bond" refers to a covalent bond with the symbol "-".

"deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

"hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

"hydroxy" refers to an-OH group.

"halogen" means a fluorine, chlorine, bromine or iodine atom.

"amino" means-NH ₂ A group.

"cyano" refers to a-CN group.

"nitro" means-NO ₂ A group.

"oxo" or "oxo" refers to an =o group.

"carboxy" refers to the-C (O) OH group.

"carboxylate" means-C (O) O (alkyl), -C (O) O (cycloalkyl), (alkyl) C (O) O-or (cycloalkyl) C (O) O-, wherein alkyl and cycloalkyl are as defined above.

"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "optionally alkyl-substituted heterocyclyl" means that alkyl groups may be, but need not be, present, and the description includes both cases where heterocyclyl is substituted with alkyl groups and cases where heterocyclyl is not substituted with alkyl groups.

"substituted" means that one or more hydrogen atoms in the group, preferably up to 6, more preferably 1 to 5, even more preferably 1 to 3, are independently substituted with a corresponding number of substituents. The person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated bonds (e.g., olefinic).

"pharmaceutical composition" refers to a mixture of one or more of the compounds described in this disclosure or a physiologically/pharmaceutically acceptable salt or prodrug thereof and other chemical components (e.g., physiologically/pharmaceutically acceptable carriers and excipients). The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism, facilitating the absorption of the active ingredient and thus the exertion of biological activity.

By "pharmaceutically acceptable salt" is meant a salt of a compound of the present disclosure which is safe and effective and has the corresponding biological activity when used in a mammal.

Salts may be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate nitrogen atom with the appropriate acid. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, hydrogen disulfide, and organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid, ditartaric acid, ascorbic acid, maleic acid, benzenesulfonic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and related inorganic and organic acids.

Base addition salts can be prepared by reacting the carboxyl groups with a suitable base (e.g., a hydroxide, carbonate or bicarbonate of a metal cation) or with ammonia or an organic primary, secondary or tertiary amine during the final isolation and purification of the compound. Cations of pharmaceutically acceptable salts include, but are not limited to, lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations (e.g., ammonium, tetramethyl ammonium, tetraethyl ammonium), methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N-dimethylaniline, N-methylpiperidine, and N-methylmorpholine.

As will be appreciated by those of skill in the art, the compounds of formula (I), formula (II), formula (III), and table a disclosed herein, or pharmaceutically acceptable salts thereof, may exist in prodrug or solvate forms, all of which are encompassed by the present disclosure.

The phrase "therapeutically effective amount" refers to an amount capable of any detectable amount of a drug administered alone or as part of a pharmaceutical composition to a subject in a single dose or as part of a series of doses that, when administered to a subject, has a positive effect on any symptom, aspect or feature of a disease, disorder or condition. The therapeutically effective amount can be determined by measuring the relevant physiological effects and can be adjusted according to the dosing regimen and diagnostic analysis of the subject's condition. For example, measuring the serum level of a RAF inhibitor (or, e.g., a metabolite thereof) at a particular time after administration may indicate whether a therapeutically effective amount has been used.

As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.

The terms "treatment", "treatment" or "treatment" refer to: (I) Inhibiting the disease, disorder or condition, i.e., arresting its development; and (II) alleviating the disease, disorder or condition, i.e., causing regression of the disease, disorder and/or condition. In addition, the compounds of the present disclosure may be used for their prophylactic effect, preventing the occurrence of a disease, disorder, or condition in a subject who may be susceptible to the disease, disorder, and/or condition but who has not yet been diagnosed as having the disease.

The term "subject" or "patient" refers to a mammal.

The term "mammal" or "mammal" includes, but is not limited to, humans, dogs, cats, horses, pigs, cows, monkeys, rabbits, and mice. The preferred mammal is a human.

As used herein, the singular forms "a," "an," and "the" include plural referents and vice versa, unless the context clearly dictates otherwise.

When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter may vary by + -10%, and sometimes more preferably within + -5%. As will be appreciated by those skilled in the art, when a parameter is not a critical parameter, the number is generally given for illustration purposes only and is not limiting.

Methods of synthesizing compounds of the present disclosure

To accomplish the purpose of the present disclosure, the present disclosure applies, but is not limited to, the following technical solutions:

scheme 1

A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the steps of:

carrying out Suzuki coupling reaction or Negishi coupling reaction on the compound shown in the formula (IA) or salt thereof and the compound shown in the formula (V) to obtain a compound shown in the formula (I) or pharmaceutically acceptable salt thereof;

wherein:

x is halogen; preferably, X is iodine;

y is selected from halogen,

Scheme 2

A process for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof, comprising the steps of:

carrying out Suzuki coupling reaction or Negishi coupling reaction on the compound shown in the formula (IIA) or salt thereof and the compound shown in the formula (V-1) to obtain a compound shown in the formula (II) or pharmaceutically acceptable salt thereof;

Wherein:

x is halogen; preferably, X is iodine;

y is selected from halogen,

Ring a, ring B, R ¹ To R ⁴ M and n are as defined for formula (II).

Scheme 3

A process for preparing a compound of formula (III) or a pharmaceutically acceptable salt thereof, comprising the steps of:

carrying out Suzuki coupling reaction or Negishi coupling reaction on the compound shown in the formula (IIIA) or salt thereof and the compound shown in the formula (V-1) to obtain a compound shown in the formula (III) or pharmaceutically acceptable salt thereof;

wherein:

x is halogen; preferably, X is iodine;

y is selected from halogen,

R isHydrogen or alkyl; preferably Y is selected from iodine,And is also provided with

Ring a, ring B, R ² To R ⁴ M and n are as defined in formula (III).

Scheme 4

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reacting a compound of formula (IIB) or a salt thereof with a compound of formula (VI) under basic conditions (preferably in the presence of HOBt) to obtain a compound of formula (II) or a pharmaceutically acceptable salt thereof;

wherein:

R ^t selected from halogen, hydroxy and alkoxy; and is also provided with

Ring a, ring B, R ¹ To R ⁴ M and n are as defined for formula (II).

Scheme 5

Reacting a compound of formula (IIIB) or a salt thereof with a compound of formula (VI) under basic conditions (preferably in the presence of HOBt) to obtain a compound of formula (III) or a pharmaceutically acceptable salt thereof;

wherein:

R ^t selected from halogen, hydroxy and alkoxy; and is also provided with

Ring a, ring B, R ² To R ⁴ M and n are as defined in formula (III).

The Suzuki coupling reaction is preferably carried out in the presence of a base (e.g. potassium carbonate, cesium carbonate) and a metal catalyst (e.g. Pd (dppf) Cl) ₂ 、Pd(dppf)Cl ₂ .CH ₂ Cl ₂ Or XPhos-Pd-G ₂ ) In the presence of a catalyst.

The Negishi coupling reaction is preferably carried out in the presence of a base (e.g., t-butyllithium), a metal catalyst (e.g., znCl) ₂ 、Pd(dppf)Cl ₂ And Pd (PPh) ₃ ) ₄ ) Optionally with the addition of a ligand.

Reagents that provide basic conditions include organic bases including, but not limited to, triethylamine (TEA), N-Diisopropylethylamine (DIPEA), N-butyllithium, t-butyllithium, lithium diisopropylamide, potassium acetate, sodium t-butoxide, N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (EDCI), potassium bis (trimethylsilyl) amide (KHMDS), and potassium t-butoxide, and inorganic bases including, but not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, and cesium carbonate.

The reaction is preferably carried out in a solvent, wherein solvents used herein include, but are not limited to, acetic acid, methanol, ethanol, toluene, acetone, tetrahydrofuran, dichloromethane, dichloroethane, dimethyl sulfoxide, 1, 4-dioxane, water, N-dimethylformamide, trimethyl phosphate, methyl t-butyl ether, pyridine, and mixtures thereof.

Examples

The following examples are presented to illustrate the disclosure, but should not be construed as limiting. If the specific conditions for the experimental methods are not specified in the examples of the present disclosure, they generally conform to the conventional or recommended conditions of raw materials and product manufacturers. Reagents not specifying a particular source are commercially available, conventional reagents or reagents readily prepared by available literature procedures.

The structure of the compounds is determined by Mass Spectrometry (MS) and/or Nuclear Magnetic Resonance (NMR). NMR shift (. Delta.) of 10 ^-6 (ppm) is given in units.

Mass Spectrometry (MS) was determined using Shimadzu LCMS-2020 liquid chromatography-mass spectrometer.

NMR measurements were performed on Bruker AVANCE-400 and 500Ultrashield nuclear magnetic resonance spectrometers. The solvent is deuterated dimethyl sulfoxide (DMSO-d 6), deuterated chloroform (CDCl) ₃ ) And deuterated methanol (methanol-d 4),the internal standard is Tetramethylsilane (TMS).

HPLC was performed using a Shimadzu OPTION BOX-L high pressure liquid chromatograph (Gemini 5 μm NX-C18100X21.2mm column).

The Thin Layer Chromatography (TLC) silica gel plate used was Agela Technologies T-CSF10050-M silica gel plate, specification 50mm.

Column chromatography is typically performed using a CombiFlash rf+ automated flash chromatography system (teldyne ISCO) with a Agela Technologies flash column silica gel-CS pre-column.

Known starting materials of the present disclosure may be synthesized according to methods known in the art or may be purchased from Acros Organics, sigma-Aldrich chemical company, astaTech, and others. Unless otherwise indicated in the examples, the reaction was carried out under an argon atmosphere or a nitrogen atmosphere. An argon or nitrogen atmosphere means that the reaction flask was attached to about 1L of argon or nitrogen balloon.

The hydrogen atmosphere means that the reactor flask is connected to about 1L of hydrogen balloon. The hydrogenation reaction system is usually evacuated, then hydrogen is charged, and the reaction is carried out after repeating 3 times.

The microwave reaction was carried out using a CEM Discover-S908860 microwave reactor.

Unless otherwise indicated in the examples, the reaction temperature was room temperature between 20 ℃ and 30 ℃.

The progress of the reaction in the examples was monitored using Thin Layer Chromatography (TLC) or LC-MS chromatography. Column chromatography eluent for purifying compounds and developing solvent systems for thin layer chromatography include: a: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: dichloromethane/ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound. Small amounts of triethylamine, acetic acid, other basic or acidic reagents may be used to improve separation.

DCC is N, N' -dicyclohexylcarbodiimide,

DDQ is 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone,

Pd(PPh ₃ ) ₄ is tetrakis (triphenylphosphine) palladium (0),

Pd(dppf)Cl ₂ is [1,1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride, the palladium (II) dichloride,

XPhos-Pd-G ₂ for the second generation XPhos pre-catalyst, chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl)]Palladium (II) and (iii),

NIS is N-iodosuccinimide,

(BPin) ₂ is bis (pinacolato) diboron,

TMEDA is N, N, N ', N' -tetramethyl ethylenediamine,

the TEA is triethylamine, and the TEA is the triethylamine,

the TESH is triethylsilane, and the catalyst is a catalyst,

TMSCl is trimethyl silane chloride,

the HCl is a solution of HCl in hydrochloric acid,

Cs ₂ CO ₃ is cesium carbonate and is used as a catalyst,

K ₂ CO ₃ is the potassium carbonate, the potassium carbonate is the potassium carbonate,

the KOAc is potassium acetate and the potassium acetate,

KO ^t bu is potassium tert-butoxide, and the total content of Bu is potassium tert-butoxide,

the NaH is sodium hydride, and the sodium hydride,

NH ₄ the OH is ammonium hydroxide and the hydroxyl radical is ammonium hydroxide,

BH ₃ THF is a borane-tetrahydrofuran which is used as a starting material,

the EtOAc was ethyl acetate and the water was added to the solution,

the DME is dimethoxyethane and the DME is dimethoxyethane,

the MeOH is methanol and the solvent is methanol,

the IPA is isopropyl alcohol and the isopropyl alcohol is isopropyl alcohol,

the DMSO is dimethyl sulfoxide (DMSO),

the PE is petroleum ether, the petroleum ether,

the THF is tetrahydrofuran, and the solvent is tetrahydrofuran,

Et ₂ o is diethyl ether, and the water is the mixture of the diethyl ether and the water,

the DCM was taken to be dichloromethane,

the DMF is dimethylformamide and the solvent is dimethylformamide,

MgSO ₄ is made of magnesium sulfate, and the magnesium sulfate is prepared from magnesium sulfate,

Na ₂ SO ₄ is sodium sulfate, and

MS is mass spectrometry, where (+) refers to the positive mode, typically giving m+h absorption, where m=molecular weight.

Intermediate 1 (Int-1)

5-iodo-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-4-amine

The synthetic route is as follows:

step 1,2, 5-Dioxopyrrolidin-1-yl-isobutyrate Int-1b

DCC (46.8 g,227 mmol) was added to a mixture of the compound isobutyric acid Int-1a (20 g,227mmol,1.0 equiv.) and 1-hydroxypyrrolidine-2, 5-dione (26.1 g,227 mmol) in DME (400 mL) at 0deg.C. The reaction was stirred at room temperature for 16 hours, and then the mixture was filtered. The filtrate was concentrated in vacuo to give crude 2, 5-dioxopyrrolidin-1-yl isobutyrate Int-1b (41 g, 98% yield), which was used in the next step without further purification.

¹ H NMR(400MHz,CDCl ₃ ):δ2.92-2.88(m,1H),2.78(s,4H),1.20(d,J＝8.0Hz,6H)ppm。

Step 2N- ((3-amino-5-oxo-4, 5-dihydro-1, 2, 4-triazin-6-yl) methyl) isobutyramide Int-1d

To a solution of 3-amino-6- (aminomethyl) -1,2, 4-triazin-5 (4H) -one 1nt-1c (3.8 g,17.8 mmol) in water (90 mL) at 0deg.C was added NaHCO ₃ Aqueous (1.0M, 40mL,40 mmol). The resulting mixture was warmed to room temperature and then 2, 5-dioxopyrrolidin-1-yl isobutyrate Int-1b (4.2 g,22.6 mmol) in THF: ACN (1:1, 30 mL) was slowly added. The mixture was stirred at room temperature for 20 hours and then concentrated to 50mL. The reaction mixture was filtered and the solid was taken up in water and Et ₂ O-washing and then drying under vacuum afforded N- ((3-amino-5-oxo-4, 5-dihydro-1, 2, 4-triazin-6-yl) methyl) isobutyramide Int-1d (3.45 g, 92% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ12.01(brs,1H),7.83(s,1H),6.74(s,2H),4.03(s,2H),2.48-2.39(m,1H),0.97(d,J＝8.0Hz,6H)ppm。

Step 3 2-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-4 (3H) -one Int-1e

POCl was added to a suspension of N- ((3-amino-5-oxo-4, 5-dihydro-1, 2, 4-triazin-6-yl) methyl) isobutyramide Int-1d (3.46 g,16.38 mmol) in DCE (100 mL) under reflux ₃ (12.0 mL,131 mmol) and the mixture was stirred at reflux for an additional 5 hours. After cooling, the mixture was concentrated under vacuum. The residue was suspended in MeOH in water (2:1, 45 mL) and filtered through celite. With 1% NH ₃ The residue was washed with MeOH (3X 15 mL) and the solution was concentrated in vacuo to give 2-amino-7-isopropylimidazo [5,1-f][1,2,4]Triazin-4 (3H) -one Int-1e (3.1 g, 99% yield), which was used in the next step without further purification.

Step 4 2-amino-5-iodo-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-4 (3H) -one Int-1f

To 2-amino-7-isopropylimidazo [5,1-f][1,2,4]To a solution of triazin-4 (3H) -one Int-1e (3.0 g,16.5 mmol) in DMF (60 mL) was added NIS (7.0 g,31 mmol). The resulting mixture was stirred at room temperature for 18 hours. The mixture was then quenched with water (50 mL) and extracted with EtOAc (50 ml×3). The combined organic phases were taken up in Na ₂ S ₂ O ₃ Aqueous (1M, 2X 50 mL) and brine (3X 30 mL) were washed over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (2-5% meoh in DCM) to give 2-amino-5-iodo-7-isopropylimidazo [5,1-f][1,2,4]Triazin-4 (3H) -one Int-1f (3.44 g, 60% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ10.76(brs,1H),6.11(s,2H),2.23(m,1H),1.19(d,J＝8.0Hz,6H)ppm。

Step 5-iodo-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-4 (3H) -one Int-1g

To 2-amino-5-iodo-7-isopropylimidazo [5,1-f][1,2,4]To a solution of triazin-4 (3H) -one Int-1f (3.46 g,10.8 mmol) in THF: DMF (6:1, 70 mL) was added dropwise tert-butyl nitrite (5.6 g,54 mmol). The resulting mixture was stirred at room temperature for 3.5 hours. The mixture was then quenched with water (50 mL) and extracted with EtOAc (50 mL. Times.3)). The combined organic phases were washed with brine (3X 30 mL), dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (25% etoac in PE) to give 5-iodo-7-isopropylimidazo [5,1-f][1,2,4]Triazin-4 (3H) -one Int-1g (2.4 g, 74% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ11.76(brs,1H),7.86(s,1H),3.34(m,1H),1.23(d,J＝8.0Hz,6H)ppm。

Step 6 5-iodo-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-4-amine Int-1

POCl was added dropwise to a solution of 1,2, 4-triazole (2.94 g,42.7 mmol) in pyridine (30 mL) at 0deg.C ₃ (2.91 g,19 mmol) and the resulting mixture was slowly warmed and stirred at room temperature for 15 minutes. Slowly dropwise adding 5-iodo-7-isopropylimidazo [5,1-f ] to the reaction mixture ][1,2,4]A solution of triazin-4 (3H) -one Int-1g (1.44 g,4.74 mmol) in pyridine (30 mL). The resulting mixture was stirred at room temperature for 3.5 hours and then cooled again to 0 ℃. Then, NH is added dropwise ₃ (2M, 155 mL). The resulting mixture was slowly warmed to room temperature and stirred for 75 minutes, then concentrated under vacuum. The mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL. Times.3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (25% etoac in PE) to give 5-iodo-7-isopropylimidazo [5,1-f][1,2,4]Triazin-4-amine Int-1 (1.08 g, 75% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.39(brs,1H),7.84(s,1H),6.74(brs,1H),3.43-3.34(m,1H),1.25(d,J＝8.0Hz,6H)ppm；LCMS:MS m/z(ESI):304.1[M+H] ⁺ 。

Intermediate 2 (Int-2, int-2A, int-2B)

5-iodo-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-4-amine Int-2

(R) -5-iodo-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-4-amine Int-2A

(S) -5-iodo-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-4-amine Int-2B

Step 1:3, 3-trifluoro-2-methylpropanoic acid Int-2b

A mixture of 2- (trifluoromethyl) acrylic acid Int-2a (10 g,71.40 mmol) and Pd/C (1.5 g) in EtOAc (150 mL) was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated in vacuo to give 3, 3-trifluoro-2-methylpropanoic acid Int-2b (7.8 g, 78% yield), which was used in the next step without further purification.

Step 2, 5-Dioxopyrrolidin-1-yl 3, 3-trifluoro-2-methylpropionate Int-2c

DCC (11.3 g,54.9 mmol) was added to a mixture of 3, 3-trifluoro-2-methylpropanoic acid Int-2b (7.8 g,54.9 mmol) and 1-hydroxypyrrolidine-2, 5-dione (6.3 g,54.9 mmol) in DME (120 mL) at 0deg.C. The mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 2, 5-dioxopyrrolidin-1-yl 3, 3-trifluoro-2-methylpropionate Int-2c (13 g, 99% yield), which was used in the next step without further purification.

¹ H NMR(400MHz,CDCl ₃ ):δ3.56-3.49(m,1H),2.81(s,4H),1.55(d,J＝8.0Hz,3H)ppm。

Step 3:N- ((3-amino-5-oxo-4, 5-dihydro-1, 2, 4-triazin-6-yl) methyl) -3, 3-trifluoro-2-methylpropanamide Int-2d

To a solution of 3-amino-6- (aminomethyl) -1,2, 4-triazin-5 (4H) -one Int-1c (3.8 g,17.8 mmol) in water (90 mL) at 0deg.C was added NaHCO ₃ Aqueous (1.0M, 44.4mL,44.4 mmol). The resulting mixture was slowly warmed to room temperature, then a solution of 2, 5-dioxopyrrolidin-1-yl 3, 3-trifluoro-2-methylpropionate Int-2c (6.0 g,24.9 mmol) in THF: ACN (1:1, 60 mL) was slowly added. The mixture was stirred at room temperature for 90 hours and then concentrated to 50mL. The reaction mixture was filtered and the solid was taken up in water and Et ₂ O washing and drying under vacuum to give N- ((3-amino-5-oxo-4, 5-dihydro-1, 2, 4-triazin-6-yl) methyl) -3, 3-trifluoro-2-methylpropanoyl Amine Int-2d (3.81 g,80% yield), which was used in the next step without further purification.

¹ H NMR(400MHz,DMSO-d ₆ ):δ12.07(brs,1H),8.43(s,1H),6.78(s,2H),4.09(s,2H),3.41-3.39(m,1H),1.22(d,J＝4.0Hz,3H)ppm。

Step 4 2-amino-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-4 (3H) -one Int-2e

POCl was added to a suspension of DCE (100 mL) of N- ((3-amino-5-oxo-4, 5-dihydro-1, 2, 4-triazin-6-yl) methyl) -3, 3-trifluoro-2-methylpropanamide Int-2d (4.5 g,17 mmol) at reflux ₃ (12.4 mL,136 mmol). The mixture was stirred at reflux for 2.5 hours and then cooled. After concentration in vacuo, the residue was suspended in MeOH in water (2:1, 45 mL) and filtered through celite. With 1% NH ₃ The residue was washed with MeOH (3X 15 mL) and the solution was concentrated to give 2-amino-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f][1,2,4]Triazin-4 (3H) -one Int-2e (4.2 g,100% yield), which is used in the next step without further purification.

Step 5 2-amino-5-iodo-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-4 (3H) -one Int-2f

To 2-amino-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f][1,2,4]To a solution of triazin-4 (3H) -one Int-2e (3.8 g,15.5 mmol) in DMF (80 mL) was added NIS (7.0 g,31 mmol) and the resulting mixture was stirred at room temperature for 18 hours. The mixture was then quenched with water (50 mL) and then extracted with EtOAc (50 ml×2). The combined organic phases were taken up in Na ₂ S ₂ O ₃ Aqueous (1M, 2X 50 mL) and brine (3X 30 mL) were washed over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (2-5% meoh in DCM) to give 2-amino-5-iodo-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f][1,2,4]Triazin-4 (3H) -one Int-2f (4.1 g,71% yield). ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.95(brs,1H),6.21(s,2H),4.14-4.10(m,1H),1.44(d,J＝8.0Hz,3H)ppm。

Step 6 5-iodo-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-4 (3H) -one Int-2g

To 2-amino-5-iodo-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f][1,2,4]To a solution of triazin-4 (3H) -one Int-2f (4.1 g,11 mmol) in THF: DMF (6:1, 105 mL) was added dropwise tert-butyl nitrite (5.7 g,55 mmol). The resulting mixture was stirred at room temperature for 3.5h. The mixture was then quenched with water (50 mL) and then extracted with EtOAc (50 ml×3). The combined organic phases were washed with brine (3X 30 mL), dried over anhydrous Na ₂ SO ₄ Dried and concentrated under vacuum. The residue was purified by silica gel chromatography (25% etoac in PE) to give 5-iodo-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f][1,2,4]Triazin-4 (3H) -one Int-2g (3.3 g,83.6% yield).

Step 7 5-iodo-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-4-amine Int-2

POCl was added dropwise to a solution of 1,2, 4-triazole (1.24 g,18 mmol) in pyridine (10 mL) at 0deg.C ₃ (1.2 g,8 mmol) and the resulting mixture was stirred at room temperature for 15 minutes, then 5-iodo-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] was slowly added][1,2,4]A solution of triazin-4 (3H) -one Int-2g (720 mg,2.0 mmol) in pyridine (6 mL). The resulting mixture was stirred at room temperature for 3.5 hours and then cooled again to 0 ℃. Then, NH is added dropwise ₃ (2M, 50 mL) and the resulting mixture was slowly warmed to room temperature and stirred for an additional 75 minutes. After concentration in vacuo, the residue was dissolved with EtOAc (50 mL) and washed with water (50 ml×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (20% etoac in PE) to give 5-iodo-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f][1,2,4]Triazin-4-amine Int-2 (545 mg, 79% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.60(brs,1H),6.90(brs,1H),4.42-4.38(m,1H),1.50(d,J＝4.0Hz,3H)ppm；LCMS:MS m/z(ESI):357.90[M+H] ⁺ 。

Step 8 (R) -5-iodo-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-4-amine Int-2A and (S) -5-iodo-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-4-amine Int-2B

5-Iodo-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f][1,2,4]Triazin-4-amine Int-2 (1.74 g) was resolved by chiral HPLC (supercritical CO ₂ MeOH (+0.1% 7.0mol/L MeOH in ammonia), 70g/min,35 ℃, 250 x 25mm 10 μm) gives two enantiomers (800 mg and 800mg respectively).

(R) -5-iodo-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f][1,2,4]Triazin-4-amine Int-2A: ¹ HNMR(400MHz,CDCl ₃ ) Delta 7.89 (s, 1H), 6.55 (br, 1H), 5.95 (br, 1H), 4.39-4.33 (m, 1H), 1.65 (d, 3H) ppm; chiral HPLC (supercritical CO ₂ MeOH(0.1％DEA),3.0mL/min,35℃,DAICEL250mm*4.6mm*5μm):Rt:2.495min,ee:100％；LCMS:MS m/z(ESI):357.9[M+H] ⁺ 。

(S) -5-iodo-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f][1,2,4]Triazin-4-amine Int-2B: ¹ HNMR (400 MHz, DMSO): delta 8.63 (br, 1H), 7.96 (s, 1H), 6.95 (br, 1H), 4.48-4.38 (m, 1H), 1.51 (d, 3H) ppm; chiral HPLC (supercritical CO ₂ MeOH(0.1％DEA),3.0mL/min,35℃,DAICEL250mm*4.6mm*5μm):Rt:Rt:2.848min,ee:97.16％；LCMS:MS m/z(ESI):357.9[M+H] ⁺ 。

Intermediate 3 (Int-3)

5- (4- (aminomethyl) phenyl) -7-isopropylimidazo [5,1-f ] [1,2,4] triazin-4-amine

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Step 1 (tert-butyl 4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) carbamate Int-3b

Under nitrogen atmosphere, 5-iodo-7-isopropylimidazo [5,1-f ] is introduced into a closed tube at 100deg.C][1,2,4]Triazin-4-amine Int-1 (80 mg, 0).1 mmol), (4- (((tert-butoxycarbonyl) amino) methyl) phenyl) boronic acid Int-3a (80 mg,0.26 mmol), pd (PPh) ₃ ) ₄ (10 mg,0.0086 mmol) and Na ₂ CO ₃ (82 mg,0.78 mmol) in 1, 4-dioxane (3 mL) was stirred in a Biotage microwave reactor for 40 min. After cooling, the reaction mixture was diluted with EtOAc (2 mL) and washed with water (2 mL). The combined organic phases were washed with brine (3X 3 mL), dried over anhydrous MgSO ₄ Dried and concentrated in vacuo. The residue was purified by silica gel chromatography to give (4- (4-amino-7-isopropylimidazo [5, 1-f)][1,2,4]Triazin-5-yl) benzyl) carbamic acid tert-butyl ester Int-3b (60 mg, 60% yield). LCMS MS m/z (ESI): 383.0[ M+H ]] ⁺ 。

Step 2 5- (4- (aminomethyl) phenyl) -7-isopropylimidazo [5,1-f ] [1,2,4] triazin-4-amine Int-3

At room temperature (4- (4-amino-7-isopropylimidazo [5, 1-f)][1,2,4]A solution of t-butyl triazin-5-yl) benzyl carbamate Int-3b (76 mg,0.2 mmol) in a mixture of TFA (0.5 mL) and DCM (1 mL) was stirred overnight. The resulting mixture was concentrated in vacuo to give 5- (4- (aminomethyl) phenyl) -7-isopropylimidazo [5,1-f][1,2,4]Triazin-4-amine Int-3 is used in the next step without further purification. LCMS MS m/z (ESI): 283.0[ M+H ]] ⁺ 。

Intermediate 4 (Int-4)

5-iodo-7- (tetrahydro-2H-pyran-4-yl) imidazo [5,1-f ] [1,2,4] triazin-4-amine Int-4

Step 1,2, 5-Dioxopyrrolidin-1-yl-tetrahydro-2H-pyran-4-carboxylate Int-4b

DCC (19.67 g,95.34 mmol) was slowly added to a solution of tetrahydro-2H-pyran-4-carboxylic acid Int-4a (11.28 g,86.67 mmol), 1-hydroxypyrrolidine-2, 5-dione (10.97 g,95.34 mmol) and DMAP (116.48 mg, 953.42. Mu. Mol) in THF (430 mL) at room temperature under argon. The reaction mixture was stirred at room temperature for 48 hours, then filtered. The filtrate was concentrated in vacuo and the resulting residue was purified by column chromatography (PE/EtOAc) to give the title compound 2, 5-dioxopyrrolidin-1-yl-tetrahydro-2H-pyran-4-carboxylate Int-4b (16.4 g, 83.28% yield).

Step 2N- ((3-amino-5-oxo-4, 5-dihydro-1, 2, 4-triazin-6-yl) methyl) tetrahydro-2H-pyran-4-carboxamide Int-4c

To a solution of 3-amino-6- (aminomethyl) -1,2, 4-triazin-5 (4H) -one Int-1c (3.3 g,18.58 mmol) in water (80 mL) at 0deg.C was added NaHCO ₃ Aqueous solution (1M aqueous solution, 42mL,42 mmol). The resulting mixture was slowly warmed to room temperature, then a solution of 2, 5-dioxopyrrolidin-1-yl-tetrahydro-2H-pyran-4-carboxylate Int-4b (5.36 g,23.60 mmol) in THF: ACN (1:1, 70 mL) was slowly added. The mixture was stirred at room temperature overnight and then filtered. The solid was washed with TBME (100 mL) and then dried in vacuo to give N- ((3-amino-5-oxo-4, 5-dihydro-1, 2, 4-triazin-6-yl) methyl) tetrahydro-2H-pyran-4-carboxamide Int-4c (3.1 g, yield 65.88%), which was used in the next step without further purification. LCMS MS m/z (ESI): 254.1[ M+H ]] ⁺ 。

Step 3 2-amino-7- (tetrahydro-2H-pyran-4-yl) imidazo [5,1-f ] [1,2,4] triazin-4 (3H) -one Int-4d

N- ((3-amino-5-oxo-4, 5-dihydro-1, 2, 4-triazin-6-yl) methyl) tetrahydro-2H-pyran-4-carboxamide Int-4c (2.0 g,7.90 mmol) at 90℃in POCl ₃ (30 mL) of the mixture for 48 hours. After cooling, the solution was concentrated in vacuo. NaOH solution (5M aqueous solution) was added to the resulting mixture to adjust pH 8. The precipitated solid was filtered and then washed with MeOH. The combined organic solvents were concentrated in vacuo to give the crude title compound 2-amino-7- (tetrahydro-2H-pyran-4-yl) imidazo [5,1-f ][1,2,4]Triazin-4 (3H) -one Int-4d is used in the next step without further purification.

LCMS:MS m/z(ESI):236.2[M+H] ⁺ 。

Step 4 2-amino-5-iodo-7- (tetrahydro-2H-pyran-4-yl) imidazo [5,1-f ] [1,2,4] triazin-4 (3H) -one Int-4e

To 2-amino-7- (tetrahydro-2H-pyran-4-yl) imidazo [5,1-f][1,2,4]To a solution of triazin-4 (3H) -one Int-4d (1.34 g,5.70 mmol) in DMF (20 mL) was added NIS (71.92 g,8.50 mmol). The resulting mixture was stirred at 35 ℃ overnight for 18 hours. The mixture was then quenched with water (50 mL), followed by extraction with EtOAc (50 ml×2). The combined organic phases were taken up in Na ₂ S ₂ O ₃ Aqueous (50 mL) and brine (50 mL) washed with anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under vacuum. The residue was purified by C18 column to give 2-amino-5-iodo-7- (tetrahydro-2H-pyran-4-yl) imidazo [5,1-f][1,2,4]Triazin-4 (3H) -one Int-4e (1.2 g, 58.33% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ6.40(s,1H),3.92(d,11.2Hz,2H),3.44-3.25(m,3H),1.79-1.75(m,4H)ppm。

Step 5-iodo-7- (tetrahydro-2H-pyran-4-yl) imidazo [5,1-f ] [1,2,4] triazin-4 (3H) -one Int-4f

To a solution of 2-amino-5-iodo-7- (tetrahydro-2H-pyran-4-yl) imidazo [5,1-f ] [1,2,4] triazin-4 (3H) -one Int-4e (1.2 g,3.32 mmol) in THF: DMF (6:1, 28 mL) was added dropwise tert-butyl nitrite (1.63 g,15.82 mmol). The resulting mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was purified by silica gel chromatography (DCM/meoh=20/1) to give 5-iodo-7- (tetrahydro-2H-pyran-4-yl) imidazo [5,1-f ] [1,2,4] triazin-4 (3H) -one Int-4f (0.85 g, 73.91%).

¹ H NMR(400MHz,DMSO-d ₆ ):δ11.84(br,1H),7.91(s,1H),3.95-3.90(m,2H),3.47-3.36(m,3H),1.83-1.78(m,4H)ppm。

Step 6 5-iodo-7- (tetrahydro-2H-pyran-4-yl) imidazo [5,1-f ] [1,2,4] triazin-4-amine Int-4

POCl was added dropwise to a solution of 1,2, 4-triazole (178 mg,2.6 mmol) in pyridine (1.5 mL) at room temperature ₃ (0.09 ml,0.925 mmol). The resulting mixture was stirred at room temperature for 15 minutes, then 5-iodo-7- (tetrahydro-2H-pyran-4-yl) imidazo [5,1-f was slowly added][1,2,4]A solution of triazin-4 (3H) -one Int-4f (100 mg,0.29 mmol) in pyridine (3 mL). The resulting mixture was stirred at room temperature for 3.5 hours, after which it was cooled to 0 ℃. Then, NH is added dropwise ₃ (2M, 7 mL) and the resulting mixture was slowly warmed to room temperature and stirred for an additional 2 hours. After concentration in vacuo, the residue was dissolved in EtOAc: PE (1:1, 4 mL). The mixture was filtered and the solid was further dried under vacuum to give crude 5-iodo-7- (tetrahydro-2H-pyran-4-yl) imidazo [5,1-f][1,2,4]Triazin-4-amine Int-4 50mg,50% yield) which is used in the next step without further purification.

LCMS:MS m/z(ESI):345.9[M+H] ⁺ 。

Intermediate 5 (Int-5)

5-iodo-7- (tetrahydrofuran-3-yl) imidazo [5,1-f ] [1,2,4] triazin-4-amine Int-5

Step 1,2, 5-Dioxapyrrolidin-1-yl-tetrahydrofuran-3-carboxylate Int-5b

DCC (19.67 g,95.34 mmol) was slowly added to a solution of tetrahydrofuran-3-carboxylic acid Int-5a (12.5 g,107.65 mmol), 1-hydroxypyrrolidine-2, 5-dione (13.63 g,118.42 mmol) and DMAP (1.45 g,11.84 mmol) in THF (438 mL) at room temperature under argon. The reaction mixture was stirred at room temperature for 48 hours and then filtered. The filtrate was concentrated in vacuo and the final residue was purified by silica gel column (PE/etoac=2:1) to give 2, 5-dioxapyrrolidin-1-yl-tetrahydrofuran-3-carboxylate Int-5b (20.3 g, 88.45% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ3.98-3.82(m,2H),3.81-3.75(m,1H),3.73-3.70(m,1H),3.61-3.53(m,1H),2.83(brs,4H),2.32-2.23(m,1H),2.15-2.06(m,1H)。

Step 2N- ((3-amino-5-oxo-4, 5-dihydro-1, 2, 4-triazin-6-yl) methyl) tetrahydrofuran-3-carboxamide Int-5c

To an aqueous solution (200 mL) of 3-amino-6- (aminomethyl) -1,2, 4-triazin-5 (4H) -one Int-1c (5.52 g,39.09 mmol) at 0deg.C was added NaHCO ₃ Aqueous (1M water, 86mL,86 mmol). The reaction mixture was slowly warmed to room temperature, then a mixed solution of 2, 5-dioxapyrrolidin-1-yl-tetrahydrofuran-3-carboxylate Int-5b (10 g,46.91 mmol) in THF: ACN (1:1, 100 mL) was slowly added. The reaction mixture was stirred at room temperature overnight and then filtered. The solid was washed with TBME (200 mL) and then dried in vacuo to give N- ((3-amino-5-oxo-4, 5-dihydro-1, 2, 4-triazin-6-yl) methyl) tetrahydrofuran-3-carboxamide Int-5c (5.26 g, 56.25% yield), which was used in the next step without further purification.

¹ H NMR(400MHz,DMSO-d ₆ ):δ12.1(br,1H),8.11(t,1H),6.81(brs,2H),4.08(d,2H),3.83(t,1H),3.75-3.59(m,3H),3.01-2.97(m,1H),2.00-1.94(m,2H)ppm；LCMS:MS m/z(ESI):240.2[M+H] ⁺ 。

Step 3 2-amino-7- (tetrahydrofuran-3-yl) imidazo [5,1-f ] [1,2,4] triazin-4 (3H) -one Int-5d

POCl of N- ((3-amino-5-oxo-4, 5-dihydro-1, 2, 4-triazin-6-yl) methyl) tetrahydrofuran-3-carboxamide Int-5c (500.00 mg,2.09 mmol) was introduced in a pressure tank at 90 ℃ ₃ (10 mL) the solution was stirred overnight. After cooling, the reaction solution was concentrated in vacuo. NaOH solution (5M water) is added to adjust the pH value to 8. The precipitate was filtered and washed with MeOH. Vacuum concentrating the mixed organic solvent to obtain 2-amino-7- (tetrahydrofuran-3-yl) imidazole [5,1-f ][1,2,4]Triazin-4 (3H) -one Int-5d (180 mg, yield 38.93%), which was used in the next step without further purification.

¹ H NMR(400MHz,DMSO-d ₆ ):δ6.95(s,1H),4.01(t,1H),3.85-3.70(m,3H),3.65-3.55(m,2H),2.22-2.10(m,2H)ppm；LCMS:MS m/z(ESI):222.0[M+H] ⁺ 。

Step 4 2-amino-5-iodo-7- (tetrahydrofuran-3-yl) imidazo [5,1-f ] [1,2,4] triazin-4 (3H) -one Int-5e

In 2-amino-7- (tetrahydrofuran-3-yl) imidazole [5,1-f][1,2,4]To a solution of triazin-4 (3H) -one Int-5d (180 mg, 813.68. Mu. Mol) in DMF (4 mL) was added NIS (274.60 mg,1.22 mmol). The reaction mixture was stirred overnight at 50 ℃ for 18 hours. The reaction mixture was then quenched with water (10 mL) and then extracted with EtOAc (10 mL. Times.2). The mixed organic phase is treated with Na ₂ S ₂ O ₃ (1.0M, 4 mL. Times.2) aqueous solution and saturated saline (4 mL. Times.3) were washed, anhydrous Na ₂ SO ₄ Drying, filtering and concentrating in vacuum. Purification of the residue on a silica gel column (DCM: meoh=50:1) gave 2-amino-5-iodo-7- (tetrahydrofuran-3-yl) imidazo [5,1-f][1,2,4]Triazin-4 (3H) -one Int-5e (57 mg, 20.18% yield).

LCMS:MS m/z(ESI):348.0[M+H] ⁺ 。

Step 5-iodo-7- (tetrahydrofuran-3-yl) imidazo [5,1-f ] [1,2,4] triazin-4 (3H) -one Int-5f

To a mixed solution of 2-amino-5-iodo-7- (tetrahydrofuran-3-yl) imidazo [5,1-f ] [1,2,4] triazin-4 (3H) -one Int-5e (57 mg, 164.21. Mu. Mol) in THF (6 mL) and DMF (1 mL) was added tert-butyl nitrite (184.67 mg, 821.06. Mu. Mol). The reaction mixture was stirred at room temperature for 3.5 hours and then concentrated in vacuo. The residue was purified by column chromatography over silica gel (DCM: meoh=100:1) to give 5-iodo-7- (tetrahydrofuran-3-yl) imidazo [5,1-f ] [1,2,4] triazin-4 (3H) -one Int-5f (54 mg, 99.02%).

¹ H NMR(400MHz,DMSO-d ₆ ):δ11.85(br,1H),7.92(s,1H),4.04-4.02(m,1H),3.89-3.76(m,4H),2.35-2.19(m,2H)ppm；LCMS:MS m/z(ESI):332.9[M+H] ⁺ 。

Step 6 5-iodo-7- (tetrahydrofuran-3-yl) imidazo [5,1-f ] [1,2,4] triazin-4-amine Int-5

POCl was added dropwise to a solution of 1,2, 4-triazole (103 mg,1.49 mmol) in pyridine (1 mL) at room temperature ₃ (81.26 mg,0.53 mmol). The reaction mixture was stirred at room temperature for 15 minutes, and then 5-iodo-7- (tetrahydrofuran-3-yl) imidazo [5,1-f was slowly added dropwise][1,2,4]A solution of triazin-4 (3H) -one Int-5f (55 mg,0.17 mmol) in pyridine (2 mL). The resulting mixture was stirred at room temperature for 3.5 hours and then cooled to 0 ℃. Then, NH is added dropwise ₃ (2M, 4 mL). The resulting mixture was stirred at 0 ℃ for 30 minutes and then slowly warmed to room temperature. Concentrated in vacuo, the residue was dissolved in EtOAc (25 mL) and saturated NaHCO was added ₃ Aqueous extraction (25 mL). The organic extract is treated with anhydrous Na ₂ SO ₄ Dried, filtered, and then concentrated under reduced pressure. The residue was purified by column on silica gel (DCM: meoh=50:1) to give 5-iodo-7- (tetrahydrofuran-3-yl) imidazoleAnd [5,1-f][1,2,4]Triazin-4-amine Int-5 (55 mg, 100% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.49(br,1H),7.89(s,1H),6.90(br,1H),4.06(t,1H),3.89-3.78(m,4H),2.27-2.23(m,2H)ppm；LCMS:MS m/z(ESI):331.9[M+H] ⁺ 。

Example A1

N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -5-fluoro-2-methoxybenzamide A1

Step 1N- (4-bromobenzyl) -5-fluoro-2-methoxybenzamide A1b

To a solution of (4-bromophenyl) methylamine A1a (1 g,5.37 mmol) and HATU (2.45 g,6.45 mmol) in DMF (10 mL) was added 5-fluoro-2-methoxy-benzoic acid (1.10 g,6.45 mmol) and TEA (1.09 g,10.75 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was then dissolved in EtOAc (50 ml×2) and washed with water (50 mL). The organic layer was treated with anhydrous Na ₂ SO ₄ Dried and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE/ea=20%) to give N- (4-bromobenzyl) -5-fluoro-2-methoxybenzamide A1b (1.65 g, yield 90.78%).

¹ H NMR(400MHz,CDCl ₃ ):δ8.24(brs,1H),7.94(dd,J＝9.6Hz,3.2Hz,1H),7.46(dd,J＝8.8Hz,2.0Hz,2H),7.23(d,J＝8.4Hz,2H),7.17-7.11(m,1H),6.93(dd,J＝8.8Hz,4.0Hz,1H),4.62(d,J＝5.6Hz,2H),3.91(s,3H)ppm。

Step 2 5-fluoro-2-methoxy-N- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) benzyl) benzamide A1c

N- (4-bromobenzyl) -5-fluoro-2-methoxybenzamide A1b (4.54 g,13.43 mmol), (BPin) was reacted under nitrogen at 90 ℃ ₂ (5.11g,20.14mmol)、Pd(dppf)Cl ₂ (2.19 g,2.69 mmol) and KOAc (3.95 g,40.28 mmol) in 1, 4-dioxane (25 mL) were stirred for 1.5 h. After cooling, the mixture was diluted with EtOAc (200 mL) and washed with water (200 mL). The organic layer was treated with anhydrous Na ₂ SO ₄ Dried and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE/ea=20%) to give 5-fluoro-2-methoxy-N- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) benzyl) benzamide A1c (4.6 g, yield 88.94%).

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.82(t,J＝6.0Hz,1H),7.64(d,J＝8.0Hz,2H),7.49(dd,J＝9.2Hz,3.2Hz,2H),7.37-7.31(m,1H),7.18(dd,J＝9.2Hz,4.4Hz,1H),4.51(d,J＝6.0Hz,2H),3.88(s,3H),1.28(s,12H)ppm；LCMS:MS m/z(ESI):386.1[M+H] ⁺ 。

Step 3:N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -5-fluoro-2-methoxybenzamide A1

(4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl), 5-fluoro-2-methoxy-N- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) benzamide A1c (30 mg,0.1 mmol), 5-iodo-7-isopropylimidazo [5, 1-f) was treated in a closed tube at 100deg.C under nitrogen atmosphere ][1,2,4]Triazin-4-amine Int-1 (30 mg,0.1 mmol), pd (dppf) Cl ₂ (10 mg,0.0086 mmol) and Cs ₂ CO ₃ (32 mg,0.3 mmol) in 1, 4-dioxane (3 mL) and water (0.3 mL) was stirred in a Biotage microwave reactor for 30 min. After cooling, the reaction mixture was diluted with EtOAc (2 mL) and washed with water (2 mL). The combined organic layers were washed with brine (3×3 mL), dried over anhydrous MgSO ₄ Dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to give N- (4- (4-amino-7-isopropylimidazo [5, 1-f)][1,2,4]Triazin-5-yl) benzyl) -5-fluoro-2-methoxybenzamide A1 (28 mg, 65% yield).

¹ H NMR(400MHz,CDCl ₃ )δ8.18(brs,1H),7.89(d,1H),7.80(s,1H),7.59(d,2H),7.39(d,2H),7.08-7.11(m,1H),6.86-6.89(m,1H),5.75-5.95(b,2H),4.65(d,2H),3.87(s,3H),3.54-3.60(m,1H),1.39(d,6H)ppm；LCMS:MS m/z(ESI):435.0[M+H] ⁺ 。

Example A2, A2a, A2bN- (4- (4-amino-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -5-fluoro-2-methoxybenzamide A2

(R) -N- (4- (4-amino-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -5-fluoro-2-methoxybenzamide A2a

(S) -N- (4- (4-amino-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -5-fluoro-2-methoxybenzamide A2b

Step 1N- (4- (4-amino-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -5-fluoro-2-methoxybenzamide A2

Step 1 of example A2 was prepared in analogy to step 3 of example A1 using 5-iodo-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-4-amine Int-2 and 5-fluoro-2-methoxy-N- (4, 5-tetramethyl-1, 3, 2-dioxapentan-2-yl) benzyl) benzamide A1 c. The residue was purified by silica gel chromatography to give N- (4- (4-amino-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -5-fluoro-2-methoxybenzamide A2.

¹ H NMR(400MHz,CDCl ₃ ):δ8.26(brs,1H),7.90(d,1H),7.86(s,1H),7.58(d,2H),7.43(d,2H),7.07-7.12(m,1H),6.87-6.90(m,1H),4.67(d,2H),4.34-4.42(m,1H),3.88(s,3H),1.63(d,3H)ppm；LCMS:MS m/z(ESI):489.0[M+H] ⁺ 。

Step 2:

By chiral HPLC (EtOH+0.1% NH) ₄ OH/hexane, 20mL/min,35 ℃, chiralPak IE,20 mm. Times.250 mm,5 μm) isolation of N- (4- (4-amino-7- (1, 1-trifluoropropan-2-yl) imidazo [5, 1-f)][1,2,4]Triazin-5-yl) benzyl) -5-fluoro-2-methoxybenzamide A2 (172 mg) gives two enantiomers (70 mg and 73mg respectively).

Enantiomer 1 (shorter retention time): ¹ H NMR(500MHz,CDCl ₃ ) Delta 8.33 (s, 1H), 7.96 (s, 2H), 7.58 (d, j=7.31 hz, 4H), 7.17 (s, 1H), 6.96 (s, 1H), 5.76 (s, 2H), 4.75 (s, 2H), 4.46 (s, 1H), 3.95 (s, 3H), 1.61 (s, 3H) ppm; chiral HPLC (EtOH/hexane 30/70,1.0mL/min,35 ℃, chiralPak IE, 150. Times.4.6 mm,5 μm): rt:8.488min, ee:99.37%; LCMS MS m/z (ESI): 489.3[ M+H ] ] ⁺ 。

Enantiomer 2 (longer retention time): ¹ H NMR(500MHz,CDCl ₃ ) Delta 8.33 (s, 1H), 8.05-7.85 (m, 2H), 7.58 (d, j=7.29 hz, 4H), 7.17 (s, 1H), 6.95 (s, 1H), 5.83 (s, 2H), 4.74 (s, 2H), 4.45 (s, 1H), 3.95 (s, 3H), 1.71 (s, 3H) ppm; chiral HPLC (EtOH/hexane 30/70,1.0mL/min,35 ℃, chiralPak IE, 150. Times.4.6 mm,5 μm): rt:10.212min, ee:99.39%; LCMS MS m/z (ESI): 489.3[ M+H ]] ⁺ 。

Example A3

N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-ethoxybenzyl) -5-fluoro-2-methoxybenzamide A3

Step 1 4-bromo-3-ethoxybenzoic acid ethyl ester A3b

At room temperature, ethyl 4-bromo-3-hydroxybenzoate A3a (4 g,16.32 mmol) and K ₂ CO ₃ To a solution of (6.77 g,48.97 mmol) in DMF (40 mL) was added iodoethane (5.09 g,32.64 mmol). The resulting mixture was stirred at 80℃for 16 hours. After cooling, the reaction mixture was quenched with water (100 mL) and then extracted with EtOAc (100 ml×2). The combined organic extracts were subjected to anhydrous Na ₂ SO ₄ Dried, filtered and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH: DCM-0:1 to 1:15) to give ethyl 4-bromo-3-ethoxybenzoate A3b (4 g, yield 89.73%).

¹ H NMR(400MHz,DMSO-d ₆ ):δ7.73(d,J＝8.4Hz,1H),7.51(d,J＝4.0Hz,1H),7.45(dd,J＝8.0Hz,4.0Hz,1H),4.33(q,J＝7.2Hz,2H),4.17(q,J＝6.8Hz,2H),1.39(t,J＝6.8Hz,3H),1.33(t,J＝6.8Hz,3H)ppm。

Step 2 4-bromo-3-ethoxybenzamide A3c

To a solution of ethyl 4-bromo-3-ethoxybenzoate A3b (4 g,14.65 mmol) in MeOH (40 mL) at room temperature was added NH ₃ (85%, 4.76 g). The resulting mixture was then warmed up and stirred at 80 ℃ for 16 hours. After cooling, the reaction mixture was quenched with water (100 mL) and then extracted with EtOAc (100 ml×2). The organic layer was treated with anhydrous Na ₂ SO ₄ Dried, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH: dcm=0:1 to 1:15) to give 4-bromo-3-ethoxybenzamide A3c (2.56 g, 71.70% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.05(s,1H),7.65(d,J＝8.0Hz,1H),7.53(d,J＝2.0Hz,1H),7.46(s,1H),7.38(dd,J＝8.0Hz,2.0Hz,1H),4.16(q,J＝7.2Hz,2H),1.38(t,J＝7.2Hz,3H)ppm。

Step 3 4-bromo-3-ethoxybenzonitrile A3d

To a solution of 4-bromo-3-ethoxybenzamide A3c (500 mg,2.05 mmol) in pyridine (5 mL) at 0deg.C was added POCl ₃ (575.75 mg,3.75 mmol). The resulting mixture was slowly warmed to room temperature and stirred for 3 hours, then quenched with water (100 mL). The resulting mixture was then extracted with EtOAc (100 mL. Times.2). The combined organic extracts were subjected to anhydrous Na ₂ SO ₄ Dried, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc: pe=0:1 to 1:10) to give 4-bromo-3-ethoxybenzonitrile A3d (397 mg, yield 85.73%).

¹ H NMR(400MHz,DMSO-d ₆ ):δ7.81(d,J＝8.4Hz,1H),7.59(d,J＝2.0Hz,1H),7.35(dd,J＝8.0Hz,2.0Hz,1H),4.19(q,J＝7.2Hz,2H),1.37(t,J＝7.2Hz,3H)ppm。

Step 4 (4-bromo-3-ethoxyphenyl) methylamine A3e

4-bromo-3-ethoxybenzonitrile A3d (600 mg,2.65 mmol) was added to BH at 60 ℃ ₃ The mixture in THF (10 mL,2.65 mmol) was stirred for 3 hours. After cooling, the reaction MeOH (20 mL) and HC1 (20 mL,12M aqueous) were quenched. The resulting solution was extracted with EtOAc (200 mL. Times.3) and the combined organic layers were taken up over anhydrous Na ₂ SO ₄ Drying and filteringAnd concentrated in vacuo to give crude (4-bromo-3-ethoxyphenyl) methylamine A3e (600 mg, 98.25% yield), which was used directly in the next step.

Step 5N- (4-bromo-3-ethoxybenzyl) -5-fluoro-2-methoxybenzamide A3f

To a solution of (4-bromo-3-ethoxyphenyl) methylamine A3e (340 mg,1.48 mmol) and TEA (448.52 mg,4.43 mmol) in DCM (5 mL) under nitrogen at 0deg.C was added 5-fluoro-2-methoxy-benzoyl chloride (417.95 mg,2.22 mmol). The resulting mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL). The combined organic extracts were washed with saturated brine (20 mL), dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc: pe=0:1 to 1:3) to give N- (4-bromo-3-ethoxybenzyl) -5-fluoro-2-methoxybenzamide A3f (371 mg, 65.69%).

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.79(t,J＝6.0Hz,1H),7.52-7.45(m,2H),7.36-7.31(m,1H),7.18(dd,J＝9.2Hz,4.4Hz,1H),7.08(d,J＝1.2Hz,1H),6.84(dd,J＝8.0Hz,1.6Hz,1H),4.45(d,J＝6.0Hz,2H),4.09(q,J＝7.2Hz,2H),3.88(s,3H),1.36(t,J＝7.2Hz,3H)ppm。

Step 6 (2-ethoxy-4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) boronic acid A3g

N- (4-bromo-3-ethoxybenzyl) -5-fluoro-2-methoxybenzamide A3f (371 mg,0.970 mmol), pd (dppf) Cl was reacted under nitrogen at 90deg.C ₂ (71.02mg,0.097mmol)、KOAc(285.78mg,2.91mmol)、(BPin) ₂ (492.96 mg,1.94 mmol) in 1, 4-dioxane (4 mL) was stirred for 16 h. After cooling, the reaction mixture was diluted with EtOAc (100 mL) and then washed with water (50 ml×2). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ Dried, and concentrated under reduced pressure. The residue was purified by preparative HPLC using ACN/H ₂ O/NH ₄ OH elution afforded (2-ethoxy-4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) boronic acid A3g (50.66 mg, 15.03% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.76(t,J＝6.0Hz,1H),7.63(s,2H),7.55(d,J＝7.2Hz,1H),7.47(dd,J＝9.2Hz,3.2Hz,1H),7.36-7.31(m,1H),7.18(dd,J＝9.2Hz,4.4Hz,1H),6.97(s,1H),6.90(d,J＝7.6Hz,1H),4.48(d,J＝6.0Hz,2H),4.09(q,J＝7.2Hz,2H),3.88(s,3H),1.36(t,J＝7.2Hz,3H)ppm；LCMS:MS m/z(ESI):348.2[M+H] ⁺ 。

Step 7N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-ethoxybenzyl) -5-fluoro-2-methoxybenzamide A3

Example A3 was prepared following a procedure similar to that described in step 3 of example A1. The crude product was purified by silica gel chromatography using 5-iodo-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-4-amine Int-1 and (2-ethoxy-4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) boronic acid A3g to give N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-ethoxybenzyl) -5-fluoro-2-methoxybenzamide A3.

¹ H NMR(400MHz,CDCl ₃ ):δ8.18(t,1H),7.90(d,1H),7.76(s,1H),7.46(d,1H),7.12-7.01(m,1H),7.01(d,1H),6.96(s,1H),6.86-6.96(m,1H),5.80(b,2H),4.62(d,2H),4.00(q,2H),3.87(s,3H),3.59-3.52(m,1H),1.39(d,6H),1.22(t,3H)ppm；LCMS:MS m/z(ESI):479.0[M+H] ⁺ 。

Examples A4, A4a, A4b

N- (4- (4-amino-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-ethoxybenzyl) -5-fluoro-2-methoxybenzamide A4

(S) -N- (4- (4-amino-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-ethoxybenzyl) -5-fluoro-2-methoxybenzamide A4a

(R) -N- (4- (4-amino-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-ethoxybenzyl) -5-fluoro-2-methoxybenzamide A4b

Step 1N- (4- (4-amino-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-ethoxybenzyl) -5-fluoro-2-methoxybenzamide A4

Step 1 of example A4 was prepared in analogy to step 3 of example A1 using 5-iodo-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-4-amine Int-2 and (2-ethoxy-4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) boronic acid A3 g. The crude product was purified by silica gel chromatography to give N- (4- (4-amino-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-ethoxybenzyl) -5-fluoro-2-methoxybenzamide A4.

¹ H NMR(400MHz,CDCl ₃ ):δ8.29(t,1H),7.99(d,1H),7.90(s,1H),7.54(d,1H),7.16-7.21(m,1H),7.11(d,1H),7.06(s,1H),6.96-6.98(m,1H),5.90(b,2H),4.72(d,2H),4.42-4.50(m,1H),4.07-4.12(m,2H),3.97(s,3H),1.75(d,3H),1.30(t,3H)ppm；LCMS:MS m/z(ESI):533.0[M+H] ⁺ 。

Step 2:

By chiral HPLC (supercritical CO ₂ /IPA(+N),60mL/min,35℃,25mm x 250mm,10 μm) isolation of N- (4- (4-amino-7- (1, 1-trifluoropropan-2-yl) imidazo [5, 1-f)][1,2,4]Triazin-5-yl) -3-ethoxybenzyl) -5-fluoro-2-methoxybenzamide A4 (90 mg) gives two enantiomers (22 mg and 24mg respectively).

Enantiomer 1 (shorter retention time): ¹ H NMR(400MHz,DMSO-d ₆ )δ8.54(t,J＝6.0Hz,1H),8.32(br,1H),7.92(s,1H),7.50(dd,J＝8.8Hz,3.2Hz,1H),7.40(d,J＝8.0Hz,1H),7.37-7.31(m,1H),7.20(dd,J＝9.2Hz,4.4Hz,1H),7.14(s,1H),7.06(d,J＝8.4Hz,1H),6.18(br,1H),4.56(d,J＝6.0Hz,2H),4.51-4.46(m,1H),4.08(q,J＝7.2Hz,2H),3.90(s,3H),1.58(d, j=7.2 hz,3 h), 1.21 (t, j=7.2 hz,3 h) ppm; chiral HPLC (supercritical CO ₂ In MeOH (0.1% DEA), 1.0mL/min,35 ℃,100*3.0mm 3μm):Rt:2.451min,ee:100％；LCMS:MS m/z(ESI):533.2[M+H] ⁺ 。

enantiomer 2 (longer retention time): ¹ H NMR(400MHz,DMSO-d ₆ ) Delta 8.30 (brs, 1H), 7.98 (dd, j=9.2 hz,3.2hz, 1H), 7.88 (s, 1H), 7.55 (d, j=7.6 hz, 1H), 7.21-7.15 (m, 1H), 7.11 (d, j=8.0 hz, 1H), 7.07 (s, 1H), 6.96 (dd, j=8.8 hz,4.0hz, 1H), 6.35 (br, 1H), 4.72 (d, j=6.0 hz, 2H), 4.48-4.40 (m, 1H), 4.11 (q, j=6.8 hz, 2H), 3.96 (s, 3H), 1.72 (d, j=7.2 hz, 3H), 1.30 (t, j=6.8 hz, 3H) ppm; chiral HPLC (supercritical CO ₂ In MeOH (0.1% DEA), 1.0mL/min,35 ℃,100*3.0mm 3μm):Rt:2.544min,ee:99.46％；LCMS:MS m/z(ESI):533.2[M+H] ⁺ 。

example A5

N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-fluorobenzyl) -5-fluoro-2-methoxybenzamide A5

Step 1 (4-bromo-3-fluorophenyl) methylamine A5b

To a solution of 4-bromo-3-fluorobenzonitrile A5a (5 g,25.00 mmol) in THF (10 mL) at 0deg.C under nitrogen was added BH ₃ THF (6.72 g,80mL,80.00 mmol). The mixture was slowly warmed up and stirred at 60 ℃ for 3 hours. After cooling, the mixture was quenched with MeOH and HCl, then diluted with EtOAc (100 mL). After washing with water (50 mL. Times.2), the organic layer was washed with brine (30 mL) and dried over anhydrous Na ₂ SO ₄ Drying, filtration and concentration under reduced pressure gave crude (4-bromo-3-fluorophenyl) methylamine A5b (4 g, 42% yield), which was used in the next step without further purification.

LCMS:MS m/z(ESI):205.9[M+H] ⁺ 。

Step 2N- (4-bromo-3-fluorobenzyl) -5-fluoro-2-methoxybenzamide A5c

To a stirred solution of (4-bromo-3-fluorophenyl) methylamine A5b (892.62 mg,4.37 mmol) and TEA (885.36 mg,8.75 mmol) in DCM (15 mL) at 0deg.C was added 5-fluoro-2-methoxy-benzoyl chloride (550 mg,2.92 mmol). The resulting mixture was slowly warmed to room temperature and then concentrated under vacuum. The residue was purified by silica gel column (PE: eeoac=5:1) to give N- (4-bromo-3-fluorobenzyl) -5-fluoro-2-methoxybenzamide A5c (510 mg, yield 49.10%).

LCMS:MS m/z(ESI):356.0[M+H] ⁺ 。

Step 3 5-fluoro-N- (3-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) benzyl) -2-methoxybenzamide A5d

N- (4-bromo-3-fluorobenzyl) -5-fluoro-2-methoxybenzamide A5c (400 mg,1.12 mmol), pd (dppf) Cl under nitrogen at 90deg.C ₂ (41.10mg,0.056mmol)、(BPin) ₂ A mixture of (570.53 mg,2.25 mmol) and KOAc (220.12 mg,2.25 mmol) in 1, 4-dioxane (10 mL) was stirred overnight. After cooling, the mixture was diluted with EtOAc and then washed with water. The organic phase was treated with anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under vacuum. The mixture was purified by column chromatography on silica gel (PE: etoac=4:1) to give 5-fluoro-N- (3-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) benzyl) -2-methoxybenzamide A5d (177.3 mg,39.15% yield).

¹ H NMR(400MHz,CDCl ₃ ):δ7.95(dd,J＝9.2Hz,3.2Hz,1H),7.73-7.69(m,1H),7.18-7.10(m,2H),7.03(d,J＝10.0Hz,1H),6.95-6.90(m,1H),4.68(d,J＝5.6Hz,2H),3.95-3.88(m,3H),1.36(s,12H)ppm；LCMS:MS m/z(ESI):404.2[M+H] ⁺ 。

Step 4N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-fluorobenzyl) -5-fluoro-2-methoxybenzamide A5

Example A5 was prepared in analogy to step 3 of example A1 using 5-iodo-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-4-amine Int-1 and 5-fluoro-N- (3-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxapentalan-2-yl) benzyl) -2-methoxybenzamide A5 d. The crude product was purified by silica gel chromatography to give N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-fluorobenzyl) -5-fluoro-2-methoxybenzamide A5.

¹ H NMR(400MHz,CDCl ₃ ):δ8.28(t,1H),7.88(d,1H),7.80(s,1H),7.50(t,1H),7.08-7.52(m,3H),6.87-6.91(m,1H),5.53(b,2H),4.66(d,2H),3.90(s,3H),3.53-3.60(m,1H),1.39(d,6H)ppm；LCMS:MS m/z(ESI):453.0[M+H] ⁺ 。

Example A6

N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-ethoxy-5-fluorobenzyl) -5-fluoro-2-methoxybenzamide A6

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Step 1 4-bromo-3-ethoxy-5-fluorobenzonitrile A6b

To a solution of ethanol (0.66 g,14.34 mmol) in THF (25 mL) was added NaH (0.57 g,14.34 mmol) at room temperature. The resulting solution was stirred for 30 minutes, then 4-bromo-3, 5-difluorobenzonitrile A6a (2.50 g,11.47 mmol) was added. The mixture was stirred at room temperature for 6 hours, then saturated NH ₄ The aqueous Cl solution was quenched. After extraction with EtOAc (3×50 mL), the combined organic layers were washed with brine (3×3 mL), dried over anhydrous MgSO4, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0-40% dcm in hexane) to give the title compound 4-bromo-3-ethoxy-5-fluorobenzonitrile A6b.

¹ H NMR(400MHz,CDCl ₃ ):δ7.07(d,1H),6.93(s,1H),4.17(q,2H),1.54(t,3H)ppm。

Step 2 (4-bromo-3-ethoxy-5-fluorophenyl) methylamine A6c

To a solution of 4-bromo-3-ethoxy-5-fluorobenzonitrile A6b (0.98 g,4 mmol) in THF (15 mL) at room temperature was added boronAlkyldimethyl sulfide (2M in THF, 4.0mL,8.0 mmol). The mixture was then heated to 80 ℃ and stirred for 2 hours. After cooling, 6N aqueous HCl was slowly added to the reaction, and the resulting mixture was again heated to 80 ℃. After stirring at this temperature for 1 hour, the reaction was cooled and taken up with saturated NaHCO ₃ Quenching with water solution. After extraction with EtOAc, the combined organic phases were washed with brine (3×3 mL), over anhydrous MgSO ₄ Dried and concentrated in vacuo to give the crude title compound (4-bromo-3-ethoxy-5-fluorophenyl) methylamine A6c, which was used in the next step without further purification.

LCMS:MS m/z(ESI):249.0[M+H] ⁺ 。

Step 3:N- (4-bromo-3-ethoxy-5-fluorobenzyl) -5-fluoro-2-methoxybenzamide A6d

DIPEA (1.39 mL,8.0 mmol) was added to a solution of (4-bromo-3-ethoxy-5-fluorophenyl) methylamine A6c (0.99 g,4.0 mmol), 5-fluoro-2-methoxybenzoic acid (0.68 g,4.0 mmol), HATU (1.82 g,4.8 mmol) in DCM (15 mL) at room temperature. The resulting mixture was stirred for 2 hours and then concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0-30% etoac in DCM) to give the title compound N- (4-bromo-3-ethoxy-5-fluorobenzyl) -5-fluoro-2-methoxybenzamide A6d.

LCMS:MS m/z(ESI):402.0[M+H] ⁺ 。

Step 4N- (3-ethoxy-5-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) benzyl) -5-fluoro-2-methoxybenzamide A6e

N- (4-bromo-3-ethoxy-5-fluorobenzyl) -5-fluoro-2-methoxybenzamide A6d (480 mg,1.2 mmol), (BPin) was reacted under nitrogen at 100deg.C ₂ (457mg,1.8mmol)、Pd(dppf)Cl ₂ (88 mg,0.12 mmol) and KOAc (353 mg,3.6 mmol) in 1, 4-dioxane (10 mL) were stirred for 7 hours. After cooling, the mixture was diluted with EtOAc and then washed with water. The organic phase was dried over anhydrous MgSO ₄ Dried, filtered and concentrated in vacuo to give crude N- (3-ethoxy-5-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) benzyl) -5-fluoro-2-methoxybenzamide A6e, which was used in the next step without further purification.

At nitrogenN- (4-bromo-3-ethoxy-5-fluorobenzyl) -5-fluoro-2-methoxybenzamide A6d (600 mg,1.5 mmol), (BPin) was reacted at 90℃in an atmosphere ₂ (572mg,2.25mmol)、Pd(dppf)Cl ₂ (55 mg,0.075 mmol) and KOAc (441 mg,4.5 mmol) in 1, 4-dioxane (15 mL) were stirred and reacted for 3 hours. After cooling, a solution (BPin) was added to the reaction mixture ₂ (572mg,2.25mmol),Pd(dppf)Cl ₂ (55 mg,0.075 mmol) and KOAc (441 mg,4.5 mmol). The reaction mixture was then reacted under nitrogen at 90℃for a further 3 hours. After cooling, the reaction mixture was filtered through celite and the organic solvent was concentrated in vacuo. The residue was then dissolved in EtOAc (75 mL), washed with water (75 ml×2). The mixed organic layer was washed with saturated brine (30 mL), and dried over anhydrous MgSO ₄ Drying, filtering and concentrating in vacuum. The residue was purified by column on silica gel (0-35% etoac in DCM/N-hexane (1:1)) to give N- (3-ethoxy-5-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) benzyl) -5-fluoro-2-methoxybenzamide A6e (235 mg, 35% yield).

LCMS:MS m/z(ESI):448.0[M+H] ⁺ 。

Step 5N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-ethoxy-5-fluorobenzyl) -5-fluoro-2-methoxybenzamide A6

In a similar procedure to step 4 of example A5, 5-iodo-7-isopropylimidazo [5,1-f][1,2,4]Triazin-4-amine Int-1 and N- (3-ethoxy-5-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) benzyl) -5-fluoro-2-methoxybenzamide A6e step 5 of example A6 is prepared. The crude mixture was purified by preparative HPLC using ACN/H ₂ O/TFA elution to give N- (4- (4-amino-7-isopropylimidazo [5, 1-f)][1,2,4]Triazin-5-yl) -3-ethoxy-5-fluorobenzyl) -5-fluoro-2-methoxybenzamide A6.

¹ H NMR(400MHz,MeOD):δ7.92(s,1H),7.63(m,1H),7.29(m,1H),7.21(m,1H),7.02(s,1H),6.94(d,1H),4.68(s,2H),4.12(q,2H),4.01(s,3H),3.73(m,1H),1.45(d,6H),1.27(t,3H)ppm；LCMS:MS m/z(ESI):497.0[M+H] ⁺ 。

Examples A7, A7a, A7b

N- (4- (4-amino-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-ethoxy-5-fluorobenzyl) -5-fluoro-2-methoxybenzamide A7

N- (4- (4-amino-7- ((R) -1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-ethoxy-5-fluorobenzyl) -5-fluoro-2-methoxybenzamide A7a

N- (4- (4-amino-7- ((S) -1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-ethoxy-5-fluorobenzyl) -5-fluoro-2-methoxybenzamide A7b

Step 1N- (4- (4-amino-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-ethoxy-5-fluorobenzyl) -5-fluoro-2-methoxybenzamide A7

N- (3-ethoxy-5-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxapenta-borane-2-yl) benzyl) -5-fluoro-2-methoxybenzamide A6e (25 mg,0.056 mmol), 5-iodo-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] is reacted under nitrogen at 85 ℃][1,2,4]Triazin-4-amine Int-2 (16 mg,0.045 mmol), pd (dppf) Cl ₂ (4 mg,0.0045 mmol) and Cs ₂ CO ₃ A mixture of (29 mg,0.090 mmol) in 1, 4-dioxane (0.25 mL) and water (0.04 mL) was stirred for 1 hour. After cooling, the mixture was concentrated in vacuo and the resulting residue was purified by prep HPLC with MeCN/H ₂ O/TFA elution to give N- (4- (4-amino-7- (1, 1-trifluoropropan-2-yl) imidazo [5, 1-f)][1,2,4]Triazin-5-yl) -3-ethoxy-5-fluorobenzyl) -5-fluoro-2-methoxybenzamide A7 (2.5 mg).

¹ H NMR(400MHz,MeOD)δ7.85(s,1H),7.51(m,1H),7.17(m,1H),7.09(m,1H),6.89(s,1H),6.81(d,1H),4.57(s,2H),4.45(m,1H),4.00(q,2H),3.90(s,3H),1.56(d,3H),1.13(t,3H)ppm；LCMS:MS m/z(ESI):551[M+H] ⁺ 。

Step 2N- (4- (4-amino-7- ((R) -1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-ethoxy-5-fluorobenzyl) -5-fluoro-2-methoxybenzamide A7a

Under nitrogen atmosphere, at 80 c,n- (3-ethoxy-5-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) benzyl) -5-fluoro-2-methoxybenzamide A6e (134 mg,0.3 mmol), int-2A (71 mg,0.2 mmol), XPhos-Pd-G ₂ (8 mg,0.01 mmol) and potassium phosphate (85 mg,0.4 mmol) 1, 4-dioxane (3.5 mL) and water (0.5 mL) were stirred and reacted for 1 hour. After cooling, the reaction mixture was concentrated and the residue was purified by column on silica gel (0-8% meoh in DCM/n-hexane (1:1)) to give the title compound A7a (54 mg, 49% yield).

¹ H NMR(400MHz,CDCl ₃ ):δ8.25(s,1H),7.89(dd,1H),7.85(d,1H),7.11(m,1H),6.90(dd,1H),6.76(d,1H),5.52(s,2H),4.62(m,2H),4.38(m,1H),3.98(m,2H),3.91(s,3H),1.64(d,3H),1.17(t,3H)ppm；LCMS:MS m/z(ESI):551[M+H] ⁺ 。

Step 3:N- (4- (4-amino-7- ((S) -1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-ethoxy-5-fluorobenzyl) -5-fluoro-2-methoxybenzamide A7b

N- (3-ethoxy-5-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) benzyl) -5-fluoro-2-methoxybenzamide A6e (134 mg,0.3 mmol), int-2B (71 mg,0.2 mmol), XPhos-Pd-G was reacted under nitrogen at 80 ℃under nitrogen atmosphere ₂ A mixed solution of (8 mg,0.01 mmol) and potassium phosphate (85 mg,0.4 mmol) in 1, 4-dioxane (3.5 mL) and water (0.5 mL) was stirred and reacted for 1 hour. After cooling, the reaction mixture was concentrated and the residue was purified by column on silica gel (0-8% meoh in DCM/n-hexane (1:1)) to give the title compound A7b (65 mg, 60% yield).

¹ H NMR(400MHz,CDCl ₃ ):δ8.32(s,1H),7.94(m,2H),7.20(m,1H),6.99(m,1H),6.83(m,2H),5.58(s,2H),4.70(m,2H),4.47(m,1H),4.07(m,2H),3.99(s,3H),1.72(d,3H),1.25(t,3H)ppm；LCMS:MS m/z(ESI):551[M+H] ⁺ 。

Example A8

N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -2-methoxybenzamide A8

Step 1N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -2-methoxybenzamide A8

To a solution of 5- (4- (aminomethyl) phenyl) -7-isopropylimidazo [5,1-f ] [1,2,4] triazin-4-amine Int-3 (5.6 mg,0.02 mmol) and TEA (6 mg,0.06 mmol) in DCM (1 mL) was added 2-methoxybenzoic acid A8a (3 mg,0.02 mmol), followed by EDCI (4 mg,0.02 mmol) and HOBt (2.7 mg,0.02 mmol). The reaction mixture was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo and the residue was purified by preparative HPLC eluting with ACN/water/TFA to give N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -2-methoxybenzamide A8 (5.6 mg, 67% yield).

¹ H NMR(400MHz,MeOD):δ7.95(t,1H),7.81(d,1H),7.56(d,2H),7.51(d,2H),7.40-7.52(m,1H),7.07(d,1H),6.97(t,1H),4.62(s,2H),3.89(s,3H),3.63-3.70(m,1H),1.37(d,6H)ppm；LCMS:MS m/z(ESI):417.0[M+H] ⁺ 。

Example A9

N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -2-fluoro-6-methoxybenzamide A9

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Step 1N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -2-fluoro-6-methoxybenzamide A9

In a similar procedure to step 1 of example A8, 5- (4- (aminomethyl) phenyl) -7-isopropylimidazo [5,1-f ][1,2,4]Preparation of triazin-4-amine Int-3 and 2-fluoro-6-methoxybenzoic acid A9a example A9 was prepared. The crude mixture was purified by preparative HPLC using ACN/H ₂ O/TFA elution to give N- (4- (4-amino-7-isopropylimidazo [5, 1-f)][1,2,4]Triazin-5-yl) benzyl) -2-fluoro-6-methoxybenzamide A9.

¹ H NMR(400MHz,MeOD):δ7.86(s,1H),7.54(q,J＝8.24Hz,2H),7.31(q,J＝6.8Hz,1H),6.85(d,J＝8.44Hz,2H),6.68(d,J＝8.6Hz,2H),7.56(s,2H),3.79(s,3H),3.66-3.59(m,1H),1.35(d,J＝7.0Hz,6H)ppm；LCMS:MS m/z(ESI):435.0[M+H] ⁺ 。

Example A10

N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -3-fluoro-2-methoxybenzamide A10

Step 1N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -3-fluoro-2-methoxybenzamide A10

In a similar procedure to step 1 of example A8, 5- (4- (aminomethyl) phenyl) -7-isopropylimidazo [5,1-f][1,2,4]Preparation of triazin-4-amine Int-3 and 3-fluoro-2-methoxybenzoic acid a10a example a10 was prepared. The crude mixture was purified by preparative HPLC using ACN/H ₂ O/TFA elution to give N- (4- (4-amino-7-isopropylimidazo [5, 1-f)][1,2,4]Triazin-5-yl) benzyl) -3-fluoro-2-methoxybenzamide a10.

¹ H NMR(400MHz,MeOD):δ7.89(s,1H),7.57(d,J＝8.08Hz,2H),7.51(d,J＝8.04Hz,2H),7.45(d,J＝7.8Hz,1H),7.25-7.20(m,1H),7.10-7.05(m,1H),4.60(s,2H),3.90(s,3H),3.68-3.61(m,1H),1.36(d,J＝7.0Hz,6H)ppm；LCMS:MS m/z(ESI):435.0[M+H] ⁺ 。

Example A11

N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -2- (trifluoromethoxy) benzamide A11

Step 1N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -2- (trifluoromethoxy) benzamide A11

In a similar procedure to step 1 of example A8, 5- (4- (aminomethyl) phenyl) -7-isopropylimidazo [5,1-f][1,2,4]Preparation of triazin-4-amine Int-3 and 2- (trifluoromethoxy) benzoic acid a11a example a11 is prepared. The crude mixture was purified by preparative HPLC using ACN/H ₂ O/TFA elution to give N- (4- (4-amino-7-isopropylimidazo [5, 1-f)][1,2,4]Triazin-5-yl) benzyl) -2- (trifluoromethoxy) benzamide a11.

¹ H NMR(400MHz,MeOD):δ7.91(s,1H),7.58-7.50(m,4H),7.38-7.31(m,4H),4.57(s,2H),3.69-3.62(m,1H),1.37(d,J＝7.0Hz,6H)ppm；LCMS:MS m/z(ESI):471.0[M+H] ⁺ 。

Example A12

N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -2- (difluoromethoxy) benzamide A12

Step 1N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -2- (difluoromethoxy) benzamide A12

In a similar procedure to step 1 of example A8, 5- (4- (aminomethyl) phenyl) -7-isopropylimidazo [5,1-f][1,2,4]Preparation of triazine-4-amine Int-3 and 2- (difluoromethoxy) benzoic acid a12a example a12 was prepared. The crude mixture was purified by preparative HPLC using ACN/H ₂ O/TFA elution to give N- (4- (4-amino-7-isopropylimidazo [5, 1-f)][1,2,4]Triazin-5-yl) benzyl) -2- (difluoromethoxy) benzamide a12.

¹ H NMR(400MHz,MeOD):δ7.89(s,1H),7.58-7.42(m,5H),7.24-7.17(m,4H),4.58(s,2H),3.68-3.61(m,1H),1.36(d,J＝7.0Hz,6H)ppm；LCMS:MS m/z(ESI):453.0[M+H] ⁺ 。

Example A13

N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) benzo [ d ] [1,3] dioxole-4-carboxamide A13

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Step 1N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) benzo [ d ] [1,3] dioxole-4-carboxamide A13

In a similar procedure to step 1 of example A8, 5- (4- (aminomethyl) phenyl) -7-isopropylimidazo [5,1-f][1,2,4]Triazin-4-amine Int-3 and benzo [ d ]][1,3]Preparation of dioxole-4-carboxylic acid A13a example A13 was prepared. The crude mixture was purified by preparative HPLC using ACN/H ₂ O/TFA elution to give N- (4- (4-amino-7-isopropylimidazo [5, 1-f)][1,2,4]Triazin-5-yl) benzyl) benzo [ d][1,3]Dioxole-4-carboxamide A13.

¹ H NMR(400MHz,MeOD):δ7.94(s,1H),7.55(d,J＝8.12Hz,2H),7.49(d,J＝8.12Hz,2H),7.28(d,J＝8.04Hz,1H),6.94-6.85(m,2H),6.02(s,2H),4.61(s,2H),3.68-3.61(m,1H),1.36(d,J＝7.0Hz,6H)ppm；LCMS:MS m/z(ESI):431.0[M+H] ⁺ 。

Example A14

N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -2, 2-difluorobenzo [ d ] [1,3] dioxole-4-carboxamide A14

Step 1N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -2, 2-difluorobenzo [ d ] [1,3] dioxole-4-carboxamide A14

In a similar procedure to step 1 of example A8, 5- (4- (aminomethyl) phenyl) -7-isopropylimidazo [5,1-f][1,2,4]Triazin-4-amine Int-3 and 2, 2-difluorobenzo [ d ]][1,3]Preparation of dioxole-4-carboxylic acid A14a example A14 was prepared. The crude mixture was purified by prep HPLC using a CN/H ₂ O/TFA elution to give N- (4- (4-amino-7-isopropylimidazo [5, 1-f)][1,2,4]Triazin-5-yl) benzyl) -2, 2-difluorobenzo [ d ]][1,3]Dioxole-4-carboxamide A14.

¹ H NMR(400MHz,MeOD):δ9.43(s,1H),9.1-8.99(m,3H),8.84(d,J＝7Hz,2H),8.81-8.68(m,2H),6.12(s,2H),5.20-5.15(m,1H),2.86(d,J＝8.48Hz,6H)ppm；LCMS:MS m/z(ESI):467.0[M+H] ⁺ 。

Example A15

N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) picolinamide A15

Step 1N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) picolinamide A15

In a similar procedure to step 1 of example A8, 5- (4- (aminomethyl) phenyl) -7-isopropylimidazo [5,1-f][1,2,4]Preparation of triazin-4-amine Int-3 and pyridine carboxylic acid a15a example a15 was prepared. The crude mixture was purified by preparative HPLC using ACN/H ₂ O/TFA elution to give N- (4- (4-amino-7-isopropylimidazo [5, 1-f)][1,2,4]Triazin-5-yl) benzyl) picolinamide a15.

¹ H NMR(400MHz,MeOD):δ8.56(brs,1H),8.02(d,J＝7.7Hz,2H),7.94(s,1H),7.88(t,1H),7.56(d,J＝8.24Hz,2H),7.50(d,J＝8.08Hz,2H),4.63(s,2H),3.69-3.2(m,1H),1.36(d,J＝7.0Hz,6H)ppm；LCMS:MS m/z(ESI):388.0[M+H] ⁺ 。

Example A16

N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -4-methoxy nicotinamide A16

Step 1N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -4-methoxy nicotinamide A16

In a similar procedure to step 1 of example A8, 5- (4- (aminomethyl) phenyl) -7-isopropylimidazo [5,1-f][1,2,4]Preparation of triazin-4-amine Int-3 and 4-methoxy nicotinic acid a16a example a16 was prepared. The crude mixture was purified by preparative HPLC using ACN/H ₂ O/TFA elution to give N- (4- (4-amino-7-isopropylimidazo [5, 1-f)][1,2,4]Triazin-5-yl) benzyl) -4-methoxy nicotinamide a16.

¹ H NMR(400MHz,MeOD):δ8.92(s,1H),8.68(d,J＝6.72Hz,1H),7.87(s,1H),7.63(d,J＝6.8Hz,1H),7.56(d,J＝8.08Hz,2H),7.49(d,J＝8.08Hz,2H),4.63(s,2H),4.17(s,3H),3.66-3.59(m,1H),1.35(d,J＝7.0Hz,6H)ppm；LCMS:MS m/z(ESI):418.0[M+H] ⁺ 。

Example A17

N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) chromane-8-carboxamide A17

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Step 1N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) chromane-8-carboxamide A17

In a similar procedure to step 1 of example A8, 5- (4- (aminomethyl) phenyl) -7-isopropylimidazo [5,1-f][1,2,4]Preparation of triazine-4-amine Int-3 and chromane-8-carboxylic acid a17a example a17 was prepared. The crude mixture was purified by preparative HPLC using ACN/H ₂ O/TFA elution to give N- (4- (4-amino-7-isopropylimidazo [5, 1-f)][1,2,4]Triazin-5-yl) benzyl) chromane-8-carboxamide a17.

¹ H NMR(400MHz,MeOD):δ7.92(brs,1H),7.62(d,J＝7.64Hz,1H),7.55(d,J＝7.96Hz,2H),7.49(d,J＝8.0Hz,2H),7.13(d,J＝7.28Hz,1H),6.82(t,J＝7.64Hz,1H),4.60(s,2H),4.27(t,J＝5.12Hz,2H),3.69-3.62(m,1H),2.77(t,J＝4.77Hz,2H),1.99-1.93(m,2H),1.36(d,J＝7.0Hz,6H)ppm；LCMS:MS m/z(ESI):443.0[M+H] ⁺ 。

Example A18

N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -2, 3-dihydrobenzofuran-7-carboxamide A18

Step 1N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -2, 3-dihydrobenzofuran-7-carboxamide A18

In a similar procedure to step 1 of example A8, 5- (4- (aminomethyl) phenyl) -7-isopropylimidazo [5,1-f][1,2,4]Triazin-4-amine Int-3 and 2, 3-dihydrobenzofuran-7-carboxylic acid A18a example A18 was prepared. The crude mixture was purified by preparative HPLC using ACN/H ₂ O/TFA elution to give N- (4- (4-amino-7-isopropylimidazo [5, 1-f)][1,2,4]Triazin-5-yl) benzyl) -2, 3-dihydrobenzofuran-7-carboxamide a18.

¹ H NMR(400MHz,MeOD):δ8.01(s,1H),7.76(d,J＝7.84Hz,1H),7.67(d,J＝8.04Hz,2H),7.59(d,J＝3.68Hz,2H),7.44(d,J＝7.12Hz,1H),6.99(t,J＝7.6Hz,1H),4.78(t,2H),4.74(s,2H),3.79-3.72(m,1H),3.42-3.38(m,2H),1.36(d,J＝7.0Hz,6H)ppm；LCMS:MS m/z(ESI):429.0[M+H] ⁺ 。

Example A19

N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -3-methoxythiophene-2-carboxamide A19

Step 1N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -3-methoxythiophene-2-carboxamide A19

In a similar procedure to step 1 of example A8, 5- (4- (aminomethyl) phenyl) -7-isopropylimidazo [5,1-f][1,2,4]Triazin-4-amine Int-3 and 3-methoxythiophene-2-carboxylic acidA19a preparation example A19. The crude mixture was purified by preparative HPLC using ACN/H ₂ O/TFA elution to give N- (4- (4-amino-7-isopropylimidazo [5, 1-f)][1,2,4]Triazin-5-yl) benzyl) -3-methoxythiophene-2-carboxamide a19.

¹ H NMR(400MHz,MeOD):δ7.99(d,J＝3.56Hz,1H),7.92(s,1H),7.56(d,J＝8.12Hz,2H),7.48(d,J＝8.08Hz,2H),6.59(d,J＝3.6Hz,1H),4.59(s,2H),3.89(s,3H),3.69-3.63(m,1H),1.37(d,J＝7.0Hz,6H)ppm；LCMS:MS m/z(ESI):423.0[M+H] ⁺ 。

Example A20

N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -2- (dimethylamino) benzamide A20

Step 1N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -2- (dimethylamino) benzamide A20

In a similar procedure to step 1 of example A8, 5- (4- (aminomethyl) phenyl) -7-isopropylimidazo [5,1-f ][1,2,4]Preparation of triazine-4-amine Int-3 and 2- (dimethylamino) benzoic acid a20a example a20 was prepared. The crude mixture was purified by preparative HPLC using ACN/H ₂ O/TFA elution to give N- (4- (4-amino-7-isopropylimidazo [5, 1-f)][1,2,4]Triazin-5-yl) benzyl) -2- (dimethylamino) benzamide a20.

¹ H NMR(400MHz,MeOD):δ7.98(d,J＝7.88Hz,1H),7.86-7.70(m,4H),7.57(d,J＝8.16Hz,2H),7.52(d,J＝8Hz,2H),4.66(s,2H),3.65-3.58(m,1H),3.26(s,6H),1.34(d,J＝6.96Hz,6H)ppm；LCMS:MS m/z(ESI):430.0[M+H] ⁺ 。

Example A21

N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -4-methoxythiophene-3-carboxamide A21

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Step 1N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -4-methoxythiophene-3-carboxamide A21

In a similar procedure to step 1 of example A8, 5- (4- (aminomethyl) phenyl) -7-isopropylimidazo [5,1-f][1,2,4]Preparation of triazin-4-amine Int-3 and 4-methoxythiophene-3-carboxylic acid a21a example a21 was prepared. The crude mixture was purified by preparative HPLC using ACN/H ₂ O/TFA elution to give N- (4- (4-amino-7-isopropylimidazo [5, 1-f)][1,2,4]Triazin-5-yl) benzyl) -4-methoxythiophene-3-carboxamide a21.

¹ H NMR(400MHz,MeOD):δ7.87(s,1H),7.55-7.52(m,3H),7.45(d,J＝7.68Hz,2H),6.98(d,J＝5.5Hz,1H),4.57(s,2H),3.96(s,3H),3.61-3.59(m,1H),1.35(d,J＝7.00Hz,6H)ppm；LCMS:MS m/z(ESI):423.0[M+H] ⁺ 。

Example A22

N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -2- (methylsulfonyl) benzamide A22

Step 1N- (4- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -2- (methylsulfonyl) benzamide A22

In a similar procedure to step 1 of example A8, 5- (4- (aminomethyl) phenyl) -7-isopropylimidazo [5,1-f][1,2,4]Preparation of triazine-4-amine Int-3 and 2- (methylsulfonyl) benzoic acid a22a example a22 was prepared. The crude mixture was purified by preparative HPLC using ACN/H ₂ O/TFA elution to give N- (4- (4-amino-7-isopropylimidazo [5, 1-f)][1,2,4]Triazin-5-yl) benzyl) -2- (methylsulfonyl) benzamide a22.

¹ H NMR(400MHz,MeOD):δ7.99(d,J＝7.72Hz,1H),7.87(s,1H),7.71-7.54(m,7H),4.57(s,2H),3.67-3.60(m,1H),3.23(s,3H),1.35(d,J＝7.00Hz,6H)ppm；LCMS:MS m/z(ESI):465.0[M+H] ⁺ 。

Example A23

N- ((5- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) bicyclo [4.2.0] oct-1, 3, 5-trien-2-yl) methyl) -5-fluoro-2-methoxybenzamide A23

Step 1 2, 5-bis (trimethylsilyl) bicyclo [4.2.0] oct-1 (6), 3-diene A23b

TMSCL (46.9 g, 433 mmol) was added slowly to a solution of lithium (3.97 g,576 mmol) in THF (300 mL) at 0deg.C followed by 1, 2-dihydrobenzocyclobutene A23a (15 g,144 mmol) dropwise. The resulting reaction mixture was stirred at room temperature for 6 days. The reaction mixture was then aspirated off unreacted lithium with a syringe and quenched with MeOH (100 mL) at 0 ℃. Water (250 mL) was added and the resulting solution was extracted with PE (3X 200 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na ₂ SO ₄ Drying, filtering and concentrating under vacuum to obtain crude 2, 5-bis (trimethylsilyl) bicyclo [4.2.0] ]Octyl-1 (6), 3-diene A23b (35 g, 97%) was used in the next step without further purification.

LCMS:MS m/z(ESI):249.0[M+H] ^- 。

Step 2, 5-bis (trimethylsilyl) bicyclo [4.2.0] oct-1, 3, 5-triene A23c

To crude 2, 5-bis (trimethylsilyl) bicyclo [4.2.0 at 40 ]]A solution of octyl-1 (6), 3-diene A23b (30.0 g,120 mmol) in THF (350 mL) was added dropwise to a solution of DDQ (13.62 g,60 mmol) in THF (150 mL). The resulting solution was stirred at 40℃for a further 1 hour. After cooling, the reaction mixture was quenched with water (500 mL) and then extracted with EtOAc (250 mL). Water (500 mL), saturated Na ₂ CO ₃ The organic layer was washed with brine (750 mL) and brine (350 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ Drying, filtering and concentrating under vacuum to obtain crude 2, 5-bis (trimethyl)Alkylsilyl) bicyclo [4.2.0]Oct-1, 3, 5-triene a23c (27.6 g, 93%) was used in the next step without further purification.

Step 3 2, 5-dibromobicyclo [4.2.0] oct-1, 3, 5-triene A23d

At 0 ℃, to Br ₂ To a solution of (4.66 mL,333 mmol) in MeOH (50 mL) was added crude 2, 5-bis (trimethylsilyl) bicyclo [4.2.0]A solution of oct-1, 3, 5-triene A23c (27.6 g,111 mmol) in MeOH (300 mL). The resulting reaction mixture was stirred at room temperature overnight, then quenched with water (300 mL) and further extracted with PE (3×200 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The residue was passed through a pad of flash silica gel (100% PE) to give crude 2, 5-dibromobicyclo [4.2.0]Oct-1, 3, 5-triene a23d (16.38 g, 57%) was used in the next step without further purification.

Step 4 5-bromobicyclo [4.2.0] oct-1, 3, 5-triene-2-carbaldehyde A23e

To crude 2, 5-dibromobicyclo [4.2.0] under nitrogen at-78 DEG C]To a solution of oct-1, 3, 5-triene A23d (19.38 g,74 mmol) in THF (200 mL) was added n-BuLi (2.5M, 29.6mL,74 mmol) dropwise. The mixture was stirred at-78℃for 1h, then DMF (5.4 g,74 mmol) was added. The resulting reaction mixture was stirred at-78 ℃ for 1 hour and then slowly warmed to room temperature, after which it was stirred for another 30 minutes. Saturated NH for reaction ₄ Cl (10 mL) was quenched and extracted with EtOAc (3X 100 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (EA/pe=1:100) to give 5-bromobicyclo [4.2.0]Octyl-1, 3, 5-triene-2-carbaldehyde A23e (12.4 g, 79%).

¹ H NMR(400MHz,CDCl ₃ ):δ3.12(s,2H),3.07(s,2H),7.10-7.00(m,1H),7.30-7.22(m,1H)ppm。

Step 5 methyl ((5-bromobicyclo [4.2.0] oct-1, 3, 5-trien-2-yl) methyl) carbamate A23f

To 5-bromobicyclo [4.2.0] under nitrogen atmosphere]A solution of octyl-1, 3, 5-triene-2-carbaldehyde A23e (12.4 g,58.75 mmol) in MeCN (130 mL) was added methyl carbonate (6.6 g,88.13 mmol) followed by TFA (13.54 g,117.5 mmol) l) and TESH (13.7 g,117.5 mmol). The mixture was slowly warmed to 80 ℃ and stirred for 16 hours. After cooling, the reaction was quenched with water (100 mL) and extracted with EtOAc (3X 100 mL). The organic layer was taken up in saturated Na ₂ CO ₃ Washing with an aqueous solution, passing through anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/ea=20:1) to give compound ((5-bromobicyclo [ 4.2.0)]Methyl octa-1, 3, 5-trien-2-yl) carbamate a23f (4.0 g, 25%).

LCMS:MS m/z(ESI):270.0[M+H] ⁺ 。

Step 6 (5-bromobicyclo [4.2.0] oct-1, 3, 5-trien-2-yl) methylamine A23g

((5-bromobicyclo [ 4.2.0)]To a solution of methyl octyl-1, 3, 5-trien-2-yl) carbamate A23f (4.0 g,14.86 mmol) in THF: meOH (1:1, 40 mL) was added an aqueous solution of LiOH (6.6 g,148.6mmol,10 eq.) (20 mL). The mixture was then heated to 80 ℃ and stirred for 16 hours. After cooling, the reaction was quenched with water (40 mL) and extracted with EtOAc (3X 60 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/ea=1:1) to give (5-bromobicyclo [4.2.0]Oct-1, 3, 5-trien-2-yl) methylamine A23g (1.1 g, 35%).

¹ H NMR(400MHz,CDCl ₃ ):δ7.24(d,J＝8.0Hz,2H),6.97(d,J＝8.0Hz,1H),3.75(s,2H),3.06-3.20(m,4H)ppm；LCMS:MS m/z(ESI):212[M+H] ⁺ 。

Step 7N- ((5-bromobicyclo [4.2.0] oct-1, 3, 5-trien-2-yl) methyl) -5-fluoro-2-methoxybenzamide A23h

Step 8 5-fluoro-2-methoxy-N- ((5- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) bicyclo [4.2.0] oct-1, 3, 5-trien-2-yl) methyl) benzamide A23i

Step 9N- ((5- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) bicyclo [4.2.0] oct-1, 3, 5-trien-2-yl) methyl) -5-fluoro-2-methoxybenzamide A23

In a similar manner to steps 1-3 of example A1, from (5-bromobicyclo [ 4.2.0)]Preparation example A23 starting from oct-1, 3, 5-trien-2-yl) methylamine A23gStep 7-9 of (a). The crude mixture was purified by preparative HPLC using ACN/H ₂ O/TFA elution to give N- ((5- (4-amino-7-isopropylimidazo [5, 1-f)][1,2,4]Triazin-5-yl) bicyclo [4.2.0]Oct-1, 3, 5-trien-2-yl) methyl) -5-fluoro-2-methoxybenzamide a23.

¹ H NMR(400MHz,MeOD):δ7.83(s,1H),7.55(dd,J＝9.24,3.2Hz,1H),7.30-7.07(m,4H),4.54(s,2H),3.89(s,3H),3.63-3.54(m,1H),3.15(s,4H),1.32(d,J＝7.04Hz,6H)ppm；LCMS:MS m/z(ESI):461.0[M+H] ⁺ 。

Example A24

N- ((5- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) thiophen-2-yl) methyl) -5-fluoro-2-methoxybenzamide A24

Steps 1-3 of example a24 were prepared in analogy to steps 1-3 of example A1, starting from (5-bromothiophen-2-yl) methylamine a24 a. The product was purified by preparative HPLC using ACN/H ₂ O/TFA elution to give N- ((5- (4-amino-7-isopropylimidazo [5, 1-f)][1,2,4]Triazin-5-yl) thiophen-2-yl) methyl) -5-fluoro-2-methoxybenzamide a24.

¹ H NMR(400MHz,MeOD):δ7.87(s,1H),7.54(dd,J＝9.24,3.20Hz,1H),7.18-7.05(m,4H),4.72(s,2H),3.87(s,3H),3.71-3.58(m,1H),1.36(d,J＝6.96Hz,6H)ppm；LCMS:MS m/z(ESI):441.0[M+H] ⁺ 。

Example A25

N- ((2- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) thiazol-5-yl) methyl) -5-fluoro-2-methoxybenzamide A25

Steps 1-3 of example a25 were prepared in analogy to steps 1-3 of example A1, starting from (2-bromothiazol-5-yl) methylamine 25 a. The product was purified by preparative HPLC using ACN/H ₂ O/TFA elution to give N- ((2- (4-amino-7-isopropylimidazo [5, 1-f)][1,2,4]Triazin-5-yl) thiazol-5-yl) methyl) -5-fluoro-2-methoxybenzamide a25.

¹ H NMR(400MHz,MeOD):δ8.64(brs,1H),7.73(d,J＝3.24Hz,1H)7.71(s,1H),7.14-7.09(m,1H),6.96-6.93(m,1H),4.75(d,J＝5.4Hz,2H),3.89(s,3H),3.58-3.43(m,1H),1.32(d,J＝7.00Hz,6H)ppm；LCMS:MS m/z(ESI):442.0[M+H] ⁺ 。

Example A26

N- ((3- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) bicyclo [1.1.1] pentan-1-yl) methyl) -5-fluoro-2-methoxybenzamide A26

Step 1 5-fluoro-N- ((3-iodobicyclo [1.1.1] pentan-1-yl) methyl) -2-methoxybenzamide A26c

Example a26c was prepared in analogy to step 5 of example A3 using (3-iodobicyclo [1.1.1] pentan-1-yl) methylamine a26a and 5-fluoro-2-methoxybenzoyl chloride a26 b.

Step 2N- ((3- (4-amino-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-5-yl) bicyclo [1.1.1] pentan-1-yl) methyl) -5-fluoro-2-methoxybenzamide A26

To 5-fluoro-N- ((3-iodobicyclo [ 1.1.1) under nitrogen at-78 DEG C]To a solution of pentane-1-yl) methyl) -2-methoxybenzamide A26c (20 mg,0.053 mmol) in THF (3 mL) was added ZnCl ₂ (0.5 mL of THF solution, 1mL,0.5 mmol) followed by tert-butyllithium (1.7M in pentane, 0.16mL,0.27 mmol). The resulting solution was slowly warmed to room temperature and stirred for 1 hour, then cooled again to-78 ℃. Additional tert-butyllithium (1.7M in pentane, 0.6mL,1.02 mmol) was added to the reaction mixture, and the mixture was slowly warmed to room temperature. Under nitrogen atmosphere, willThe resulting mixture was added to 5-iodo-7-isopropylimidazo [5,1-f][1,2,4]Triazin-4-amine Int-1 (40 mg,0.13 mmol), pd (PPh) ₃ ) ₄ (10 mg) and Pd (dppf) Cl ₂ (10 mg) in THF (3 mL). The resulting mixture was slowly warmed to 80 ℃ and stirred at that temperature overnight. After cooling, the residue was purified rapidly by silica gel column chromatography (DCM: meOH) and then further purified by preparative HPLC using ACN/H ₂ O/formic acid elution to give N- ((3- (4-amino-7-isopropylimidazo [5, 1-f)][1,2,4]Triazin-5-yl) bicyclo [1.1.1]Pentane-1-yl) methyl) -5-fluoro-2-methoxybenzamide A26 (0.7 mg, 3% yield).

¹ H NMR(400MHz,MeOD):δ8.45(s,3H),7.64(s,1H),7.51(dd,J＝11.92,8.72Hz,1H),7.17-7.05(m,2H),3.89(s,3H),2.17(s,6H),1.27(d,J＝7.00Hz,6H)ppm；LCMS:MS m/z(ESI):425.0[M+H] ⁺ 。

Example A27

N- (4- (4-amino-7- (tetrahydro-2H-pyran-4-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-ethoxybenzyl) -5-fluoro-2-methoxybenzamide A27

Step 1N- (4- (4-amino-7- (tetrahydro-2H-pyran-4-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-ethoxybenzyl) -5-fluoro-2-methoxybenzamide A27

Under nitrogen atmosphere, 5-iodo-7- (tetrahydro-2H-pyran-4-yl) imidazo [5,1-f is reacted at 85 DEG C][1,2,4]Triazin-4-amine Int-4 (45 mg,0.13 mmol), (2-ethoxy-4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) boronic acid A3g (56 mg,0.13 mmol), K ₂ CO ₃ (54 mg,0.39 mmol) and Pd (dppf) Cl ₂ (9.5 mg,0.013 mmol) in 1, 4-dioxane: water (4:1, 3 mL) was stirred for 16 h. After cooling, the resulting mixture was filtered through celite. Concentrating the filtrate, and using Na ₂ SO ₄ Redissolved and concentrated in vacuo. The residue was purified by prep. HPLC using MeCN/H ₂ O/TFA elution afforded the title compound N- (4- (4-amino-7- (tetrahydro-2H-pira)Pyran-4-yl) imidazo [5,1-f][1,2,4]Triazin-5-yl) -3-ethoxybenzyl) -5-fluoro-2-methoxybenzamide a27 (23 mg, 34% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.82(t,J＝6.0Hz,1H),8.13(brs,1H),7.84(s,1H),7.50(dd,J＝8.8Hz,3.2Hz,1H),7.40(d,J＝8.0Hz,1H),7.37-7.31(m,1H),7.19(dd,J＝9.2Hz,4.4Hz,1H),7.13(s,1H),7.05(d,J＝8.0Hz,1H),6.04(br,1H),4.56(d,J＝6.0Hz,2H),4.08(q,J＝6.8Hz,2H),3.97-3.93(m,2H),3.90(s,3H),3.54-3.43(m,3H),1.92-1.87(m,4H),1.21(t,J＝6.8Hz,3H)ppm；LCMS:MS m/z(ESI):521.2[M+H] ⁺ 。

Example A28

(S) -N- (4- (4-amino-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-methoxybenzyl) -5-fluoro-2-methoxybenzamide A28

Step 1 (4-bromo-3-methoxyphenyl) methylamine A28b

BH was added to 4-bromo-3-methoxybenzonitrile A28a (5 g,23.58 mmol) at 85℃under nitrogen ₃ THF (1N THF,235 mL) was stirred for 16 h. After cooling, the reaction was quenched with MeOH and TFA, and the mixture was concentrated in vacuo to give crude (4-bromo-3-methoxyphenyl) methylamine a28b (7.10 g, 100% yield), which was used in the next step without further purification.

LCMS:MS m/z(ESI):199.1[M-NH ₂ ] ⁺ . Step 2N- (4-bromo-3-methoxyphenyl) -5-fluoro-2-methoxybenzamide A28c

To a solution of (4-bromo-3-methoxyphenyl) methylamine A28b (7.10 g,23.58 mmol) and 5-fluoro-2-methoxybenzoic acid (4.01 g,23.58 mmol) in DMF (150 mL) was added HATU (13.45 g,35.37 mmol) and TEA (11.93 g,117.90 mmol). The reaction mixture was stirred at room temperature for 30min. Then, the reaction was quenched by addition of water (100 mL) and extracted with EtOAc (100 mL. Times.3). The organic phase was purified by Na ₂ S ₂ O ₃ (1M, 2X 50 mL) aqueous solution and saturated brine (3X 30 mL), anhydrous Na ₂ SO ₄ Drying and filteringConcentrating in vacuum. The residue was purified by silica gel column (PE: etoac=2:1) to give N- (4-bromo-3-methoxyphenyl) -5-fluoro-2-methoxybenzamide a28c (7.1 g, yield 81.78%).

LCMS:MS m/z(ESI):370.3[M+H] ⁺ 。

Step 3 5-fluoro-2-methoxy-N- (3-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) benzyl) benzamide A28d

N- (4-bromo-3-methoxyphenyl) -5-fluoro-2-methoxybenzamide A28c (4 g,10.86 mmol), (BPin) was reacted under argon at 90 ℃ ₂ (8.28g,32.59mmol)、Pd(PPh ₃ )Cl ₂ (760.46 mg,1.09 mmol) and KOAc (3.20 g,32.59 mmol) in 1, 4-dioxane (80 mL) were stirred overnight. Cooled, the reaction mixture was concentrated in vacuo and the residue was purified by silica gel column purification (PE: etoac=2:1) to give 5-fluoro-2-methoxy-N- (3-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) benzamide a28d (3.4 g, 75.37% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.17(br,1H),7.96(dd,1H),7.65(d,1H),7.17-7.11(m,1H),6.94-6.89(m,2H),6.85(s,1H),4.66(d,2H),3.88(s,3H),3.83(s,3H),1.35(s,12H)ppm；LCMS:MS m/z(ESI):416.5[M+H] ⁺ 。

Step 4 (S) -N- (4- (4-amino-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-methoxybenzyl) -5-fluoro-2-methoxybenzamide A28

5-fluoro-2-methoxy-N- (3-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxapentan-2-yl) benzyl) benzamide A28d (82 mg, 197.5. Mu. Mol), int-2B (70.51 mg, 197.47. Mu. Mol), pd (dppf) Cl was reacted under nitrogen at 100deg.C ₂ .CH ₂ Cl ₂ (16.44 mg, 19.75. Mu. Mol) and K ₂ CO ₃ A solution of (81.88 mg, 592.40. Mu. Mol) 1, 4-dioxane (4 mL) was stirred overnight for reaction. Cooled, the reaction mixture concentrated in vacuo and the residue purified by silica gel column (DCM: meoh=100:1) to give the title compound a28 (90 mg, 87.91% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.85(t,1H),8.27(br,1H),7.93(s,1H),7.51(dd,1H),7.38(d,1H),7.37-7.32(m,1H),7.20(dd,1H),7.16(s,1H),7.07(d,1H),6.10(br,1H),4.58(d,2H),4.53-4.44(m,1H),3.91(s,3H),3.79(s,3H),1.58(d,3H)ppm；LCMS:MS m/z(ESI):519.3[M+H] ⁺ 。

Example A29

(S) -N- (4- (4-amino-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-cyclopropyloxybenzyl) -5-fluoro-2-methoxybenzamide A29

Step 1 4-bromo-3- (2-chloroethoxy) benzoic acid ethyl ester A29a

Ethyl 4-bromo-3-hydroxybenzoate A3a (25 g,102.01 mmol), 2-chloroethyl 4-methylbenzenesulfonate (23.94 g,102.01 mmol) and Cs were added at 70 ℃ ₂ CO ₃ A solution of (64 g,204.02 mmol) in DMF (300 mL) was stirred for 3 hours. After cooling, the reaction mixture was diluted with water and then extracted with EtOAc (2L). The mixed organic phase was treated with anhydrous Na ₂ SO ₄ Drying, filtering and concentrating in vacuum. The residue was purified by silica gel column (PE: etoac=5:1) to give ethyl 4-bromo-3- (2-chloroethoxy) benzoate a29a (20 g, 63.74% yield).

¹ H NMR(400MHz,CDCl ₃ ):7.62(d,1H),7.55(dd,1H),7.54(s,1H),4.41-4.34(m,4H),3.89(t,2H),1.40(t,3H)ppm。

Step 2 4-bromo-3- (vinyloxy) benzoic acid A29b

Ethyl 4-bromo-3- (2-chloroethoxy) benzoate A29a (20 g,65.03 mmol) and KO at 75deg.C ^t A solution of Bu (35 g,325.13 mmol) in THF (300 mL) was stirred for 3 hours. After cooling, the reaction mixture was diluted with water and then extracted with EtOAc (1L). The mixed organic phase was treated with anhydrous Na ₂ SO ₄ Drying, filtration and concentration in vacuo gave crude 4-bromo-3- (vinyloxy) benzoic acid a29b (10 g, 63.27% yield), which was used in the next step without further purification.

LCMS:MS m/z(ESI):241.1[M-H] ^- 。

Step 3 4-bromo-3- (vinyloxy) benzoic acid methyl ester A29c

4-bromo-3- (vinyloxy) benzoic acid A29b (10 g,41.14 mmol), methyl iodide (11.68 g,82.29 mmol) and K at room temperature ₂ CO ₃ A solution of (17 g,123.43 mmol) of DMF (100 mL) was stirred for 15h. The reaction mixture was diluted with water and extracted with EtOAc (500 mL). The mixed organic phase adopts anhydrous Na ₂ SO ₄ Drying, filtering and concentrating in vacuum. The residue was purified by silica gel column (PE: etoac=10:1) to give methyl 4-bromo-3- (vinyloxy) benzoate a29c (8 g, yield 75.64%).

¹ H NMR(400MHz,CDCl ₃ ):7.68-7.64(m,3H),6.64(dd,1H),4.85(dd,1H),4.60(dd,1H),3.92(s,3H)ppm。

Step 4 methyl 4-bromo-3- (cyclopropyloxy) benzoate A29d

A solution of methyl 4-bromo-3- (vinyloxy) benzoate A29C (8 g,31.12 mmol) and chloromethane (19.76 g,112.03 mmol) in DCE (100 mL) was stirred under nitrogen at 0deg.C for 20min, then Zn (C) was added dropwise ₂ H ₅ ) ₂ N-hexane solution (0.5M, 187mL,93.36 mmol). The reaction mixture was stirred at 0 ℃ for 3 hours and then slowly warmed to room temperature. The reaction mixture was diluted with water and then extracted with EtOAc (500 mL). The mixed organic phase adopts anhydrous Na ₂ SO ₄ Drying, filtering and concentrating in vacuum. The residue was purified by silica gel column (PE: etoac=3:1) to give methyl 4-bromo-3- (cyclopropyloxy) benzoate a29d (5 g, yield 59.27%).

¹ H NMR(400MHz,CDCl ₃ ):7.89(d,1H),7.59(d,1H),7.52(dd,1H),3.92(s,3H),3.91-3.85(m,1H),0.90-0.87(m,4H)ppm。

Step 5 4-bromo-3-cyclopropyloxy benzamide A29e

Methyl 4-bromo-3- (cyclopropyloxy) benzoate A29d (1.3 g,4.80 mmol) and NH were combined in a sealed tube at 80 ℃ ₄ OH (33% aqueous, 20 mL) was stirred overnight. After cooling, the reaction mixture was concentrated in vacuo. The residue was purified by column on silica gel (DCM: meoh=15:1) to give 4-bromo-3-cyclopropyloxy benzamide a29e (1.01 g, 82.25% yield).

LCMS:MS m/z(ESI):256.0[M+H] ⁺ 。

Step 6 (4-bromo-3-cyclopropyloxyphenyl) methylamine A29f

BH of 4-bromo-3-cyclopropyloxy benzamide A29e (1.51 g,5.90 mmol) was added at 60 ℃ ₃ A solution of THF (1N THF,25 mL) was stirred overnight. After cooling, the reaction was quenched with MeOH (10 mL) and TFA (30 mL). The reaction mixture was concentrated in vacuo to give crude (4-bromo-3-cyclopropyloxyphenyl) methylamine A29f (2.0 g, 100.00% yield), which was used in the next step without further purification.

LCMS:MS m/z(ESI):225.1[M-H ₂ O] ⁺ 。

Step 7N- (4-bromo-3-cyclopropyloxybenzyl) -5-fluoro-2-methoxybenzamide A29g

To a solution of (4-bromo-3-cyclopropyloxyphenyl) methylamine A29f (1.43 g,5.91 mmol) and 5-fluoro-2-methoxybenzoic acid (1.00 g,5.91 mmol) in DMF (40 mL) was added HATU (3.37 g,8.86 mmol) and TEA (2.99 g,29.53 mmol). The reaction mixture was stirred at room temperature for 30min, and then quenched with water. The reaction mixture was then extracted with EtOAc (250 mL). The mixed organic phase was treated with anhydrous Na ₂ SO ₄ Drying, filtering and concentrating in vacuum. The residue was purified by silica gel column (PE: etoac=3:1) to give N- (4-bromo-3-cyclopropyloxybenzyl) -5-fluoro-2-methoxybenzamide a29g (1.84 g, 79.02% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.83(t,1H),7.51(d,1H),7.48(dd,1H),7.37-7.31(m,2H),7.18(dd,1H),6.88(dd,1H),4.48(d,2H),3.91-3.87(m,1H),3.88(s,3H),0.82-0.78(m,2H),0.72-0.67(m,2H)ppm；LCMS:MS m/z(ESI):395.9[M+H] ⁺ 。

Step 8N- (3-Cyclopropyloxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl) -5-fluoro-2-methoxybenzamide A29h

N- (4-bromo-3-cyclopropyloxybenzyl) -5-fluoro-2-methoxybenzamide A29g (1 g,2.54 mmol), (BPin) was reacted under nitrogen at 90 ℃ ₂ (1.93g,7.61mmol)、Pd(PPh ₃ )Cl ₂ (177.56 mg, 253.66. Mu. Mol) and KOAc (746.82 mg,7.61 mmol) in 1, 4-dioxane (20 mL) were stirred overnight. After cooling, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel column (PE: ea=2:1) to give N- (3-cyclopropyloxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl) -5-fluoro-2-methoxybenzamide a29h (850 mg, yield 75.93%).

LCMS:MS m/z(ESI):442.1[M+H] ⁺ 。

Step 9 (S) -N- (4- (4-amino-7- (1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-cyclopropyloxybenzyl) -5-fluoro-2-methoxybenzamide A29

N- (3-Cyclopropoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl) -5-fluoro-2-methoxybenzamide A29h (74.00 mg, 167.69. Mu. Mol), int-2B (59.88 mg, 167.69. Mu. Mol), pd (dppf) Cl was reacted under nitrogen at 100deg.C ₂ .CH ₂ Cl ₂ (13.96 mg, 16.77. Mu. Mol) and K ₂ CO ₃ A mixture of (69.53 mg, 503.06. Mu. Mol) 1, 4-dioxane (4 mL) and water (1 mL) was stirred overnight for reaction. After cooling, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel column (DCM: meoh=100:1) to give the title compound a29 (50 mg, yield 54.76%).

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.86(t,1H),8.30(br,1H),7.92(s,1H),7.52(dd,1H),7.44(s,1H),7.40(d,1H),7.38-7.32(m,1H),7.21(dd,1H),7.09(d,1H),6.01(br,1H),4.59(d,2H),4.52-4.43(m,1H),3.91(s,3H),3.86-3.82(m,1H),1.57(d,3H),0.75-0.72(m,2H),0.68-0.65(m,2H)；LCMS:MS m/z(ESI):545.2[M+H] ⁺ 。

Example A30

N- (4- (4-amino-7- (tetrahydro-2H-pyran-4-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-methoxybenzyl) -5-fluoro-2-methoxybenzamide A30

Step 1N- (4- (4-amino-7- (tetrahydro-2H-pyran-4-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-methoxybenzyl) -5-fluoro-2-methoxybenzamide A30

Under nitrogen atmosphere5-fluoro-2-methoxy-N- (3-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl) benzamide A28d (60 mg,0.17 mmol), 5-iodo-7- (tetrahydrofuran-2H-pyran-4-yl) imidazo [5,1-f, at 85 ℃][1,2,4]Triazin-4-amine Int-4 (65 mg,0.17 mmol), pd (dppf) Cl ₂ (12 mg,0.017 mmol) and K ₂ CO ₃ (70 mg,0.51 mmol) in a mixture of 1, 4-dioxane/water (4/1, 3 mL) was stirred overnight. After cooling, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (DCM: meoh=50:1) to give N- (4- (4-amino-7- (tetrahydro-2H-pyran-4-yl) imidazo [5,1-f][1,2,4]Triazin-5-yl) -3-methoxybenzyl) -5-fluoro-2-methoxybenzamide a30 (30 mg, 34% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.84(t,1H),8.10(br,0.6H),7.85(s,1H),7.51(dd,1H),7.39-7.32(m,2H),7.22-7.18(m,1H),7.14(s,1H),7.06(d,1H),5.92(br,1H),4.58(d,2H),3.97-3.92(m,2H),3.91(s,3H),3.78(s,3H),3.54-3.47(m,3H),1.89-1.87(m,4H)ppm；LCMS:MS m/z(ESI):507.2[M+H] ⁺ 。

Example A31

N- (4- (4-amino-7- (tetrahydro-2H-pyran-4-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -5-fluoro-2-methoxybenzamide A31

Step 1N- (4- (4-amino-7- (tetrahydro-2H-pyran-4-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -5-fluoro-2-methoxybenzamide A31

Under nitrogen atmosphere, 5-iodo-7- (tetrahydrofuran-2H-pyran-4-yl) imidazo [5,1-f is treated at 85deg.C ][1,2,4]Triazin-4-amine Int-4 (70 mg,0.18 mmol), 5-fluoro-2-methoxy-N- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) benzyl) benzamide A1c (65 mg,0.18 mmol), pd (dppf) Cl ₂ (13 mg,0.018 mmol) and K ₂ CO ₃ (74 mg,0.54 mmol) in a mixture of 1, 4-dioxane/water (4/1, 3 mL) was stirred overnight. After cooling, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (DCM: meoh=)50:1) to give N- (4- (4-amino-7- (tetrahydro-2H-pyran-4-yl) imidazo [5, 1-f)][1,2,4]Triazin-5-yl) benzyl) -5-fluoro-2-methoxybenzamide a31 (35 mg, 39% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.88(t,1H),8.20(br,1H),7.94(s,1H),7.61(d,2H),7.53(dd,1H),7.48(d,1H),7.38-7.32(m,1H),7.19(dd,1H),6.18(br,1H),4.57(d,2H),3.98-3.93(m,2H),3.91(s,3H),3.55-3.47(m,3H),1.94-1.87(m,4H)ppm；LCMS:MS m/z(ESI):477.1[M+H] ⁺ 。

Example A32

N- (4- (4-amino-7- (tetrahydro-2H-pyran-4-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-cyclopropyloxybenzyl) -5-fluoro-2-methoxybenzamide A32

Step 1N- (4- (4-amino-7- (tetrahydro-2H-pyran-4-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-cyclopropyloxybenzyl) -5-fluoro-2-methoxybenzamide A32

Pd (dppf) Cl under nitrogen at 85deg.C ₂ .CH ₂ Cl ₂ (14.53 mg, 17.45. Mu. Mol), N- (3-cyclopropyloxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl) -5-fluoro-2-methoxybenzamide A29H (77 mg,174.48 mmol), 5-iodo-7- (tetrahydrofuran-2H-pyran-4-yl) imidazo [5,1-f ][1,2,4]Triazin-4-amine Int-4 (60.22 mg,174.48 mmol) and K ₂ CO ₃ (72.35 mg,523.45 mmol) in a mixture of 1, 4-dioxane (4 mL) and water (1 mL) was stirred overnight. After cooling, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (DCM: meoh=50:1) to give N- (4- (4-amino-7- (tetrahydro-2H-pyran-4-yl) imidazo [5,1-f][1,2,4]Triazin-5-yl) -3-cyclopropyloxybenzyl) -5-fluoro-2-methoxybenzamide a32 (40 mg, 43.05% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.84(t,1H),8.10(br,1H),7.84(s,1H),7.52(dd,1H),7.43(s,1H),7.39(d,1H),7.38-7.32(m,1H),7.21(dd,1H),7.07(d,1H),5.88(br,1H),4.59(d,2H),3.97-3.93(m,2H),3.90(s,3H),3.86-3.81(m,1H),3.54-3.43(m,3H),1.92-1.86(m,4H),0.75-0.65(m,2H),0.65-0.55(m,2H)ppm；LCMS:MS m/z(ESI):533.2[M+H] ⁺ 。

Example A33

N- (4- (4-amino-7- (tetrahydrofuran-3-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -5-fluoro-2-methoxybenzamide A33

Step 1N- (4- (4-amino-7- (tetrahydrofuran-3-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -5-fluoro-2-methoxybenzamide A33

Under nitrogen atmosphere, 5-iodo-7- (tetrahydrofuran-3-yl) imidazo [5,1-f is treated at 100deg.C][1,2,4]Triazin-4-amine Int-5 (20 mg,0.06 mmol), pd (dppf) Cl ₂ .CH ₂ Cl ₂ (5 mg, 0.006mmol), 5-fluoro-2-methoxy-N- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) benzyl) benzamide A1c (23 mg,0.06 mmol) and K ₂ CO ₃ (25 mg,0.18 mmol) was reacted in a mixture of 1, 4-dioxane (2 mL) and water (0.5 mL) under stirring overnight. Cooled and the reaction solution concentrated in vacuo. The residue was purified by silica gel chromatography (DCM: meoh=50:1) to give N- (4- (4-amino-7- (tetrahydrofuran-3-yl) imidazo [5, 1-f) ][1,2,4]Triazin-5-yl) benzyl) -5-fluoro-2-methoxybenzamide a33 (2 mg, yield 7.14%).

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.85(t,1H),8.25(br,0.6H),7.94(s,1H),7.60(d,2H),7.52(dd,1H),7.47(d,2H),7.37-7.31(m,1H),7.19(dd,1H),6.30(br,0.6H),4.57(d,2H),4.12(t,1H),3.97-3.81(m,4H),3.90(s,3H),2.37-2.31(m,2H)ppm；LCMS:MS m/z(ESI):463.2[M+H] ⁺ 。

Example A34

N- (4- (4-amino-7- (tetrahydro-2H-pyran-4-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-ethoxy-5-fluorobenzyl) -5-fluoro-2-methoxybenzamide A34

Step 1N- (4- (4-amino-7- (tetrahydro-2H-pyran-4-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-ethoxy-5-fluorobenzyl) -5-fluoro-2-methoxybenzamide A34

Under nitrogen atmosphere at 80deg.C 5-iodo-7- (tetrahydrofuran-2H-pyran-4-yl) imidazo [5,1-f][1,2,4]Triazin-4-amine Int-4 (26 mg,0.075 mmol), N- (3-ethoxy-5-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) benzyl) -5-fluoro-2-methoxybenzamide A6e (50 mg,0.113 mmol), XPhos-Pd-G ₂ (4.5 mg,0.0056 mmol) and potassium phosphate (40 mg,0.188 mmol) were reacted in a mixture of 1, 4-dioxane (1.25 mL) and water (0.25 mL) for 1.5 hours. After cooling, the reaction mixture was concentrated and the residue was purified by silica gel chromatography (DCM/N-hexane (1:1) with 0-8% meoh) to give N- (4- (4-amino-7- (tetrahydro-2H-pyran-4-yl) imidazo [5, 1-f)][1,2,4]Triazin-5-yl) -3-ethoxy-5-fluorobenzyl) -5-fluoro-2-methoxybenzamide a34 (28 mg, 70% yield).

¹ H NMR(400MHz,CDCl ₃ ):δ8.24(s,1H),7.89(m,1H),7.80(s,1H),7.11(m,1H),6.90(m,1H),6.76(m,2H),5.42(s,2H),4.62(m,2H),4.00(m,4H),3.90(s,3H),3.53(m,3H),2.10(m,2H),1.95(m,2H),1.19(t,3H)ppm；LCMS:MS m/z(ESI):539[M+H] ⁺ 。

Biological testing

The present disclosure will be further described with reference to the following test examples, which should not be construed as limiting the scope of the present disclosure.

Test example 1, test of the Activity of the compounds of the present disclosure against BTK-WT and BTK-C481S kinases

These tests were performed to determine the extent of inhibition of BTK-WT and BTK-C481S mutant kinase activity by measuring the amount of ADP produced during the enzymatic reaction. Full length human BTK-WT (ABCAM, 205800) and BTK-C481S (ABCAM, 204166) kinase proteins were expressed and purified from Baculovirus (Baculovirus) -infected Sf9 cells. The Km values of ATP and substrate poly (4:1 glutamate, tyrosine) (Signal Chem, P61-58) in the test were determined to be 30. Mu.M and 2 ng/. Mu.L, respectively. Compounds, BTK enzyme, ATP and substrate were all measured at 1x kinasePreparation in a defined buffer by H ₂ O was diluted with 5 Xkinase assay buffer III (Signal Chem, K03-09) stock and DTT (Thermo Scientific, A39255) was added to a final concentration of 50. Mu.M. The total volume of 5 μl of compound and BTK kinase protein was dispensed into solid white flat bottom 384 well plates (Corning, 3824) and spun at 1000rpm for 2 minutes. The plate was then kept at room temperature with shaking for 30min to allow the compound to bind to the protein. After pre-incubation, a total of 5 μl of ATP and substrate was added to each well. The plate was then rotated at 1000rpm for 2 minutes and shaken at room temperature for 90 minutes. ADP detection was performed according to the direction of the ADP-Glo kinase detection kit (Promega, V9101). Briefly, 10. Mu.L of ADP-Glo reagent was added to each well. The plate was then rotated at 1000rpm for 2 minutes and shaken at room temperature for 60 minutes. mu.L of kinase assay solution was added to each well. The plates were incubated for 30 minutes in the dark at room temperature. Immediately after 30 minutes incubation, the luminescence signal of the plate was read in Tecan M1000. By calculating luminescence signal changes, the relative inhibition of BTK kinase activity was analyzed:

Data were input into GraphPad Prism and IC was calculated using the function "log (inhibitor) versus response-variable slope (four parameters)" ₅₀ Values.

TABLE 1 inhibition of BTK kinase by the compounds of the present disclosure

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Test example 2, compounds of the present disclosure carry stably expressed BTK-WT and BTK-C481S in HEK293 cells BTK-Y223 autophosphorylation

HEK293 cells stably expressing wild-type BTK or mutant C481S BTK (purchased from ATCC, CRL 1573) were generated by lentiviral transduction of constructs (constructs) containing human BTK-WT or BTK-C481S mutants (Genecopoeia, lv201 vector). Cells expressing BTK protein were selected by puromycin treatment (1 μm). Protein expression was confirmed by western blotting of BTK and BTK-Y223 autophosphorylation. Cells were cultured in MEM medium (Sigma, M2279), 10% heat-inactivated FBS (Gibco, 10100), penicillin streptomycin (Thermal Fisher, 15140122) and puromycin (InvivoGen, QLL-41-03). BTK-Y223 phosphorylation was quantified using the BTK phospho-Y223 kit (Cisbio, 63ADK017 PEG). HEK 293/BTK-stable cells were seeded at a density of 1 ten thousand cells/well in 96-well plates in a total volume of 100. Mu.L of medium. Cells were incubated at 5% CO ₂ The cells were incubated overnight at 37℃in a cell incubator. The next day, at 37℃in wet 5% CO ₂ In the cell incubator, the cells were treated with the diluted compound for 2 hours. The medium was removed from each well and 50 μl of 1X lysis buffer from the assay kit was added to each well. Cells were incubated for 30 min at room temperature with shaking. mu.L of lysate was then transferred to PROXIPLATE 384 well plates (Perkinelmer, 6008230) and 4. Mu.L HTRF pre-mix antibody was added. After overnight incubation at room temperature, the fluorescent signal in the plate was read on a PHERAstar FSX instrument using HTRF settings (665 nM/620 nM).

Relative cellular pBTK inhibition was calculated by HTRF signal changes:

the average of the positive control well readings and the average of the negative control well readings were used as controls to calculate the percent inhibition.

Data were input into GraphPad Prism using the function "log (inhibitor) versus response-variable slope (four parameters)" to arrive at IC ₅₀ Values.

TABLE 2 autophosphorylation of BTK-Y223 in cells of the compounds of the present disclosure

Test example 3 BTK dependent cell proliferation in human TMD-8 diffuse large B cell lymphoma cells with compounds of the present disclosure Effect of the germ

Human TMD-8DLBCL cancer cells were cultured in RPMI medium with high glucose and glutamine (Genese, 25-506), 20% heat inactivated FBS (Gibco, 10100), penicillin streptomycin (Thermal Fisher, 15140122), and 1mM sodium pyruvate (Thermal Fisher, 11360070). TMD-8 cells were centrifuged at 300g for 5 min and the cells were resuspended in fresh cell culture medium. Cells were counted and made into 130 ten thousand/mL cell stock. Then 75 μl of cells were inoculated into each well of a white 96-well cell culture plate (Corning # 353286). A series of dilutions of the compound were prepared and 25 μl was added to each well. The plates were exposed to moisture at 37℃in 5% CO ₂ Incubate in atmosphere for 3 days. Inhibition of Cell growth by compounds was determined by measuring the level of ATP produced by the cells using the Cell Titer-Glo luminescent Cell viability kit (Promega, G7572). The assay procedure was performed according to the protocol provided by Promega. Briefly, the treated cell culture plates and their contents were equilibrated at room temperature for about 30 minutes. Will be 100 mu LReagents were added to each cell culture well and their contents were mixed on an orbital shaker for 2 minutes to induce cell lysis. Plates were incubated for 10 min at room temperature to stabilize the luminescence signal. The resulting luminescence signal is read immediately using a TECAN board reader. Relative Cell growth inhibition was calculated by Cell Titer-Glo luminescence signal change.

Only the average readings of the medium wells and the readings of the positive control wells (no compound treatment) were used to calculate the percentage response.

Data were entered into GraphPad Prism and curve fit was performed using the function "log (inhibitor) versus response-variable slope (four parameters)". Computing absolute IC using interpolation function ₅₀ Values.

TABLE 3 Effect of Compounds on BTK-dependent cell proliferation in human TMD-8 cells

Examples numbering	IC ₅₀ (nM)
		A1	27
A2	99
		Compounds corresponding to shorter retention times in A2a and A2b	73
Compounds corresponding to longer retention times in A2a and A2b	20
		A3	38
A4	17
		Compounds corresponding to shorter retention times in A4a and A4b	23
Corresponding to longer retention times in A4a and A4bCompounds of formula (I)	33
		A5	62
A6	70
		A7	30
A7a	27
		A7b	29
A8	86
		A18	220
A19	70
		A27	18
A28	110
		A29	230
A30	84
		A31	89
A32	150
		A33	88
A34	17

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

2. a compound or salt thereof selected from:

3. a pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

4. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 3 in the manufacture of a medicament for the treatment of a disease or condition modulated by BTK.

5. The use according to claim 4, wherein the disease or disorder modulated by BTK is selected from cancer, immune diseases and inflammation.

6. The use of claim 4, wherein the disease or disorder modulated by BTK is selected from B-cell lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, non-hodgkin's lymphoma, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia, waldenstrom's macroglobulinemia, multiple myeloma, arthritis, multiple sclerosis, inflammatory bowel disease, crohn's disease, sjogren's syndrome, and lupus.

7. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 3, in the manufacture of a medicament for the treatment of a disease or disorder selected from: b cell lymphoma, diffuse large B cell lymphoma, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia, waldensted giant globulinemia, multiple myeloma, chronic lymphocytic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, lymph node marginal zone B cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary exudative lymphoma, burkitt's lymphoma/leukemia, inflammatory bowel disease, arthritis, lupus, myasthenia gravis, hashimoto thyroiditis, orde thyroiditis, graves 'disease, sjogren's syndrome, multiple sclerosis green-barre syndrome, acute disseminated encephalomyelitis, ankylosing spondylitis, idiopathic thrombocytopenic purpura, scleroderma, warm autoimmune hemolytic anemia, psoriasis, asthma, appendicitis, bronchitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dermatitis, encephalitis, endocarditis, endometritis, enterocolitis, epididymitis, fasciitis, gastritis, gastroenteritis, hepatitis, laryngitis, mastitis, meningitis, myelitis, myositis, nephritis, oophoritis, orchitis, pancreatitis, parotitis, pharyngitis, pleurisy, pneumonia, proctitis, prostatitis, rhinitis, salpingitis, tonsillitis, vaginitis, vulvitis, fatty liver disease, liver cirrhosis, chronic progressive nephropathy, radiation nephropathy and glomerulosclerosis.

8. The use of claim 7, wherein the pneumonia is general interstitial pneumonia or regional pneumonia; the cystitis is interstitial cystitis; the scleroderma is kidney scleroderma; the hepatitis is autoimmune hepatitis or nonalcoholic steatohepatitis; the liver cirrhosis disease is primary biliary cirrhosis; the fatty liver disease is non-alcoholic fatty liver disease; the nephritis is selected from pyelonephritis, glomerulonephritis, chronic interstitial nephritis and progressive glomerulonephritis; the rhinitis is allergic rhinitis; the dermatitis is atopic dermatitis; the nephritis is bronchiolitis obliterans; the myositis is dermatomyositis or myocarditis; the glomerulosclerosis is focal segmental glomerulosclerosis.

9. The use according to claim 6 or 7, wherein the non-hodgkin's lymphoma is B-cell non-hodgkin's lymphoma; wherein the arthritis is selected from the group consisting of rheumatoid arthritis, psoriatic arthritis, osteoarthritis and juvenile arthritis.