CN114634512A

CN114634512A - Compound as Bruton's tyrosine kinase inhibitor, preparation method and medical application thereof

Info

Publication number: CN114634512A
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: 2022-06-17
Anticipated expiration: 2041-12-15
Also published as: CN114634512B

Abstract

The present disclosure relates to compounds that are inhibitors of bruton's tyrosine kinaseA process for their preparation and their use in medicine. In particular, the present disclosure relates to compounds of formula (I) as Bruton's Tyrosine Kinase (BTK) inhibitors, pharmaceutical compositions containing these compounds, methods 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 disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders, and neurological disorders.

Description

Compound as Bruton's tyrosine kinase inhibitor, 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 BTKs, for treating diseases or disorders associated with BTK, 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 an enzymatically active kinase domain (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 (PIP3) produced by phosphatidylinositol-3 kinase (PI 3K). Transmembrane proteins (e.g.B cell receptor (BCR) complexes) promote phosphorylation of BTK at Y551 by either 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-. BTK was initially shown to be mutated in human primary immunodeficiency X-linked agammaglobulinemia (XLA). XLA patients are characterized by a low number of B cells and by their circulation by few antibodies (Vetrie D, et al, Nature.1993,361: 226-. BTK can also be expressed in certain types of myeloid cells, such as macrophages, neutrophils, and mast cells. In these innate immune cells, BTK is shown in toll-like receptor (TLR), Fc receptor (FCR) and chemokine receptor mediated signaling (Crofford et al, Expert Rev Clin Immunol,2016,12: 763-. Activation of BTK stimulates several downstream signaling pathways, such as the NF κ B and MAP (mitogen-activated protein) kinase pathways. Aberrant expression and/or activation of BTK has been found in a variety of B cell malignancies, which are critical for cancer cell survival and autoimmune disease.

BTK inhibitors have been developed with the aim 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 in B cell malignancies. However, these inhibitors target the cysteine residue C481 in the BTK kinase domain to covalently bind to the side chain thiol. Drug resistance has emerged with clinical treatment of covalent BTK inhibitors in cancer patients. Mutations within the BTK protein have been reported in recurrent cancers, such as C481S, C481Y, C481R and C481F, and have been shown to result in the loss of the covalent binding site for drugs (Liu L et al, Future Med Chem,2018,10: 343-356).

Recurrence of cancers such as CLL or Mantle Cell Lymphoma (MCL) following treatment with a covalent BTK inhibitor is an increasingly clinically significant problem (Wayach JA et al, J Clin Oncol,2017,35: 1437-. It is therefore an object of the present disclosure to provide BTK inhibitors that are non-covalently bound, more specifically, as reversible inhibitors. These reversible inhibitors are expected to be comparable to the clinically available BTK inhibitors, but are also effective against BTK mutants.

Disclosure of Invention

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

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

or a pharmaceutically acceptable salt thereof,

wherein:

R¹selected from hydrogen, alkyl, -OR⁵、-NR^6aR^6bCyano and-C (O) NR^6aR^6b；

R²Selected from hydrogen, alkyl halideA group, 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 substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, -NR^7aR^7b、-OR⁸、-OC(O)R⁹、-C(O)R⁹、-C(O)OR⁸、-NR^dC(O)R⁹、-C(O)NR^7aR^7b、-NR^dS(O)_tR⁹、-S(O)_tR⁹、-S(O)_tOR⁸、-S(O)_tNR^7aR^7bOne or more, sometimes preferably one to five, sometimes more preferably one to three, of cyano, oxo, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

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

each occurrence of R³Are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, cyano, -NR^10aR^10b、-OR¹¹Oxo, -C (O) R¹²、-C(O)OR¹¹、-C(O)NR^10aR^10b、-S(O)_tR¹²、-S(O)_tOR¹¹Cycloalkyl, heterocyclyl, aryl and heteroaryl;

or two adjacent R³Substituents together with ring a may be optionally linked to form cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by 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;

L₁is-CR^aR^b-；

L₂is-NR^c-；

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

each occurrence of R⁴Are the same or different and eachIndependently selected from hydrogen, halogen, alkyl, cyano, -NR^10aR^10b、-OR¹¹、-S(O)_tR¹²Hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by a substituent selected from the group consisting of halogen, alkyl, haloalkyl, -NR^7aR^7b、-OR⁸One or more, sometimes preferably one to five, sometimes more preferably one to three, of cyano, oxo, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

or two adjacent R⁴Substituents together with ring B may optionally be linked to form cycloalkyl, heterocyclyl, aryl and heteroaryl groups; wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by 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^cand R^dAre the same or different and are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, and hydroxyalkyl;

R⁵、R^6a、R^6b、R^7a、R^7b、R⁸、R⁹、R^10a、R^10b、R¹¹and R¹²Are the same or different and are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl 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;

t is 0,1 or 2;

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

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 is₁is-CR^aR^b-，R^aAnd R^bAre all hydrogen.

In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein L is₂is-NR^c-，R^cIs hydrogen.

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

or a pharmaceutically acceptable salt thereof,

wherein:

ring A, ring B, R¹To R⁴M 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 is¹Selected from hydrogen, C_1-6Alkyl, -OR⁵、-NR^6aR^6bCyano and-C (O) NR^6aR^6b(ii) a Preferably, R¹is-NR^6aR^6b；R⁵、R^6aAnd R^6bAs defined in formula (I).

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

or a pharmaceutically acceptable salt thereof,

wherein:

ring A, ring B, R²To R⁴M and n are as defined for formula (I).

In some embodiments, the present disclosure provides a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereofAn acceptable salt, 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 a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, wherein 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; 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 a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, wherein R is²Is selected from C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Hydroxyalkyl, 3-to 6-membered cycloalkyl and 3-to 12-membered heterocyclyl; preferably, R²Is selected from C_1-6Alkyl radical, C_1-6Haloalkyl and 3 to 6 membered heterocyclyl; more preferably, R²Is C_1-6Alkyl or C_1-6A haloalkyl group; most preferably, R²Is C_1-6A haloalkyl group.

In some embodiments, the present disclosure provides a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, wherein R is²Selected from the group consisting of isopropyl, 1,1, 1-trifluoropropan-2-yl, tetrahydrofuranyl and tetrahydropyranyl; preferably, R²Selected from isopropyl, 1,1, 1-trifluoropropan-2-yl and tetrahydropyranyl; more preferably, R²Is isopropyl or 1,1, 1-trifluoropropan-2-yl; most preferably, R²Is 1,1, 1-trifluoropropan-2-yl.

In some embodiments, the present disclosure provides a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, wherein each occurrence of R³Are the same or different and are each independently selected from hydrogen, halogen, C_1-6Alkyl radical, C_1-6A halogenated alkyl group,C_1-6Hydroxyalkyl, cyano and-OR¹¹(ii) a Wherein R is¹¹Selected from hydrogen, C_1-6Alkyl radical, C_1-6Haloalkyl, 3-to 8-membered cycloalkyl and 3-to 12-membered heterocyclyl; preferably, each occurrence of R³Are the same OR different and are each independently selected from hydrogen, halogen and-OR¹¹(ii) a Wherein R is¹¹Is selected from C_1-6Alkyl radical, C_1-6Haloalkyl and 3 to 6-membered cycloalkyl; more preferably, each occurrence of R³The same or different and each is independently selected from hydrogen, fluorine, methoxy, ethoxy and cyclopropoxy.

In some embodiments, the present disclosure provides a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, wherein each occurrence of R³Are the same or different and are each independently selected from hydrogen, halogen, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Hydroxyalkyl, cyano and-OR¹¹(ii) a Wherein R is¹¹Selected from hydrogen, C_1-6Alkyl and C_1-6A haloalkyl group; preferably, each occurrence of R³Are the same or different and are each independently selected from hydrogen, fluorine, methoxy and ethoxy.

In some embodiments, the present disclosure provides a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, wherein two adjacent R are³Substituents together with ring a may optionally be linked to form a3 to 8 membered cycloalkyl; wherein said 3 to 8 membered cycloalkyl is optionally independently selected from halogen, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy and C_1-6One or more, sometimes preferably one to five, sometimes more preferably one to three, of the hydroxyalkyl groups; preferably, two adjacent R³The substituents together with ring A may optionally be joined to form a 3-6 membered cycloalkyl group.

In some embodiments, the present disclosure provides a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, wherein each occurrence of R⁴Are the same or different and are each independently selected from hydrogen, halogen, C_1-6Alkyl, -NR^10aR^10b、-OR¹¹、-S(O)_tR¹²And C_1-6A hydroxyalkyl group; wherein R is^10a、R^10b、R¹¹And R¹²Are the same or different and are each independently selected from hydrogen, C_1-6Alkyl and C_1-6A haloalkyl group; t is 2; preferably, each occurrence of R⁴Are the same or different and are each independently selected from the group consisting of hydrogen, fluorine, methoxy, ethoxy, OCF₃、OCHF₂、N(CH₃)₂And S (O)₂CH₃。

In some embodiments, the present disclosure provides a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, wherein two adjacent R are⁴Substituents together with ring B may optionally be linked to form a 3-to 12-membered heterocyclyl; wherein said 3-to 12-membered heterocyclyl is optionally independently selected from halogen, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy and C_1-6One or more groups in the hydroxyalkyl group are substituted, sometimes preferably by one to five, sometimes more preferably by one to three.

In some embodiments, the present disclosure provides a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, wherein two adjacent R are⁴Substituents together with ring B may optionally be linked to form a5 or 6 membered heterocyclyl containing one to two oxygen atoms; wherein said 5 or 6 membered heterocyclyl is optionally independently selected from halogen, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy and C_1-6One or more groups, sometimes preferably one to five, sometimes more preferably one to three, of the haloalkoxy groups are substituted.

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 thereofAn acceptable salt, wherein

Is selected 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

Is selected from

Is selected from

Is selected 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 R is²Is selected from C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Hydroxyalkyl, 3-to 6-membered cycloalkyl and 3-to 12-membered heterocyclyl;

is selected from

Is selected 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 R is²Is selected from C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Hydroxyalkyl, 3-6 membered cycloalkyl and 3-12 membered heterocyclyl;

is selected from

Is selected from

In some casesIn an embodiment, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R is²Is selected from C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Hydroxyalkyl, 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; each occurrence of R³Are the same or different and are each independently selected from hydrogen, halogen, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Hydroxyalkyl, cyano and-OR¹¹(ii) a Wherein R is¹¹Selected from hydrogen, C_1-6Alkyl radical, C_1-6Haloalkyl, 3-to 8-membered cycloalkyl and 3-to 12-membered heterocyclyl; or two adjacent R³Substituents together with ring a may optionally be linked to form a3 to 8 membered cycloalkyl; wherein said 3 to 8 membered cycloalkyl is optionally independently selected from halogen, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy and C_1-6One to three groups in hydroxyalkyl; each occurrence of R⁴Are the same or different and are each independently selected from hydrogen, halogen, C_1-6Alkyl, -NR^10aR^10b、-OR¹¹、-S(O)_tR¹²And C_1-6A hydroxyalkyl group; wherein R is^10a、R^10b、R¹¹And R¹²Are the same or different and are each independently selected from hydrogen, C_1-6Alkyl and C_1-6A haloalkyl group; t is 2; or two adjacent R⁴Substituents together with ring B may optionally be linked to form a5 or 6 membered heterocyclyl containing one to two oxygen atoms; wherein said 5 or 6 membered heterocyclyl is optionally independently selected from halogen, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy and C_1-6One to three groups of haloalkoxy; 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 is²Is selected from C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Hydroxyalkyl, 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; each occurrence of R³Are the same or different and are each independently selected from hydrogen, halogen, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Hydroxyalkyl, cyano and-OR¹¹(ii) a Wherein R is¹¹Selected from hydrogen, C_1-6Alkyl and C_1-6A haloalkyl group; or two adjacent R³Substituents together with ring a may optionally be linked to form a3 to 8 membered cycloalkyl; wherein said 3 to 8 membered cycloalkyl is optionally independently selected from halogen, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy and C_1-6One to three groups in hydroxyalkyl; each occurrence of R⁴Are the same or different and are each independently selected from hydrogen, halogen, C_1-6Alkyl, -NR^10aR^10b、-OR¹¹、-S(O)_tR¹²And C_1-6A hydroxyalkyl group; wherein R is^10a、R^10b、R¹¹And R¹²Are the same or different and are each independently selected from hydrogen, C_1-6Alkyl and C_1-6A haloalkyl group; t is 2; or two adjacent R⁴Substituents together with ring B may optionally be linked to form a5 or 6 membered heterocyclyl containing one to two oxygen atoms; wherein said 5 or 6 membered heterocyclyl is optionally independently selected from halogen, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy and C_1-6One to three groups of haloalkoxy; 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 is²Is selected from C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Hydroxyalkyl, 3-to 6-membered cycloalkyl and 3-to 12-membered heterocyclyl;

is selected from

Is selected from

is selected from

Is selected from

In some embodiments, the present disclosure provides a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R is²Selected from the group consisting of isopropyl, 1,1, 1-trifluoropropan-2-yl, and tetrahydropyranyl;

is selected from

Is selected from

is selected from

Is 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; r²Is selected from C_1-6Alkyl radical, C_1-6Haloalkyl and 3 to 6 membered heterocyclyl; each occurrence of R³Are the same OR different and are each independently selected from hydrogen, halogen and-OR¹¹(ii) a Wherein R is¹¹Is selected from C_1-6Alkyl radical, C_1-6Haloalkyl and 3 to 6-membered cycloalkyl; or two adjacent R³Substituents together with ring A may optionally be linked to form a 3-6 membered cycloalkyl group; each occurrence ofR⁴Are the same or different and are each independently selected from hydrogen, halogen, C_1-6Alkyl, -NR^10aR^10b、-OR¹¹、-S(O)_tR¹²And C_1-6A hydroxyalkyl group; wherein R is^10a、R^10b、R¹¹And R¹²Are the same or different and are each independently selected from hydrogen, C_1-6Alkyl and C_1-6A 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, R¹To R³And m is as defined for formula (II).

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

or a salt thereof, or a pharmaceutically acceptable salt thereof,

wherein:

ring A, R²、R³And m is as defined for 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 process for 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 give 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 provided with

Ring A, ring B, L₁、L₂、R¹To R⁴M 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,

R is hydrogen or alkyl; preferably, Y is selected from iodine,

And is

Ring A, ring B, R¹To R⁴M 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 give a compound of formula (III) 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

Ring A, ring B, R²To R⁴M and n are as defined for formula (III).

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

wherein:

R^tselected from halogen, hydroxy and alkoxy; and is

Ring A, ring B, R¹To R⁴M 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 give a compound of formula (III) or a pharmaceutically acceptable salt thereof;

wherein:

R^tselected from halogen, hydroxy and alkoxy; and is

Ring A, ring B, R²To R⁴M and n are as defined for formula (III).

The present disclosure also provides a pharmaceutical composition comprising a compound of formula (I), formula (II), formula (III) and 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 disclosure also relates to the use of a compound of formula (I), formula (II), formula (III), and shown in 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 disclosure also relates to the use of a compound of formula (I), formula (II), formula (III), and shown in 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 disclosure also relates to compounds of formula (I), formula (II), formula (III) and table a, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use as a medicament.

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

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

In some embodiments, the disease or disorder treatable by modulation/inhibition of BTK may be selected from: cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolic/endocrine function disorders, and neurological disorders; preferably, the disorder modulated by BTK is selected from the group consisting of B-cell malignancies, B-cell lymphomas, diffuse large B-cell lymphomas, chronic lymphocytic leukemia, non-hodgkin's lymphomas (e.g., ABC-DLBCL), mantle cell lymphomas, follicular lymphomas, hairy cell leukemia, B-cell non-hodgkin's lymphomas, waldenstrom's macroglobulinemia, multiple myeloma, bone cancer, bone metastases, 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 condition selected from: b cell malignancies, B cell lymphomas, diffuse large B cell lymphomas, 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, follicular lymphoma, 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 effusion lymphoma, Burkitt lymphoma/leukemia (burkitt lymphoma/leukakia), lymphoma-like granuloma, lymphomatoid granulomatosis, lymphomatosis, lymphomatoid granulomatosis, lymphomas, lymphomatoid granulomatosis, and lymphomas, Inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, alder's thyroiditis, Graves ' disease, sjogren's syndrome, multiple sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, ocular clonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, idiopathic scleroderma, primary scleroderma, and rheumatoid arthritis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, familial autonomic dysfunction, endometriosis, interstitial cystitis, neuromuscular stiffness, scleroderma, vulvodynia, graft-versus-host disease, transplantation, blood transfusion, anaphylaxis (anaphylaxis), allergy (allergy), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, atopic dermatitis, asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, colitis, conjunctivitis, cholecystitis, dacryitis, dermatitis, dermatomyositis, encephalitis, endocarditis, cystitis, enterocolitis, small intestine colitis, Takayasu's arteritis, chronic fatigue, familial autonomic nerve dysfunction, chronic fatigue, familial endometriosis, interstitial cystitis, neuromuscular sclerosis, scleroderma, graft-versus-host disease, graft-versus-induced allergic reactions, allergic rhinitis, atopic dermatitis, colitis, inflammatory bowel disease, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteomyelitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, focal pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, vulvitis, pulmonary fibrosis, Idiopathic Pulmonary Fibrosis (IPF), interstitial pneumonia (UIP), interstitial lung disease, cryptogenic fibrofolliculitis fibrositis (CFA), bronchiolitis obliterans, bronchiectasis, fatty liver disease, fatty degeneration (e.g., nonalcoholic fatty hepatitis (e.g., cholesclerosis (PBC)), and stasis liver disease (e.g., Primary Biliary Cirrhosis (PBC))), Liver cirrhosis, 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, or d), autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD), progressive massive fibrosis, exposure to toxins or irritants (e.g., alcohol, drugs, and environmental toxins), kidney fibrosis (e.g., chronic kidney fibrosis), kidney disease associated with injury/fibrosis (e.g., chronic kidney disease associated with diabetes (e.g., diabetic nephropathy)), lupus, nephroscleroderma, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, kidney fibrosis associated with human Chronic Kidney Disease (CKD), chronic progressive kidney disease (CPN), tubulointerstitial fibrosis, chronic kidney disease associated with Chronic Kidney Disease (CKD), chronic progressive renal fibrosis (e.g., chronic kidney disease), chronic liver fibrosis, chronic liver disease, liver fibrosis, including but not limited to liver fibrosis associated with alcoholism, Ureteral occlusion, chronic uremia, chronic interstitial nephritis, radiation nephropathy, glomerulosclerosis, Progressive Glomerulonephritis (PGN), endothelial/thrombotic microangiopathy injury, HIV-associated nephropathy, or fibrosis associated with exposure to toxins, irritants or chemotherapeutic agents, fibrosis associated with scleroderma; radiation-induced intestinal fibrosis; fibrosis associated with foregut inflammatory diseases such as Barrett's esophagus and chronic gastritis, and/or fibrosis associated with post-inflammatory bowel 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 present disclosure relates to a method of treating a disease or condition selected from: b cell malignancies, B cell lymphomas, diffuse large B cell lymphomas, 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, follicular lymphoma, 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 effusion lymphoma, Burkitt lymphoma/leukemia (burkitt lymphoma/leukakia), lymphoma-like granuloma, lymphomatoid granulomatosis, lymphomatosis, lymphomatoid granulomatosis, lymphomas, lymphomatoid granulomatosis, and lymphomas, Inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, alder's thyroiditis, Graves' disease, sjogren's syndrome, multiple sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, ocular clonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, leiomyelitis, primary scleroderma's syndrome, Hyperactive arteritis (Takayasu's arteritis), temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, familial autonomic nerve abnormality, endometriosis, interstitial cystitis, neuromuscular stiffness, scleroderma, vulvodynia, graft-versus-host disease, transplantation, blood transfusion, anaphylaxis (anaphylaxis), allergy (allergy), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, atopic dermatitis, asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, colitis, conjunctivitis, cystitis, dacryitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, small intestine colitis, epididymitis, and other diseases, Fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, focal pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, vulvitis, pulmonary fibrosis, Idiopathic Pulmonary Fibrosis (IPF), common interstitial pneumonia (UIP), interstitial lung disease, cryptogenic fibrofolliculitis fibrosis (CFA), bronchiolitis obliterans, bronchiectasis, fatty liver disease, steatosis (e.g., non-alcoholic steatohepatitis (NASH)), primary silted liver disease (e.g., primary biliary cirrhosis (pbch)), primary myelitis, and myelitis, Liver cirrhosis, 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, or d), autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD), progressive massive fibrosis, exposure to toxins or irritants (e.g., alcohol, drugs, and environmental toxins), kidney fibrosis (e.g., chronic kidney fibrosis), kidney disease associated with injury/fibrosis (e.g., chronic kidney disease associated with diabetes (e.g., diabetic nephropathy)), lupus, nephroscleroderma, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, kidney fibrosis associated with human Chronic Kidney Disease (CKD), chronic progressive kidney disease (CPN), tubulointerstitial fibrosis, chronic kidney disease associated with Chronic Kidney Disease (CKD), chronic progressive renal fibrosis (e.g., chronic kidney disease), chronic liver fibrosis, chronic liver disease, liver fibrosis, including but not limited to liver fibrosis associated with alcoholism, Ureteral occlusion, chronic uremia, chronic interstitial nephritis, radiation nephropathy, glomerulosclerosis, Progressive Glomerulonephritis (PGN), endothelial/thrombotic microangiopathy injury, HIV-associated nephropathy, or fibrosis associated with exposure to toxins, irritants or chemotherapeutic agents, fibrosis associated with scleroderma; radiation-induced intestinal fibrosis; fibrosis associated with foregut inflammatory diseases such as Barrett's esophagus and chronic gastritis, and/or fibrosis associated with post-inflammatory bowel 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. Thus, the active compounds of the present disclosure may be formulated in a variety of dosage forms for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular, or subcutaneous), rectal, inhalation, 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 composition may be prepared according to any method known in the art for preparing pharmaceutical compositions. Such compositions may contain one or more additives selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide a pleasant and palatable pharmaceutical preparation. Tablets contain the active ingredient in association with 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 to delay disintegration and absorption of the drug in the gastrointestinal tract and thereby provide a sustained release effect 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.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents and may be naturally occurring phospholipids. The aqueous suspensions may also contain one or more preservatives, one or more colouring agents, one or more flavouring agents and one or more sweetening agents.

Oil suspensions may be formulated by suspending the active ingredient in a vegetable or mineral oil. The oil suspension may contain a thickener. Sweetening agents such as those set forth above, 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 formulated by the addition of water into dispersible powders or granules suitable for the preparation of aqueous suspensions. 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 oil-in-water emulsions. The oily phase may be a vegetable oil, or a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids. 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 a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed 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 the oil phase. The injection solution or microemulsion may be injected into the bloodstream of an individual by local bulk injection. Alternatively, it may be advantageous to apply the solution or microemulsion in a manner that maintains a constant circulating concentration of the compound of the present disclosure. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump model Deltec CADD-PLUS. TM.5400.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using 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 non-toxic diluent or solvent. In addition, sterile, fixed oils may be conveniently employed as a solvent or suspending medium, or fatty acids may be employed to prepare injections.

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 therefore will melt in the rectum to release the drug.

For buccal administration, the compositions may be formulated as tablets or lozenges by conventional means.

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 from a pressurized container or nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, 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 (made, for example, from 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 the drug depends on a variety of factors, including but not limited to the following: the activity of the particular compound used, the age of the patient, the weight of the patient, the health condition 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 treatment regimen, such as mode of treatment, daily dosage, or type of pharmaceutically acceptable salt thereof, may be verified according to conventional treatment protocols.

Description of the terms

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

"alkyl" means containing C₁-C₁₂A straight or branched chain 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)_1-8Alkyl), sometimes more preferably, the alkyl is an alkyl having 1 to 6 carbon atoms (i.e., C)_1-6Alkyl groups). 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-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, 2, 3-dimethylpentyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-ethylhexyl, 2-methyl-2-ethyl-pentyl, 2-ethylhexyl, 2-ethyl-pentyl, 2-ethyl, 2-pentyl, 2-hexyl, 2-ethyl, 2-pentyl, 2-hexyl, 2-pentyl, 2, or-hexyl, 2-pentyl, 2, or-hexyl, 2-hexyl, or-hexyl, 2' -pentyl, or a, N-decyl, 3-diethylhexyl, 2-diethylhexyl, and branched isomers thereof. In some embodiments, alkyl is sometimes more preferably lower alkyl having 1 to 6 carbon atoms (i.e., C)_1-6Lower alkyl), sometimes more preferably lower alkyl having 1 to 4 carbon atoms (i.e., C)_1-4Lower 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 substituents independently selected from halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, mercapto, hydroxy, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycle, cycloalkylthio, heterocyclylthio and oxo.

"alkenyl" means an alkyl group as defined above having at least two carbon atoms and at least one carbon-carbon double bond, e.g., ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like, preferably C_2-12Alkenyl, sometimes more preferably C_2-8Alkenyl, sometimes more preferably C_2-6Alkenyl, sometimes even more preferably C_2-4An alkenyl group. Alkenyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably 1 to 5, sometimes more preferably 1 to 3, independently selected from halogen, alkoxy, alkynyl, alkylsulfo, alkylamino, mercapto, hydroxy, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocyclyl, cycloalkylthio, heterocyclylthio 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_2-12Alkynyl, sometimes more preferably C_2-8Alkynyl, sometimes more preferably C_2-6Alkynyl, sometimes even more preferably C_2-4Alkynyl. Alkynyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, preferably 1 to 5, sometimes more preferably 1 to 3, independently selected from alkenyl, alkoxy, alkylsulfo, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.

The term "alkylene" refers to a saturated straight or branched chain divalent aliphatic hydrocarbon radical derived by the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane. Straight or branched chain radicals (i.e. C) containing from 1 to 12 carbon atoms (e.g. 1,2, 3,4,5, 6, 7, 8, 9, 10, 11 and 12 carbon atoms)_1-12Alkylene). Alkylene groups having 1 to 8 carbon atoms (i.e., C) are preferred_1-8Alkylene), more preferably alkylene of 1 to 6 carbon atoms (i.e., C)_1-6Alkylene) and sometimes more preferably 1 to 4 carbon atoms (i.e., C)_1-4Alkylene). Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH)₂-), 1-ethylidene (-CH (CH)₃) -), 1, 2-ethylene (-CH)₂CH₂) -, 1-propylene (-CH (CH)₂CH₃) -), 1, 2-propylene (-CH)₂CH(CH₃) -), 1, 3-propylene (-CH)₂CH₂CH₂-)、14-butylene (-CH)₂CH₂CH₂CH₂-) and the like. Alkylene groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably 1 to 5, sometimes more preferably 1 to 3, independently selected from alkenyl, alkynyl, alkoxy, alkylsulfo, 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_2-12Alkenylene, sometimes more preferably C_2-8Alkenylene, sometimes more preferably C_2-6Alkenylene, sometimes even more preferably C_2-4An alkenylene group. Non-limiting examples of alkenylene include, but are not limited to, -CH ═ CH-, -CH ═ CHCH₂-、-CH＝CHCH₂CH₂-、-CH₂CH＝CHCH₂-and the like. Alkenylene groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably 1 to 5, sometimes more preferably 1 to 3, independently selected from alkynyl, alkoxy, alkylsulfo, alkylamino, halo, 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., a3 to 20 membered cycloalkyl group), sometimes more preferably 3 to 8 carbon atoms (i.e., a3 to 8 membered cycloalkyl group), and sometimes even more preferably 3 to 6 carbon atoms (i.e., a3 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 groups include those having spirocyclic, fused, or bridged ring cycloalkyl groups.

"spirocycloalkyl" refers to a5 to 20 membered polycyclic group wherein the rings are connected by a common carbon atom (referred to 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). Spirocycloalkyl groups may be divided into unispirocycloalkyl or polyspirocycloalkyl groups (e.g. a bisspirocycloalkyl group) depending on the number of common spiro atoms, preferably meaning unispirocycloalkyl or bisspirocycloalkyl groups, more preferably 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/6-membered unispirocycloalkyl groups. Representative examples of spirocycloalkyl groups include, but are not limited to, the following groups:

"fused-ring alkyl" refers to a polycyclic group that is a cycloalkyl group joined in a fused fashion to one or more, preferably one to five, 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 fused ring alkyl group may be classified into bicyclic, tricyclic, tetracyclic, etc. polycyclic fused ring alkyl groups, preferably bicyclic or tricyclic fused ring alkyl groups, more preferably aryl-fused C groups, depending on the number of ring members_5-8Cycloalkyl, heteroaryl fused C_5-8Cycloalkyl, 4-membered heterocyclyl fused C_5-8Cycloalkyl, 5-membered heterocyclyl fused C_5-8Cycloalkyl radical, C₆Cycloalkyl-fused C_5-8Cycloalkyl or C₅Cycloalkyl-fused C_5-8A cycloalkyl group. Representative examples of fused ring alkyl groups include, but are not limited to, the following groups:

"bridged cycloalkyl" refers to a5 to 20 membered polycyclic hydrocarbon group in which each two rings in the system share two atoms not directly attached. Wherein the ring may have one or more, preferably one to three, double bonds. Preferably, the bridged cycloalkyl group is 6 to 14 membered, more preferably 7 to 10 membered (e.g., 7, 8, 9 and 10 membered). The bridged cycloalkyl group may be classified into bicyclic, tricyclic, tetracyclic, etc. polycyclic bridged cycloalkyl groups, preferably, bicyclic, tricyclic, or tetracyclic bridged cycloalkyl groups, more preferably, bicyclic or tricyclic bridged cycloalkyl groups, depending on the number of the ring members. Representative examples of bridged cycloalkyl groups include, but are not limited to, the following groups:

the cycloalkyl group may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is cycloalkyl. Representative examples include, but are not limited to, indanyl (e.g.

) Tetrahydronaphthyl (e.g. tetrahydronaphthyl)

) Benzocycloheptalkyl (e.g. phenyl-cycloheptyl)

) And the like. Cycloalkyl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably 1 to 5, sometimes more preferably 1 to 3, independently selected from alkyl, halo, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, mercapto, hydroxy, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocyclyl, cycloalkylthio, heterocyclylthio and oxo.

"Heterocyclyl" means a 3-to 20-membered saturated or partially unsaturated monocyclic or polycyclic group having as ring members one or more, preferably one to five, sometimes more preferably one to three heteroatoms selected from N, O and S, said S optionally being oxo (i.e. forming S (O) and S (O))₂) But do not contain-O-, -O-S-and-S-in the ring, and the remaining ring atoms are C. Preferably, heterocyclyl is a group having 1 to 4 heteroatoms3-to 12-membered (e.g., 3,4,5, 6, 7, 8, 9, 10, 11, and 12-membered) heterocyclic groups (i.e., 3-to 12-membered heterocyclic groups) of the sub (e.g., 1,2, 3, and 4 heteroatoms); more preferably 3 to 8-membered (e.g., 3,4,5, 6, 7 and 8-membered) heterocyclic groups having 1 to 3 heteroatoms (e.g., 1,2 and 3 heteroatoms) (i.e., 3 to 8-membered heterocyclic groups); even more preferably a 3-to 6-membered (e.g., 3-, 4-, 5-, and 6-membered) heterocyclic group having 1 to 3 heteroatoms (e.g., 1,2, and 3 heteroatoms) (i.e., a 3-to 6-membered heterocyclic group); most preferred are 5 or 6 membered heterocyclic groups (i.e., 5 or 6 membered heterocyclic 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 heterocyclic groups include heterocyclic groups having spiro, fused, or bridged rings.

"Spiroheterocyclyl" refers to a5 to 20 membered polycyclic heterocyclyl group connected between 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., to form S (O) and S (O))₂) And the remaining ring atoms are C, wherein one or more of the rings may contain one or more double bonds. Preferably, the spiroheterocyclyl group 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, spiro heterocyclic groups may be classified as mono-or polyspiroheterocyclic groups (e.g., as di-spiro heterocyclic groups), preferably referring to mono-or di-spiro heterocyclic groups, more preferably 3-or 5-or 3-or 6-or 4-or 5-or 4-or 6-or 5-or 6-membered mono-spiro heterocyclic groups. Representative examples of spiro heterocyclic groups include, but are not limited to, the following:

"fused heterocyclyl" refers to a polycyclic group that is a heterocyclic group joined in a fused fashion 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 disclosed in the disclosureAnd (4) defining. The fused heterocyclic group may be classified into bicyclic, tricyclic, tetracyclic and other polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic fused heterocyclic groups, more preferably aryl-fused 5-to 8-membered heterocyclic groups, heteroaryl-fused 5-to 8-membered heterocyclic groups, C_5-8Cycloalkyl-fused 4-membered heterocyclic group, C_5-8Cycloalkyl-fused 5-membered heterocyclic group, C_5-8Cycloalkyl fused 6-membered heterocyclyl.

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

"bridged heterocyclyl" means a5 to 14 membered (e.g., 5,6, 7, 8, 9, 10, 11, 12, 13 and 14 membered) polycyclic heterocycloalkyl group in which each two rings in the system share two atoms not directly attached, wherein the rings may have one or more, preferably one to three, double bonds, and the rings have as ring atoms one or more, preferably one to five, sometimes more preferably one to three heteroatoms independently selected from the group consisting of N, O and S, 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 heterocyclic group is a6 to 14 membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 membered), more preferably a7 to 10 membered bridged heterocyclic group. The bridged heterocyclic group may be classified into a bicyclic, tricyclic, tetracyclic, etc. polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic bridged heterocyclic group, more preferably a bicyclic or tricyclic bridged heterocyclic group, depending on the number of the membered rings. Representative examples of bridged heterocyclic groups include, but are not limited to, the following:

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:

and the like.

A 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), sometimes more preferably 1 to 3 independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.

"aryl" refers to a6 to 14 membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13, and 14 membered) all carbon monocyclic or fused polycyclic (a "fused" ring system refers to each ring in the system sharing a pair of adjacent carbon atoms with another 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 can be fused to a ring of a heteroaryl, heterocyclyl, or cycloalkyl group, wherein the ring attached to the parent structure is aryl. Representative examples include, but are not limited to, the following groups:

the aryl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably 1 to 5, sometimes more preferably 1 to 3, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, 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 selected from O, S and N (e.g., 1,2, 3, and 4 heteroatoms) 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, furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl and the like. The heteroaryl group can be fused to a ring of an aryl, heterocyclyl, or cycloalkyl group, 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), sometimes more preferably 1 to 3 independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, 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), sometimes more preferably 1 to 3 independently selected from the group consisting of alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.

"amino protecting group" refers to derivatives of groups that are commonly used to block or protect amino groups when reacting to 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, and p-methoxybenzyl (Pmb), and the like.

"hydroxy protecting group" refers to derivatives of a hydroxy group that are commonly used to block or protect a hydroxy group when reacting other functional groups on a compound. Examples of such protecting groups include triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, and the like; or C_1-10Alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C_1-6Alkoxy-substituted C_1-6Alkyl or phenyl substituted C_1-6Alkyl, most preferably C_1-4Alkoxy-substituted C_1-4Alkyl groups, for example: methyl, t-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-Tetrahydropyranyl (THP), and the like; or (C)_1-10Alkyl or aryl) acyl groups such as formyl, acetyl, benzoyl, p-nitrobenzoyl and the like; or (C)_1-6Alkyl or C_6-10Aryl) sulfonyl; or (C)_1-6Alkoxy or C_6-10Aryloxy) carbonyl group.

"bond" refers to a covalent bond of 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 hydroxyl groups, wherein alkyl is as defined above.

"hydroxy" means an-OH group.

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

"amino" means-NH₂A group.

"cyano" refers to the group-CN.

"nitro" means-NO₂A group.

"oxo" or "oxo" refers to an ═ O group.

"carboxy" refers to a-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, "heterocyclyl optionally substituted with alkyl" means that alkyl may, but need not, be present, and the description includes the case where heterocyclyl is substituted with alkyl and the case where heterocyclyl is not substituted with alkyl.

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

"pharmaceutical composition" refers to a mixture of one or more 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 administration of the compound to an organism, facilitate absorption of the active ingredient and exert biological activity.

"pharmaceutically acceptable salt" refers to salts of the disclosed compounds which are safe and effective and have corresponding biological activities when used in mammals.

Salts may be prepared in the course of the final isolation and purification of the compound or separately by reacting the appropriate nitrogen atom with an 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 during the final isolation and purification of the compounds by reacting the carboxyl group with a suitable base, such as the hydroxide, carbonate or bicarbonate of a metal cation, or with ammonia or an organic primary, secondary or tertiary amine. 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, tetramethylammonium, tetraethylammonium), methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N-dimethylaniline, N-methylpiperidine, and N-methylmorpholine.

As will be understood by those skilled in the art, the compounds of formula (I), formula (II), formula (III), and shown in table a, or pharmaceutically acceptable salts thereof, disclosed herein, 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 having any detectable amount of a drug administered to a subject, alone or as part of a pharmaceutical composition, 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. A 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 can 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 with a reasonable benefit/risk ratio, and which are effective for their intended use.

The terms "treatment", "treating" or "treatment" refer to: (I) inhibiting the disease, disorder or condition, i.e., arresting its development; and (II) relieving 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 predisposed to the disease, disorder, and/or condition, but has not yet been diagnosed as having the disease.

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

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

As used herein, the singular forms "a," "an," and "the" include plural references 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 those skilled in the art will appreciate, when parameters are not critical, numbers are generally given for illustrative purposes only and are not limiting.

Synthesis of the Compounds of the 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 of formula (IA) or the salt thereof and the compound of formula (V) to obtain the compound of formula (I) or the 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

Ring A, ring B, L₁、L₂、R¹To R⁴M and n are as defined for formula (I).

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 of the formula (IIA) or salt thereof and the compound of the formula (V-1) to obtain a compound of the formula (II) or 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

Ring A, ring B, R¹To R⁴M 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 of the formula (IIIA) or the salt thereof and the compound of the formula (V-1) to obtain a compound of a formula (III) 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

Ring A, ring B, R²To R⁴M and n are as defined for formula (III).

Scheme 4

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 give a compound of formula (II) or a pharmaceutically acceptable salt thereof;

wherein:

R^tselected from halogen, hydroxy and alkoxy; and is

Ring A, ring B, R¹To R⁴M 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 give a compound of formula (III) or a pharmaceutically acceptable salt thereof;

wherein:

R^tselected from halogen, hydroxy and alkoxy; and is

Ring A, ring B, R²To R⁴M and n are as defined for 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)Cl₂.CH₂Cl₂Or XPhos-Pd-G₂) In the presence of oxygen.

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)Cl₂And Pd (PPh)₃)₄) Optionally adding a ligand.

Reagents that provide basic conditions include organic and inorganic bases, wherein the organic bases include, but are 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 wherein the inorganic bases include, but are 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 tert-butyl ether, pyridine, and mixtures thereof.

Examples

The following examples are illustrative of the present disclosure, but are not to be construed as limiting. If specific conditions for the experimental methods are not specified in the examples of the present disclosure, they generally comply with the conventional or recommended conditions of raw material and product manufacturers. Reagents from a particular source are not indicated to be commercially available, conventional or readily preparable by available literature procedures.

The structure of the compound is determined by Mass Spectrometry (MS) and/or Nuclear Magnetic Resonance (NMR). NMR shift (. delta.) of 10^-6(ppm) is given as unit.

Mass Spectra (MS) were determined using a Shimadzu LCMS-2020 liquid chromatography-mass spectrometer.

NMR measurements were performed on Bruker AVANCE-400 and 500Ultrashield NMR spectrometers. The solvent is deuterated dimethyl sulfoxide (DMSO-d6) or deuterated chloroform (CDCl)₃) And deuterated methanol (methanol-d 4) with Tetramethylsilane (TMS) as internal standard.

HPLC was performed using 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 an Agela Technologies T-CSF10050-M silica gel plate, 50mm in size.

Column chromatography is typically performed using a CombiFlash Rf + automated flash chromatography system (TELEDYNE ISCO) with an 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, Asatech, and others. Unless otherwise stated in the examples, the reactions were carried out under an argon atmosphere or a nitrogen atmosphere. An argon or nitrogen atmosphere means that the reaction flask is connected to an approximately 1L argon or nitrogen balloon.

Hydrogen atmosphere means that the reaction flask is connected with about 1L hydrogen balloon. The hydrogenation reaction system is generally evacuated, refilled with hydrogen, and repeated 3 times before the reaction.

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

Unless otherwise stated in the examples, the reaction temperature is between 20 ℃ and 30 ℃ room temperature.

The progress of the reaction in the examples was monitored using Thin Layer Chromatography (TLC) or LC-MS chromatography. Column chromatography eluents for purifying compounds and developer systems for thin layer chromatography comprise: 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 the separation.

DCC is N, N' -dicyclohexylcarbodiimide,

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

Pd(PPh₃)₄is tetrakis (triphenylphosphine) palladium (0),

Pd(dppf)Cl₂is [1,1' -bis (diphenylphosphino) ferrocene]A palladium (II) dichloride,

XPhos-Pd-G₂as a second generation XPhos precatalyst, chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl)](II) a palladium (II),

NIS is N-iodosuccinimide,

(BPin)₂is bis (pinacolato) diboron,

TMEDA is N, N, N ', N' -tetramethyl ethylene diamine,

TEA is triethylamine and is a compound of the formula,

the TESH is triethyl silicane,

TMSCl is trimethylsilyl chloride,

the HCl is the acid solution of hydrochloric acid,

Cs₂CO₃is the cesium carbonate, and the cesium carbonate is used,

K₂CO₃is potassium carbonate, and the active ingredient is potassium carbonate,

KOAc is potassium acetate, and KOAc is potassium acetate,

KO^tbu is potassium tert-butoxide and can be used as the catalyst,

the NaH is sodium hydride, and the NaH is sodium hydride,

NH₄OH is the ammonium hydroxide, and the hydroxyl is the ammonium hydroxide,

BH₃-THF is borane-tetrahydrofuran,

the EtOAc is ethyl acetate which is the mixture of the ethyl acetate,

the DME is a dimethoxyethane and the DME is a dimethoxyethane,

the MeOH is methanol, and the MeOH is methanol,

the IPA is an isopropyl alcohol,

the DMSO is dimethyl sulfoxide, and the DMSO is dimethyl sulfoxide,

the PE is petroleum ether, and the mixture is,

the THF is tetrahydrofuran, and the THF is tetrahydrofuran,

Et₂o is the ethyl ether, and the N is the methyl ether,

the DCM is the methylene chloride, and the DCM is the methylene chloride,

the DMF is dimethyl formamide which is a mixture of dimethyl formamide,

MgSO₄is the magnesium sulfate, and the magnesium sulfate,

Na₂SO₄is sodium sulfate, and

MS is mass spectrometry, where (+) refers to 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 (46.8g,227mmol) was added to a mixture of the compound isobutyric acid Int-1a (20g,227mmol,1.0equiv.) and 1-hydroxypyrrolidine-2, 5-dione (26.1g,227mmol) in DME (400mL) at 0 deg.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 (41g, 98% yield), which was used in the next step without further purification.

¹H NMR(400MHz,CDCl₃):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 3-amino-6- (aminomethyl) -1,2, 4-triazin-5 (4H) -one 1nt-1c (3.8g,17.8mmol) in water (90mL) was added NaHCO₃Aqueous solution (1.0M,40mL,40 mmol). The resulting mixture was allowed to warm to room temperature, then 2, 5-dioxopyrrolidin-1-yl isobutyrate Int-1b (4.2g,22.6mmol) in THF ACN (1:1,30mL) was added slowly. The mixture was stirred at room temperature for 20 hours and then concentrated to 50 mL. The reaction mixture was filtered and the solid was washed with water and Et₂O wash and then dry under vacuum to give N- ((3-amino-5-oxo-4, 5-dihydro-1, 2, 4-triazin-6-yl) methyl) isobutyramide Int-1d (3.45g, 92% yield).

¹H NMR(400MHz,DMSO-d₆):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

To a suspension of N- ((3-amino-5-oxo-4, 5-dihydro-1, 2, 4-triazin-6-yl) methyl) isobutyramide Int-1d (3.46g,16.38mmol) in DCE (100mL) was added POCl at reflux₃(12.0mL,131mmol) and the mixture was stirred under reflux for an additional 5 hours. After cooling, the mixture was concentrated under vacuum. The residue was suspended in MeOH in water (2:1,45mL) and filtered through celite. With 1% NH₃Washed the residue with MeOH (3X 15mL), 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 (3.1g, 99% yield) 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 (3.0g,16.5mmol) in DMF (60mL) was added NIS (7.0g,31 mmol). The resulting mixture was stirred at room temperature for 18 hours. The mixture was then quenched with water (50mL) and extracted with EtOAc (50 mL. times.3). The combined organic phases are washed with Na₂S₂O₃Aqueous solution (1M, 2X 50mL) and brine (3X 30mL) were washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (2-5% M)eOH in DCM) to give 2-amino-5-iodo-7-isopropylimidazo [5, 1-f)][1,2,4]Triazin-4 (3H) -one Int-1f (3.44g, 60% yield).

¹H NMR(400MHz,DMSO-d₆):δ10.76(brs,1H),6.11(s,2H),2.23(m,1H),1.19(d,J＝8.0Hz,6H)ppm。

Step 5-5-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 (3.46g,10.8mmol) in THF/DMF (6:1,70mL) was added dropwise tert-butyl nitrite (5.6g,54 mmol). The resulting mixture was stirred at room temperature for 3.5 hours. The mixture was then quenched with water (50mL) and extracted with EtOAc (50 mL. times.3). The combined organic phases were washed with brine (3X 30mL) and over anhydrous Na₂SO₄Dried, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (25% EtOAc in PE) to afford 5-iodo-7-isopropylimidazo [5,1-f][1,2,4]Triazin-4 (3H) -one Int-1g (2.4g, 74% yield).

¹H NMR(400MHz,DMSO-d₆):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

To a solution of 1,2, 4-triazole (2.94g,42.7mmol) in pyridine (30mL) at 0 deg.C was added POCl dropwise₃(2.91g,19mmol) 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]Solution of triazin-4 (3H) -one Int-1g (1.44g,4.74mmol) in pyridine (30 mL). The resulting mixture was stirred at room temperature for 3.5 hours and then cooled again to 0 ℃. Then, NH was added dropwise₃IPA solution (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 (50mL) and extracted with EtOAc (50 mL. times.3). The combined organic phases were washed with brine (30mL) and over anhydrous Na₂SO₄Dried, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (25% EtOAc in PE) to give 5-iodo-7-isopropylimidazoleAzolo [5, 1-f)][1,2,4]Triazin-4-amine Int-1(1.08g, 75% yield).

¹H NMR(400MHz,DMSO-d₆):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, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-4-amine Int-2

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

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

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

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

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

DCC (11.3g,54.9mmol) was added to a mixture of 3,3, 3-trifluoro-2-methylpropionic acid Int-2b (7.8g,54.9mmol) and 1-hydroxypyrrolidine-2, 5-dione (6.3g,54.9mmol) in DME (120mL) at 0 ℃. 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, 3-trifluoro-2-methylpropionate Int-2c (13g, 99% yield), which was used in the next step without further purification.

¹H NMR(400MHz,CDCl₃):δ3.56-3.49(m,1H),2.81(s,4H),1.55(d,J＝8.0Hz,3H)ppm。

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

To a solution of 3-amino-6- (aminomethyl) -1,2, 4-triazin-5 (4H) -one Int-1c (3.8g,17.8mmol) in water (90mL) at 0 deg.C was added NaHCO₃Aqueous solution (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, 3-trifluoro-2-methylpropionate Int-2c (6.0g,24.9mmol) in THF ACN (1:1,60mL) was slowly added. The mixture was stirred at room temperature for 90 hours and then concentrated to 50 mL. The reaction mixture was filtered and the solid was washed with water and Et₂O wash and dry under vacuum to give N- ((3-amino-5-oxo-4, 5-dihydro-1, 2, 4-triazin-6-yl) methyl) -3,3, 3-trifluoro-2-methylpropanamide Int-2d (3.81g, 80% yield), which was used in the next step without further purification.

¹H NMR(400MHz,DMSO-d₆):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, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-4 (3H) -one Int-2e

To a suspension of N- ((3-amino-5-oxo-4, 5-dihydro-1, 2, 4-triazin-6-yl) methyl) -3,3, 3-trifluoro-2-methylpropanamint-2 d (4.5g,17mmol) in DCE (100mL) under reflux was added POCl₃(12.4mL,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/water (2:1,45mL) and filtered through celite. With 1% NH₃Washed residue with MeOH (3X 15mL) and concentrated solution to give 2-amino-7- (1,1, 1-trifluoropropan-2-yl) imidazo [5, 1-f)][1,2,4]Triazin-4 (3H) -one Int-2e (4.2g, 100% yield), which was used in the next step without further purification.

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

To 2-amino-7- (1,1, 1-trifluoropropan-2-yl) imidazo [5, 1-f)][1,2,4]To a solution of triazin-4 (3H) -one Int-2e (3.8g,15.5mmol) in DMF (80mL) was added NIS (7.0g,31mmol) and the resulting mixture was stirred at room temperature for 18H. Then theThe mixture was quenched with water (50mL) and then extracted with EtOAc (50 mL. times.2). The combined organic phases were washed with Na₂S₂O₃Aqueous solution (1M, 2X 50mL) and brine (3X 30mL) were washed with anhydrous Na₂SO₄Dried, 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, 1-trifluoropropan-2-yl) imidazo [5, 1-f)][1,2,4]Triazin-4 (3H) -one Int-2f (4.1g, 71% yield).¹H NMR(400MHz,DMSO-d₆):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, 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, 1-trifluoropropan-2-yl) imidazo [5,1-f][1,2,4]To a solution of triazin-4 (3H) -one Int-2f (4.1g,11mmol) in THF DMF (6:1,105mL) was added tert-butyl nitrite (5.7g,55mmol) dropwise. The resulting mixture was stirred at room temperature for 3.5 h. The mixture was then quenched with water (50mL) and extracted with EtOAc (50 mL. times.3). The combined organic phases were washed with brine (3X 30mL) and over anhydrous Na₂SO₄Dried and concentrated under vacuum. The residue was purified by silica gel chromatography (25% EtOAc in PE) to give 5-iodo-7- (1,1, 1-trifluoropropan-2-yl) imidazo [5, 1-f)][1,2,4]Triazin-4 (3H) -one Int-2g (3.3g, 83.6% yield).

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

To a solution of 1,2, 4-triazole (1.24g,18mmol) in pyridine (10mL) at 0 deg.C was added POCl dropwise₃(1.2g,8mmol) and the resulting mixture stirred at room temperature for 15 minutes, then 5-iodo-7- (1,1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] was added slowly][1,2,4]Triazine-4 (3H) -one Int-2g (720mg,2.0mmol) in pyridine (6 mL). The resulting mixture was stirred at room temperature for 3.5 hours and then cooled again to 0 ℃. Then, NH was added dropwise₃IPA (2M,50mL), and the resulting mixture was slowly warmed to room temperature and stirred for a further 75 minutes. After concentration in vacuo, the residue was dissolved with EtOAc (50mL) and washed with water (50 mL. times.3). The combined organic layers were washed with brine (30mL) and driedWater Na₂SO₄Dried, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (20% EtOAc in PE) to give 5-iodo-7- (1,1, 1-trifluoropropan-2-yl) imidazo [5, 1-f)][1,2,4]Triazin-4-amine Int-2(545mg, 79% yield).

¹H NMR(400MHz,DMSO-d₆):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, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-4-amine Int-2A and (S) -5-iodo-7- (1,1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-4-amine Int-2B

5-iodo-7- (1,1, 1-trifluoropropan-2-yl) imidazo [5, 1-f)][1,2,4]Triazine-4-amine Int-2(1.74g) was resolved by manual HPLC (supercritical CO₂MeOH (+ 0.1% 7.0mol/L ammonia in MeOH), 70g/min, 35 deg.C,

250 x 25mm 10 μm) to give two enantiomers (800 mg and 800mg respectively).

(R) -5-iodo-7- (1,1, 1-trifluoropropan-2-yl) imidazo [5, 1-f)][1,2,4]Triazine-4-amine Int-2A:¹HNMR(400MHz,CDCl₃) δ 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℃,DAICEL

250mm*4.6mm*5μm):Rt:2.495min,ee:100％；LCMS:MS m/z(ESI):357.9[M+H]⁺。

(S) -5-iodo-7- (1,1, 1-trifluoropropan-2-yl) imidazo [5, 1-f)][1,2,4]Triazine-4-amine Int-2B:¹HNMR (400MHz, 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℃,DAICEL

250mm*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

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

Under nitrogen atmosphere, in a closed tube, at 100 ℃, adding 5-iodine-7-isopropyl imidazo [5,1-f ℃][1,2,4]Triazin-4-amine Int-1(80mg,0.1mmol), (4- (((tert-butoxycarbonyl) amino) methyl) phenyl) boronic acid Int-3a (80mg,0.26mmol), Pd (PPh)₃)₄(10mg,0.0086mmol) and Na₂CO₃(82mg,0.78mmol) in 1, 4-dioxane (3mL) was stirred in a Biotage microwave reactor for 40 min. After cooling, the reaction mixture was diluted with EtOAc (2mL) and washed with water (2 mL). The combined organic phases were washed with brine (3X 3mL) over anhydrous MgSO₄Dried 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 (60mg, 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-isopropyl-imidazo [5, 1-f))][1,2,4]Triazin-5-yl) benzyl) a solution of tert-butyl carbamate Int-3b (76mg,0.2mmol) in a mixture of TFA (0.5mL) and DCM (1mL) 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, which was 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-yltetrahydro-2H-pyran-4-carboxylic acid ester Int-4b

DCC (19.67g,95.34mmol) was slowly added to a solution of tetrahydro-2H-pyran-4-carboxylic acid Int-4a (11.28g,86.67mmol), 1-hydroxypyrrolidine-2, 5-dione (10.97g,95.34mmol) and DMAP (116.48mg, 953.42. mu. mol) in THF (430mL) 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 resulting residue was purified by column chromatography (PE/EtOAc) to give the title compound, 2, 5-dioxopyrrolidin-1-yltetrahydro-2H-pyran-4-carboxylic acid ester Int-4b (16.4g, 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 (3.3g,18.58mmol) in water (80mL) at 0 deg.C was added NaHCO₃Aqueous solution (1M aqueous solution, 42mL,42 mmol). The resulting mixture was slowly warmed to room temperature, then a solution of 2, 5-dioxopyrrolidin-1-yltetrahydro-2H-pyran-4-carboxylate Int-4b (5.36g,23.60mmol) in THF ACN (1:1,70mL) was slowly added. The mixture was stirred at room temperature overnight and then filtered. The solid was washed with TBME (100mL) 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 (3.1g, 65.88% yield), which was used in the next step without further purification. LCMS is 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 at 90 DEG CYl) tetrahydro-2H-pyran-4-carboxamide Int-4c (2.0g,7.90mmol) in POCl₃(30mL) for 48 hours. After cooling, the solution was concentrated in vacuo. A NaOH solution (5M aqueous solution) was added to the resulting mixture to adjust the pH to 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, which was 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 (1.34g,5.70mmol) in DMF (20mL) was added NIS (71.92g,8.50 mmol). The resulting mixture was stirred at 35 ℃ overnight for 18 hours. The mixture was then quenched with water (50mL) before extraction with EtOAc (50 mL. times.2). The combined organic phases were washed with Na₂S₂O₃The aqueous solution (50mL) and brine (50mL) were washed over anhydrous Na₂SO₄Dried, 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 (1.2g, 58.33% yield).

¹H NMR(400MHz,DMSO-d₆):δ6.40(s,1H),3.92(d,11.2Hz,2H),3.44-3.25(m,3H),1.79-1.75(m,4H)ppm。

Step 5-5-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 (1.2g,3.32mmol) in THF DMF (6:1,28mL) was added tert-butyl nitrite (1.63g,15.82mmol) dropwise. The resulting mixture was stirred at room temperature overnight and then concentrated under vacuum. 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 (0.85g, 73.91% yield).

¹H NMR(400MHz,DMSO-d₆):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

To a solution of 1,2, 4-triazole (179mg,2.6mmol) in pyridine (1.5mL) at room temperature was added POCl dropwise₃(0.09ml,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 added slowly][1,2,4]Triazine-4 (3H) -one Int-4f (100mg,0.29mmol) 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 was added dropwise₃IPA solution (2M,7mL) 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-450 mg, 50% yield), which was 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-Dioxopyrrolidin-1-yltetrahydrofuran-3-carboxylate Int-5b

DCC (19.67g,95.34mmol) was slowly added to a solution of tetrahydrofuran-3-carboxylic acid Int-5a (12.5g,107.65mmol), 1-hydroxypyrrolidine-2, 5-dione (13.63g,118.42mmol) and DMAP (1.45g,11.84mmol) in THF (438mL) under argon at room temperature. 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 on silica gel column (PE/EtOAc ═ 2:1) to give 2, 5-dioxapyrrolidin-1-yltetrahydrofuran-3-carboxylate Int-5b (20.3g, 88.45% yield).

¹H NMR(400MHz,DMSO-d₆):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 3-amino-6- (aminomethyl) -1,2, 4-triazin-5 (4H) -one Int-1c (5.52g,39.09mmol) in water (200mL) was added NaHCO at 0 deg.C₃Aqueous solution (1M water, 86mL,86 mmol). The reaction mixture was slowly warmed to room temperature, then a mixed solution of 2, 5-dioxapyrrolidin-1-yltetrahydrofuran-3-carboxylate Int-5b (10g,46.91mmol) in THF: ACN (1:1,100mL) was slowly added. The reaction mixture was stirred at room temperature overnight and then filtered. The solid was washed with TBME (200mL) 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 (5.26g, 56.25% yield), which was used in the next step without further purification.

¹H NMR(400MHz,DMSO-d₆):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

N- ((3-amino-5-oxo-4, 5-dihydro-1, 2, 4-triazin-6-yl) methyl) tetrahydrofuran-3-carboxamide Int-5c (500.00mg,2.09mmol) in POCl at 90 ℃ in a pressure pot₃The solution (10mL) was stirred overnight for reaction. After cooling, the reaction was concentrated in vacuo. NaOH solution (5M water) was added to adjust the pH 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 (180mg, 38.93% yield), which was used in the next step without further purification.

¹H NMR(400MHz,DMSO-d₆):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) imidazo [5,1-f][1,2,4]To a solution of triazin-4 (3H) -one Int-5d (180mg, 813.68. mu. mol) in DMF (4mL) was added NIS (274.60mg,1.22 mmol). The reaction mixture was stirred overnight at 50 ℃ for 18 hours. The reaction mixture was then quenched with water (10mL) and extracted with EtOAc (10 mL. times.2). The mixed organic phase is Na₂S₂O₃(1.0M,4 mL. times.2) aqueous solution and saturated brine (4 mL. times.3) were washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. The residue was purified by silica gel column (DCM: MeOH ═ 50:1) to give 2-amino-5-iodo-7- (tetrahydrofuran-3-yl) imidazo [5,1-f ] imidazole][1,2,4]Triazin-4 (3H) -one Int-5e (57mg, 20.18% yield).

LCMS:MS m/z(ESI):348.0[M+H]⁺。

Step 5-5-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 (57mg, 164.21. mu. mol) in THF (6mL) and DMF (1mL) was added tert-butyl nitrite (184.67mg, 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 silica gel column (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 (54mg, 99.02% yield).

¹H NMR(400MHz,DMSO-d₆):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

To a solution of 1,2, 4-triazole (103mg,1.49mmol) in pyridine (1mL) was added dropwise at room temperaturePOCl₃(81.26mg,0.53 mmol). The reaction mixture was stirred at room temperature for 15 minutes, then 5-iodo-7- (tetrahydrofuran-3-yl) imidazo [5,1-f ] was slowly added dropwise][1,2,4]Triazine-4 (3H) -one Int-5f (55mg,0.17mmol) in pyridine (2 mL). The resulting mixture was stirred at room temperature for 3.5 hours and then cooled to 0 ℃. Thereafter, NH was added dropwise₃IPA solution (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 (25mL) and then saturated NaHCO was added₃Aqueous extraction (25 mL). The organic extract is treated with anhydrous Na₂SO₄Dried, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column (DCM: MeOH ═ 50:1) to give 5-iodo-7- (tetrahydrofuran-3-yl) imidazo [5, 1-f)][1,2,4]Triazin-4-amine Int-5(55mg, 100% yield).

¹H NMR(400MHz,DMSO-d₆):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 (1g,5.37mmol) and HATU (2.45g,6.45mmol) in DMF (10mL) was added 5-fluoro-2-methoxy-benzoic acid (1.10g,6.45mmol) and TEA (1.09g,10.75 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was then dissolved in EtOAc (50 mL. times.2) and washed with water (50 mL). Subjecting the organic layer to anhydrous Na₂SO₄Dried 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 (1.65g, yield 90.78%).

¹H NMR(400MHz,CDCl₃):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- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) benzamide A1c

Under nitrogen, at 90 deg.C, N- (4-bromobenzyl) -5-fluoro-2-methoxybenzamide A1b (4.54g,13.43mmol), (BPin)₂(5.11g,20.14mmol)、Pd(dppf)Cl₂The mixture of (2.19g,2.69mmol) and KOAc (3.95g,40.28mmol) in 1, 4-dioxane (25mL) was stirred for 1.5 h. After cooling, the mixture was diluted with EtOAc (200mL) and washed with water (200 mL). Subjecting the organic layer to anhydrous Na₂SO₄Dried and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE/EA ═ 20%) to give 5-fluoro-2-methoxy-N- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) benzamide A1c (4.6g, yield 88.94%).

¹H NMR(400MHz,DMSO-d₆):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 3N- (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- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) benzamide A1c (30mg,0.1mmol), 5-iodo-7-isopropylimidazo [5,1-f ] in a closed tube at 100 ℃ under nitrogen][1,2,4]Triazin-4-amine Int-1(30mg,0.1mmol), Pd (dppf) Cl₂(10mg,0.0086mmol) and Cs₂CO₃A mixture of (32mg,0.3mmol) in 1, 4-dioxane (3mL) and water (0.3mL) was stirred in a Biotage microwave reactor for 30 minutes. After cooling, the reaction mixture was diluted with EtOAc (2mL) and washed with water (2 mL). The combined organic layers were washed with brine (3X 3mL) over anhydrous MgSO₄Dried, filtered and concentrated in vacuo. Passing the residue throughPurifying by silica gel chromatography to obtain N- (4- (4-amino-7-isopropyl imidazo [5, 1-f))][1,2,4]Triazin-5-yl) benzyl) -5-fluoro-2-methoxybenzamide a1(28mg, 65% yield).

¹H NMR(400MHz,CDCl₃)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, 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, 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, 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, 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 a similar procedure as step 3 of example A1 using 5-iodo-7- (1,1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-4-amine Int-2 and 5-fluoro-2-methoxy-N- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) benzamide A1 c. The residue was purified by silica gel chromatography to give N- (4- (4-amino-7- (1,1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) benzyl) -5-fluoro-2-methoxybenzamide a 2.

¹H NMR(400MHz,CDCl₃):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)₄OH/Hexane, 20mL/min,35 ℃, ChiralPak IE,20mm 250mm,5 μm) isolation of N- (4- (4-amino-7- (1,1, 1-trifluoropropan-2-yl) imidazo [5, 1-f)][1,2,4]Triazin-5-yl) benzyl) -5-fluoro-2-methoxybenzamide A2(172mg) gave two enantiomers (70mg and 73mg respectively).

Enantiomer 1 (shorter retention time):¹H NMR(500MHz,CDCl₃) δ 8.33(s,1H),7.96(s,2H),7.58(d, J ═ 7.31Hz,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 x 4.6mm,5 μm) Rt 8.488min, ee 99.37%; LCMS MS M/z (ESI) 489.3[ M + H ]]⁺。

Enantiomer 2 (longer retention time):¹H NMR(500MHz,CDCl₃) δ 8.33(s,1H), 8.05-7.85 (m,2H),7.58(d, J ═ 7.29Hz,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 x 4.6mm,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 Ethyl 4-bromo-3-ethoxybenzoate A3b

To ethyl 4-bromo-3-hydroxybenzoate A3a (4g,16.32mmol) and K at room temperature₂CO₃(6.77g,48.97mmol) of DMF (N-dimethylformamide)40mL) was added iodoethane (5.09g,32.64 mmol). The resulting mixture was stirred at 80 ℃ for 16 hours. After cooling, the reaction mixture was quenched with water (100mL) and then extracted with EtOAc (100 mL. times.2). Subjecting the combined organic extracts to anhydrous Na₂SO₄Dried, filtered and 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 (4g, yield 89.73%).

¹H NMR(400MHz,DMSO-d₆):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 (4g,14.65mmol) in MeOH (40mL) at room temperature was added NH₃(iv) 4.76 g). The resulting mixture was then warmed and stirred at 80 ℃ for 16 hours. After cooling, the reaction mixture was quenched with water (100mL) and then extracted with EtOAc (100 mL. times.2). Subjecting the organic layer to anhydrous Na₂SO₄Dried, 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 (2.56g, 71.70% yield).

¹H NMR(400MHz,DMSO-d₆):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 (500mg,2.05mmol) in pyridine (5mL) at 0 deg.C was added POCl₃(575.75mg,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). Subjecting the combined organic extracts to anhydrous Na₂SO₄Dried, 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 (397mg, 85.73% yield).

¹H NMR(400MHz,DMSO-d₆):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 (600mg,2.65mmol) in BH at 60 ℃₃The mixture in THF (10mL,2.65mmol) was stirred for 3 hours. After cooling, the reaction MeOH (20mL) and HC1(20mL,12M aq) were quenched. The resulting solution was extracted with EtOAc (200 mL. times.3), and the combined organic layers were washed with anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave crude (4-bromo-3-ethoxyphenyl) methylamine A3e (600mg, 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 (340mg,1.48mmol) and TEA (448.52mg,4.43mmol) in DCM (5mL) under nitrogen at 0 deg.C was added 5-fluoro-2-methoxy-benzoyl chloride (417.95mg,2.22 mmol). The resulting mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction mixture was quenched with water (20mL) and extracted with ethyl acetate (20 mL). The combined organic extracts were washed with saturated brine (20mL) and dried over anhydrous Na₂SO₄Dried, 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 (371mg, yield 65.69%).

¹H NMR(400MHz,DMSO-d₆):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-methoxybenzamido) methyl) phenyl) boronic acid A3g

N- (4-bromo-3-ethoxybenzyl) is reacted at 90 ℃ under a nitrogen atmosphereYl) -5-fluoro-2-methoxybenzamide A3f (371mg,0.970mmol), Pd (dppf) Cl₂(71.02mg,0.097mmol)、KOAc(285.78mg,2.91mmol)、(BPin)₂(492.96mg,1.94mmol) in 1, 4-dioxane (4mL) was stirred for 16 h. After cooling, the reaction mixture was diluted with EtOAc (100mL) and washed with water (50 mL. times.2). The combined organic extracts were washed with brine (30mL) and dried over anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by preparative HPLC using ACN/H₂O/NH₄OH was eluted to give (2-ethoxy-4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) boronic acid A3g (50.66mg, yield 15.03%).

¹H NMR(400MHz,DMSO-d₆):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 similar procedure as described in step 3 of example a 1. 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-methoxybenzamido) 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.

¹H NMR(400MHz,CDCl₃):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, 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, 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, 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, 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, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-4-amine Int-2 and (2-ethoxy-4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) boronic acid A3 g. The crude product was purified by silica gel chromatography to give N- (4- (4-amino-7- (1,1, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-ethoxybenzyl) -5-fluoro-2-methoxybenzamide a 4.

¹H NMR(400MHz,CDCl₃):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 250mm,10 μm) separation of N- (4- (4-amino-7- (1,1, 1-trifluoropropan-2-yl) imidazo [5, 1-f)][1,2,4]Triazin-5-yl) -3-ethoxybenzyl) -5-fluoro-2-methoxybenzamide A4(90mg) gave two enantiomers (22 mg and 24mg respectively).

Enantiomer 1 (shorter retention time):¹H NMR(400MHz,DMSO-d₆) δ 8.54(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 ═ 7.2, 2H),3.90(s,3H),1.58(d, J ═ 2, 2H), 3.21H, 7.58 (t, 3.2H), 3.21H, 3.7 (t, 3.2H); chiral HPLC (supercritical CO)₂1.0mL/min in MeOH (0.1% DEA), 35 deg.C,

100*3.0mm 3μm):Rt:2.451min,ee:100％；LCMS:MS m/z(ESI):533.2[M+H]⁺。

enantiomer 2 (longer retention time):¹H NMR(400MHz,DMSO-d₆) δ 8.30(brs,1H),7.98(dd, J ═ 9.2Hz,3.2Hz,1H),7.88(s,1H),7.55(d, J ═ 7.6Hz,1H),7.21-7.15(m,1H),7.11(d, J ═ 8.0Hz,1H),7.07(s,1H),6.96(dd, J ═ 8.8Hz,4.0Hz,1H),6.35(br,1H),4.72(d, J ═ 6.0Hz,2H),4.48-4.40(m,1H),4.11(q, J ═ 6.8Hz,2H),3.96(s,3H),1.72(d, J ═ 7.2Hz,3H),1.30(t, J ═ 6.8Hz, 3H); chiral HPLC (supercritical CO)₂1.0mL/min in MeOH (0.1% DEA), 35 deg.C,

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 (5g,25.00mmol) in THF (10mL) under a nitrogen atmosphere at 0 deg.C was added BH₃THF (6.72g,80mL,80.00 mmol). The mixture was slowly warmed 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 (30mL) over anhydrous Na₂SO₄Drying, filtration and concentration under reduced pressure gave crude (4-bromo-3-fluorophenyl) methylamine A5b (4g, 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 (892.62mg,4.37mmol) and TEA (885.36mg,8.75mmol) in DCM (15mL) at 0 deg.C was added 5-fluoro-2-methoxy-benzoyl chloride (550mg,2.92 mmol). The resulting mixture was slowly warmed to room temperature and then concentrated under vacuum. The residue was purified by column on silica gel (PE: eoac ═ 5:1) to give N- (4-bromo-3-fluorobenzyl) -5-fluoro-2-methoxybenzamide A5c (510mg, yield 49.10%).

LCMS:MS m/z(ESI):356.0[M+H]⁺。

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

N- (4-bromo-3-fluorobenzyl) -5-fluoro-2-methoxybenzamide A5c (400mg,1.12mmol), Pd (dppf) Cl at 90 ℃ under a nitrogen atmosphere₂(41.10mg,0.056mmol)、(BPin)₂A mixture of (570.53mg,2.25mmol) and KOAc (220.12mg,2.25mmol) in 1, 4-dioxane (10mL) was stirred overnight. After cooling, the mixture was diluted with EtOAc and then washed with water. Passing the organic phase over anhydrous Na₂SO₄Dried, filtered and concentrated under vacuum. The mixture was purified by silica gel column (PE: EtOAc ═ 4:1) to give 5-fluoro-N- (3-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) -2-methoxybenzeneAmide A5d (177.3mg, 39.15% yield).

¹H NMR(400MHz,CDCl₃):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 a similar procedure as example A1, step 3, using 5-iodo-7-isopropylimidazo [5,1-f ] [1,2,4] triazin-4-amine Int-1 and 5-fluoro-N- (3-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-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 a 5.

¹H NMR(400MHz,CDCl₃):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

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

To a solution of ethanol (0.66g,14.34mmol) in THF (25mL) at room temperature was added NaH (0.57g,14.34 mmol). The resulting solution was stirred for 30 minutes, then 4-bromo-3, 5-difluorobenzonitrile A6a (2.50g,11.47mmol) was added. Will be provided withThe mixture was stirred at room temperature for 6 hours, then saturated NH was added₄And (4) quenching by using a Cl aqueous solution. After extraction with EtOAc (3X 50mL), the combined organic layers were washed with brine (3X 3mL), 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 A6 b.

¹H NMR(400MHz,CDCl₃):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 (0.98g,4mmol) in THF (15mL) at room temperature was added borane dimethylsulfide (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 heated again to 80 ℃. After stirring at this temperature for 1 hour, the reaction was cooled and saturated NaHCO was used₃And (4) quenching the aqueous solution. After extraction with EtOAc, the combined organic phases were washed with brine (3X 3mL) over anhydrous MgSO₄Dried 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 3N- (4-bromo-3-ethoxy-5-fluorobenzyl) -5-fluoro-2-methoxybenzamide A6d

To a solution of (4-bromo-3-ethoxy-5-fluorophenyl) methylamine A6c (0.99g,4.0mmol), 5-fluoro-2-methoxybenzoic acid (0.68g,4.0mmol), HATU (1.82g,4.8mmol) in DCM (15mL) at room temperature was added DIPEA (1.39mL,8.0 mmol). 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 A6 d.

LCMS:MS m/z(ESI):402.0[M+H]⁺。

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

N- (4-bromo-3-ethoxy-5-fluorobenzyl) -5-fluoro-2-methoxybenzamide A6d (480mg,1.2mmol), (BPin) under nitrogen at 100 deg.C₂(457mg,1.8mmol)、Pd(dppf)Cl₂A solution of (88mg,0.12mmol) and KOAc (353mg,3.6mmol) in 1, 4-dioxane (10mL) was stirred for 7 hours. After cooling, the mixture was diluted with EtOAc and then washed with water. The organic phase was passed over anhydrous MgSO₄Dried, filtered and concentrated in vacuo to give crude N- (3-ethoxy-5-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) -5-fluoro-2-methoxybenzamide A6e, which was used in the next step without further purification.

N- (4-bromo-3-ethoxy-5-fluorobenzyl) -5-fluoro-2-methoxybenzamide A6d (600mg,1.5mmol), (BPin) under nitrogen at 90 deg.C₂(572mg,2.25mmol)、Pd(dppf)Cl₂A solution of (55mg,0.075mmol) and KOAc (441mg,4.5mmol) in 1, 4-dioxane (15mL) was stirred for a reaction time of 3 hours. After cooling, add (BPin) to the reaction mixture₂(572mg,2.25mmol),Pd(dppf)Cl₂(55mg,0.075mmol) and KOAc (441mg,4.5 mmol). The reaction mixture was then reacted for an additional 3 hours at 90 ℃ under nitrogen atmosphere. After cooling, the reaction mixture was filtered through celite and the organic solvent was concentrated in vacuo. The residue was then dissolved in EtOAc (75mL) and washed with water (75 mL. times.2). The combined organic layers were washed with saturated brine (30mL) and anhydrous MgSO₄Drying, filtering and vacuum concentrating. The residue was purified by silica gel column (0-35% EtOAc in DCM/hexanes (1:1)) to give N- (3-ethoxy-5-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) -5-fluoro-2-methoxybenzamide A6e (235mg, 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 procedure analogous to step 4 of example A5, using 5-iodo-7-isopropylimidazo [5,1-f][1,2,4]Triazin-4-amine Int-1 and N- (3-ethoxy-5-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxan)Pentaborane-2-yl) benzyl) -5-fluoro-2-methoxybenzamide A6e preparation of example A6, step 5. The crude mixture was purified by preparative HPLC using ACN/H₂Eluting with O/TFA to obtain N- (4- (4-amino-7-isopropyl imidazo [5, 1-f)][1,2,4]Triazin-5-yl) -3-ethoxy-5-fluorobenzyl) -5-fluoro-2-methoxybenzamide a 6.

¹H 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, 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, 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, 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, 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- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) -5-fluoro-2-methoxybenzamide A6e (25mg,0.056mmol), 5-iodo-7- (1,1, 1-trifluoropropan-2-yl) imidazo [5, 1-f) is reacted at 85 ℃ under nitrogen][1,2,4]Triazin-4-amine Int-2(16mg,0.045mmol), Pd (dppf) Cl₂(4mg,0.0045mmol) and Cs₂CO₃A mixture of (29mg,0.090mmol) in 1, 4-dioxane (0.25mL) and water (0.04mL) was stirred for 1 hour. After cooling, the mixture was concentrated in vacuo and the resulting residue was purified by preparative HPLCMeCN/H₂Elution with O/TFA to give N- (4- (4-amino-7- (1,1, 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).

¹H 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, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-ethoxy-5-fluorobenzyl) -5-fluoro-2-methoxybenzamide A7a

N- (3-ethoxy-5-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) -5-fluoro-2-methoxybenzamide A6e (134mg,0.3mmol), Int-2A (71mg,0.2mmol), XPhos-Pd-G at 80 ℃ under nitrogen₂1, 4-dioxane (3.5mL) (8mg,0.01mmol) and potassium phosphate (85mg,0.4mmol) was stirred with water (0.5mL) 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/hexanes (1:1)) to give the title compound A7a (54mg, 49% yield).

¹H NMR(400MHz,CDCl₃):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 3N- (4- (4-amino-7- ((S) -1,1, 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- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) -5-fluoro-2-methoxybenzamide A6e (134mg,0.3mmol), Int-2B (71mg,0.2mmol), XPhos-Pd-G at 80 ℃ under nitrogen₂A mixed solution of 1, 4-dioxane (3.5mL) (8mg,0.01mmol) and potassium phosphate (85mg,0.4mmol) in water (0.5mL) was stirred for reaction for 1 hour. After cooling, the reaction mixture was concentrated and the residue was purified by silica gel column (0-8% MeOH in DCM/hexanes (1:1)) to giveThe title compound A7b (65mg, 60% yield).

¹H NMR(400MHz,CDCl₃):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(5.6mg,0.02mmol) and TEA (6mg,0.06mmol) in DCM (1mL) was added 2-methoxybenzoic acid A8a (3mg,0.02mmol) followed by EDCI (4mg,0.02mmol) and HOBt (2.7mg,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(5.6mg, 67% yield).

¹H 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

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 as step 1 of example A8, using 5- (4- (aminomethyl) phenyl) -7-isopropylimidazo [5, 1-f)][1,2,4]Triazine-4-amine Int-3 and 2-fluoro-6-methoxybenzoic acid A9a preparation example A9. The crude mixture was purified by preparative HPLC using ACN/H₂Eluting with O/TFA to obtain N- (4- (4-amino-7-isopropyl imidazo [5, 1-f)][1,2,4]Triazin-5-yl) benzyl) -2-fluoro-6-methoxybenzamide a 9.

¹H 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 as step 1 of example A8, using 5- (4- (aminomethyl) phenyl) -7-isopropylimidazo [5, 1-f)][1,2,4]Triazine-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/H₂O/TFA elution to give N- (4- (4-amino-7-isopropylimidazo [5, 1-f)][1,2,4]Triazin-5-yl) benzyl) -3-fluoro-2-methoxybenzamide a 10.

¹H 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 as step 1 of example A8, using 5- (4- (aminomethyl) phenyl) -7-isopropylimidazo [5, 1-f)][1,2,4]Preparation of example A11 with triazin-4-amine Int-3 and 2- (trifluoromethoxy) benzoic acid A11 a. The crude mixture was purified by preparative HPLC using ACN/H₂Eluting with O/TFA to obtain N- (4- (4-amino-7-isopropyl imidazo [5, 1-f)][1,2,4]Triazin-5-yl) benzyl) -2- (trifluoromethoxy) benzamide a 11.

¹H 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 as step 1 of example A8, using 5- (4- (aminomethyl) phenyl) -7-isopropylimidazo [5, 1-f)][1,2,4]Preparation of example A12 with triazin-4-amine Int-3 and 2- (difluoromethoxy) benzoic acid A12 a. Mixing the crude productPurification by preparative HPLC using ACN/H₂Eluting with O/TFA to obtain N- (4- (4-amino-7-isopropyl imidazo [5, 1-f)][1,2,4]Triazin-5-yl) benzyl) -2- (difluoromethoxy) benzamide a 12.

¹H 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

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 as step 1 of example A8, using 5- (4- (aminomethyl) phenyl) -7-isopropylimidazo [5, 1-f)][1,2,4]Triazin-4-amine Int-3 and benzo [ d][1,3]Dioxole-4-carboxylic acid A13a example A13 was prepared. The crude mixture was purified by preparative HPLC using ACN/H₂Eluting with O/TFA to obtain N- (4- (4-amino-7-isopropyl imidazo [5, 1-f)][1,2,4]Triazin-5-yl) benzyl) benzo [ d][1,3]Dioxole-4-carboxamide A13.

¹H 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 as step 1 of example A8, using 5- (4- (aminomethyl) phenyl) -7-isopropylimidazo [5, 1-f)][1,2,4]Triazine-4-amine Int-3 and 2, 2-difluorobenzo [ d][1,3]Dioxole-4-carboxylic acid A14a example A14 was prepared. The crude mixture was purified by preparative HPLC using ACN/H₂Eluting with O/TFA to obtain N- (4- (4-amino-7-isopropyl imidazo [5, 1-f)][1,2,4]Triazin-5-yl) benzyl) -2, 2-difluorobenzo [ d][1,3]Dioxole-4-carboxamide A14.

¹H 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 as step 1 of example A8, using 5- (4- (aminomethyl) phenyl) -7-isopropylimidazo [5, 1-f)][1,2,4]Preparation of example A15 with triazin-4-amine Int-3 and pyridine carboxylic acid A15 a. The crude mixture was purified by preparative HPLC using ACN/H₂Eluting with O/TFA to obtain N- (4- (4-amino-7-isopropyl imidazo [5, 1-f)][1,2,4]Triazin-5-yl) benzyl) picolinamide a 15.

¹H 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-methoxynicotinamide A16

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

In a similar procedure as step 1 of example A8, using 5- (4- (aminomethyl) phenyl) -7-isopropylimidazo [5, 1-f)][1,2,4]Preparation of example A16 with triazin-4-amine Int-3 and 4-methoxynicotinic acid A16 a. The crude mixture was purified by preparative HPLC using ACN/H₂Eluting with O/TFA to obtain N- (4- (4-amino-7-isopropyl imidazo [5, 1-f)][1,2,4]Triazin-5-yl) benzyl) -4-methoxynicotinamide a 16.

¹H 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

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 as step 1 of example A8, using 5- (4- (aminomethyl) phenyl) -7-isopropylimidazo [5, 1-f)][1,2,4]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/H₂Eluting with O/TFA to obtain N- (4- (4-amino-7-isopropyl imidazo [5, 1-f)][1,2,4]Triazin-5-yl) benzyl) chromane-8-carboxamide a 17.

¹H 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 as step 1 of example A8, using 5- (4- (aminomethyl) phenyl) -7-isopropylimidazo [5, 1-f)][1,2,4]Preparation of example A18 with triazin-4-amine Int-3 and 2, 3-dihydrobenzofuran-7-carboxylic acid A18 a. The crude mixture was purified by preparative HPLC using ACN/H₂Eluting with O/TFA to obtain N- (4- (4-amino-7-isopropyl imidazo [5, 1-f)][1,2,4]Triazin-5-yl) benzyl) -2, 3-dihydrobenzofuran-7-carboxamide a 18.

¹H 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 as step 1 of example A8, using 5- (4- (aminomethyl) phenyl) -7-isopropylimidazo [5, 1-f)][1,2,4]Preparation of example A19 with triazine-4-amine Int-3 and 3-methoxythiophene-2-carboxylic acid A19 a. The crude mixture was purified by preparative HPLC using ACN/H₂Eluting with O/TFA to obtain N- (4- (4-amino-7-isopropyl imidazo [5, 1-f)][1,2,4]Triazin-5-yl) benzyl) -3-methoxythiophene-2-carboxamide a 19.

¹H 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 as step 1 of example A8, using 5- (4- (aminomethyl) phenyl) -7-isopropylimidazo [5, 1-f)][1,2,4]Preparation of example A20 with triazin-4-amine Int-3 and 2- (dimethylamino) benzoic acid A20 a. The crude mixture was purified by preparative HPLC using ACN/H₂Eluting with O/TFA to obtain N- (4- (4-amino-7-isopropylimidazole)And [5,1-f ]][1,2,4]Triazin-5-yl) benzyl) -2- (dimethylamino) benzamide a 20.

¹H 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

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 as step 1 of example A8, using 5- (4- (aminomethyl) phenyl) -7-isopropylimidazo [5, 1-f)][1,2,4]Preparation of example A21 with triazine-4-amine Int-3 and 4-methoxythiophene-3-carboxylic acid A21 a. The crude mixture was purified by preparative HPLC using ACN/H₂Eluting with O/TFA to obtain N- (4- (4-amino-7-isopropyl imidazo [5, 1-f)][1,2,4]Triazin-5-yl) benzyl) -4-methoxythiophene-3-carboxamide a 21.

¹H 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 as step 1 of example A8, using 5- (4- (aminomethyl) phenyl) -7-isopropylimidazo [5, 1-f)][1,2,4]Preparation of example A22 with triazin-4-amine Int-3 and 2- (methylsulfonyl) benzoic acid A22 a. The crude mixture was purified by preparative HPLC using ACN/H₂O/TFA elution to give N- (4- (4-amino-7-isopropylimidazo [5, 1-f)][1,2,4]Triazin-5-yl) benzyl) -2- (methylsulfonyl) benzamide a 22.

¹H 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 12, 5-bis (trimethylsilyl) bicyclo [4.2.0] octa-1 (6), 3-diene A23b

To a solution of lithium (3.97g,576mmol) in THF (300mL) at 0 deg.C was added TMSCl (46.9g,432mmol) slowly followed by the dropwise addition of 1, 2-dihydrobenzocyclobutene A23a (15g,144 mmol). The resulting reaction mixture was stirred at room temperature for 6 days. The reaction mixture was then aspirated off unreacted lithium using a syringe and quenched with MeOH (100mL) at 0 ℃. Water (250mL) was added and the resulting solution was extracted with PE (3X 200 mL). The combined organic layers were washed with brine (300mL) and over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo afforded the crude 2, 5-bis (trimethylsilyl) bicyclo [4.2.0]Octane-1 (6), 3-diene A23b (35g, 97%), which 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] octa-1, 3, 5-triene A23c

To crude 2, 5-bis (trimethylsilyl) bicyclo [4.2.0] at 40 deg.C]To a solution of octa-1 (6), 3-diene A23b (30.0g,120mmol) in THF (350mL) was added dropwise a solution of DDQ (13.62g,60mmol) 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 (500mL) and then extracted with EtOAc (250 mL). Water (500mL), saturated Na₂CO₃The organic layer was washed (750mL) and brine (350 mL). The combined organic layers were passed over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo afforded the crude 2, 5-bis (trimethylsilyl) bicyclo [4.2.0]Octa-1, 3, 5-triene A23c (27.6g, 93%) was used in the next step without further purification.

Step 32, 5-dibromo-bicyclo [4.2.0] octa-1, 3, 5-triene A23d

At 0 ℃ to Br₂(4.66mL,333mmol) in MeOH (50mL) was added crude 2, 5-bis (trimethylsilyl) bicyclo [4.2.0]A solution of octa-1, 3, 5-triene A23c (27.6g,111mmol) in MeOH (300 mL). The resulting reaction mixture was stirred at room temperature overnight, then quenched with water (300mL) and further extracted with PE (3X 200 mL). The combined organic layers were washed with brine (300mL) and over anhydrous Na₂SO₄Dried, 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] crude]Octa-1, 3, 5-triene A23d (16.38g, 57%) was used in the next step without further purification.

Step 4-5-Bromobicyclo [4.2.0] octa-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 octa-1, 3, 5-triene A23d (19.38g,74mmol) in THF (200mL) was added n-BuLi (2.5M,29.6mL,74mmol) dropwise. The mixture was stirred at-78 ℃ for 1h, then DMF (5.4g,74mmol) was added. The resulting reaction mixture was stirred at-78 ℃ for an additional 1 hour, then slowly warmed to room temperature, and then stirred for an additional 30 minutes. Reacting with saturated NH₄Cl (10mL) was quenched and extracted with EtOAc (3X 100 mL). Combining the organic layersWashed with brine (300mL) over anhydrous Na₂SO₄Dried, 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]Oct-1, 3, 5-triene-2-carbaldehyde A23e (12.4g, 79%).

¹H NMR(400MHz,CDCl₃):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 octa-1, 3, 5-triene-2-carbaldehyde A23e (12.4g,58.75mmol) in MeCN (130mL) was added methyl carbonate (6.6g,88.13mmol), followed by TFA (13.54g,117.5mmol) and TESH (13.7g,117.5 mmol). The mixture was slowly warmed to 80 ℃ and stirred for 16 hours. After cooling, the reaction was quenched with water (100mL) and extracted with EtOAc (3X 100 mL). The organic layer was washed with saturated Na₂CO₃Washing with aqueous solution, and passing through anhydrous Na₂SO₄Dried, 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)]Octyl-1, 3, 5-trien-2-yl) methyl) carbamic acid methyl ester A23f (4.0g, 25%).

LCMS:MS m/z(ESI):270.0[M+H]⁺。

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

To ((5-bromobicyclo [4.2.0]]To a solution of octyl-1, 3, 5-trien-2-yl) methyl) carbamate A23f (4.0g,14.86mmol) in THF: MeOH (1:1,40mL) was added an aqueous solution (20mL) of LiOH (6.6g,148.6mmol,10 eq.). The mixture was then heated to 80 ℃ and stirred for 16 hours. After cooling, the reaction was quenched with water (40mL) and extracted with EtOAc (3X 60 mL). The combined organic layers were washed with brine, over anhydrous Na₂SO₄Dried 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)]Octa-1, 3, 5-trien-2-yl) methylamine A23g (1.1g, 35%).

¹H NMR(400MHz,CDCl₃):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- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-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 procedure analogous to steps 1-3 of example A1, starting from (5-bromobicyclo [ 4.2.0)]Octa-1, 3, 5-trien-2-yl) methylamine a23g preparation example a23, steps 7-9 was started. The crude mixture was purified by preparative HPLC using ACN/H₂Elution with O/TFA 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 a 23.

¹H 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 the procedure of steps 1-3 of example A1, starting from (5-bromothien-2-yl) methylamine A24 a. The product was purified by preparative HPLC using ACN/H₂O/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 a 24.

¹H 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 the procedure of steps 1-3 of example A1, starting from (2-bromothiazol-5-yl) methylamine 25 a. The product was purified by preparative HPLC using ACN/H₂Elution with O/TFA 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 a 25.

¹H 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 a similar procedure as 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 atmosphere at-78 deg.C]Pentane-1-yl) methyl) -2-methoxybenzamide A26c (20mg,0.053mmol) in THF (3mL) was added ZnCl₂(0.5mL in THF, 1mL,0.5mmol) 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,1.02mmol) was added to the reaction mixture and the mixture was slowly warmed to room temperature. The resulting mixture was added to 5-iodo-7-isopropylimidazo [5,1-f ] under nitrogen atmosphere][1,2,4]Triazine-4-amine Int-1(40mg,0.13mmol), Pd (PPh)₃)₄(10mg) and Pd (dppf) Cl₂(10mg) in a mixture of THF (3 mL). The resulting mixture was slowly warmed to 80 ℃ and stirred at that temperature overnight. After cooling, the residue was flash purified by silica gel column chromatography (DCM: MeOH) and then further purified by preparative HPLC using ACN/H₂Eluting with O/formic acid to obtain N- ((3- (4-amino-7-isopropyl imidazo [5, 1-f)][1,2,4]Triazin-5-yl) bicyclo [1.1.1]Pentan-1-yl) methyl) -5-fluoro-2-methoxybenzamide a26(0.7mg, 3% yield).

¹H 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(45mg,0.13mmol), (2-ethoxy-4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) boronic acid A3g (56mg,0.13mmol), K₂CO₃(54mg,0.39mmol) and Pd (dppf) Cl₂A mixture of (9.5mg,0.013mmol) in 1, 4-dioxane: water (4:1,3mL) was stirred for 16 h. After cooling, the resulting mixture was filtered through celite. Concentrating the filtrate with Na₂SO₄Redissolved and concentrated in vacuo. The residue was purified by preparative HPLC using MeCN/H₂O/TFA elution gave the title compound 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(23mg, 34% yield).

¹H NMR(400MHz,DMSO-d₆):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, 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

To 4-bromo-3-methoxybenzonitrile A28a (5g,23.58mmol) was added BH under nitrogen at 85 deg.C₃THF (1N THF,235mL) 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 (7.10g, yield100%) which was used in the next step without further purification.

LCMS:MS m/z(ESI):199.1[M-NH₂]⁺. Step 2N- (4-bromo-3-methoxyphenyl) -5-fluoro-2-methoxybenzamide A28c

To a solution of (4-bromo-3-methoxyphenyl) methylamine A28b (7.10g,23.58mmol) and 5-fluoro-2-methoxybenzoic acid (4.01g,23.58mmol) in DMF (150mL) was added HATU (13.45g,35.37mmol) and TEA (11.93g,117.90 mmol). The reaction mixture was stirred at room temperature for 30 min. Then, the reaction was quenched by addition of water (100mL) and extracted with EtOAc (100 mL. times.3). The organic phase is passed through Na₂S₂O₃(1M, 2X 50mL) of the aqueous solution and saturated brine (3X 30mL) were washed with anhydrous Na₂SO₄Drying, filtering and vacuum concentrating. The residue was purified by silica gel column (PE: EtOAc ═ 2:1) to give N- (4-bromo-3-methoxyphenyl) -5-fluoro-2-methoxybenzamide a28c (7.1g, 81.78% yield).

LCMS:MS m/z(ESI):370.3[M+H]⁺。

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

N- (4-bromo-3-methoxyphenyl) -5-fluoro-2-methoxybenzamide A28c (4g,10.86mmol), (BPin) was reacted at 90 ℃ under argon₂(8.28g,32.59mmol)、Pd(PPh₃)Cl₂A solution of (760.46mg,1.09mmol) and KOAc (3.20g,32.59mmol) in 1, 4-dioxane (80mL) was stirred overnight for reaction. The reaction mixture was cooled and concentrated in vacuo, and the residue was purified by silica gel column (PE: EtOAc ═ 2:1) to give 5-fluoro-2-methoxy-N- (3-methoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) benzamide a28d (3.4g, 75.37% yield).

¹H NMR(400MHz,DMSO-d₆):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, 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- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) benzamide A28d (82mg, 197.5. mu. mol), Int-2B (70.51mg, 197.47. mu. mol), Pd (dppf) Cl at 100 ℃ under nitrogen atmosphere₂.CH₂Cl₂(16.44mg, 19.75. mu. mol) and K₂CO₃A solution of (81.88mg, 592.40. mu. mol) in 1, 4-dioxane (4mL) was stirred overnight for reaction. Cool, the reaction mixture was concentrated in vacuo, and the residue was purified by column on silica gel (DCM: MeOH ═ 100:1) to give the title compound a28(90mg, 87.91% yield).

¹H NMR(400MHz,DMSO-d₆):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, 1-trifluoropropan-2-yl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-cyclopropaneoxybenzyl) -5-fluoro-2-methoxybenzamide A29

Step 1 Ethyl 4-bromo-3- (2-chloroethoxy) benzoate A29a

Ethyl 4-bromo-3-hydroxybenzoate A3a (25g,102.01mmol), 2-chloroethyl 4-methylbenzenesulfonate (23.94g,102.01mmol) and Cs were reacted at 70 deg.C₂CO₃A solution of (64g,204.02mmol) in DMF (300mL) was stirred for 3 hours. After cooling, the reaction mixture was diluted with water and extracted with EtOAc (2L). Anhydrous Na is used for mixed organic phase₂SO₄Drying, filtering and vacuum concentrating. The residue was purified by silica gel column (PE: EtOAc ═ 5:1) to give 4-bromo-3- (2-chloroethoxy) benzoic acid ethyl ester a29a (20g, 63.74% yield).

¹H NMR(400MHz,CDCl₃):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

4-bromo-3- (2-chloroethoxy) benzoic acid ethyl ester A29a (20g,65.03mmol) and KO were mixed at 75 deg.C^tBu (35g,325.13mmol) in THF (300mL) was stirred for 3 hours. After cooling, the reaction mixture was diluted with water and extracted with EtOAc (1L). Anhydrous Na is used for mixed organic phase₂SO₄Drying, filtration and concentration in vacuo afforded crude 4-bromo-3- (vinyloxy) benzoic acid A29b (10g, yield 63.27%), which was used in the next step without further purification.

LCMS:MS m/z(ESI):241.1[M-H]^-。

Step 3 methyl 4-bromo-3- (vinyloxy) benzoate A29c

4-bromo-3- (vinyloxy) benzoic acid A29b (10g,41.14mmol), methyl iodide (11.68g,82.29mmol) and K at room temperature₂CO₃A solution of (17g,123.43mmol) in DMF (100mL) was stirred for 15 h. The reaction mixture was diluted with water and extracted with EtOAc (500 mL). The mixed organic phase adopts anhydrous Na₂SO₄Drying, filtering and vacuum concentrating. The residue was purified by silica gel column (PE: EtOAc ═ 10:1) to give methyl 4-bromo-3- (vinyloxy) benzoate a29c (8g, yield 75.64%).

¹H NMR(400MHz,CDCl₃):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- (cyclopropaneoxy) benzoate A29d

A solution of 4-bromo-3- (vinyloxy) benzoic acid methyl ester A29C (8g,31.12mmol) and chloro (iodo) methane (19.76g,112.03mmol) in DCE (100mL) was stirred at 0 ℃ for 20min under nitrogen and then Zn (C) was added dropwise₂H₅)₂In hexane (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 Na₂SO₄Drying, filtering and vacuum concentrating. The residue was purified by silica gel column (PE: EtOAc ═ 3:1) to giveTo methyl 4-bromo-3- (cyclopropaneoxy) benzoate A29d (5g, yield 59.27%).

¹H NMR(400MHz,CDCl₃):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-cyclopropaneoxybenzamide A29e

4-bromo-3- (cyclopropyloxy) benzoic acid methyl ester A29d (1.3g,4.80mmol) and NH were placed in a sealed tube at 80 deg.C₄OH (33% aq, 20mL) was stirred overnight. After cooling, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel column (DCM: MeOH ═ 15:1) to give 4-bromo-3-cyclopropaneoxybenzamide a29e (1.01g, yield 82.25%).

LCMS:MS m/z(ESI):256.0[M+H]⁺。

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

4-bromo-3-cyclopropaneoxybenzamide A29e (1.51g,5.90mmol) was reacted at 60 ℃ with BH₃A solution of/THF (1N THF,25mL) was stirred overnight. After cooling, the reaction was quenched with MeOH (10mL) and TFA (30 mL). The reaction mixture was concentrated in vacuo to give crude (4-bromo-3-cyclopropyloxyphenyl) methylamine a29f (2.0g, 100.00% yield), which was used in the next step without further purification.

LCMS:MS m/z(ESI):225.1[M-H₂O]⁺。

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

To a solution of (4-bromo-3-cyclopropaneoxyphenyl) methylamine A29f (1.43g,5.91mmol) and 5-fluoro-2-methoxybenzoic acid (1.00g,5.91mmol) in DMF (40mL) was added HATU (3.37g,8.86mmol) and TEA (2.99g,29.53 mmol). The reaction solution was stirred at room temperature for 30min, and then quenched by addition of water. The reaction mixture was then extracted with EtOAc (250 mL). Anhydrous Na is used for mixed organic phase₂SO₄Drying, filtering and vacuum concentrating. The residue was purified by silica gel column (PE: EtOAc ═ 3:1) to give N- (4-bromo-3-cyclopropaneoxybenzyl) -5-fluoro-2-methoxybenzamide a29g (1.84g, 79.02% yield).

¹H NMR(400MHz,DMSO-d₆):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-Cyclopropaneoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) -5-fluoro-2-methoxybenzamide A29h

N- (4-bromo-3-cyclopropaneoxybenzyl) -5-fluoro-2-methoxybenzamide A29g (1g,2.54mmol), (BPin) was reacted at 90 ℃ under nitrogen₂(1.93g,7.61mmol)、Pd(PPh₃)Cl₂A solution of (177.56mg, 253.66. mu. mol) and KOAc (746.82mg,7.61mmol) in 1, 4-dioxane (20mL) was stirred overnight. After cooling, the reaction mixture was concentrated in vacuo. The residue was purified by column on silica gel (PE: EA ═ 2:1) to give N- (3-cyclopropaneoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl) -5-fluoro-2-methoxybenzamide a29h (850mg, yield 75.93%).

LCMS:MS m/z(ESI):442.1[M+H]⁺。

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

N- (3-Cyclopropaneoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl) -5-fluoro-2-methoxybenzamide A29h (74.00mg, 167.69. mu. mol), Int-2B (59.88mg, 167.69. mu. mol), Pd (dppf) Cl at 100 ℃ under a nitrogen atmosphere₂.CH₂Cl₂(13.96mg, 16.77. mu. mol) and K₂CO₃(69.53mg, 503.06. mu. mol) was stirred overnight into a mixture of 1, 4-dioxane (4mL) and water (1 mL). 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(50mg, yield 54.76%).

¹H NMR(400MHz,DMSO-d₆):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

5-fluoro-2-methoxy-N- (3-methoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) benzamide A28d (60mg,0.17mmol), 5-iodo-7- (tetrahydrofuran-2H-pyran-4-yl) imidazo [5, 1-f) was reacted at 85 ℃ under a nitrogen atmosphere][1,2,4]Triazin-4-amine Int-4(65mg,0.17mmol), Pd (dppf) Cl₂(12mg,0.017mmol) and K₂CO₃(70mg,0.51mmol) was stirred in a mixture of 1, 4-dioxane/water (4/1,3mL) 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(30mg, 34% yield).

¹H NMR(400MHz,DMSO-d₆):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) at 85 deg.C][1,2,4]Triazin-4-amine Int-4(70mg,0.18mmol), 5-fluoro-2-methoxy-N- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) benzamide A1c (65mg,0.18mmol), pd (dppf) Cl₂(13mg,0.018mmol) and K₂CO₃(74mg,0.54mmol) was stirred in a mixture of 1, 4-dioxane/water (4/1,3mL) 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(35mg, 39% yield).

¹H NMR(400MHz,DMSO-d₆):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-cyclopropaneoxybenzyl) -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-cyclopropaneoxybenzyl) -5-fluoro-2-methoxybenzamide A32

Pd (dppf) Cl was added at 85 ℃ under nitrogen atmosphere₂.CH₂Cl₂(14.53mg, 17.45. mu. mol), N- (3-cyclopropaneoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) -5-fluoro-2-methoxybenzamide A29h (77mg,174.48mmol), 5-iodo-7- (tetrahydrofuran)pyran-2H-pyran-4-yl) imidazo [5,1-f][1,2,4]Triazin-4-amine Int-4(60.22mg,174.48mmol) and K₂CO₃(72.35mg,523.45mmol) was stirred in a mixture of 1, 4-dioxane (4mL) and water (1mL) 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-cyclopropaneoxybenzyl) -5-fluoro-2-methoxybenzamide A32(40mg, 43.05% yield).

¹H NMR(400MHz,DMSO-d₆):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) at 100 ℃][1,2,4]Triazin-4-amine Int-5(20mg,0.06mmol), Pd (dppf) Cl₂.CH₂Cl₂(5mg,0.006mmol), 5-fluoro-2-methoxy-N- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) benzamide A1c (23mg,0.06mmol) and K₂CO₃(25mg,0.18mmol) was stirred in a mixture of 1, 4-dioxane (2mL) and water (0.5mL) 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(2mg, 7.14% yield).

¹H NMR(400MHz,DMSO-d₆):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, 5-iodo-7- (tetrahydrofuran-2H-pyran-4-yl) imidazo [5, 1-f) at 80 deg.C][1,2,4]Triazin-4-amine Int-4(26mg,0.075mmol), N- (3-ethoxy-5-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) -5-fluoro-2-methoxybenzamide A6e (50mg,0.113mmol), XPhos-Pd-G₂(4.5mg,0.0056mmol) and potassium phosphate (40mg,0.188mmol) were stirred in a mixture of 1, 4-dioxane (1.25mL) and water (0.25mL) for 1.5 hours. After cooling, the reaction mixture was concentrated and the residue was purified by silica gel chromatography (0-8% MeOH in DCM/hexanes (1:1)) 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(28mg, 70% yield).

¹H NMR(400MHz,CDCl₃):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 assay

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 Activity test of the Compounds of the present disclosure on BTK-WT and BTK-C481S kinase

These tests determined the degree of inhibition of the activity of BTK-WT and BTK-C481S mutant kinases 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 (baculovir) infected Sf9 cells. Km values for ATP and the substrate poly (4:1 glutamate, tyrosine) (Signal Chem, P61-58) in the assay were determined to be 30. mu.M and 2 ng/. mu.L, respectively. The compound, BTK enzyme, ATP and substrate were all prepared in 1 Xkinase assay buffer using H₂Stock 5 Xkinase assay buffer III (Signal Chem, K03-09) was diluted O and DTT (Thermo Scientific, A39255) was added to reach a final concentration of 50. mu.M. The compound and BTK kinase protein were dispensed in a total volume of 5 μ Ι _ into a solid white flat bottom 384 well plate (Corning, 3824) and spun at 1000rpm for 2 minutes. The plate was then kept shaking at room temperature for 30min to allow the compound to bind to the protein. After pre-incubation, a total of 5 μ L ATP and substrate were added to each well. The plate was then spun at 1000rpm for 2 minutes and shaken at room temperature for 90 minutes. ADP detection was performed according to the guidance 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 spun at 1000rpm for 2 minutes and shaken at room temperature for 60 minutes. 20 μ L of kinase detection solution was added to each well. The plates were incubated for 30 minutes at room temperature in the dark. Immediately after incubation for 30 minutes, the plate was read for luminescence signal in Tecan M1000. Relative inhibition of BTK kinase activity was analyzed by calculating the change in luminescence signal:

data were input into GraphPad Prism and IC calculated using the function "log (inhibitor) versus response — variable slope (four parameters)"₅₀The value is obtained.

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

Test example 2 in HEK293 cells carrying stably expressed BTK-WT and BTK-C481S, Compounds of the disclosure BTK-Y223 autophosphorylation

HEK293 cells stably expressing either wild type BTK or mutant C481S BTK (purchased from ATCC, CRL1573) were generated by lentivirus transduction of constructs (constracts) containing either human BTK-WT or BTK-C481S mutant (Genecopoeia, Lv201 vector). Cells expressing BTK protein were selected by treatment with puromycin (1 μ M). Protein expression was confirmed by western blotting of BTK and autophosphorylation of BTK-Y223. 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 Pho-Y223 kit (Cisbio, 63ADK017 PEG). HEK293/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% CO₂The cells were incubated overnight at 37 ℃ in a cell incubator. The next day, at 37 ℃, in 5% CO in moisture₂In the cell incubator, cells were treated with diluted compounds for 2 hours. The medium was removed from each well and 50 μ Ι _ of 1X lysis buffer from the assay kit was added to each well. Cells were incubated at room temperature for 30 minutes with shaking. Then 16 μ L of lysate was transferred to a PROXIPLATE 384 well plate (Perkinelmer, 6008230) and 4 μ L of HTRF pre-mix antibody was added. After overnight incubation at room temperature, the fluorescence signal in the plate was read on a PHERAStar FSX instrument using an HTRF setting (665nM/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 to GraphPad Prism using the function "log (inhibitor) versus response- -variable slope (four parameters)" to obtain IC₅₀The value is obtained.

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

Test example 3 BTK-dependent cell proliferation in human TMD-8 diffuse Large B-cell lymphoma cells with Compounds of the present disclosure Action of reproduction

Human TMD-8DLBCL cancer cells were cultured in RPMI medium with high glucose and glutamine (Genesee, 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 minutes and the cells were resuspended in fresh cell culture medium. Cells were counted and made into 130 ten thousand/mL cell stock. Then 75 μ L of cells were seeded into each well of a white 96-well cell culture plate (Corning # 353286). Dilutions of a series of compounds were prepared and 25 μ L was added to each well. Plates were incubated at 37 ℃ in moist 5% CO₂Incubate in atmosphere for 3 days. The inhibitory effect of compounds on Cell growth 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. Mixing 100 μ L

Reagents were added to each cell culture well and their contents were mixed on an orbital shaker for 2 minutes to induce cell lysis. The plate was incubated at room temperature for 10 minutes to stabilize the luminescence signal. The resulting luminescence signal was immediately read using a TECAN reader. Relative Cell growth inhibition was calculated by the change in Cell Titer-Glo luminescence signal.

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

Data were input into GraphPad Prism and curve fitted using the function "log (inhibitor) versus response — variable slope (four parameters)". Computing absolute IC using interpolation function₅₀The value is obtained.

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

Example numbering	IC₅₀(nM)
		A1	27
A2	99
		Compounds corresponding to shorter retention times in A2a and A2b	73
Combinations of A2a and A2b with longer retention timesArticle (A)	20
		A3	38
A4	17
		Compounds corresponding to shorter retention times in A4a and A4b	23
Compounds corresponding to longer retention times in A4a and A4b	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 of formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

R²Selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, 3-to 6-membered cycloalkyl, heterocyclyl, aryl and heteroarylA group; wherein said alkyl, 3-to 6-membered cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by a group selected from halogen, alkyl, haloalkyl, -NR^7aR^7b、-OR⁸、-OC(O)R⁹、-C(O)R⁹、-C(O)OR⁸、-NR^dC(O)R⁹、-C(O)NR^7aR^7b、-NR^dS(O)_tR⁹、-S(O)_tR⁹、-S(O)_tOR⁸、-S(O)_tNR^7aR^7bCyano, oxo, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

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

or two adjacent R³Substituents together with ring a may be optionally linked to form cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more groups selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxy, oxo and hydroxyalkyl;

L₁is-CR^aR^b-；

L₂is-NR^c-；

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

each occurrence of R⁴Are identical or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, cyano, -NR^10aR^10b、-OR¹¹、-S(O)_tR¹²Hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with a substituent selected from the group consisting of halogen, alkyl, haloalkyl, -NR^7aR^7b、-OR⁸Cyano, oxo, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

or two adjacent R⁴Substituents together with ring B may optionally be linked to form cycloalkyl, heterocyclyl, aryl and heteroaryl groups; wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more groups selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxy, oxo and hydroxyalkyl;

R⁵、R^6a、R^6b、R^7a、R^7b、R⁸、R⁹、R^10a、R^10b、R¹¹and R¹²Are 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 are each independently optionally substituted with one or more groups selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxy, oxo, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

t is 0,1 or 2;

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

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

2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L₁is-CR^aR^b-，R^aAnd R^bAre all hydrogen.

3. According to claimThe compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein L₂is-NR^c-，R^cIs hydrogen.

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is a compound of formula (II):

or a pharmaceutically acceptable salt thereof,

wherein:

ring A, ring B, R¹To R⁴M and n are as defined in claim 1.

5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R¹Selected from hydrogen, C_1-6Alkyl, -OR⁵、-NR^6aR^6bCyano and-C (O) NR^6aR^6b(ii) a Preferably, R¹is-NR^6aR^6b；R⁵、R^6aAnd R^6bAs defined in claim 1.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, is a compound of formula (III):

or a pharmaceutically acceptable salt thereof,

wherein:

ring A, ring B, R²To R⁴M and n are as defined in claim 1.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from 3 to 8 membered cycloalkyl3-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

8. the compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein 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; preferably, ring B is phenyl or 5 or 6 membered heteroaryl; more preferably, ring B is selected from phenyl, pyridyl, thienyl and thiazolyl.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R²Is selected from C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Hydroxyalkyl, 3-to 6-membered cycloalkyl and 3-to 12-membered heterocyclyl.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein each occurrence of R³Are the same or different and are each independently selected from hydrogen, halogen, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Hydroxyalkyl, cyano and-OR¹¹(ii) a Wherein R is¹¹Selected from hydrogen, C_1-6Alkyl radical, C_1-6Haloalkyl, 3-to 8-membered cycloalkyl and 3-to 12-membered heterocyclyl.

11. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein two adjacent R³Substituents together with ring a may optionally be linked to form a3 to 8 membered cycloalkyl; wherein said 3 to 8 membered cycloalkyl is optionally independently selected from halogen, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy and C_1-6In hydroxyalkyl radicalsSubstituted by one or more groups.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein each occurrence of R⁴Are the same or different and are each independently selected from hydrogen, halogen, C_1-6Alkyl, -NR^10aR^10b、-OR¹¹、-S(O)_tR¹²And C_1-6A hydroxyalkyl group; wherein R is^10a、R^10b、R¹¹And R¹²Are the same or different and are each independently selected from hydrogen, C_1-6Alkyl and C_1-6A haloalkyl group; t is 2.

13. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein two adjacent R⁴Substituents together with ring B may optionally be linked to form a 3-to 12-membered heterocyclyl; wherein said 3-to 12-membered heterocyclyl is optionally independently selected from halogen, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy and C_1-6Substituted with one or more groups of hydroxyalkyl groups.

14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

15. a compound of formula (IIB):

or a salt thereof,

wherein:

ring A, R¹To R³And m is as defined in claim 4.

16. A compound or salt thereof selected from:

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

wherein:

x is halogen; preferably, X is iodine;

y is selected from halogen,

R is hydrogen or alkyl; and is

Ring A, ring B, L₁、L₂、R¹To R⁴M and n are as defined in claim 1.

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

wherein:

R^tselected from halogen, hydroxy and alkoxy; and

ring A, ring B, R¹To R⁴M and n are as defined in claim 4.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

20. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 or a pharmaceutical composition according to claim 19 in the manufacture of a medicament for the treatment of a disease or disorder modulated by BTK.

21. The use according to claim 20, wherein the disease or disorder modulated by BTK is selected from cancer, immune diseases, cardiovascular diseases, viral infections, inflammation, metabolic/endocrine function disorders and neurological disorders; preferably, the disease or disorder modulated by BTK is selected from the group consisting of B-cell malignancies, B-cell lymphomas, diffuse large B-cell lymphomas, chronic lymphocytic leukemia, non-hodgkin's lymphoma, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia, B-cell non-hodgkin's lymphoma, waldenstrom's macroglobulinemia, multiple myeloma, bone cancer, bone metastases, arthritis, multiple sclerosis, osteoporosis, irritable bowel syndrome, inflammatory bowel disease, crohn's disease, sjogren's syndrome, and lupus.

22. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, or a pharmaceutical composition according to claim 19, in the manufacture of a medicament for the treatment of a disease or condition selected from: b cell malignancies, B cell lymphomas, diffuse large B cell lymphomas, 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, follicular lymphoma, 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 effusion lymphoma, Burkitt lymphoma/leukemia, lymphoma-like granulomas, inflammatory bowel disease, colon cancer, and colon cancer, and colon cancer, Arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, still's disease, juvenile arthritis, diabetes, myasthenia gravis, hashimoto's thyroiditis, aldthyroiditis, graves ' disease, sjogren's syndrome, multiple sclerosis, guillain-barre syndrome, acute disseminated encephalomyelitis, addison's disease, clonotrysm syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, reiter's syndrome, takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, wegener's granulomatosis, psoriasis, alopecia universalis, behcet's disease, chronic fatigue, familial autonomic nerve abnormality, multiple sclerosis, diabetes mellitus, myasthenia gravis syndrome, hashimoto's syndrome, autoimmune disease, autoimmune hemolytic anemia, rheumatoid arthritis, autoimmune anemia, rheumatoid arthritis, multiple sclerosis, endometriosis, interstitial cystitis, neuromuscular stiffness, scleroderma, vulvodynia, graft-versus-host disease, transplantation, blood transfusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, atopic dermatitis, asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, lymphadenitis, and other diseases, Phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, vulvitis, pulmonary fibrosis, Idiopathic Pulmonary Fibrosis (IPF), interstitial pneumonia of the general type (UIP), interstitial lung disease, Cryptogenic Fibrosing Alveolitis (CFA), bronchiolitis obliterans, bronchiectasis, fatty liver disease, steatosis (e.g., non-alcoholic 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, hepatitis c, b or delta hepatitis), autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD), progressive massive fibrosis, exposure to toxins or irritants (e.g., alcohol, drugs, and environmental toxins), renal fibrosis (e.g., chronic renal fibrosis), kidney disease associated with injury/fibrosis (e.g., chronic kidney disease associated with diabetes (e.g., diabetic nephropathy)), lupus, nephroscleroderma, glomerulonephritis, focal segmental glomerulosclerosis, IgA renal fibrosis associated with human Chronic Kidney Disease (CKD), chronic progressive kidney disease (CPN), tubulointerstitial fibrosis, ureteral occlusion, chronic uremia, chronic interstitial nephritis, radiation nephropathy, glomerulosclerosis, Progressive Glomerulonephritis (PGN), endothelial/thrombotic microangiopathy injury, kidney disease associated with HIV, or exposure to toxins, inflammatory bowel disease, Progressive Glomerulosclerosis (PGN), endothelial/thrombotic microangiopathy injury, kidney disease associated with HIV, or kidney disease associated with exposure to toxins, inflammatory bowel disease, irritation or chemotherapeutic agent-related fibrosis, scleroderma-related fibrosis; radiation-induced intestinal fibrosis; fibrosis associated with inflammatory diseases of the foregut, such as barrett's esophagus and chronic gastritis, and/or fibrosis associated with inflammatory diseases of the hindgut, such as Inflammatory Bowel Disease (IBD), ulcerative colitis and crohn's disease, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity and neovascular glaucoma.