CN113264945A

CN113264945A - Spiro derivative, preparation method and medical application thereof

Info

Publication number: CN113264945A
Application number: CN202110184884.0A
Authority: CN
Inventors: 赵鹏; 王祥柱; 庄凌航; 武和平; 黄菘; 董平; 李心; 胡齐悦; 周玉; 刘苏星; 贺峰; 陶维康
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Shandong Shengdi Pharmaceutical Co ltd; Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2020-02-17
Filing date: 2021-02-10
Publication date: 2021-08-17
Anticipated expiration: 2041-02-10
Also published as: CN113264945B

Abstract

The invention relates to a spiro derivative, a preparation method thereof and application thereof in medicine. In particular, the disclosure relates to a spiro derivative represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and a use of the derivative as a therapeutic agent, in particular, a use of the derivative as a RAF inhibitor and a use of the derivative in preparation of a medicament for treating or preventing various diseases (including cancer) associated with over-expression RAF activity.

Description

Spiro derivative, preparation method and medical application thereof

Technical Field

The present invention relates to compounds and methods useful for inhibiting RAF. The invention further provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various diseases associated with over-expression of RAF activity, including cancer.

Background

The receptor tyrosine kinase RAF, also named rapid accelerated fibrosarcoma, is a serine/threonine specific protein kinase family from the TKL (tyrosine kinase-like) kinase group. There are three known mammalian subtypes of RAF: A. b and C-Raf (also called Raf-1). RAF kinase is involved in the RAS-RAF-MEK-ERK signaling reaction in the Mitotically Activated Protein Kinase (MAPK) cascade (Rapp UR et al, Structure and biological activity of v-RAF, a unique on gene transferred by a retroviruses, Proc Natl Acad Sci.1983; Sutrace P et al, Nucleotide sequence of video on gene v-RAF. Nature.1984; Moelling K et al, series-and thionic-specific protein kinase activity of purified gag-enzyme and gag-RAF proteins, Nature.1984). The Ras-Raf-MAPK channel coordinates various cellular responses by transmitting signals from membrane-bound receptors to a variety of membrane-based, cytoplasmic and nuclear targets, thereby controlling a variety of cellular physiological processes. Extensive studies have shown that RAF family kinases play a key role in regulating cell survival, proliferation, differentiation, apoptosis and many other physiological processes through MAPK cascades (Lavoie H et al, Regulation of RAF protein kinases in ERK signalling. nat. rev. mol. cell biol. 2015). Abnormalities of the Ras-Raf-MAPK channel are implicated in a variety of biological processes associated with human disease. Excessive activity of Ras-Raf-MAPK channel components is a common mechanism of proliferative diseases (e.g., cancer) (Wellbrock C et al, The RAF proteins take centre stage, Nat Rev Mol Cell biol. 2004; Leicht DT et al, Raf kinases: function, regulation and role in human cancer, Biochim Biophys acta.2007; Dhillon AS et al, MAP kinase signalling pathways in cancer, oncogene.2007).

In view of the close correlation between RAF activity and cancer, RAF has been used as a target for drug discovery in cancer therapy and the like. A wide range of ATP-competitive RAF inhibitors (PLX4032/Vemurafenib, Dabrafenaib, Sorafenib, etc.) have been approved for the treatment of metastatic melanoma patients and have been shown to have positive clinical efficacy against melanoma with a recurrent allele of BRAFV600E (Holdfield, M. et al, Targeting RAF kinases for cancer therapy: BRAF-mutated tumor and after, nat. Rev. cancer.2014; Chapman, PB et al, Improved clearance with mutated breast in melanoma with BRA. V600. 600E. N, Engl. J. Med.2011; Hauschild, A. et al, Danbfenb in mutated tumor measure: Brand. variable, Larafenib. 3. vary. Unfortunately, although the structural basis is still unclear at present, resistance to these drugs is always partly acquired through a mechanism that stimulates RAF dimerization. At the same time, RAS activity is exhibited due to hyperactive RAS mutations, whereas tumors with wild-type for BRAF show major resistance to these first generation RAF inhibitors. In contrast, RAF inhibitors have been found to induce ERK signaling under conditions of elevated RAS activity, thereby increasing tumor cell proliferation. This counterintuitive phenomenon, called paradoxical effect, is also observed in normal tissues that rely on RAS physiological activity. This is the basis for some of the adverse effects observed with RAF inhibitors in melanoma patients. The underlying mechanism is due to the ability of the compound to promote Kinase domain dimerization (Poulikoss, PI. et al, RAF inhibitor resistance is mediated by differentiation of inhibition specific BRAF (V600E). Nature.2011; Hatzivassiliou, G. et al, RAF inhibitor with type RAF to activity the MAPK pathway and enhancement growth. Nature.2010; Heidorn, SJ et al, Kinase-end BRAF and oncogene RAS specific drive texture depth measurement CRAF. 2010. Poulikos, PI et al, RAF inhibitor cross receptor cross primer cross tissue type and native cell type. Overall, RAF inhibitors that have been developed that are effective against tumors with the BRAFV600E mutation may be less effective in tumors with wild-type BRAF or RAS mutations.

To avoid the limitations of the first generation of RAF inhibitors, the present invention relates to compounds and methods useful for inhibiting RAF kinase and the use of these compounds in the treatment of diseases associated with hyperactive RAF, including cancer. The compounds are useful for treating tumors with aberrant MAPK pathways, including RAF and/or RAS mutations or alterations.

Disclosure of Invention

The invention aims to provide a compound shown in a general formula (I),

or a tautomer, cis or trans isomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof,

wherein:

is a single bond or a double bond;

W¹、W²and W³Are the same or different and are each independently N or CR³；

P is selected from CR⁴R⁵、C(O)、NR⁶O, S and S (O)₂；

X, Y and Z are the same or different and are each independently selected from CR⁷R⁸、CR⁷、C(O)、C(NH)、S(O)₂、NR⁹N, O and S;

G¹selected from O, S, C (O), C (O) NH, NR¹⁰、CR¹¹R¹²And S (O)₂；

M is N or CR¹³；

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

ring B is selected from phenyl, pyridyl, thiazolyl, thienyl and pyridonyl;

l is selected from a bond,

Phenyl, heteroaryl and heterocyclyl, wherein said phenyl, heterocyclyl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R^L1Selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, wherein said alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl groups, alkoxy groups, halogens, haloalkyl groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups;

R^L2selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and heterocyclyl;

R⁰are the same OR different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, -C (O) OR¹⁴Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R¹are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, -C: (C) O)NR¹⁵R¹⁶、-S(O)₂R¹⁸Oxo, NR¹⁵R¹⁶、S-R¹⁸、C(O)R¹⁸Cycloalkyl, -O-cycloalkyl, heterocyclyl, -O-heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R²the same or different, and each is independently selected from the group consisting of hydrogen atoms, halogens, alkyl groups, deuterated alkyl groups, oxo groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups, wherein the alkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl groups, alkoxy groups, halogens, haloalkyl groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

R³the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R⁴、R⁵、R⁷And R⁸The same OR different, and each is independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, C (O) OR¹⁴、NR¹⁵R¹⁶、NR¹⁵C(O)OR¹⁴、OR¹⁷、NR¹⁵S(O)₂R¹⁸、NR¹⁵C(O)R¹⁸、R¹⁹Cycloalkyl, heterocyclyl, aryl and heteroaryl;

R⁶、R⁹and R¹⁰Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, an amino group, a cycloalkyl group, a,Heterocyclic group, C (O) OR¹⁴、C(O)R¹⁸Aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, C (O) OR¹⁴、NR¹⁵R¹⁶、NR¹⁵C(O)OR¹⁴、R¹⁹Cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R¹¹and R¹²Are the same OR different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, C (O) OR¹⁴、NR¹⁵R¹⁶、NR¹⁵S(O)R¹⁸、NR¹⁵C(O)R¹⁸、NR¹⁵C(O)OR¹⁴Aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Or R¹¹And R¹²Together form a cycloalkyl or heterocyclyl group, wherein each of said cycloalkyl or heterocyclyl groups is independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R¹³selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

R¹⁴selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

R¹⁵and R¹⁶The same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkaneAryl, heteroaryl, heterocyclyl, and heteroaryl;

R¹⁷selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

R¹⁸selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups, wherein said alkyl groups, alkoxy groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups are each independently optionally selected from the group consisting of alkyl groups, alkoxy groups, halogens, haloalkyl groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, NR groups ¹⁵C(O)OR¹⁴Cycloalkyl, heterocyclyl, aryl and heteroaryl;

R¹⁹selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

k is 0 or 1;

s is 0, 1 or 2;

t is 0, 1 or 2;

q is 0, 1, 2, 3 or 4;

n is 0, 1, 2 or 3;

m is 0, 1, 2, 3 or 4.

In one aspect of the present invention, there is provided a compound represented by the general formula (I),

wherein:

is a single bond or a double bond;

P is selected from CR⁴R⁵、C(O)、NR⁶O, S and S (O) ₂；

G¹selected from O, S, C (O), C (O) NH, NR¹⁰、CR¹¹R¹²And S (O)₂；

M is N or CR¹³；

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

ring B is selected from phenyl, pyridyl, thiazolyl, thienyl and pyridonyl;

l is selected from a bond,

R^L1selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, wherein said alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups are each independently optionally substituted with a group selected from the group consisting of alkyl groups, alkoxy groups, halogens, haloalkyl groups, hydroxy groups, and hydroxy groups, or hydroxy groups,Hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R⁰are the same OR different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, -C (O) OR ¹⁴Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R¹the same or different, and each is independently selected from the group consisting of hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups, wherein the alkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl groups, alkoxy groups, halogens, haloalkyl groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

R²the same or different, and each is independently selected from the group consisting of hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups, wherein the alkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl groups, alkoxy groups, halogens, haloalkyl groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

R⁶、R⁹and R¹⁰Are the same OR different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, an amino group, a cycloalkyl group, a heterocyclic group, C (O) OR¹⁴、C(O)R¹⁸Aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, C (O) OR¹⁴、NR¹⁵R¹⁶、NR¹⁵C(O)OR¹⁴、R¹⁹Cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R¹¹and R¹²Are the same OR different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, C (O) OR ¹⁴、NR¹⁵R¹⁶、NR¹⁵S(O)R¹⁸、NR¹⁵C(O)R¹⁸、NR¹⁵C(O)OR¹⁴Aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

or R¹¹And R¹²Together form a cycloalkyl or heterocyclyl group, wherein each of said cycloalkyl or heterocyclyl groups is independently optionally substituted with a group selected from alkyl, alkoxy, halogen,Haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R¹⁵and R¹⁶The same or different, and each is independently selected from the group consisting of hydrogen atom, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, hydroxyl group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group;

R¹⁸Selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups, wherein said alkyl groups, alkoxy groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups are each independently optionally selected from the group consisting of alkyl groups, alkoxy groups, halogens, haloalkyl groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, NR groups¹⁵C(O)OR¹⁴Cycloalkyl, heterocyclyl, aryl and heteroaryl;

k is 0 or 1;

s is 0, 1 or 2;

t is 0, 1 or 2;

q is 0, 1, 2, 3 or 4;

n is 0, 1, 2 or 3;

m is 0, 1, 2, 3 or 4.

In some embodiments of the invention, a compound of formula (I), or a tautomer, cis or trans isomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is provided, wherein

Is selected from

G¹、P、X、Y、Z、W¹、W²、W³、R⁰S, t and q are as defined in formula (I).

In some embodiments of the invention, a compound of formula (I), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is provided, wherein W is¹、W²And W³Are the same or different and are each independently CR³，R³As defined in formula (I).

In some embodiments of the invention, a compound of formula (I), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is a compound of formula (II) or formula (III), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof,

wherein:

G¹p, X, Y, Z, L, M, ring B, ring A, R⁰、R¹、R²S, t, q, n and m are as defined in formula (I).

Is selected from

Preference is given to

G¹、R⁰、R⁷、R⁸、R⁹And q is as defined in formula (I).

In some embodiments of the invention, a compound of formula (II) or formula (III), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein

Selected from:

preferably, the first and second liquid crystal materials are,

G¹、R⁰、R⁷、R⁸、R⁹and q is as defined for the compound of formula (I).

Is selected from

G¹、R⁰、R⁷、R⁸、R⁹And q is as defined in formula (I).

Selected from:

G¹、R⁰、R⁷、R⁸、R⁹and q is as defined in formula (I).

In some embodiments of the invention, a compound of formula (I), formula (II) or formula (III), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein

Is selected from

M¹Is an N atom or CR¹³；M²、M³And M⁴Identical or different and are each independently CR²Or M is²、M³And M⁴One of them being an N atom and the other two being CR²；

Preferably, the first and second electrodes are formed of a metal,

is selected from

R²And n is as defined in formula (I).

In some embodiments of the invention, the compounds of formula (I), formula (II) and formula (III), or tautomers, cis or trans isomers, meso, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein

Is selected from

R²And n is as defined in formula (I).

In some embodiments of the invention, the compounds of formula (I), formula (II) and formula (III), or tautomers, cis or trans isomers, meso, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein P is selected from O, S, NH, N (OH), S (O) ₂And CH₂(ii) a Preferably O.

In some embodiments of the invention, the compounds of formula (I), (II) and (III), or tautomers, cis or trans isomers, meso, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein X is CR⁷R⁸Or C (O); y and Z are the same or different and are each independently selected from CR⁷R⁸、C(O)、C(NH)、S(O)₂、NR⁹O and S; r⁷And R⁸As defined in formula (I).

In some embodiments of the invention, the compounds of formula (I), (II) and (III), or tautomers, cis or trans isomers, meso, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein L is selected from the group consisting of a bond, -NH-, wherein L is selected from the group consisting of,

Preferably, it is

Preferably, it is

In some embodiments of the invention, the compounds of formula (I), or tautomers, cis-or trans-isomers thereof,A meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is a compound represented by the general formula (IVG), or a tautomer, cis or trans isomer, a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof,

wherein:

R⁰、R¹、R²、R⁷、R⁸、R⁹、R¹³Ring A, m and q are as defined in formula (I).

In some embodiments of the invention, a compound of formula (I), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is a compound of formula (IV), formula (V), or formula (VI), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof,

Wherein R is^2aSelected from hydrogen atom, halogen, alkyl, alkoxy, deuterated alkyl, halogenated alkoxy, hydroxyl, hydroxyalkyl and cyanoAmino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R⁰、R¹、R²、R⁷、R⁸、R⁹、G¹ring A, n, m and q are as defined in formula (I).

In some embodiments of the invention, a compound of formula (IV), formula (V) or formula (VI), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: r^2aSelected from the group consisting of hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, wherein said alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl groups, alkoxy groups, halogens, haloalkyl groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups;

In some embodiments of the invention, the compound of formula (I), formula (II), formula (III), formula (IVG), formula (IV), formula (V) or formula (VI), or a tautomer, cis or trans isomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein ring a is selected from the group consisting of 3-to 10-membered cycloalkyl, 3-to 10-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 14-membered heteroaryl.

In some embodiments of the invention, a compound of formula (I), formula (II), formula (III), formula (IVG), formula (IV), formula (V) or formula (VI), or a tautomer, cis or trans isomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein ring a is selected from the group consisting of 3-to 10-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 14-membered heteroaryl.

In some embodiments of the invention, a compound of formula (I), formula (II), formula (III), formula (IVG), formula (IV), formula (V) or formula (VI), or a tautomer, cis or trans isomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein

Is selected from

R¹And m is as defined for the compound of formula (I).

Is selected from

R¹And m is as defined in formula (I).

In some embodiments of the invention, a compound of formula (I), formula (II), formula (III), formula (IV), formula (V) or formula (VI), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein G is¹Is O.

In some embodiments of the invention, a compound of formula (I), formula (II), formula (III), formula (IVG), formula (IV), formula (V) or formula (VI), or a tautomer, cis or trans isomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R is a pharmaceutically acceptable salt, solvate, or prodrug thereof ⁰Is a hydrogen atom or an alkyl group.

In some embodiments of the invention, a compound of formula (I), formula (II), formula (III), formula (IVG), formula (IV), formula (V) or formula (VI), or a tautomer, cis or trans isomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R is a pharmaceutically acceptable salt, solvate, or prodrug thereof¹Are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, cyano, -C (O) NR¹⁵R¹⁶、-S(O)₂R¹⁸Oxo, NR¹⁵R¹⁶、S-R¹⁸、C(O)R¹⁸Cycloalkyl, -O-cycloalkyl, heterocyclyl, -O-heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more groups selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy and hydroxyalkylIs substituted with one or more substituents of (1); r¹⁵、R¹⁶And R¹⁸As defined for compounds of general formula (I); preferably, R¹Are the same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, cycloalkyl, -O-cycloalkyl, heterocyclyl and-O-heterocyclyl.

In some embodiments of the invention, a compound of formula (I), formula (II), formula (III), formula (IVG), formula (IV), formula (V) or formula (VI), or a tautomer, cis or trans isomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R is a pharmaceutically acceptable salt, solvate, or prodrug thereof²The same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, deuterated alkyl, oxo, haloalkyl, alkoxy, haloalkoxy, cyano, and hydroxyalkyl; preferably, R²Are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a cyano group and a hydroxyalkyl group.

In some embodiments of the invention, a compound of formula (I), formula (II), formula (III), formula (IVG), formula (IV), formula (V) or formula (VI), or a tautomer, cis or trans isomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R is a pharmaceutically acceptable salt, solvate, or prodrug thereof ^2aAre the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a cyano group and a hydroxyalkyl group.

In some embodiments of the invention, a compound of formula (I), formula (II), formula (III), formula (IVG), formula (IV), formula (V) or formula (VI), or a tautomer, cis or trans isomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R is a pharmaceutically acceptable salt, solvate, or prodrug thereof⁷And R⁸Same or differentAnd each is independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, -C (O) OR¹⁴、-NR¹⁵R¹⁶、-NR¹⁵C(O)OR¹⁴、-OR¹⁷、-NR¹⁵C(O)R¹⁸Cycloalkyl, heterocyclyl, aryl and heteroaryl; r¹⁴～R¹⁸As defined in formula (I).

In some embodiments of the invention, a compound of formula (I), formula (II), formula (III), formula (IVG), formula (IV), formula (V) or formula (VI), or a tautomer, cis or trans isomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R is a pharmaceutically acceptable salt, solvate, or prodrug thereof ⁹Selected from the group consisting of hydrogen atoms, alkyl groups and hydroxyalkyl groups, wherein said alkyl groups are optionally substituted by groups selected from the group consisting of alkoxy, halogen, hydroxy, hydroxyalkyl and-NR¹⁵R¹⁶Is substituted with one or more substituents of (1); r¹⁵And R¹⁶As defined in formula (I).

Exemplary compounds of the invention include, but are not limited to: a compound selected from the group consisting of:

in another aspect of the present invention, there is provided a process for preparing a compound of formula (I), or a tautomer, cis or trans isomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, comprising

Carrying out coupling reaction on the compound with the general formula (IA) and the compound with the general formula (IB) to obtain a compound with a general formula (I);

wherein:

R^xis halogen; preferably Br;

R^gis composed of

Ring A, ring B, M, L, R⁰、R¹、R²、W¹、W²、W³、P、X、Y、Z、G¹S, t, k, q, n and m are as defined in formula (I).

In another aspect of the present invention, there is provided a process for preparing a compound represented by the general formula (II), or a tautomer, cis or trans isomer, meso form, racemic form, enantiomer form, diastereomer form, or mixture form thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, which comprises

Carrying out coupling reaction on the compound with the general formula (IIA) and the compound with the general formula (IB) to obtain a compound with a general formula (II);

wherein:

R^xis halogen; preferably Br;

R^gis composed of

Ring A, ring B, M, L, R⁰、R¹、R²、P、Y、Z、G¹S, t, q, n and m are as defined in formula (II).

In another aspect of the present invention, there is provided a process for preparing a compound of formula (III), or a tautomer, cis or trans isomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, comprising

Carrying out coupling reaction on the compound with the general formula (IIIA) and the compound with the general formula (IB) to obtain a compound with a general formula (III);

wherein:

R^xis halogen; preferably Br;

R^gis composed of

Ring A, ring B, M, L, R⁰、R¹、R²、P、X、Y、Z、G¹S, t, q, n and m are as defined in formula (III).

In another aspect of the present invention, there is provided a process for preparing a compound of formula (IV), or a tautomer, cis or trans isomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, comprising

Carrying out coupling reaction on the compound with the general formula (IVA) and the compound with the general formula (IVB) to obtain a compound with a general formula (IV);

Wherein:

R^xis halogen; preferably Br;

R^gis composed of

Ring A, R⁰、R¹、R²、R^2a、R⁷、R⁸、R⁹、G¹Q, n and m are as defined in formula (IV).

In another aspect of the present invention, there is provided a process for preparing a compound represented by the general formula (V), or a tautomer, cis or trans isomer, meso form, racemic form, enantiomer form, diastereomer form, or mixture form thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, which comprises

Carrying out coupling reaction on a compound with a general formula (VA) and a compound with a general formula (IVB) to obtain a compound with a general formula (V);

wherein:

R^xis halogen; preferably Br;

R^gis composed of

Ring A, R⁰、R¹、R²、R^2a、R⁷、R⁸、R⁹、G¹Q, n and m are as defined in formula (V).

In another aspect of the present invention, there is provided a process for preparing a compound of formula (VI), or a tautomer, cis or trans isomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, comprising

Carrying out coupling reaction on the compound with the general formula (VIA) and the compound with the general formula (IVB) to obtain a compound with a general formula (VI);

wherein:

R^xis halogen; preferably Br;

R^gis composed of

Ring A, R⁰、R¹、R²、R^2a、R⁹、G¹Q, n and m are as defined in formula (VI).

In another aspect of the present invention, there is provided a process for preparing a compound represented by the general formula (IVG), or a tautomer, cis or trans isomer, meso form, racemic form, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, which comprises

Carrying out coupling reaction on a compound with a general formula (IVGA) and a compound with a general formula (IVGB) to obtain a compound with a general formula (IVG); wherein:

R^xis halogen; preferably Br;

R^gis composed of

Ring A, M¹、M²、M³、M⁴、R⁰、R¹、R⁷-R⁹Q and m are as defined in formula (IVG).

The invention provides a pharmaceutical composition, which contains a compound shown as a general formula (I) or a tautomer, a cis-isomer, a trans-isomer, a meso-isomer, a racemic body, an enantiomer, a diastereoisomer, a mixture form thereof, or a pharmaceutically acceptable salt, a solvate or a prodrug form thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

The invention provides an application of a compound shown as a general formula (I) or a tautomer, a cis-isomer or a trans-isomer, a meso-isomer, a racemate, an enantiomer, a diastereoisomer or a mixture form thereof, or a pharmaceutically acceptable salt, a solvate or a prodrug thereof, or a pharmaceutical composition containing the compound in preparation of drugs for inhibiting RAF.

The invention provides an application of a compound shown as a general formula (I) or a tautomer, a cis-isomer or a trans-isomer, a meso-isomer, a racemate, an enantiomer, a diastereoisomer or a mixture form thereof, or a pharmaceutically acceptable salt, a solvate or a prodrug thereof, or a pharmaceutical composition containing the compound in preparation of medicines for treating RAF-mediated diseases or disorders. Preferably, the RAF mediated disease or disorder is a tumor; more preferably, the RAF mediated disease or disorder is cancer. Wherein the tumor (preferably cancer) is selected from the group consisting of lymphoma, leukemia, breast cancer, lung cancer, prostate cancer, ovarian cancer, liver cancer, melanoma, rhabdomyosarcoma, synovial sarcoma, mesothelioma, cervical cancer, colon cancer, rectal cancer, stomach cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, bone cancer, kidney cancer, bladder cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, glioma, glioblastoma, head and neck cancer, and myeloma; lymphoma, leukemia, breast cancer, lung cancer, prostate cancer, ovarian cancer, liver cancer, melanoma, rhabdomyosarcoma, synovial sarcoma, and mesothelioma are preferred.

The present invention provides a method of inhibiting RAF comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer, cis or trans isomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition comprising the same.

The present invention provides a method of treating a RAF mediated disease or disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition comprising the same. Preferably, the RAF mediated disease or disorder is a tumor; more preferably, the RAF mediated disease or disorder is cancer. Wherein the tumor (preferably cancer) is selected from the group consisting of lymphoma, leukemia, breast cancer, lung cancer, prostate cancer, ovarian cancer, liver cancer, melanoma, rhabdomyosarcoma, synovial sarcoma, mesothelioma, cervical cancer, colon cancer, rectal cancer, stomach cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, bone cancer, kidney cancer, bladder cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, glioma, glioblastoma, head and neck cancer, and myeloma; lymphoma, leukemia, breast cancer, lung cancer, prostate cancer, ovarian cancer, liver cancer, melanoma, rhabdomyosarcoma, synovial sarcoma, and mesothelioma are preferred.

In another aspect, the present invention provides a compound represented by the general formula (I) or a tautomer, cis or trans isomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

In another aspect, the present invention provides a compound represented by the general formula (I) or a tautomer, cis or trans isomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition comprising the same, which is useful as a medicament for inhibiting RAF.

In another aspect, the present invention provides a compound of formula (I) or a tautomer, cis or trans isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition comprising the same, for use in the treatment of a RAF mediated disease or disorder. Preferably, the RAF mediated disease or disorder is a tumor; more preferably, the RAF mediated disease or disorder is cancer. Wherein the tumor (preferably cancer) is selected from the group consisting of lymphoma, leukemia, breast cancer, lung cancer, prostate cancer, ovarian cancer, liver cancer, melanoma, rhabdomyosarcoma, synovial sarcoma, mesothelioma, cervical cancer, colon cancer, rectal cancer, stomach cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, bone cancer, kidney cancer, bladder cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, glioma, glioblastoma, head and neck cancer, and myeloma; lymphoma, leukemia, breast cancer, lung cancer, prostate cancer, ovarian cancer, liver cancer, melanoma, rhabdomyosarcoma, synovial sarcoma, and mesothelioma are preferred.

The active compound may be formulated so as to be suitable for administration by any suitable route, preferably in unit dose form, or in such a way that the patient may self-administer it in a single dose. The unit dose of a compound or composition of the invention may be expressed in the form of a tablet, capsule, cachet, bottle, powder, granule, lozenge, suppository, reconstituted powder or liquid.

The dosage of the compound or composition used in the methods of treatment of the present invention will generally vary with the severity of the disease, the weight of the patient and the relative efficacy of the compound. However, as a general guide, a suitable unit dose may be 0.1 to 1000 mg.

The pharmaceutical compositions of the invention may contain, in addition to the active compound, one or more adjuvants selected from the following: fillers (diluents), binders, wetting agents, disintegrants, excipients, and the like. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of active compound.

The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a pleasant to the eye and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents and lubricating agents. These tablets may be uncoated or they may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

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 or an oil vehicle.

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. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a 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 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, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. 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 be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, and the injection or microemulsion may be injected into the bloodstream of a patient by local mass injection. Alternatively, it may be desirable to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the disclosed compounds. 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. The suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned 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 are conventionally employed as a solvent or suspending medium. Any blend fixed oil may be used for this purpose. In addition, fatty acids can also be prepared into 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.

As is well known to those skilled in the art, the dosage of a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular compound employed, 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 the mode of treatment, the daily amount of compound (I) of the formula or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Detailed description of the invention

Unless stated to the contrary, terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms. Non-limiting examples include 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-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-ethyl, 2-2, 2-2, 2-2, or, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include 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. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylthio, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycle, cycloalkylthio, heterocyclylthio and oxo.

The term "alkenyl" refers to an alkyl compound containing a carbon-carbon double bond in the molecule, wherein alkyl is as defined above. For example, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. Preferably 2 to 20 carbon atoms, more preferably 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, most preferably 2 to 6 carbon atoms, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, halo, alkoxy, alkenyl, alkynyl, alkylthio, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycle, cycloalkylthio, heterocycloalkylthio and oxo.

The term "alkynyl" refers to an alkyl compound containing a carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. For example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-or 3-butynyl and the like. Preferably 2 to 20 carbon atoms, more preferably 2 to 12 (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, most preferably 2 to 6 carbon atoms. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycle, alkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio and heterocycloalkylthio.

The term "alkylene" refers to a saturated straight or branched chain aliphatic hydrocarbon group having 2 residues derived from the parent alkane by removal of two hydrogen atoms from the same carbon atom or two different carbon atoms, and is a straight or branched chain group containing 1 to 20 carbon atoms, preferably 1 to 12 (e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably 1 to 6 carbon atoms. 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-) 1, 4-butylene (-CH₂CH₂CH₂CH₂-) and the like. The alkylene group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxyHeterocyclic alkoxy, cycloalkylthio and heterocyclic alkylthio.

The term "alkenylene" refers to an alkylene compound containing a carbon-carbon double bond in the molecule, wherein alkylene is as defined above. Preferably 2 to 20 carbon atoms, more preferably 2 to 12 (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, most preferably 2 to 6 carbon atoms. Non-limiting examples of alkenylene include, but are not limited to, ethenylene (-CH-), propenylene (-CH-CHCH) ₂-, 1-butenylene (-CH ═ CHCH)₂CH₂-, 2-butenylene (-CH)₂CH＝CHCH₂-) and the like. Alkenylene may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio and heterocycloalkylthio.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably 3 to 10 carbon atoms, and most preferably 3 to 8 carbon atoms or 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like. Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain one or more double bonds. Preferably 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14) and more preferably 7 to 10 (e.g., 7, 8, 9 and 10). Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Non-limiting examples of spirocycloalkyl groups include:

The term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds. Preferably 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14) and more preferably 7 to 10 (e.g., 7, 8, 9 and 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered and 6-membered/6-membered bicycloalkyl groups. Non-limiting examples of fused ring alkyl groups include:

the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds. Preferably 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14) and more preferably 7 to 10 (e.g., 7, 8, 9 and 10). They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic, depending on the number of constituent rings. Non-limiting examples of bridged cycloalkyl groups include:

Such cycloalkyl rings include those wherein the above cycloalkyl is fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, halo, alkoxy, alkenyl, alkynyl, alkylthio, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocyclyl, cycloalkylthio, heterocycloalkylthio and oxo.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, sulfur, S (O) or S (O)₂But does not include the ring moiety of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferably 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (e.g., 1, 2, 3 and 4) are heteroatoms; more preferably 3 to 10 ring atoms, of which 1 to 3 are heteroatoms; more preferably 6 to 10 ring atoms, of which 1 to 3 are heteroatoms; most preferably 5 to 6 ring atoms, of which 1-2 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a 5-to 20-membered polycyclic heterocyclic group in which one atom (referred to as the spiro atom) is shared between monocyclic rings, and in which one or more of the ring atoms is selected from nitrogen, oxygen, sulfur, S (O) or S (O)₂The remaining ring atoms are carbon. It may contain one or more double bonds. Preferably 6 to 14 (e.g. 6, 7, 8, 9, 10, 11, 12, 13 and 14), more preferably 7 to 10. The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferred are 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclic groups. Non-limiting examples of spiro heterocyclic groups include:

the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, and one or more of the rings may contain one or more double bonds in which one or more of the ring atoms is selected from nitrogen, oxygen, sulfur, S (O) or S (O)₂The remaining ring atoms are carbon. Preferably 6 to 14 (e.g. 6, 7, 8, 9, 10, 11, 12, 13 and 14), more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

The term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms which are not directly attached, which may contain one or more double bonds in which one or more ring atoms is selected from nitrogen, oxygen, sulfur, S (O) or S (O)₂The remaining ring atoms are carbon. Preferably 6 to 14 (e.g. 6, 7, 8, 9, 10, 11, 12, 13 and 14), more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

such heterocyclyl rings include those wherein the heterocyclyl group described above is fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclyl, non-limiting examples of which include:

and the like.

The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio and heterocycloalkylthio.

The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl, most preferably phenyl. Such aryl rings include those wherein the above-described aryl group is fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

the aryl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 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. Such heteroaryl rings include those wherein the heteroaryl group described above is fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:

Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio and heterocycloalkylthio.

The above-mentioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups have 1 residue derived from the parent ring atom by removal of one hydrogen atom, or 2 residues derived from the parent ring atom by removal of two hydrogen atoms from the same or two different ring atoms, i.e., "divalent cycloalkyl", "divalent heterocyclyl", "arylene", "heteroarylene".

The term "alkoxy" refers to-O- (alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy and butoxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

The term "bond" refers to a covalent bond of the symbol "-".

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

The term "hydroxy" refers to-OH.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens wherein alkyl is as defined above.

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

The term "amino" refers to the group-NH₂。

The term "cyano" refers to — CN.

The term "nitro" means-NO₂。

The term "oxo" refers to "═ O".

The term "carbonyl" refers to C ═ O.

The term "carboxy" refers to-C (O) OH.

The term "carboxylate" refers to-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, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.

"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is 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 (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.

Synthesis of the Compounds of the invention

In order to achieve the purpose of the invention, the invention adopts the following technical scheme:

scheme one

The invention relates to a method for preparing a compound shown in a general formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof, a pharmaceutically acceptable salt thereof, or a solvate and a prodrug thereof, which comprises the following steps:

carrying out coupling reaction on the compound of the general formula (IA) and the compound of the general formula (IB) under alkaline conditions and in the presence of a catalyst to obtain a compound of the general formula (I);

wherein

R^xIs halogen, preferably Br;

R^gis that

Ring A, ring B, M, L, R ⁰、R¹、R²、W¹、W²、W³、P、X、Y、Z、G¹S, t, k, q, n and m are as defined in formula (I).

Scheme two

The invention relates to a method for preparing a compound shown as a general formula (II) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof, a pharmaceutically acceptable salt thereof, or a solvate and a prodrug thereof, which comprises the following steps:

carrying out coupling reaction on the compound of the general formula (IIA) and the compound of the general formula (IB) under alkaline conditions and in the presence of a catalyst to obtain a compound of a general formula (II);

wherein:

R^xis halogen, preferably Br;

R^gis that

Scheme three

The invention relates to a method for preparing a compound shown as a general formula (III) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof, a pharmaceutically acceptable salt thereof, or a solvate and a prodrug thereof, which comprises the following steps:

carrying out coupling reaction on the compound of the general formula (IIIA) and the compound of the general formula (IB) under alkaline conditions and in the presence of a catalyst to obtain a compound of a general formula (III);

wherein:

R^xis halogen, preferably Br;

R^gis that

Scheme four

The invention relates to a method for preparing a compound shown as a general formula (IV) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof, a pharmaceutically acceptable salt thereof, or a solvate and a prodrug thereof, which comprises the following steps:

carrying out a coupling reaction of the compound of the general formula (IVA) and the compound of the general formula (IVB) under an alkaline condition and in the presence of a catalyst to obtain a compound of the general formula (IV);

wherein:

R^xis halogen, preferably Br;

R^gis that

Scheme five

The invention relates to a method for preparing a compound shown as a general formula (V) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof, a pharmaceutically acceptable salt thereof, or a solvate and a prodrug thereof, which comprises the following steps:

carrying out a coupling reaction of a compound of a general formula (VA) and a compound of a general formula (IVB) under an alkaline condition and in the presence of a catalyst to obtain a compound of a general formula (V);

wherein:

R^xis halogen, preferably Br;

R^gis that

Scheme six

The invention relates to a method for preparing a compound shown in a general formula (VI) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof, a pharmaceutically acceptable salt thereof, or a solvate and a prodrug thereof, which comprises the following steps:

Carrying out a coupling reaction of the compound of the general formula (VIA) and the compound of the general formula (IVB) under an alkaline condition and in the presence of a catalyst to obtain a compound of the general formula (VI);

wherein:

R^xis halogen, preferably Br;

R^gis that

Scheme seven

The invention relates to a method for preparing a compound shown in a general formula (IVG) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof, a pharmaceutically acceptable salt thereof, or a solvate and a prodrug thereof, which comprises the following steps:

carrying out coupling reaction on a compound of a general formula (IVGA) and a compound of a general formula (IVGB) under alkaline conditions and in the presence of a catalyst to obtain a compound of a general formula (IVG);

wherein:

R^xis halogen, preferably Br;

R^gis that

The reagents in the above synthesis schemes that provide basic conditions include organic bases including, but not limited to, triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, or potassium tert-butoxide, and inorganic bases including, but not limited to, magnesium chloride, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, and cesium carbonate.

Catalysts described in the above synthetic schemes include, but are not limited to, palladium on carbon, raney nickel, tetrakis-triphenylphosphine palladium, palladium dichloride, palladium acetate, [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (Pd (dppf) Cl₂) Dichloro-bis (triphenylphosphine) palladium, [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride or tris (dibenzylideneacetone) ferrocenepalladium, preferably [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride, bis (triphenylphosphine) palladium dichloride or tetrakis (triphenylphosphine).

The above reaction is preferably carried out in a solvent including, but not limited to: acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, 1, 4-dioxane, water, N-dimethylformamide and mixtures thereof.

Detailed Description

Examples

The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention. If specific conditions for the experimental methods are not specified in the examples of the present invention, they are generally according to conventional conditions or recommended conditions of raw material and product manufacturers. No indication is made that the reagents of particular origin are commercially available conventional reagents.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. delta.) of 10 ^-6The units in (ppm) are given. NMR was measured using Bruker AVANCE-300, AVANCE-400 or AVANCE-500 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d) as the solvent₆) Deuterated chloroform (CDCl)₃) Deuterated methanol (CD)₃OD)。

Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18150X 4.6mm column) for High Performance Liquid Chromatography (HPLC) measurements.

Chiral HPLC analytical determination using LC-10A (Shimadzu) or SFC-analytical (Berger Instruments Inc.).

MS was measured using a SHIMADZU (ESI) liquid chromatography-mass spectrometer (Shimadzu, model: LC-20AD, LCMS-2020).

Average inhibition rate of kinase and IC₅₀The values were measured using a Microplate reader (BMG, Germany).

The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

Silica gel column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.

The CombiFlash rapid preparation instrument uses CombiFlash Rf200(TELEDYNE ISCO).

Known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Shao Yuan Chemical technology (Accela ChemBio Inc), Darri Chemicals, and the like.

In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.

An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The pressure hydrogenation reaction used a hydrogenation apparatus of Parr 3916EKX type and a hydrogen generator of Qinglan QL-500 type or a hydrogenation apparatus of HC2-SS type.

The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

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

In the examples, the solution means an aqueous solution unless otherwise specified.

In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing solvent used for the reaction, a system of eluents for column chromatography used for purifying compounds and a developing solvent system for thin layer chromatography including: a: dichloromethane/methanol system, B: the volume ratio of the solvent is adjusted according to the polarity of the compound. The elution system for column chromatography, thin layer chromatography and CombiFlash flash rapid prep of purified compounds comprises: a: dichloromethane and methanol, B: hexane and ethyl acetate. The volume ratio of the solvent may be adjusted depending on the polarity of the compound, and a small amount of a basic agent such as ammonia or an acidic agent such as acetic acid may be added in some cases.

The final compound was purified by Shimadzu (LC-20AD, SPD20A) preparative HPLC (Phenomenex Gemini-NX 5uM C1821.2X 100mm column) on water/MeOH or water/CH₃Purification in CN elution System and optional additives such as HCOOH, TFA and NH₄HCO₃。

The following abbreviations are used in the examples:

TEA is triethylamine and is a compound of the formula,

HATU is 1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazolo [4,5-b ] pyridinium 3-oxide hexafluorophosphate,

HBTU is O- (1H-benzotriazole-1-yl) -N, N, N ', N' -tetramethyl isourea phosphorus hexafluoride,

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

DMF is N, N-dimethylformamide,

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

DEAD is the dimethyl-diethyl azodicarboxylate,

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

prep HPLC for preparative high performance liquid chromatography,

NMR is the nuclear magnetic resonance of a proton,

MS is mass spectrometry, where (+) refers to positive mode, typically giving M +1 (or M + H) absorption, where M ═ molecular weight.

Synthesis of intermediates

N- (4-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -2- (trifluoromethyl) isonicotinamide

Int-1

To a solution of the compound 4-methyl-3- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -aniline (4.0g, 17.16mmol) in N, N-dimethylformamide (30mL) was added 2- (trifluoromethyl) pyridine-4-carboxylic acid (3.94g, 20.59mmol) and 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (9.8g, 25.77mmol), followed by N, N-diisopropylethylamine (8.44mL, 51.07mmol, Adamas) at 0 ℃. The mixture was stirred at 30 ℃ for 1 hour. The reaction mixture was then poured into saturated sodium carbonate solution (60 mL). Filtration and concentration under reduced pressure gave the title compound Int-1(6.9g, yield: 99.0%).

¹H NMR(400MHz,CDCl₃):δ8.90(d,1H),8.10(s,1H),7.95-7.90(m,3H),7.69(d,1H),7.22(d,1H),2.53(s,3H),1.35(s,12H)。

MS m/z(ESI):407.3[M+H]⁺

7-bromo-2 ',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -4-one Int-2

Pyrrolidine (1.81g, 2.12mL, 25.4mmol) was added to a solution of 1- (4-bromo-2-hydroxyphenyl) ethan-1-one (10.9g, 50.7mmol) and tetrahydro-4H-pyran-4-one (6.60g, 65.9mmol) in methanol (100mL) at room temperature. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated, and to the resulting residue were added water (20mL), aqueous hydrochloric acid (1N, 40mL) and ethyl acetate (200 mL). The organic phase was washed with water (25 mL. times.2), dried, filtered, and concentrated under reduced pressure to give the title compound Int-2(11.8g, yield: 78.1%) which was used without purification.

¹HNMR(400MHz,CDCl₃)δ1.77-1.83(m,2H),1.97-2.01(m,2H),2.76(s,2H),3.82-3.88(m,4H),7.17(d,1H),7.27(s,1H),7.74(d,1H)。

8-bromo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] [1,4] oxazepine-2, 4 '-pyran ] -4(5H) -one Int-3 and 8- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2',3',5',6 '-tetrahydro-3H-spiro [ benzo [ b ] [1,4] oxazepine-2, 4' -pyran ] -4(5H) -one Int-4

First step of

(Z) -7-bromo-2 ',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -4-ketoxime Int-3a

To an ethanol solution (90mL) of compound Int-2(9g, 30.29mmol) were added hydroxylamine hydrochloride (6.31g, 90.87mmol) and sodium acetate (7.45g, 90.87mmol), and the reaction was heated to reflux and stirred for 2 hours. The reaction solution was diluted with saturated sodium chloride solution (150mL), extracted with ethyl acetate (100 mL. times.2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound Int-3a as a crude product (9g, yield: 95%).

MS m/z(ESI):312.1/314.1[M+H]⁺

Second step of

(Z) -7-bromo-2 ',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -4-one O-p-toluenesulfonyl oxime Int-3b

To a solution of compound Int-3a (2g, 8.64mmol) in dichloromethane (100mL) was added triethylamine (4.72g, 46.61mmol) and p-toluenesulfonic anhydride (12.17g, 37.29 mmol). The reaction was stirred at room temperature for 2 hours. Then, water (150mL) and methylene chloride (150mL) were added for extraction, and the organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane ═ 0:1 to 1:10, 200 to 300 mesh silica gel) to obtain the title compound Int-3b (9g, yield: 62%).

¹H NMR(400MHz,DMSO):δ7.91(d,J＝8.4Hz,2H),7.57(d,J＝8.4Hz,1H),7.50(d,J＝8.0Hz,2H),7.29(d,J＝2.0Hz,1H),7.18(dd,J＝8.4Hz,2.0Hz,1H),3.61(d,J＝6.4Hz,4H),3.02(s,2H),2.41(s,3H),1.72-1.57(m,4H)。

MS m/z(ESI):465.9/467.9[M+H]⁺

The third step

8-bromo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] [1,4] oxazepine-2, 4' -pyran ] -4(5H) -one Int-3

To a solution of compound Int-3b (8.8g, 18.87mmol) in dichloromethane (100mL) at 0 deg.C was added aluminum trichloride (10.06g, 75.48mmol), and the mixture was stirred at 0-10 deg.C for 2 hours. Saturated sodium bicarbonate solution was added for dilution (100mL) and concentrated HCl was added to adjust the pH to 1. The mixture was extracted with dichloromethane (150mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate: hexane ═ 0:1 to 9:1, 200 to 300 mesh silica gel) to obtain the title compound Int-3(3g, yield: 51%).

¹HNMR(400MHz,CDCl₃),δ7.61(s,1H),7.30(s,1H),7.23(s,1H),6.90(d,1H),3.98-3.85(m,4H),2.57(s,2H),2.03-2.00(m,2H),1.88-1.81(m,2H)。

MS m/z(ESI):312.0[M+H]⁺

The fourth step

8- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] [1,4] oxazepine-2, 4' -pyran ] -4(5H) -one Int-4

Compound Int-3(200mg, 640.70. mu. mol), bis-pinacolato borate (180mg, 708.84. mu. mol) and potassium acetate (200mg, 2.04mmol) were dissolved in dioxane (10mL) and the mixture was degassed and blanketed with nitrogen. Then [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (100mg, 122.45 μmol) was added, and the mixture was stirred at 90 ℃ for 16 hours. The mixture was cooled and filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether ═ 1/5) to give the title compound Int-4(200mg, yield: 86.90%).

MS m/z(ESI):360.1[M+1]⁺

8-bromo-2 ',3,3',4,5',6' -hexahydro-5H-spiro [ benzo [ f ] [1,4] oxazepin-2, 4' -pyran ] -5(4H) -one Int-5

Compound Int-2(5.0g, 16.8mmol) was dissolved in trifluoroacetic acid (50 mL). The mixture was heated to 70 ℃ and to this solution was added sodium azide (6.6g, 101mmol) in portions (0.2 g per half hour). The mixture was stirred at 70 ℃ overnight. The reaction was cooled to room temperature and concentrated. The resulting residue was diluted with ethyl acetate (50mL) and water (50 mL). The organic phase was collected and the aqueous layer was extracted with ethyl acetate (25 mL. times.2). The combined organic phases are washed successively with water, saturated sodium chloride solution and dried over magnesium sulfate. The solid magnesium sulfate was filtered off, and then the filtrate was concentrated. The resulting residue was purified to give the title products Int-5(3.78g, major, more polar) and Int-3(0.26g, minor, less polar).

Int-5:¹HNMR(400MHz,CDCl₃),δ7.66(d,1H),7.38(d,1H),7.19(s,1H),7.09(br,1H),3.98-3.87(m,4H),3.18(d,2H),1.97-1.94(m,2H),1.72-1.64(m,2H)。

MS m/z(ESI):312.0[M+H]⁺

N- (4' -acetyl-3 ' -hydroxy-6-methyl- [1,1' -biphenyl ] -3-yl) -2- (trifluoromethyl) isonicotinamide Int-A1

To a mixed solution of compound Int-1(2.23g, 5.5mmol), 1- (4-bromo-2-hydroxyphenyl) ethan-1-one (1.08g, 5.0mmol) in dioxane/water (15mL/1.5mL) was added solid sodium carbonate (1.59g, 15 mmol). The resulting cloudy suspension was sparged with nitrogen for 5 minutes, then [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (5 mol%, 0.25mmol, 200mg) was added under nitrogen protection. The mixture was heated to 100 ℃ and stirred for 4 hours. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate (30mL) and acidified to pH 5-6 with hydrochloric acid (1N). The organic layer was collected and the aqueous layer was extracted with ethyl acetate (30 mL. times.2). The organic phases were combined, washed with saturated sodium chloride solution and dried over magnesium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane (0-100%) rinse) to give the title compound Int-A1(1.12 g).

MS m/z(ESI):415.0[M+1]⁺

7-bromo-N- (oxetan-3-yl) -2',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -4-amine Int-A2

To a solution of compound Int-2(92mg, 0.31mmol), oxetan-3-amine (33mg, 0.46mmol) in anhydrous tetrahydrofuran (1mL) was added tetraisopropyl titanate (Ti (OPri) ₄131mg, 0.46 mmol). The mixture was stirred at 90 ℃ overnight. The reaction mixture was cooled to room temperature and diluted with dichloroethane-acetic acid (6mL-1 mL). To this solution was added sodium triacetoxyborohydride (100mg, 4.02mmol) in one portion, and the mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated ammonium chloride solution (10mL) and diluted with dichloromethane (15 mL). The dichloromethane layer was separated, washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (using ethyl acetate-hexane (0-100))%) to yield the title compound Int-a2(39.4 mg).

MS m/z(ESI):354.0[M+1]⁺

7' -bromo-1- (oxetan-3-yl) spiro [ azetidine-3, 2' -chromane ] -4' -one Int-A3

First step of

7' -bromo-4 ' -oxospiro [ azetidine-3, 2' -chromane ] -1-carboxylic acid tert-butyl ester Int-A3a

To a solution of 1- (4-bromo-2-hydroxyphenyl) ethan-1-one (467mg, 2.17mmol) and tert-butyl 3-oxoazetidine-1-carboxylate (744mg, 4.34mmol) in methanol (100mL) at room temperature was added pyrrolidine (308mg, 4.34mmol) and 4A molecular sieves. The mixture was heated to reflux overnight. The reaction was cooled to room temperature, filtered and the filtrate was concentrated. The resulting residue was diluted with 15mL of dilute hydrochloric acid (0.5N). The resulting residue was collected, washed with water (25 mL. times.2), and concentrated to give the title compound Int-A3a (248mg, yield: 31%) which was used in the next step without purification.

MS m/z(ESI):368.0[M+1]⁺

Second step of

7' -Bromospiro [ azetidine-3, 2' -chromane ] -4' -one hydrochloride Int-A3b

Compound Int-A3a (248mg, 0.67mmol) was dissolved in 4M hydrogen chloride in dioxane at room temperature and stirred overnight. The reaction was concentrated and the resulting residue was dried under vacuum to give the title product Int-A3b, which was used in the next step without purification.

MS m/z(ESI):268.0[M+1]⁺

The third step

7' -bromo-1- (oxetan-3-yl) spiro [ azetidine-3, 2' -chromane ] -4' -one Int-A3

To a mixed solution of compound Int-A3b (110mg, 0.36mmol) and oxetan-3-one in dichloroethane/acetic acid (3mL/0.3mL) was added sodium triacetoxyborohydride (220mg) in portions. The mixture was stirred overnight. Neutralized with saturated sodium bicarbonate solution and extracted with dichloromethane (10mL × 3). The organic phases were combined, dried over magnesium sulfate, filtered, and the filtrate was concentrated and purified to give the title compound Int-A3(100 mg).

MS m/z(ESI):324.0[M+1]⁺

7-bromo-4- (2-methoxyethoxy) -2',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] Int-A4

First step of

7-bromo-2 ',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -4-ol Int-A4a

To a solution of compound Int-2(900mg, 3.03mmol) in methanol (25mL) was added sodium borohydride (175mg, 4.63mmol), and the mixture was stirred at room temperature for 3 hours. Water (40mL) was then added and extracted with ethyl acetate (35 mL). The organic phase was dried over anhydrous sodium sulfate. Filtering and concentrating. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to give the title compound Int-A4a (700mg), yield: 77 percent.

¹H NMR(400MHz,CDCl₃):δ7.31-7.28(m,1H),7.08-7.06(m,2H),4.82(m,1H),3.88-3.75(m,4H),2.16-2.13(m,1H),1.90-1.86(m,4H),1.72-1.71(m,2H)。

Second step of

To a solution of compound Int-A4a (250mg, 0.835mmol) in ethylene glycol monomethyl ether (5mL) was added concentrated sulfuric acid (200mg), and the mixture was refluxed for 2 hours. Ethyl acetate (35mL) was then added and the mixture was washed with water (35 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to give the title compound Int-a4(135mg), yield: 45 percent.¹H NMR(400MHz,CDCl₃):δ7.27-7.25(m,1H),7.05-7.03(m,2H),4.45-4.52(m,1H),3.85-3.68(m,7H),3.59-3.56(m,3H),3.40(s,3H),2.04-2.02(m,2H),1.96-1.92(m,1H),1.84-1.80(m,1H)。

7' -Bromospiro [ azepane-4, 2' -chromane ] -4', 7-dione Int-A5

First step of

7-Bromobiro [ chromane-2, 1' -cyclohexane-4 ', 2' - [1,3] dioxolane ] -4-one Int-A5c

The title compound, Int-A5c, was prepared by a synthetic method employing intermediate Int-A3

Second step of

7' -Bromospiro [ azepane-4, 2' -chromane ] -4', 7-dione Int-A5

Compound Int-A5c (822mg, 2.33mmol) was dissolved in trifluoroacetic acid (10 mL). To the solution was added sodium azide (570mg) in portions at 65 ℃ and stirred for 2.5 hours. The reaction was cooled to room temperature, diluted with ethyl acetate (30mL) and washed with water (30 mL). The organic layer was collected and the aqueous layer was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated. The resulting residue was purified by silica gel column (ethyl acetate-hexane (0-60%) rinse) to give the title compound Int-a5(470mg), yield: 62.5 percent.

MS m/z(ESI):324.0[M+1]⁺

6-bromo-2 ',3',5',6' -tetrahydro-2H, 4H-spiro [ benzo [ e ] [1,2,4] thiadiazine-3, 4' -pyran ]1, 1-dioxide Int-B1

To a solution of 2-amino-4-bromobenzene-1-sulfonamide (125mg, 0.5mmol), tetrahydro-4H-pyran-4-one (0.1mL, 1mmol), p-toluenesulfonic acid monohydrate (19mg,0.1mmol) in toluene (8mL) was added magnesium sulfate (240mg, 2 mmol). The mixture was refluxed overnight and cooled to room temperature. Ethyl acetate (50mL) was added and filtered. The filtrate was washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, the organic phase was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to give the title compound Int-B1(139mg, yield: 83.5%).

MS m/z(ESI):333.0[M+1]⁺

7' -bromo-2, 3,5, 6-tetrahydro-1 ' H-spiro [ pyran-4, 2' -quinazolin ] -4' (3' H) -one Int-B2

To a solution of 2-amino-4-bromobenzamide (215mg, 1mmol), tetrahydro-4H-pyran-4-one (0.2mL, 2mmol), p-toluenesulfonic acid monohydrate (20mg, 0.1mmol) in toluene (8mL) was added magnesium sulfate (240mg, 2 mmol). The mixture was refluxed overnight and cooled to room temperature. Ethyl acetate (50mL) was added and filtered. The filtrate was washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, the organic phase was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (n-hexane/ethyl acetate as an eluent) to give the title compound Int-B2(123mg, yield: 41%).

MS m/z(ESI):297.0[M+1]⁺

7 '-bromo-1' -hydroxy-2, 3,5, 6-tetrahydro-1 'H-spiro [ pyran-4, 2' -quinazolin ] -4'(3' H) -one Int-B3

To a solution of 4-bromo-2-nitrobenzamide (103mg, 0.422mmol), tetrahydro-4H-pyran-4-one (0.05mL, 005mmol) in ethanol (3mL) was added tin (II) chloride dihydrate (191mg, 0.85 mmol). The reaction mixture was stirred at room temperature for 2 hours. Ethyl acetate (50mL) was added, filtered, the filtrate was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, the organic phase was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (n-hexane/ethyl acetate as eluent) to give the title compound Int-B3(113mg, yield: 85.8%). MS M/z (ESI) 313.0[ M +1 ]]⁺

7-bromo-4-oxo-3, 4-dihydrospiro [ benzo [ e ] [1,3] oxazine-2, 4 '-piperidine ] -1' -carboxylic acid tert-butyl ester Int-B4

To a solution of 4-bromo-2-hydroxybenzamide (2.15mg, 1mmol), 1-tert-butoxycarbonyl-4-piperidone (239mg, 1.2mmol) and p-toluenesulfonic acid monohydrate (10mg, 0.05mmol) in toluene (6mL) was added magnesium sulfate (120mg, 1 mmol). The mixture was refluxed overnight. Filtered and the filtrate concentrated under reduced pressure. Ethyl acetate (60mL) was added, and the organic phase was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give the title compound Int-B4(66mg, yield: 16.7%).

MS m/z(ESI):397.0[M+1]⁺

7-bromo-2 ',3',5',6' -tetrahydrospiro [ benzo [ B ] [1,4] oxazine-2, 4' -pyran ] -3(4H) -one Int-B5

First step of

4- (5-bromo-2-nitrophenoxy) tetrahydro-2H-pyran-4-carboxylic acid ethyl ester Int-B5a

A solution of sodium bis (trimethylsilyl) amide in tetrahydrofuran (1.0M, 3.6mL, 3.6mmol) was added dropwise to a solution of ethyl 4-hydroxytetrahydro-2H-pyran-4-carboxylate (413mg, 2.36mmol) in anhydrous tetrahydrofuran (10mL) at-78 deg.C under argon. The mixture was stirred at-78 ℃ for 30 minutes. A solution of 4-bromo-2-fluoronitrobenzene (1.55g, 7.08mmol) in tetrahydrofuran (5mL) was then added slowly and the mixture was allowed to warm to room temperature slowly and stirred overnight. The reaction was quenched with saturated ammonium chloride solution, ethyl acetate (60mL) was added, and the organic phase was dried over magnesium sulfate. Filtration and concentration of the filtrate gave the title compound Int-B5a, which was used directly in the next step.

Second step of

Crude Int-B5a (. about.2.36 mmol) obtained in the first step was dissolved in acetic acid (4mL) and iron powder (1.06g, 18.88mmol) was added. The mixture was stirred vigorously at 100 ℃ for 45 minutes. Ethyl acetate (100mL) was added and filtered through Celite. The organic phase was washed with saturated sodium bicarbonate solution, concentrated under reduced pressure to remove the organic solvent, and the resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to give the title compound Int-B5(464mg, 2-step yield: 66.2%).

MS m/z(ESI):298.0[M+1]⁺

8- (5-amino-1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) -2',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] [1,4] oxazepine-2, 4' -pyran ] -4(5H) -one Int-H1

First step of

1-methyl-5-nitropyridin-2 (1H) -one Int-H1b

To a solution of 5-nitropyridin-2 (1H) -one Int-H1a (10.00g, 71.38mmol) in N, N-dimethylformamide (120mL) at 0 deg.C was added potassium carbonate (19.73g, 142.76mmol) and iodomethane (20.26g, 142.76 mmol). The reaction mixture was stirred at room temperature overnight. After the reaction, ethyl acetate and water were added, the mixture was allowed to stand for separation, and the aqueous phase was extracted with ethyl acetate. The organic layers were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane ═ 1/10) to obtain the title compound Int-H1b (7.9g, yield: 71.8%).

MS m/z(ESI):155.1[M+H]⁺

Second step of

3-bromo-1-methyl-5-nitropyridin-2 (1H) -one Int-H1c

To a solution of compound Int-H1b (7.70g, 49.96mmol) in N, N-dimethylformamide (80mL) under a nitrogen atmosphere was added N-bromosuccinimide (17.78g, 99.92 mmol). The reaction mixture was heated at 40 ℃ for 3 hours. After the reaction was completed, water and ethyl acetate were added, the mixture was allowed to stand for delamination, and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with water, saturated sodium chloride solution, filtered and concentrated to dryness. The resulting residue was slurried with n-hexane and ethyl acetate, filtered, and the cake was collected to give the title compound Int-H1c (10g, yield: 85.9%).

MS m/z(ESI):232.9[M+H]⁺

The third step

8- (1-methyl-5-nitro-2-oxo-1, 2-dihydropyridin-3-yl) -2',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] [1,4] oxazepine-2, 4' -pyran ] -4(5H) -one Int-H1d

To a mixture of compound Int-4(500mg, 1.39mmol), compound Int-H1c (324.34mg, 1.39mmol) and sodium carbonate (292.83mg, 2.78mmol) in dioxane (3mL) and water (1.5mL) under a nitrogen atmosphere was added bis-triphenylphosphine palladium dichloride (48.85mg, 69.59. mu. mol). The reaction mixture was stirred at 100 ℃ overnight. After completion of the reaction, the solvent was removed in vacuo, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane: 1/2) to give the title compound Int-H1d (400mg, yield: 74.6%).

MS m/z(ESI):MS m/z(ESI):386.01[M+H]⁺

The fourth step

To a solution of compound Int-H1d (400mg, 1.04mmol) in methanol (20mL) under a hydrogen atmosphere was added palladium on carbon (88mg, 724.50. mu. mol). The reaction mixture was stirred at 45 ℃ for 3 hours. After completion of the reaction, filtration through Celite was conducted, and the filtrate was concentrated to dryness to give the title compound Int-H1(320mg, yield: 86.7%). MS M/z (ESI) 356.0[ M + H ] ]⁺

N- (4-chloro-3-iodophenyl) -2-ethoxyisonicotinamide Int-H2

To a solution of 2-ethoxyisonicotinic acid Int-J1(158.28mg, 946.87 μmol) in N, N-dimethylformamide (5mL) were added N, N-diisopropylethylamine (152.68mg, 1.18mmol) and 2- (7-azabenzotriazole) -N, N' -tetramethyluronium hexafluorophosphate (360.03mg, 946.87 μmol) in that order, stirred for 0.5H, and then 4-chloro-3-iodoaniline Int-H2a (200mg, 789.06 μmol) was added. The reaction mixture was stirred at 25 ℃ overnight. Water and ethyl acetate were added, the layers were separated by settling, the aqueous phase was extracted twice with ethyl acetate, the organic layers were combined, washed four times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 50:1 to 10:1) to obtain the title compound Int-H2(267mg, yield: 84%).

MS m/z(ESI):403.0[M+H]⁺

2-ethoxy isonicotinic acid Int-J1

To a solution of 2-chloroisonicotinic acid Int-Jla (1g, 6.35mmol) in dimethyl sulfoxide (10mL) was added potassium hydroxide (2.00g, 35.64mmol) and ethanol (3.16g, 68.50 mmol). The reaction mixture was stirred at 80 ℃ for 16 hours. After completion of the reaction, the reaction mixture was poured into water (100mL), acidified by adding 1N hydrochloric acid, and adjusted to pH 2. The mixture was then extracted with ethyl acetate (30 mL. times.2). The organic phases were combined, washed successively with water (30 mL. times.2), saturated sodium chloride solution (30mL), dried over sodium sulfate, filtered and concentrated to give the title compound Int-J1(600mg, yield: 57%).

¹H NMR(400MHz,DMSO-d₆):δ13.60(brs,1H),8.32(d,1H),7.37(dd,1H),7.15(s,1H),4.34(q,2H),1.33(t,3H)。

MS m/z(ESI):168.1[M+H]⁺.

2-Isopropoxylisonicotinic acid Int-J2

A mixture of propan-2-ol (4.71g, 78.38mmol, 6.00mL), compound Int-Jla (3.15g, 19.99mmol), potassium hydroxide (1.12g, 19.99mmol) and dimethyl sulfoxide (70mL) was stirred at 80 ℃ for 18 h. The reaction mixture was diluted with water (200mL) and extracted with ethyl acetate (100 mL. times.3). The organic layers were combined, washed with saturated sodium chloride solution (80mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (dichloromethane/methanol 100/1-10/1) to obtain the title compound Int-J2(1.1g, yield: 30%).

MS m/z(ESI):182.1[M+H]⁺

2-Cyclopropylisonicotinic acid Int-J3

First step of

2-Cyclopropylisonicotinic acid ethyl ester Int-J3b

To a solution of ethyl 2-chloroisonicotinate Int-J3a (1.0g, 5.39mmol) in toluene (20mL) was added water (1mL, Watson s), followed by palladium acetate (120mg, 534.50. mu. mol), cyclopropylboronic acid (930mg, 10.83mmol), tricyclohexylphosphine (151mg, 538.46. mu. mol) and potassium phosphate (4.0g, 18.84 mmol). The resulting mixture was degassed and replaced 3 times with nitrogen. The mixture was heated to 120 ℃ and stirred for 16 hours. After completion of the reaction, the mixture was diluted with ethyl acetate (50mL), and the organic phase was washed with water (20mL × 3), saturated sodium chloride solution (20mL), dried over sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (eluted with petroleum ether/ethyl acetate 10/1) to give the title compound Int-J3b (0.66g, yield: 64%).

MS m/z(ESI):192.1[M+H]⁺

Second step of

2-Cyclopropylisonicotinic acid Int-J3

To a solution of compound Int-J3b (0.66g, 3.45mmol) in tetrahydrofuran (10mL) was added water (3mL) and lithium hydroxide (330.65mg, 13.81 mmol). The mixture was heated to 80 ℃ and stirred for 1 hour. The reaction mixture was diluted with water (20mL) and concentrated under reduced pressure to remove the organic solvent. The aqueous phase was acidified by the addition of 1N hydrochloric acid, concentrated and the residue was slurried with ethyl acetate (10% methanol, 20mL) and stirred for 1 hour. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound Int-J3(330mg, yield: 59%).

¹H NMR(400MHz,DMSO-d₆):δ8.61(d,1H),7.78(s,1H),7.64(dd,1H),2.33-2.29(m,1H),1.09-1.01(m,4H)。

MS m/z(ESI):164.2[M+H]⁺

1-cyclopropyl-6-oxo-1, 6-dihydropyridine-3-carboxylic acid Int-J4

First step of

1-cyclopropyl-6-oxo-1, 6-dihydropyridine-3-carboxylic acid methyl ester Int-J4b

A solution of methyl 2-oxo-2H-pyran-5-carboxylate Int-J4a (4.62g, 29.98mmol) and cyclopropylamine (4.62g, 80.94mmol) in methanol (40mL) was stirred at 60 ℃ for 18H. The mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (eluting with petroleum ether/ethyl acetate 5/1-1/1) to give the title compound Int-J4b (2.50g, yield: 43.2%).

¹H NMR(400MHz,CDCl₃):δ8.17(d,1H),7.81(dd,1H),6.51(d,1H),3.86(s,3H),3.36-3.40(m,1H),1.16-1.20(m,2H),0.90-0.93(m,2H)。

Second step of

1-cyclopropyl-6-oxo-1, 6-dihydropyridine-3-carboxylic acid Int-J4

To a mixture of compound Int-J4b (1.0g, 5.18mmol) and methanol (25mL) was added aqueous lithium hydroxide (2.6M, 10 mL). The resulting mixture was heated to 50 ℃ and stirred for 18 hours. Concentrated under reduced pressure, and the resulting residue was diluted with water (20mL) and washed with diethyl ether (10mL), the aqueous layer was separated and acidified with concentrated hydrochloric acid to adjust the pH to 6-7. Then extracted with ethyl acetate (50 mL. times.3). The organic layers were combined, washed with saturated sodium chloride solution (50mL), dried over sodium sulfate, filtered, and the filtrate was concentrated to give the title compound Int-J4(600mg, yield: 64.7%).

MS m/z(ESI):178.2[M-1]^-

4- (hydroxymethyl) -3- (trifluoromethyl) benzoic acid Int-J5

First step of

4-methyl-3- (trifluoromethyl) benzoic acid methyl ester Int-J5b

To a solution of 4-methyl-3- (trifluoromethyl) benzoic acid Int-J5a (5g, 24.49mmol) in methanol (50mL) was added sulfuric acid (2.40g, 24.49mmol, 2 mL). The mixture was stirred at 80 ℃ for 16 hours. The reaction mixture was concentrated, and the resulting residue was diluted with ethyl acetate (150mL), then washed successively with water (50 mL. times.3), saturated sodium bicarbonate solution (50 mL. times.2), saturated sodium chloride solution (50mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound Int-J5b (4.7g, yield: 87.96%).

¹H NMR(400MHz,CDCl₃):δ8.28(s,1H),8.08(d,1H),7.37(d,1H),3.94(s,3H),2.55(d,3H)。

Second step of

4- (bromomethyl) -3- (trifluoromethyl) benzoic acid methyl ester Int-J5c

To a solution of compound Int-J5b (4.7g, 21.56mmol) in carbon tetrachloride (50mL) was added azobisisobutyronitrile (AIBN, 177mg, 1.08mmol) and N-bromosuccinimide (NBS, 4.61g, 25.87 mmol). The resulting mixture was heated to reflux and stirred for 16 hours. TLC showed about 30% starting material remaining. Concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluted with hexane/ethyl acetate 60/1-30/1) to give the title compound Int-J5c (2.5g, yield: 29%).

¹H NMR(400MHz,CDCl₃):δ8.32(s,1H),8.20(d,1H),7.69(d,1H),4.65(s,2H),3.96(s,3H)。

The third step

4- (hydroxymethyl) -3- (trifluoromethyl) benzoic acid Int-J5

To a solution of compound Int-J5c (750mg, 2.52mmol) in dioxane (30mL) was added water (18mL) and sodium hydroxide (1.5g, 37.50 mmol). The resulting mixture was heated to reflux and stirred for 4 hours. The organic solvent was removed under reduced pressure, the resulting residue diluted with water (30mL), and the aqueous phase was acidified with 1N hydrochloric acid. The solid was removed by filtration, the aqueous phase was extracted with ethyl acetate (30 mL. times.2), and the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound Int-J5(380mg, 1.73mmol, yield: 68.37%).

¹H NMR(400MHz,CDCl₃):δ8.37(s,1H),8.31(d,1H),7.94(d,J＝8.0Hz,1H),5.00(s,2H)。

MS m/z(ESI):219.1[M-H]^-

2-Cyclopropoxylisonicotinic acid Int-J6

First step of

4-bromo-2-cyclopropoxypyridine Int-J6b

To a solution of 4-bromo-2-fluoropyridine Int-J6a (200mg, 1.14mmol) and cyclopropanol (150mg, 2.58mmol) in N-methylpyrrolidone (3mL) was added dropwise a solution of potassium tert-butoxide (255.05mg, 2.27mmol) in tetrahydrofuran (2.5 mL). The mixture was evacuated and replaced with nitrogen 3 times, and stirred at room temperature for 30 minutes. TLC showed the reaction was complete. The reaction mixture was poured into water (50mL), extracted with ethyl acetate (25 mL. times.2), and the organic phases were combined, washed with saturated sodium chloride solution (25 mL. times.3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound Int-J6b (200mg, yield: 82%).

¹H NMR(400MHz,CDCl₃):δ8.05(d,1H),7.07(dd,1H),6.98(d,1H),4.19-4.15(m,1H),0.81-0.76(m,4H)。

Second step of

2-Cyclopropoxylisonicotinic acid Int-J6

To a solution of compound Int-J6b (200mg, 934.32 μmol) in methanol (5mL) was added [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (70mg, 95.63 μmol) and triethylamine (945mg, 9.34mmol, Titan). The mixture was evacuated and replaced 3 times with carbon monoxide. The reaction mixture was stirred at 80 ℃ for 16 hours. Concentrated under reduced pressure and the residue purified by silica gel column chromatography (eluting with petroleum ether/ethyl acetate 5/1) to give the title compound as a crude intermediate product. The crude intermediate was dissolved in tetrahydrofuran (5mL) and a solution of lithium hydroxide (90mg, 3.76mmol, Chinese medicine) in water (1mL, Watson) was added. The resulting mixture was stirred at 40 ℃ for 4 hours. Water (20mL) was added for dilution, and the mixture was concentrated under reduced pressure to remove the organic solvent. The aqueous phase was acidified to pH 2 with 1N hydrochloric acid, filtered, and the solid was collected and dried under reduced pressure to give the title compound Int-J6(90mg, yield: 54%).

¹H NMR(400MHz,CDCl₃):δ8.42(d,1H),7.52(dd,1H),7.43(s,1H),4.25-4.22(m,1H),0.85-0.81(m,4H)。

MS m/z(ESI):180.0[M+H]⁺

2- (2-hydroxyethoxy) isonicotinic acid Int-J7

To a solution of compound Int-Jla (1g, 6.35mmol) in dimethylsulfoxide (10mL) was added potassium hydroxide (2.00g, 35.64mmol) followed by ethylene glycol (3.94g, 63.47 mmol). The mixture was stirred at 80 ℃ for 16 hours. The reaction mixture was poured into water (200mL), the aqueous phase was acidified to pH 2 with 1N hydrochloric acid, extracted with ethyl acetate (50 mL. times.4), and the organic phases were combined, washed successively with water (50 mL. times.2), saturated sodium chloride solution (50 mL. times.2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound Int-J7(400mg, yield: 34%). MS M/z (ESI) 184.1[ M + H ]⁺

6- (trifluoromethyl) pyrimidine-4-carboxylic acid Int-J8

First step of

6- (trifluoromethyl) pyrimidine-4-carboxylic acid methyl ester Int-J8b

A mixture of 4-chloro-6- (trifluoromethyl) pyrimidine Int-J8a (5.0g, 27.39mmol), potassium acetate (5.4g, 27.39mmol) and [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (1.0g, 27.39mmol) in methanol (150mL) under carbon monoxide atmosphere (10atm) was heated to 60 ℃ and stirred for 18 h. The mixture was cooled to room temperature, filtered under vacuum and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (50 mL). Filtration over silica gel (100-200 mesh) and concentration of the filtrate under reduced pressure gave the title compound Int-J8b (5.5g, 97.4%). MS M/z (ESI) 207.0[ M +1]

Second step of

6- (trifluoromethyl) pyrimidine-4-carboxylic acid Int-J8

To a solution of compound Int-J8b (1.0g, 4.85mmol) in tetrahydrofuran (20mL) was added water (10mL) followed by lithium hydroxide hydrate (820mg, 19.54 mmol). The mixture was stirred at 60 ℃ for 4 hours. The reaction mixture was diluted with water (40mL) and concentrated under reduced pressure to remove the organic solvent. The aqueous phase was acidified to pH-3 with 1N hydrochloric acid, extracted with ethyl acetate (30 mL. times.3), and the organic phases were combined, washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound Int-J8(860mg, yield: 92%). MS M/z (ESI) 191.0[ M-1]

2-cyclopentyl isonicotinic acid Int-J9

First step of

2- (Cyclopent-1-en-1-yl) isonicotinic acid methyl ester Int-J9b

To a mixture of 2- (cyclopent-1-en-1-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan Int-J9a (400mg, 2.06mmol), methyl 2-bromopyridine-4-carboxylate (445.25mg,2.06mmol) and potassium carbonate (854.57mg, 6.18mmol) in 1, 4-dioxane (10mL) and water (2.5mL) was added tetrakis (triphenylphosphine) palladium (119.08mg, 103.05 μmol) under nitrogen. The reaction mixture was stirred at 90 ℃ for 3 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether ═ 1/10) to give the title product Int-J9b (410mg, yield: 97.8%).

MS m/z(ESI):204.0[M+H]⁺

Second step of

2-Cyclopentylisonicotinic acid methyl ester Int-J9c

To a solution of compound Int-J9b (410mg, 2.02mmol) in methanol (4mL) under a hydrogen atmosphere was added palladium on carbon (90mg, 741.05 μmol). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, celite was spread and filtered. The filtrate was concentrated to dryness to give the title compound Int-J9c (410mg, yield: 99%).

MS m/z(ESI):206.2[M+H]⁺

The third step

2-cyclopentyl isonicotinic acid Int-J9

To a mixed solution of compound Int-J9c (410mg, 2.00mmol) in tetrahydrofuran (4mL) and water (4mL) was added lithium hydroxide monohydrate (108.96mg, 2.60 mmol). The reaction mixture was stirred at room temperature for 3 hours. After the reaction is complete, the pH is adjusted to 5-6. The mixture was concentrated under reduced pressure to give the crude title compound Int-J9 (630 mg).

MS m/z(ESI):192.1[M+H]⁺

N- (3-bromo-4-methylphenyl) -2- (2-hydroxypropan-2-yl) isonicotinamide Int-J10

First step of

2-Acetylisonicotinic acid Int-J10b

To a solution of methyl 2-acetylisonicotinate Int-J10a (2.0g, 11.16mmol) in tetrahydrofuran (20mL) was added water (5mL, Watson) and lithium hydroxide hydrate (1.8g, 45.00 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (50mL) and concentrated under reduced pressure to remove the organic solvent. The aqueous phase was acidified to pH-3 with 1N hydrochloric acid and then extracted with ethyl acetate (30 mL. times.3). The organic phases were combined, washed with saturated sodium chloride solution (30mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude title compound Int-J10b (0.9g, yield: 49%). The product was used in the next step without purification.

MS m/z(ESI):166.2[M+H]⁺

Second step of

2-acetyl-N- (3-bromo-4-methylphenyl) isonicotinamide Int-J10d

To a solution of compound Int-J10b (0.9g, 5.45mmol) in N, N-dimethylformamide (15mL) was added 2- (7-azabenzotriazole) -N, N' -tetramethyluronium hexafluorophosphate (2.3g, 6.05 mmol). The mixture was stirred at room temperature for 20 min, then 3-bromo-4-methylaniline Int-J10c (1.12g, 5.99mmol) and N, N-diisopropylethylamine (1.5g, 11.61mmol, 1.92mL) were added. The mixture was heated to 35 ℃ and stirred for 1 hour. The mixture was poured into water (100mL) to quench the reaction. Filtration collected the filter cake, which was then stirred in dichloromethane (20mL, 0.25% methanol (v/v)) for 30 minutes. The solid was collected and dried in vacuo to give the title product Int-J10d (1.6g, yield: 88%).

¹H NMR(400MHz,DMSO-d₆):δ10.75(s,1H),8.94(d,1H),8.45(s,1H),8.14-8.12(m,2H),7.69(dd,1H),7.37(d,1H),2.70(s,3H),2.33(s,3H)。

MS m/z(ESI):333.0[M+H]⁺

The third step

N- (3-bromo-4-methylphenyl) -2- (2-hydroxypropan-2-yl) isonicotinamide Int-J10

A solution of compound Int-J10d (300mg, 900.42. mu. mol) in tetrahydrofuran (5mL) was evacuated and replaced 3 times with nitrogen, and then a solution of trimethylmagnesium chloride in tetrahydrofuran (1M, 3.99mL) was added at-50 ℃. The mixture was stirred at room temperature for 16 hours. LCMS showed about 15% starting material remaining. The reaction was quenched with ice water (30mL), extracted with ethyl acetate (20 mL. times.3), and the organic phases were combined, washed with saturated sodium chloride solution (30mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude title compound Int-J10 (260mg, yield: 83%) which was used in the next step without purification.

MS m/z(ESI):349.0[M+H]⁺.

2- (ethylsulfonyl) isonicotinic acid Int-J11

First step of

2- (ethylsulfonyl) isonicotinic acid methyl ester Int-J11b

To a solution of methyl 2-bromoisonicotinate Int-J11a (2.3g, 10.65mmol) (trifluoromethylsulfonyloxy) copper (I) (452mg,2.13mmol) and N, N' -dimethylethylenediamine (375mg,0.40mmol) in dimethylsulfoxide (20mL) under nitrogen protection was added sodium ethylsulfinate (3.71g, 31.94 mmol). The reaction mixture was stirred at 100 ℃ for 2 hours. LCMS showed starting material remaining and reaction time was not extended to continue. Ethyl acetate and water were added to the reaction solution, and the mixture was allowed to stand for separation, and the aqueous phase was extracted with ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether ═ 1/10) to give the title compound Int-J11b (445mg, yield: 18.2%).

Second step of

2- (ethylsulfonyl) isonicotinic acid Int-J11

To a mixed solution of compound Int-J11b (485mg, 2.12mmol) in tetrahydrofuran (4mL) and water (2mL) was added lithium hydroxide (65.87mg, 2.75 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the pH of the solution was adjusted to 6. The solvent was removed by concentration under reduced pressure to give the crude title compound Int-J11, which was used without further purification.

MS m/z(ESI):216.0[M+H]⁺

5- (Difluoromethoxy) nicotinic acid Int-J12

First step of

5- (Difluoromethoxy) nicotinic acid methyl ester Int-J12b

Sodium 2-chloro-2, 2-difluoroacetate (7.5g, 57.48mmol) was added to a mixture of methyl 5-hydroxynicotinate Int-J12a (3.00g, 19.60mmol) and potassium carbonate (13g, 19.59mmol) in acetonitrile (50mL) at room temperature and the reaction mixture was stirred at 100 ℃ overnight. Water (100mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL. times.2). The organic phase was washed with saturated sodium chloride solution (100mL × 3), dried and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane ═ 1/20) to give the title compound Int-J12b (211mg, 1.04mmol, yield: 5.30%).

MS m/z(ESI):204.1[M+H]⁺

Second step of

5- (Difluoromethoxy) nicotinic acid Int-J12

Lithium hydroxide (35.37mg, 1.48mmol) was added to a mixed solution of compound Int-J12b (100mg, 492.26 μmol) in water (1mL) and tetrahydrofuran (3mL), and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated, and the resulting residue was adjusted to pH 5, extracted with ethyl acetate (20mL), and the organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate, and concentrated to give the title compound Int-J12 crude product (92mg, 486.47. mu. mol, yield: 98.82%).

MS m/z(ESI):190.3[M+H]⁺

2- (Difluoromethoxy) -6-methylisonicotinic acid Int-J13

First step of

2-hydroxy-6-methylisonicotinic acid methyl ester Int-J13b

To a solution of 2-hydroxy-6-methylisonicotinic acid Int-J13a (9.5g, 62.04mmol) in methanol (100mL) in an ice bath was added thionyl chloride (29.52g, 248.15 mmol). The reaction was stirred at room temperature overnight and monitored by LC-MS. The reaction mixture was concentrated under reduced pressure and the resulting residue was repeatedly diluted with dichloromethane and concentrated in vacuo to give the title compound Int-J13b (10.9g, 65.21mmol), which was used in the next step without purification. MS M/z (ESI) 168.1[ M + H]⁺

Second step of

2- (Difluoromethoxy) -6-methylisonicotinic acid methyl ester Int-J13c

Sodium hydrogen (500mg, 12.50mmol, 60%) was added to a solution of compound Int-J13b (400mg, 2.39mmol) in acetonitrile (15mL) at 0 ℃. The mixture was stirred at room temperature for 0.5 h, then 2, 2-difluoro-2- (fluorosulfonyl) acetic acid (800mg, 4.49mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction was quenched by the addition of water (50mL), extracted with dichloromethane (25 mL. times.2), and the organic phases were combined, dried and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether ═ 1/5) to give the title compound Int-J13c (310mg, 1.43mmol, yield: 59.65%).

¹H NMR(400MHz,CDCl₃):δ7.51(t,1H),7.50(s,1H),7.24(s,1H),3.95(s,3H),2.53(s,3H).

¹⁹F NMR(376.5MHz,CDCl₃):δ-89.10(s,1F)。

The third step

2- (Difluoromethoxy) -6-methylisonicotinic acid Int-J13

Compound Int-J13c (100mg, 460.47. mu. mol) and lithium hydroxide (100mg, 4.18mmol) were dissolved in water (1mL) and methanol (5mL), and the mixture was stirred at 70 ℃ for 2 h. TLC showed the reaction was complete. The mixture was concentrated and the resulting residue was adjusted with hydrochloric acid and dried to give the crude title compound Int-J13(190mg, LiCl contained in the product) which was used in the next step without purification.

MS m/z(ESI):204.1[M+H]⁺

2- (Difluoromethoxy) -6-methoxyisonicotinic acid Int-J14

First step of

2-hydroxy-6-methoxyisonicotinic acid methyl ester Int-J14b

A mixture of 2, 6-dihydroxyisonicotinic acid Int-J14a (10g, 64.47mmol) and concentrated sulfuric acid (18.00g, 183.67mmol, 10mL) in methanol (200mL) was heated to reflux and stirred for 72 h. The reaction solution was concentrated, and the obtained residue was diluted with ethyl acetate, washed with a saturated sodium chloride solution and dried, concentrated, and the obtained residue was purified by silica gel column chromatography (ethyl acetate rinse) to obtain the title compound Int-J14b (8.1g, 44.22mmol, yield: 68.59%).

¹H NMR(400MHz,DMSO-d₆):δ11.23(brs,1H),6.62(s,2H),3.85(s,3H),3.84(s,3H)。

Second step of

2- (Difluoromethoxy) -6-methoxyisonicotinic acid methyl ester Int-J14c

Sodium hydrogen (1g, 25.00mmol, 60% purity) was added to a solution of compound Int-J14b (2g, 10.92mmol) and sodium difluorochloroacetate (5g, 32.80mmol) in N, N-dimethylformamide (25mL) at room temperature and stirred overnight at 60 ℃. The reaction was quenched by the addition of water (100mL) and extracted with ethyl acetate (50 mL. times.2). The organic phase was washed with saturated sodium chloride solution (100mL × 3), dried and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane ═ 1/5) to give the title compound Int-J14c (850mg, 3.65mmol, yield: 33.38%).

¹H NMR(400MHz,CDCl₃):δ7.40(t,1H),7.10(d,1H),7.00(d,1H),3.94(s,3H),3.93(s,3H)。

¹⁹F NMR(376.5MHz,CDCl₃):δ-88.57。

The third step

2- (Difluoromethoxy) -6-methoxyisonicotinic acid Int-J14

Lithium hydroxide (148.37mg, 6.19mmol) was added to a mixed solution of compound Int-J14c (400mg, 1.72mmol) in water (1mL) and tetrahydrofuran (5mL), and the reaction was stirred at 25 ℃ overnight. Concentrate, adjust the resulting residue to a pH of less than 5, and extract with ethyl acetate (25 mL). The organic solution was dried and concentrated to give the title compound Int-J14 crude product (68mg, 310.30. mu. mol, yield: 18.09%). The product was used in the next step without purification.

2-bromo-6- (difluoromethoxy) pyridine-4-carboxylic acid Int-J15

First step of

2-bromo-6- (difluoromethoxy) pyridine-4-carboxylic acid methyl ester Int-J15b

A mixture of methyl 2-bromo-6-hydroxyisonicotinate Int-J15a (4g, 17.24mmol), sodium 2-chloro-2, 2-difluoroacetate (7.88g, 51.72mmol) and potassium carbonate (8.8g, 51.72mmol) in N, N-dimethylformamide (50mL) was degassed and then stirred at 80 deg.C overnight. Water (80mL) was added to dilute the solution, and the solution was extracted with ethyl acetate (150 mL. times.3). The organic phases were combined, dried and concentrated. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 5:1) to give the title compound Int-J15b (4g, 14.18mmol, yield: 82.27%).

MS m/z(ESI):282.2[M+H]⁺

Second step of

2-bromo-6- (difluoromethoxy) pyridine-4-carboxylic acid Int-J15

A mixture of compound Int-J15b (2g, 7.09mmol) and lithium hydroxide (2g, 83.51mmol) in water (5mL) and tetrahydrofuran (10mL) was degassed and stirred at room temperature for 2 h. Concentration was carried out, and the resulting residue was adjusted to pH 2 and concentrated to give the crude product of the title compound Int-J15 (4g, 5.78mmol, yield: 81.52%).

MS m/z(ESI):266.1[M-H]^-

2-carbamoyl-6- (difluoromethoxy) pyridine-4-carboxylic acid Int-J16

First step of

2-cyano-6- (difluoromethoxy) isonicotinic acid methyl ester Int-J16a

A mixture of compound Int-J15b (497.80mg, 5.32mmol) and cuprous cyanide (497.80mg, 5.32mmol) in N, N-dimethylformamide (5mL) was degassed and blanketed with nitrogen. The reaction was stirred at 120 ℃ for 2 hours. Water (20mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (50 mL. times.3). The organic solution was dried and concentrated, and the resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate ═ 5:1) to give the title compound Int-J16a (56mg, 245.45 μmol, yield: 13.85%).

MS m/z(ESI):229.3[M+H]⁺

Second step of

2-carbamoyl-6- (difluoromethoxy) pyridine-4-carboxylic acid Int-J16

Compound Int-J16a (50mg, 219.15. mu. mol) and lithium hydroxide (52.49mg, 2.19mmol) were dissolved in a mixture of water (2mL) and tetrahydrofuran (2mL), degassed, and the reaction was stirred at room temperature for 8 hours. The resulting residue was adjusted to pH 2, and the reaction mixture was concentrated to give the title compound Int-J16(100mg, 212.03. mu. mol, yield: 96.75%).

MS m/z(ESI):233.4[M+H]⁺

6- (Difluoromethoxy) pyrimidine-4-carboxylic acid Int-J17

First step of

6-hydroxypyrimidine-4-carboxylic acid methyl ester Int-J17b

Dimethyl but-2-ynedioate Int-J17a (25g, 175.92mmol) and formamidine hydrochloride (14.16g, 175.92mmol) were dissolved in acetonitrile (500mL), and triethylamine (17.80g, 175.92mmol) was added dropwise to the resulting mixture. The mixture was stirred at 80 ℃ for 4 hours. The reaction mixture was cooled to room temperature and further cooled in an ice bath. Filtration and washing of the resulting residue with acetonitrile and drying yielded the crude title compound Int-J17b (17.4g, 112.90mmol, yield: 64.17%). The product was used in the next step without purification.

Second step of

6- (Difluoromethoxy) pyrimidine-4-carboxylic acid methyl ester Int-J17c

To a solution of compound Int-J17b (5g, 32.44mmol) and sodium 2-chloro-2, 2-difluoroacetate (7.42g, 48.66mmol) in acetonitrile (100mL) was added sodium carbonate (6.88g, 64.88 mmol). The reaction was stirred at 90 ℃ for 18 hours. The reaction was cooled to room temperature, water (500mL) was added, extracted with ethyl acetate (100mL × 2), and the organic phases were combined, washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 20:1) to obtain the title compound Int-J17c (1.4g, 6.86mmol, yield: 21.14%).

The third step

6- (Difluoromethoxy) pyrimidine-4-carboxylic acid Int-J17

To a solution of compound Int-J17c (100mg, 489.88 μmol) in acetonitrile (10mL) was added lithium iodide (327.85mg, 2.45 mmol). The reaction was stirred at 70 ℃ for 18 hours. The reaction was cooled to room temperature, water (20mL) was added, the pH of the solution was adjusted to 5 with 1M hydrochloric acid, extracted with ethyl acetate (20mL × 2), the organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated to give the title compound Int-J17(100 mg). The crude product was used directly in the next step.

6-oxo-1- (2,2, 2-trifluoroethyl) -1, 6-dihydropyridine-3-carboxylic acid Int-J18

First step of

6-oxo-1- (2,2, 2-trifluoroethyl) -1, 6-dihydropyridine-3-carboxylic acid methyl ester Int-J18a

A solution of compound Int-J4a (5g, 32.44mmol) and 2,2, 2-trifluoroethylamine (6.43g, 64.88mmol) in methanol (50mL) was stirred at 60 ℃ for 16 h. The reaction mixture was diluted with ethyl acetate (100mL) and washed with saturated sodium chloride solution (300 mL). The organic phase was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 1:1) to give the title compound Int-J18a (2.8g, 11.91mmol, yield: 36.70%).¹H NMR(400MHz,DMSO-d₆):δ8.57(d,,1H),7.86(dd,1H),6.55(d,1H),4.99(q,2H),3.82(s,3H)。

Second step of

Lithium hydroxide (600mg, 25.05mmol) was added to a mixed solution of compound Int-J18a (1g, 4.25mmol) in water (2mL) and tetrahydrofuran (10mL), and the reaction was stirred at room temperature overnight. Concentration, adjustment of the pH of the residue to less than 7, extraction with ethyl acetate (100mL), washing of the organic phase with saturated sodium chloride solution, drying over sodium sulfate and concentration gave the title compound Int-J18(863mg, 3.90mmol, yield 91.77%)。MS m/z(ESI):220.1[M-1]^-

2- [2- [ tert-butyl (dimethyl) silyl ] oxyethoxy ] -6- (difluoromethoxy) pyridine-4-carboxylic acid Int-J19

First step of

2- [2- [ tert-butyl (dimethyl) silyl ] oxyethoxy ] -6- (difluoromethoxy) pyridine-4-carboxylic acid methyl ester Int-J19a

2- (tert-butyldimethylsilyloxy) ethanol (300mg, 1.70mmol) was added to a solution of compound Int-J15b (300mg, 1.06mmol) and cesium carbonate (909.09mg, 2.76mmol) in toluene (7mL), followed by 2-dicyclohexylphosphonium-2, 4, 6-triisopropylbiphenyl (X-phos, 2.78mg, 188.79. mu. mol), palladium acetate (30.30mg, 133.63. mu. mol), and the reaction was stirred at 80 ℃ for 2 hours under nitrogen. The solvent was removed by concentration under reduced pressure, water (50mL) was added, extraction was performed with ethyl acetate (30 mL. times.3), and the organic phase was concentrated in vacuo. The resulting residue was purified by chromatography (hexane/dichloromethane ═ 5/1) to give the title compound Int-J19a (270mg, 715.32 μmol, yield: 67.25%).

MS m/z(ESI):378.1[M+H]⁺

Second step of

To a solution of compound Int-J19a (187.5mg, 496.76. mu. mol) in tetrahydrofuran (3.5mL) was added aqueous lithium hydroxide (1.5mL, 4mol/L) and the reaction was stirred at room temperature for 3 hours. The mixture was concentrated, then the aqueous phase pH was adjusted to less than 7 with 1N hydrochloric acid and extracted with ethyl acetate (30mL × 3). The organic phase was concentrated to give the crude title compound Int-J19 (150mg, 412.73. mu. mol, yield: 83.09%).

MS m/z(ESI):362.1[M-H]^-

2- (Difluoromethoxy) -6- (2-methoxyethoxy) isonicotinic acid Int-J20

First step of

2- (Difluoromethoxy) -6- (2-methoxyethoxy) pyridine-4-carboxylic acid methyl ester Int-J20a

Compound Int-J15b (200mg, 709.12. mu. mol), 2-methoxyethanol (53.96mg, 709.12. mu. mol), 2-dicyclohexylphospho-2, 4, 6-triisopropylbiphenyl (X-phos, 67.61mg, 141.82. mu. mol), palladium acetate (20g, 70.91. mu. mol) and cesium carbonate (600mg,2.13mmol) were dissolved in toluene (3mL), and the mixture was degassed and protected with nitrogen, followed by stirring at 80 ℃ for 2 hours. Water (30mL) was added to dilute, extracted with ethyl acetate (20 mL. times.3), the organic phase was dried and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate-ethyl acetate ═ 3:1) to give the title compound Int-J20a (70mg, 252.51 μmol, yield: 35.61%). MS M/z (ESI):278.4[ M + H ]⁺

Second step of

2- (Difluoromethoxy) -6- (2-methoxyethoxy) isonicotinic acid Int-J20

Compound Int-J20a (70mg, 252.51. mu. mol) and lithium hydroxide (70mg, 252.51. mu. mol) were dissolved in tetrahydrofuran (2mL) and water (0.5mL), and the mixture was degassed and stirred at room temperature for 3 hours. The reaction solution was adjusted to pH 1 and concentrated to give the crude product of the title compound Int-J20 (120mg, 238.72. mu. mol, yield: 94.54%, containing LiCl).

MS m/z(ESI):264.4[M+H]⁺

N- (3-bromo-4-methylphenyl) -4- (trifluoromethyl) -1H-benzo [ d ] imidazol-2-amine Int-K12

First step of

2-bromo-4-isocyanatothio-1-methylbenzene Int-K12a

3-bromo-4-methylaniline Int-J10c (2g, 10.75mmol) was added to a pre-cooled solution of thiophosgene (2.05g, 16.12mmol) in dichloromethane (20mL) at 0 deg.C, followed by triethylamine (1.30g, 12.90mmol), and the reaction was stirred at 0 deg.C for 1 hour. After completion of the reaction, the mixture was diluted with dichloromethane (30mL) and washed with saturated sodium chloride solution (50 mL). The organic phase was dried and concentrated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane ═ 1/5) to give the title compound Int-K12a (2g, 8.77mmol, yield: 81.56%).

¹H NMR(400MHz,DMSO-d₆):δ7.42(d,1H),7.19(d,1H),7.07(dd,1H),2.39(s,3H)。

Second step of

To a solution of compound Int-K12a (400mg, 1.75mmol) in N, N-dimethylformamide (10mL) at 0 deg.C was added 3-trifluoromethylbenzene-1, 2-diamine (380.00mg, 2.16mmol, Combi-Blocks) and triethylamine (250mg, 2.47 mmol). The reaction was stirred at room temperature for 1 hour, then diluted with ethyl acetate (30mL) and washed with saturated sodium chloride solution (30 mL. times.3). The organic phase was dried and concentrated to give the title compound as a crude solid. The solid was dissolved in N, N-dimethylformamide (10mL), and then ferric trichloride (20mg, 123.30. mu. mol) was added. The reaction was stirred at 80 ℃ for 4 hours. The reaction mixture turned black and LCMS showed the reaction was complete. The mixture was cooled and diluted with ethyl acetate (30mL), washed with saturated sodium chloride solution (30mL × 3), the organic phase dried and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane ═ 1/10) to give the title compound Int-K12(307mg, 824.86 μmol, yield: 38.23%).

MSm/z(ESI):370.0[M+1]⁺

3- (5-bromo-2-fluoro-4-methylphenyl) -1-methyl-1- (2- (trifluoromethyl) pyridin-4-yl) urea Int-K22

First step of

Boc-N- [2- (trifluoromethyl) -4-pyridinyl ] carbamic acid tert-butyl ester Int-K22b

To a solution of 2- (trifluoromethyl) pyridin-4-amine Int-K22a (5g, 30.84mmol) in dichloromethane (50mL) was added triethylamine (6.24g, 61.69mmol, 8.57mL), 4-dimethylaminopyridine (376.81mg, 3.08), followed by di-tert-butyl dicarbonate (14.00g, 64.15mmol, 14.7 mL). The mixture was stirred at room temperature for 16 hours. Concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluted with petroleum ether/ethyl acetate 20/1) to give the title compound Int-K22b (9.0g, yield: 81%).

MS m/z(ESI):363.0[M+H]⁺

Second step of

(2- (trifluoromethyl) pyridin-4-yl) carbamic acid tert-butyl ester Int-K22c

To a solution of compound Int-K22b (4.0g, 11.04mmol) in methanol (40mL) was added potassium carbonate (6.10g, 44.16 mmol). The mixture was stirred at 70 ℃ for 2 hours. The reaction mixture was poured into water (200mL), extracted with ethyl acetate (50 mL. times.3), and the organic phases were combined, washed with saturated sodium chloride solution (50mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting with petroleum ether/ethyl acetate 10/1) to give the title compound Int-K22c (2.3g, yield: 79%).

MS m/z(ESI):263.0[M+H]⁺

The third step

Methyl (2- (trifluoromethyl) pyridin-4-yl) carbamic acid tert-butyl ester Int-K22d

To a solution of compound Int-K22c (2.3g, 8.77mmol) in tetrahydrofuran (30mL) was added portionwise sodium hydrogen (421.01mg, 10.53mmol, 60% NaH in mineral oil) at 0 ℃. The mixture was stirred at 0 ℃ for 30 minutes, then iodomethane (1.49g, 10.53mmol, 655.23 μ l) and the mixture was stirred at room temperature for 2 hours. Water was added to quench the reaction. Diluted with ethyl acetate (200mL), washed with water (50 mL. times.2), saturated sodium chloride solution (50mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluted with petroleum ether/ethyl acetate 20/1) to give the title compound Int-K22d (2.0g, yield: 83%).

MS m/z(ESI):277.1[M+H]⁺

The fourth step

N-methyl-2- (trifluoromethyl) pyridin-4-amine Int-K22e

To a solution of compound Int-K22d (2.0g, 7.24mmol) in dioxane (10mL) was added a 4M solution of hydrogen chloride in 1, 4-dioxane (10 mL). The mixture was stirred at room temperature for 16 hours. The solvent was removed by concentration under reduced pressure, and the resulting residue was dissolved in water (50mL) and basified with saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate (30 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (30mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude title compound Int-K22e (1.1g, yield: 86%).

MS m/z(ESI):177.1[M+H]⁺

The fifth step

To a solution of compound Int-K22e (500mg, 2.84mmol) in dichloromethane (5mL) was added N, N-diisopropylethylamine (2.97g, 22.99mmol, 3.8 mL). The reaction mixture was evacuated and replaced 3 times with nitrogen, then triphosgene (1.01g, 3.41mmol) dissolved in dichloromethane (5mL) was added at 0 ℃. The mixture was stirred at 0 ℃ for 2 h, then a solution of 5-bromo-2-fluoro-4-methylaniline Int-K22f (690mg, 3.38mmol) in dichloromethane (5mL) was added and the mixture stirred at room temperature for 16 h. The reaction was quenched with water, the organic phase was separated and washed with saturated sodium chloride solution (10mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting with petroleum ether/ethyl acetate 20/1-10/1) to give the title compound Int-K22(800mg, yield: 69%).

¹H NMR(400MHz,CDCl₃):δ8.71(d,1H),8.29(d,1H),7.68(d,1H),7.47(dd,1H),6.97(d,1H),6.79(d,1H),3.49(s,3H),2.34(s,3H)。

MSm/z(ESI):406.1[M+H]⁺

1- (5-bromo-2-fluoro-4-methylphenyl) -3- (2- (difluoromethoxy) pyridin-4-yl) urea Int-K23

First step of

(2- (Difluoromethoxy) pyridin-4-Yl) carbamic acid Tert-butyl ester Int-K23b

To a mixture of 2- (difluoromethoxy) isonicotinic acid Int-K23a (1g, 5.29mmol) and triethylamine (1.61g, 15.86mmol) in t-butanol (5mL) and toluene (50mL) was added diphenyl phosphorazidate (1.93g, 7.93 mmol). The mixture was replaced with argon 3 times and then stirred at 110 ℃ overnight. Concentration and the resulting residue was purified by silica gel column (hexane: ethyl acetate 1:0 to 10:1) to obtain the title compound Int-K23b (1.4g, yield: 92.3%).

MS m/z(ESI):261.1[M+H]⁺

Second step of

2- (Difluoromethoxy) pyridin-4-amine Int-K23c

Compound Int-K23b (1.4g, 5.38mmol) was dissolved in 4M hydrogen chloride in 1, 4-dioxane (30mL) and the mixture was stirred at 50 ℃ for 5 h. Concentration gave the crude title compound, which was dissolved in dichloromethane (50mL) and water (40mL), the pH of the mixture was adjusted to 9-10 with 4M sodium hydroxide solution, the organic phase was separated, dried, and concentrated to give the title compound Int-K23c (0.6g, crude). The crude product was used without purification.

MS m/z(ESI):161.2[M+H]⁺

The third step

1-bromo-4-fluoro-5-isocyanato-2-methylbenzene Int-K23d

To a solution of triphosgene (5.8g, 19.5mmol) in dichloromethane (20mL) was added dropwise a solution of 5-bromo-2-fluoro-4-methylaniline Int-K20f (2g, 9.8mmol) in dichloromethane (5mL) followed by triethylamine (4.4g, 43.6mmol) in dichloromethane (5mL) at 0 deg.C. After stirring overnight at room temperature, the mixture was concentrated. The resulting residue was stirred in n-hexane (10mL), filtered, and the filtrate was concentrated and dried to give the title compound Int-K23d (4g, crude). The crude product was used without purification.

The fourth step

To a solution of compound Int-K23c (600mg, 3.75mmol) and triethylamine (1.14g, 11.24mmol) in 1, 4-dioxane (20mL) was added compound Int-K23d (3.45g, 14.99mmol) and the reaction stirred at 50 ℃ for 6 h. After concentration, ethyl acetate (50mL) and a saturated sodium chloride solution (30mL) were added to the resulting residue, and the mixture was allowed to stand for separation, and the aqueous phase was extracted with ethyl acetate (20 mL. times.2). The organic layer was concentrated, and the obtained residue was purified by a silica gel column (hexane: ethyl acetate 1:0 to 3:1) to obtain the title compound Int-K23(0.5g, yield: 34.2%).

MS m/z(ESI):389.9[M+H]⁺

1- (5-bromo-2-fluoro-4-methylphenyl) -3- (2, 2-difluorobenzo [ d ] [1,3] dioxolan-4-yl) urea Int-K26

To a solution of 2, 2-difluorobenzo [ d ] [1,3] dioxolan-4-amine Int-K26a (300mg, 1.73mmol) in tetrahydrofuran (3mL) at 0 deg.C was added compound Int-K23d (450mg, crude). After stirring at room temperature for 2 hours, concentration was carried out, and the resulting residue was purified by silica gel column chromatography (eluting with petroleum ether/ethyl acetate-40/1) to give the title compound Int-K26(500mg, 1.24mmol, yield: 71.74%).

MS m/z(ESI):402.9[M+H]⁺

N- (3-iodo-4-methylphenyl) -8- (trifluoromethyl) -2, 3-dihydro-4H-benzo [ b ] [1,4] oxazine-4-carboxamide

Int-K27

First step of

2-iodo-4-isocyanato-1-methylbenzene Int-K27b

To a suspension of triphosgene (576mg, 1.94mmol) in dichloromethane (10mL) was added 3-iodo-4-methylaniline Int-K27a (500mg, 2.15mmol), the mixture was stirred at room temperature for 15 min, then triethylamine (217.10mg, 2.15mmol) was added. Filtration, washing of the filter cake with dichloromethane and concentration of the filtrate gave the crude title compound Int-K27b (238mg, 918.77. mu. mol, yield: 42.82%).

Second step of

2-amino-6- (trifluoromethyl) phenol Int-K27d

To a suspension of 2-nitro-6- (trifluoromethyl) phenol Int-K27c (5g, 24.14mmol) in methanol (50mL) was added palladium on carbon (1g, 8.23 mmol). The reaction was stirred at room temperature for 2 hours under hydrogen. The precipitate was filtered, the filter cake was washed with methanol, and the filtrate was concentrated to give the crude product of the title compound Int-K27d (3.9g, 22.02mmol, yield: 91.20%).

¹H NMR(400MHz,DMSO-d₆):δ6.89-6.86(m,1H),6.76-6.71(m,2H)。

The third step

8- (trifluoromethyl) -2H-benzo [ b ] [1,4] oxazin-3 (4H) -one Int-K27e

To a solution of compound Int-K27d (2g, 11.29mmol) in dichloromethane (20mL) at 0 deg.C was added 2-chloroacetyl chloride (1.28g, 11.29mmol) and stirred for 2 h. LCMS showed reaction completion. The mixture was concentrated and redissolved in N, N-dimethylformamide (5mL), potassium carbonate (1.15g, 11.29mmol) was added, and the mixture was stirred at room temperature overnight. Dilute with ethyl acetate (25mL), wash with saturated sodium chloride solution (50mL), dry the organic phase and concentrate to give the title compound Int-K27e crude product (1.3g, 5.99mmol, yield: 53.02%).

¹H NMR(400MHz,DMSO-d₆):δ10.98(brs,1H),7.26-7.23(m,1H),7.18-7.08(m,2H),4.72(s,2H)。

The fourth step

8- (trifluoromethyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine Int-K27f

Borane tetrahydrofuran (50.84mg, 3.68mmol, 4mL) was added to a solution of compound Int-K27e (400mg, 1.84mmol) in tetrahydrofuran (5mL) at room temperature and stirred overnight. The reaction mixture was concentrated and adjusted to pH 7, diluted with ethyl acetate (30mL), and washed with saturated sodium chloride solution (50 mL). The organic phase was dried and concentrated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane ═ 1/10) to give the title compound Int-K27f (313mg, 1.54mmol, yield: 83.64%).

MS m/z(ESI):204.0[M+1]⁺

The fifth step

Int-K27

To a solution of compound Int-K27b (200mg, 772.07. mu. mol) and compound Int-K27f (125.48mg, 617.66. mu. mol) in dichloromethane (5mL) was added triethylamine (234.38mg, 2.32mmol), and the mixture was stirred at room temperature for 12 hours. Water (30mL) was added, extraction was performed with dichloromethane (10mL × 2), the organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated, and the resulting residue was purified by thin layer chromatography (ethyl acetate/hexane ═ 1/3) to give the title compound Int-K27(73mg, 174.97 μmol, yield: 22.66%).

¹H NMR(400MHz,CDCl₃):δ7.82(d,1H),7.50(d,1H),7.43(d,1H),7.32(dd,1H),7.16(d,1H),7.03(t,1H),6.98(s,1H),4.52(t,2H),3.98(t,2H),2.38(s,3H)。

1- (5-bromo-2-fluoro-4-methylphenyl) -3- (3-fluoro-2- (trifluoromethyl) pyridin-4-yl) urea Int-K28

First step of

(3-fluoro-2- (trifluoromethyl) pyridin-4-yl) carbamic acid tert-butyl ester Int-K28b

3-fluoro-2- (trifluoromethyl) isonicotinic acid Int-K28a (900mg, 4.30mmol), diphenylphosphorylazide (1.05g, 4.30mmol) and triethylamine (870mg, 8.60mmol) were dissolved in t-butanol (2.0mL) and toluene (20mL), and the mixture was heated to 110 ℃ and stirred for 18 hours. The mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (eluting with petroleum ether/ethyl acetate 5/1-1/1) to give the title compound Int-K28b (1.0g, 3.57mmol, yield: 82.91%).

MS m/z(ESI):281.0[M+H]⁺

Second step of

3-fluoro-2- (trifluoromethyl) pyridin-4-amine hydrochloride Int-K28c

To a solution of compound Int-K28b (1.09g, 3.89mmol) in 1, 4-dioxane (4mL) was added a solution of 4M hydrogen chloride in 1, 4-dioxane (4g, 3.89 mmol). The reaction mixture was stirred at 40 ℃ for 3 hours. After completion of the reaction, the solvent was removed under reduced pressure to give the title compound Int-K28c (1g, yield: 93.3%). The crude product was used directly in the next step without purification.

MS m/z(ESI):181.2[M+H]⁺

The third step

To a solution of triphosgene (150.73mg, 507.93. mu. mol) in dry dichloromethane (5mL) was added a solution of compound Int-K28c (100mg, 461.76. mu. mol) and triethylamine (116.81mg, 1.15mmol) in dichloromethane (5mL) at 0 ℃ under nitrogen. The reaction mixture was slowly warmed to room temperature. After 20 min, TLC showed complete formation of the intermediate. The solution was cooled to 0 ℃ again, a solution of compound Int-K22f (103.64mg, 507.93. mu. mol) in dichloromethane (5mL) was added dropwise, and after addition, triethylamine (116.81mg, 1.15mmol) was added dropwise and the reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, the resulting residue was slurried in ethyl acetate, insoluble materials were filtered off, the filtrate was concentrated, and purification was performed by silica gel column chromatography (hexane: ethyl acetate ═ 30:1) to give the title compound Int-K28(61mg, yield: 32.2%).

MS m/z(ESI):410.1[M+H]⁺

N- (3-bromo-4-methylphenyl) -4- (trifluoromethyl) indoline-1-carboxamide Int-K30

Int-K30b (86mg, 0.4mmol) 3-bromo-4-methylbenzoic acid, triethylamine (0.28mL, 2.0mmol) and diphenylphosphorylazide (DPPA, 0.14mL, 0.48mmol) were dissolved in 1, 4-dioxane (2mL) and the mixture was stirred at room temperature for 30 minutes. 4- (trifluoromethyl) indoline hydrochloride Int-K30a (90mg, 0.4mmol) was then added. The reaction mixture was stirred at 95 ℃ overnight under nitrogen. After completion of the reaction, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography using hexane/ethyl acetate as an eluent to give the title compound Int-K30(141mg, yield: 88.6%).

MS m/z(ESI):399.0[M+H]⁺

N- (5- (3-bromo-4-methylphenyl) -4H-1,2, 4-triazol-3-yl) -2- (trifluoromethyl) pyridin-4-amine Int-L3

First step of

3-bromo-4-methylbenzoyl isothiocyanate Int-L3a

To a solution of Int-K30b (5g, 23.25mmol) 3-bromo-4-methylbenzoic acid in dichloromethane (50mL) at 0 deg.C was added oxalyl chloride (6.00g, 47.27mmol, 4mL), followed by N, N-dimethylformamide (379.20mg, 5.19mmol, 0.4 mL). The mixture was stirred at room temperature for 1 hour. Concentrated under reduced pressure, the resulting residue was dissolved in acetonitrile (50mL), potassium thiocyanate (2.82g, 27.90mmol) was added, and the mixture was stirred at room temperature for 2 hours. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to give the crude product of the title compound Int-L3a (5.5g, yield: 92%) which was used in the next step without purification.

Second step of

3-bromo-4-methyl-N- ((2- (trifluoromethyl) pyridin-4-yl) thiocarbamoyl) benzamide Int-L3b

To a solution of 2- (trifluoromethyl) pyridin-4-amine Int-K20a (1.6g, 9.87mmol) in tetrahydrofuran (50mL) at room temperature was added compound Int-L3a (2.8g, 10.93 mmol). The mixture was heated to 60 ℃ and stirred for 16 hours. Concentrated under reduced pressure, and the resulting residue was slurried in petroleum ether (containing 25% ethyl acetate) for 2 hours, filtered, and the solid was collected and dried under reduced pressure to give the title compound Int-L3b (3.4g, yield: 82%).

¹H NMR(400MHz,CDCl₃):δ13.12(s,1H),9.09(s,1H),8.73(d,1H),8.29(d,1H),8.10(dd,2H),7.73(dd,1H),7.42(d,1H),2.51(s,3H)。

MS m/z(ESI):398.2[M+H]⁺

The third step

To a solution of compound Int-L3b (400mg, 956.41. mu. mol) in chloroform (10mL) at room temperature was added hydrazine hydrate (240mg, 4.79mmol, 240.00. mu.l). The mixture was heated to 90 ℃ and stirred for 5 hours. Concentrated under reduced pressure, and the resulting residue was slurried in methylene chloride for 1 hour, filtered with suction, and the filter cake was collected and dried under reduced pressure to give the title compound Int-L3(270mg, yield: 71%).

¹H NMR(400MHz,DMSO-d₆):δ8.44(d,1H),8.18(d,1H),8.05(s,1H),7.88(dd,1H),7.75(d,1H),7.51(d,1H),3.77(s,2H),2.41(s,3H)。

m/z(ESI):397.9[M+H]⁺

2- (4-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -5- (2- (trifluoromethyl) pyridin-4-yl) -1,3, 4-oxadiazole Int-L4

First step of

2- (2- (trifluoromethyl) isonicotinyl) hydrazine-1-carboxylic acid tert-butyl ester Int-L4b

2- (trifluoromethyl) isonicotinic acid Int-L4a (5.00g, 26.16mmol), tert-butyl carbazate (5.18g, 39.25mmol), 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (14.92g, 39.25mmol) and N, N-diisopropylethylamine (6.75g, 52.33mmol) were dissolved in dichloromethane (150mL) and the mixture stirred at room temperature for 18 h. Washed successively with water (50mL), saturated sodium chloride solution (50mL), dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (eluting with petroleum ether/ethyl acetate 20/1-10/1) to give the title compound Int-L4b (7.0g, yield: 87.6%).

MS m/z(ESI):306.1[M+1]⁺

Second step of

2- (trifluoromethyl) isonicotinyl hydrazide dihydrochloride Int-L4c

To a solution of compound Int-L4b (7.0g, 22.93mmol) in dioxane (80mL) was added dropwise a solution of 4M hydrogen chloride in 1, 4-dioxane (100 mL). The mixture was stirred at 30 ℃ for 18 hours. Concentration under reduced pressure gave the title compound Int-L4c (5.7g, yield: 88.4%).

MS m/z(ESI):206.1[M+1]⁺

The third step

4-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoic acid Int-L4e

Int-L4d (20g, 76.3mmol), pinacol diborate (29g, 114.4mmol) and potassium acetate (37.4g, 381.5mmol) 3-iodo-4-methylbenzoic acid were dissolved in N, N-dimethylformamide (200mL) under a nitrogen atmosphere, and [1,1' -bis (diphenylphosphino) ferrocene ] was added to the mixture ]Palladium dichloride (Pd (dppf) Cl₂2.79g, 3.81 mmol). The reaction mixture was heated to 100 ℃ and stirred overnight. After completion of the reaction, water (800mL) was added, acidified with 1N hydrochloric acid, and then extracted with ethyl acetate (400 mL. times.2). The organic layers were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was recrystallized from isopropyl ether and filtered to give the title compound Int-L4e (13g, yield: 65%).

¹H NMR(400MHz,CDCl₃)δ8.50(s,1H),8.04(d,1H),7.34-7.18(m,1H),2.61(s,3H),1.36(s,12H)。

The fourth step

N' - (4-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoyl) -2- (trifluoromethyl) isonicotinyl hydrazide Int-L4f

To a solution of compound Int-L4e (1.0g, 3.82mmol) in dichloromethane (10mL) was added oxalyl chloride (629.54mg, 4.96mmol) and N, N-dimethylformamide (1 drop). The mixture was stirred at 30 ℃ for 1 hour and then concentrated under reduced pressure. The resulting residue was diluted with dichloromethane (10 mL). The resulting solution was added dropwise to a solution of compound Int-L4c (0.95g, 3.43mmol) and pyridine (0.81g, 10.20mmol) in dichloromethane (20mL) at 0 deg.C. The mixture was stirred at 30 ℃ for 18 hours. The reaction mixture was diluted with dichloromethane (200mL), washed successively with saturated ammonium chloride solution (40mL), saturated sodium chloride solution (300mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluted with petroleum ether/ethyl acetate 3/1-1/1) to obtain the title compound Int-L4f (1.00g, yield: 65.0%).

MS m/z(ESI):450.3[M+1]⁺

The fifth step

To a mixture of compound Int-L4f (0.95g, 2.11mmol) in dichloromethane (60mL) was added N, N-diisopropylethylamine (0.82g, 6.34mmol) and p-toluenesulfonyl chloride (606mg, 3.17 mmol). The reaction was stirred at 30 ℃ for 18 hours. It was diluted with dichloromethane (200mL), washed successively with saturated ammonium chloride solution (40mL), saturated sodium chloride solution (300mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluted with petroleum ether/ethyl acetate 3/1-1/1) to obtain the title compound Int-L4(0.70g, yield: 76.8%).

¹H NMR(400MHz,CDCl₃):δ8.96(d,1H),8.51(d,1H),8.41(s,1H),8.23(d,1H),8.12(dd,1H),7.36(d,1H),2.64(s,3H),1.40(s,12H)。

MS m/z(ESI):432.2[M+1]⁺

4- (5- (3-bromo-4-methylphenyl) -4H-1,2, 4-triazol-3-yl) -2-cyclopropylpyridine Int-L5

First step of

2- (2-Cyclopropylisonicotinyl) hydrazine-1-carboxylic acid tert-butyl ester Int-L5a

To a suspension of compound Int-J3(1.2g, 7.35mmol) in dichloromethane (20mL) was added 2- (7-azabenzotriazole) -N, N' -tetramethyluronium hexafluorophosphate (4.2g, 11.05 mmol). The mixture was stirred at room temperature for 20 minutes, then tert-butyl carbazate (1.5g, 11.35mmol) and N, N-diisopropylethylamine (1.90g, 14.71mmol) were added. The mixture was stirred at room temperature for 16 hours. Dichloromethane (50mL) was added for dilution, and the organic phase was washed with water (20mL × 3), saturated sodium chloride solution (20mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate: 2/1) to obtain the title compound Int-L5a (1.57g, yield: 77%).

MS m/z(ESI):278.1[M+H]⁺

Second step of

2-cyclopropyl isonicotinyl hydrazide Int-L5b

To a solution of compound Int-L5a (1.56g, 5.63mmol) in dioxane (5mL) was added a 4M solution of hydrogen chloride in 1, 4-dioxane (7.03 mL). The mixture was stirred at room temperature for 16 hours. Concentration under reduced pressure gave the title compound Int-L5b (1.36g, yield: 97%) which was used in the next step without purification.

MS m/z(ESI):178.2[M+H]⁺

The third step

A mixture of compound Int-L5b (500mg, 2.00mmol), 3-bromo-4-methyl-benzonitrile Int-L5c (800mg, 4.08mmol) and potassium carbonate (1.11g, 8.00mmol) in n-butanol (6mL) was reacted at microwave 150 ℃ for 1 h. Ethyl acetate (30mL) was added for dilution, and the organic phase was washed with water (10 mL. times.3), saturated sodium chloride solution (10mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluted with petroleum ether/ethyl acetate 10/1-4: 1) to give the title compound Int-L5(210mg, yield: 30%).¹H NMR(400MHz,CDCl₃):δ8.54(d,1H),8.23(d,1H),7.84-7.82(m,2H),7.73(dd,1H),7.33(d,1H),2.45(s,3H),2.16-2.11(m,1H),1.08-1.02(m,4H)。

4- (2- (3-bromo-4-methylphenyl) -1H-imidazol-5-yl) -2- (trifluoromethyl) pyridine Int-L6

First step of

N-methoxy-N-methyl-2- (trifluoromethyl) isonicotinamide Int-L6a

To a solution of compound Int-L4a (4.97g, 26.03mmol) in dichloromethane (10mL) at 0 ℃ was added N, N-diisopropylethylamine (10.1g, 26.03mmol), 2- (7-azabenzotriazole) -N, N' -tetramethyluronium hexafluorophosphate (14.82g, 38.99mmol) and N-methoxymethylamine hydrochloride (2.98g, 30.60 mmol). The mixture was stirred at 25 ℃ for 15 hours. The reaction mixture was cooled to 0 ℃ again and quenched by addition of water (300 mL). The mixture was extracted with ethyl acetate (30 mL. times.3), and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title compound as a crude product. The crude product was purified by silica gel column chromatography (15: 1-3: 1 petroleum ether/ethyl acetate) to give the title compound Int-L6a (6.4g, 27.33 mmol).

¹H NMR(400MHz,CDCl₃):δ8.83(d,1H),7.79(s,1H),7.75(d,1H),3.56(s,3H),341(s,3H)。

Second step of

1- (2- (trifluoromethyl) pyridin-4-yl) ethan-1-one Int-L6b

A solution of methylmagnesium bromide in tetrahydrofuran (1.0M, 10mmol, 10mL) was added to a solution of compound Int-L6a (2.00g, 8.54mmol) in tetrahydrofuran (10mL) at 0 deg.C. The reaction was stirred at room temperature overnight. Quench with water (100 mL). Extract with ethyl acetate (50mL), dry the organic phase and concentrate. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane ═ 1/10) to give the title compound Int-L6b (1.45g, 7.67mmol, yield: 89.77%).

¹H NMR(400MHz,CDCl₃):δ8.94(d,1H),8.13(s,1H),7.95(dd,1H),2.70(s,3H)。

The third step

2-bromo-1- (2- (trifluoromethyl) pyridin-4-yl) ethan-1-one Int-L6c

To a solution of compound Int-L6b (1.1g, 5.82mmol) in dichloromethane (10mL) at 0 deg.C was added acetic acid (0.2g, 3.33mmol) and bromine (0.8g, 5.00 mmol). The reaction was stirred at 50 ℃ for 3 hours. The reaction mixture was cooled, filtered, the filter cake was collected, washed with toluene and dried to give the title compound Int-L6c (0.9g, 3.36mmol, yield: 57.73%) which was used in the next step without purification.

MS m/z(ESI):265.9[M-1]^-

The fourth step

3-bromo-4-methylbenzamidine hydrochloride Int-L6e

A solution of lithium hexamethyldisilazide in tetrahydrofuran (1.0M, 10.5g, 10.15mmol) was added to a solution of 3-bromo-4-methylbenzonitrile Int-L6d (2g, 10.15mmol) in tetrahydrofuran (10mL) at 0 deg.C, and the reaction was stirred at room temperature for 2 hours. Then, a hydrochloric acid/methanol solution (10mL) was added thereto at 0 ℃ and stirred for 4 hours. The mixture was concentrated, washed with ethyl acetate (50mL), dried and concentrated to give the title compound Int-L6e (1.3g, 6.07mmol, yield: 59.83%) which was used in the next step without purification.

MS m/z(ESI):212.9[M+1]⁺

The fifth step

A mixture of compound Int-L6e (1g, 4.67mmol), compound Int-L6c (0.9g, 3.36mmol) and potassium carbonate (2.6g, 18.84mmol) in tetrahydrofuran (10mL) was stirred at 75 deg.C for 12 h. After completion of the reaction, ethyl acetate (50mL) was added for dilution, and the mixture was washed with a saturated sodium chloride solution (50 mL). The organic phase was dried and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane ═ 1/5) to give the title compound Int-L6(150mg, 392.49 μmol, yield: 8.40%).

MS m/z(ESI):382.1[M+1]

5- (5- (3-bromo-4-methylphenyl) -4H-1,2, 4-triazol-3-yl) -2- (trifluoromethyl) pyridine Int-L9

First step of

2- (6- (trifluoromethyl) nicotinoyl) hydrazine-1-carboxylic acid tert-butyl ester Int-L9b

A mixture of 6- (trifluoromethyl) nicotinic acid Int-L9a (5.0g, 26.16mmol), tert-butyl N-carbamate (5.19g, 39.25mmol), 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (14.92g, 39.25mmol) and N, N-diisopropylethylamine (12.82mL, 78.49mmol) in dichloromethane (200mL) was stirred at room temperature for 18 h. The reaction mixture was washed successively with saturated ammonium chloride solution (80mL), saturated sodium chloride solution (50mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluted with petroleum ether/ethyl acetate 10/1-2/1) to give the title compound Int-L9b (7.0g, yield: 87.6%).

MS m/z(ESI):306.0[M+H]⁺

Second step of

6- (trifluoromethyl) nicotinhydrazide dihydrochloride Int-L9c

Compound Int-L9b (7.0g, 22.93mmol) was dissolved in 4M hydrogen chloride in 1, 4-dioxane (150mL) and stirred at room temperature for 18 h. Concentrating under reduced pressure. The resulting residue was washed with diethyl ether (100mL) and dried in vacuo to give the crude title compound Int-L9c (7 g).

MS m/z(ESI):206.0[M+H]⁺

The third step

To a solution of compound In-L9c (800mg, 2.88mmol) In n-butanol (10mL) was added potassium carbonate (1.6g, 11.58mmol) and compound Int-L5c (1.1g, 5.61 mmol). The mixture was heated to 150 ℃ and stirred for 4 hours. After the reaction mixture was cooled to room temperature, ethyl acetate (100mL) was added for dilution. The organic phase was washed with water (50 mL. times.2), saturated sodium chloride solution (50mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluted with petroleum ether/ethyl acetate 4/1) to give the title compound Int-L9(460mg, yield: 41.73%).

¹H NMR(400MHz,DMSO-d₆):δ14.93(brs,1H),9.39(s,1H),8.65(dd,1H),8.28(d,1H),8.05(d,1H),7.99(dd,1H),7.55(d,1H),2.42(s,3H)。

MS m/z(ESI):382.9[M+H]⁺

4- (5- (3-bromo-4-methylphenyl) -4H-1,2, 4-triazol-3-yl) -3- (trifluoromethyl) pyridine Int-L11

First step of

2- (3- (trifluoromethyl) isonicotinyl) hydrazine-1-carboxylic acid tert-butyl ester Int-L11b

A mixture of 3- (trifluoromethyl) isonicotinic acid Int-L11a (4.5g, 23.55mmol) and 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (13.5g, 35.50mmol) in dichloromethane (150mL) was stirred at room temperature for 10 min. N-Carbamate (4.8g, 36.32mmol) and N, N-diisopropylethylamine (6.3g, 48.75mmol) were then added and the mixture stirred at room temperature overnight. The mixture was washed with water (50mL), saturated sodium chloride solution (50mL), dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (eluting with petroleum ether/ethyl acetate 4/1) to give the title compound Int-L11b (3.5g, 11.47mmol, yield: 48.69%).

MS m/z(ESI):347.0[M+H+ACN]⁺

Second step of

3- (trifluoromethyl) isonicotinyl hydrazide hydrochloride Int-L11c

To a solution of compound Int-L11b (3.5g, 11.47mmol) in dioxane (40mL) was added a 4M solution of hydrogen chloride in 1, 4-dioxane (50mL) and stirred at room temperature for 2 h. The mixture was concentrated and slurried twice with dichloromethane and methanol (V/V ═ 10/1, 10mL) to give the title compound Int-L11c (3g, 10.79mmol, yield: 94.10%).

MS m/z(ESI):206.0[M+H]⁺

The third step

A mixture of compound Int-L11c (300mg, 1.46mmol), compound Int-L5c (573.40mg, 2.92mmol) and potassium carbonate (404.23mg, 2.92mmol) in n-butanol (6mL) was heated to 160 deg.C and stirred for 5 hours. Concentrating under reduced pressure. The obtained residue was purified by silica gel column (eluted with petroleum ether/ethyl acetate 20/1-3/1) to obtain the title compound Int-L11(80mg, 208.79 μmol, yield: 14.28%).

MS m/z(ESI):383.2[M+H]⁺

3- (3-bromo-4-methylphenyl) -5, 5-dimethyl-1- (2- (trifluoromethyl) pyridin-4-yl) imidazolidine-2, 4-dione

Int-L12

First step of

3- (3-bromo-4-methylphenyl) -5, 5-dimethylimidazolidine-2, 4-dione Int-12b

To a solution of 2-bromo-4-iodo-1-methylbenzene Int-12a (9.1g, 23.55mmol) and 5, 5-dimethylimidazolidine-2, 4-dione (5g, 35.50mmol) in N, N-dimethylformamide (30mL) was added copper (I) oxide (4.8g), and the reaction was stirred at 140 ℃ overnight. Ethyl acetate (100mL) was added for dilution, then washed with water (100mL), saturated sodium chloride solution (100mL), dried over sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (eluted with petroleum ether/ethyl acetate-4/1) to give the title compound Int-12b (3.5g, 11.47mmol, yield: 48.69%).

MS m/z(ESI):298.9[M+H]⁺

Second step of

3- (3-bromo-4-methylphenyl) -5, 5-dimethyl-1- (2- (trifluoromethyl) pyridin-4-yl) imidazolidine-2, 4-dione Int-12

A mixture of compound Int-12b (1g, 3.37mmol), 4-iodo-2- (trifluoromethyl) pyridine (1.4g, 5.13mmol), copper (I) iodide (130mg, 0.68mmol), potassium carbonate (930mg, 6.74mmol) and (1S,2S) -N1, N2-dimethylcyclohexane-1, 2-diamine (193mg, 1.35mmol) in toluene (10mL) was stirred under nitrogen at 115 ℃ overnight. The mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (eluting with petroleum ether/ethyl acetate ═ 10/1) to give the title compound Int-12(300mg, 0.68mmol, yield: 20.17%).

MS m/z(ESI):441.8[M+H]⁺

1- (3-bromo-4-methylphenyl) -3- (2- (trifluoromethyl) pyridin-4-yl) -1H-1,2, 4-triazol-5 (4H) -one Int-L13

First step of

(3-bromo-4-methylphenyl) hydrazine hydrochloride Int-L13a

Compound Int-J10c (5g, 26.87mmol) was dissolved in concentrated hydrochloric acid (60mL), cooled to 0 deg.C, and sodium nitrite (2.23g, 32.25mmol) was added and stirred for 2 hours. Stannous chloride dihydrate (15.16g, 67.19mmol) was added at 0 ℃ and stirred for 3 hours. TLC (hexane/ethyl acetate-1/1) showed complete consumption of starting material Int-L10 c. Filtration and vacuum drying gave the crude product of the title compound Int-L13a (6.1g, 25.68mmol, yield: 95.56%) which was used in the next step without purification.

Second step of

2- (3-bromo-4-methylphenyl) hydrazine-1-carboxylic acid tert-butyl ester Int-L13b

To a mixed solution of compound Int-L13a (3g, 14.92mmol) in tetrahydrofuran (16mL) and water (4mL) at 0 deg.C were added potassium carbonate (6.58g, 47.75mmol) and di-tert-butyl dicarbonate (3.91g, 17.90 mmol). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, ethyl acetate and water were added, and the mixture was allowed to stand for separation, the aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane: 1/20) to obtain the title compound Int-L13b (2.61g, yield: 58.1%).

¹H NMR(400MHz,CDCl₃):δ6.99(d,1H),6.96(d,1H),6.61(dd,1H),6.31(brs,1H),5.63(brs,1H),2.22(s,3H),1.39(s,9H)。

The third step

2- (trifluoromethyl) isonicotinamide Int-L13c

To a solution of compound Int-L4a (3g, 15.70mmol) in dichloromethane (30mL) was added oxalyl chloride (2.39g, 18.84mmol) and stirred for 1 h. After cooling the mixture to 0 ℃, aqueous ammonia (4.08g, 20.41mmol, 25% aqueous solution) was added and stirred for 0.5 h. TLC (dichloromethane/methanol ═ 30/1) showed complete consumption of starting material Int-L4 a. Dichloromethane (70mL) and water (100mL) were added to dilute, the layers were separated by settling, the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried over sodium sulfate, filtered and concentrated in vacuo to give the crude title compound Int-L13c (2.7g, 14.20mmol, yield: 90.47%) which was used in the next step without purification.

The fourth step

2- (3-bromo-4-methylphenyl) -2- ((2- (trifluoromethyl) isonicotinoyl) aminocarbonyl) hydrazine-1-carboxylic acid tert-butyl ester Int-L13d

To a solution of compound Int-L13b (500mg, 2.63mmol) in dry dichloromethane (20mL) was added oxalyl chloride (1.00g, 7.89mmol) dropwise at 0 deg.C under nitrogen. The mixture was heated to reflux and stirred for 2 hours. LCMS indicated complete formation of the isocyanate intermediate, the solvent was removed in vacuo and the resulting residue re-dissolved in dry dichloromethane (20mL) and a solution of compound Int-L13c (950.48mg, 3.16mmol) in dry dichloromethane (20mL) was added dropwise at 0 ℃. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 10:1 to 4:1) to obtain the title compound Int-L13d (500mg, yield: 36.7%).

MS m/z(ESI):517.1[M+H]⁺

The fifth step

To a solution of compound Int-L13d (200mg, 386.63. mu. mol) in dichloromethane (2mL) was added trifluoroacetic acid (264.50mg, 2.32 mmol). The reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, the solvent was removed in vacuo to afford the title product Int-L13 as a crude product which was not isolated Purified and directly used in the next step. MS M/z (ESI) 399.1[ M + H ]]⁺

5- (5- (3-bromo-4-methylphenyl) -4H-1,2, 4-triazol-3-yl) -2-cyclopropylpyridine Int-L14

First step of

6-Cyclopropylnicotinic acid methyl ester Int-L14b

A mixed solution of methyl 6-bromonicotinate Int-L14a (10.0g, 46.29mmol), cyclopropylboronic acid (5.01g, 58.32mmol), tricyclohexylphosphine (3.89g, 13.89mmol), tris (dibenzylideneacetone) dipalladium (4.24g, 4.63mmol) and anhydrous potassium carbonate (19.19g, 138.87mmol) in toluene (200mL) and water (20mL) was replaced with nitrogen 3 times, then heated to 100 ℃ and stirred for 18 hours. The mixture was filtered, and the filtrate was washed with a saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (eluting with petroleum ether/ethyl acetate 1/10-1/1) to give the title compound Int-L14b (7.6g, yield: 92.7%). MS M/z (ESI) 178.4[ M + H]⁺

Second step of

6-cyclopropyl nicotinoyl hydrazine Int-L14c

To a solution of compound Int-L14b (4g, 22.57mmol) in ethanol (20mL) was added hydrazine hydrate (5.64g, 112.87 mmol). The reaction mixture was stirred at 90 ℃ for 2 hours. After completion of the reaction, the solution was cooled to room temperature, filtered, and the filter cake was collected to give the title compound Int-L14c (2.1g, yield: 52.5%).

MS m/z(ESI):178.2[M+H]⁺

The third step

A mixture of compound Int-L14c (500mg, 2.82mmol), compound Int-L5c (1.11g, 5.64mmol) and potassium carbonate (1.56g, 11.29mmol) in n-butanol (6mL) was reacted with microwaves at 150 ℃ for 1 hour. After the reaction was completed, ethyl acetate and water were added, and the mixture was allowed to stand for delamination, and the aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed 3 times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane ═ 1/5) to give the title compound Int-L14(830mg, yield: 82.8%).

MS m/z(ESI):355.2[M+H]⁺

Example A1

N- (4-methyl-3- (4-oxo-2 ',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -7-yl) phenyl) -2- (trifluoromethyl) isonicotinamide A1

To a solution of compound Int-1(94mg, 0.23mmol), compound Int-2(57mg, 0.19mmol) in 1, 4-dioxane (2mL) was added a solution of sodium carbonate (2N, 0.6mmol, 0.3 mL). The resulting turbid suspension was bubbled with nitrogen for 5 minutes, then [1,1' -bis (diphenylphosphino) ferrocene ] was added under nitrogen protection]Palladium dichloride (Pd (dppf) Cl₂10 mol%, 0.02mmol, 16mg), the tube was sealed and the mixture was reacted with a microwave at 100 ℃ for 1 hour. Ethyl acetate (10mL) and water (10mL) were added to dilute and the insoluble solids were removed by filtration. The ethyl acetate layer was collected, and the aqueous phase was extracted with ethyl acetate (10 mL. times.2). The combined organic phases were washed with saturated sodium chloride solution and dried over magnesium sulfate. Filtering and concentrating. The obtained residue was purified by silica gel column chromatography with ethyl acetate-hexane (0-60%) system to give the title compound (35mg), yield: 30.7 percent.

¹HNMR(400MHz,CDCl₃),δ8.94(s,1H),8.11(s,1H),7.93-7.89(m,3H),7.57(s,2H),7.32(m,1H),7.01-6.97(m,2H),3.85-3.77(m,4H),2.78(s,2H),2.30(s,3H),2.04-2.01(m,2H),1.84-1.78(m,2H)。

MS m/z(ESI):497.0[M+1]⁺

Example A2& example A3

N- (3- ((2r,4' r) -4' -hydroxy 4-oxospiro [ chromane-2, 1' -cyclohex ] -7-yl) -4-methylphenyl) -2- (trifluoromethyl) isonicotinamide A2

N- (3- ((2s,4's) -4' -hydroxy-4-oxospiro [ chromane-2, 1' -cyclohex ] -7-yl) -4-methylphenyl) -2- (trifluoromethyl) isonicotinamide A3

To a solution of compound Int-A1(86mg, 0.21mmol) and 4-hydroxycyclohexan-1-one (36mg, 0.31mmol) in methanol (3.0mL) at room temperature was added pyrrolidine (0.31mmol) and stirred overnight. After concentration, water (20mL) was added to the resulting residue, followed by 1N hydrochloric acid (40 mL). The residue was collected and purified by high performance liquid chromatography to give the title compounds a2(19mg) and A3(12mg), total yield: 28.9 percent.¹HNMR(400MHz,CDCl₃)for A2:δ8.95(d,1H),8.15(s,1H),8.01(s,1H),7.96(d,1H),7.64(d,1H),7.52(s,1H),7.34(d,1H),7.00-6.98(m,2H),3.77-3.72(m,1H),2.74(s,2H),2.32(s,3H),2.24-2.21(m,1H),1.87-1.72(m,4H),1.55-1.47(m,4H)。

MS m/z(ESI):511.0[M+1]⁺

¹HNMR(400MHz,DMSO-d₆)for A3:δ10.67(s,1H),8.99(d,1H),8.37(s,1H),8.19(d,1H),7.81-7.69(m,3H),7.34(d,1H),7.05-6.99(m,2H),4.50(s,1H),3.81(br,1H),2.84(s,2H),2.25(s,3H),2.24-2.21(m,1H),1.87-1.81(m,2H),1.77-1.73(m,3H),1.49-1.46(m,2H)。

MS m/z(ESI):511.0[M+1]⁺

Example A4& example A5

((1 'r, 4' r) -7- (2-methyl-5- (2- (trifluoromethyl) isonicotinamido) phenyl) -4-oxospiro [ chromane-2, 1 '-cyclohex-4' -yl) carbamic acid tert-butyl ester A4

((1's, 4's) -7- (2-methyl-5- (2- (trifluoromethyl) isonicotinamido) phenyl) -4-oxospiro [ chromane-2, 1 '-cyclohex-4' -yl) carbamic acid tert-butyl ester A5

To a solution of compound Int-A1(148mg, 0.36mmol) and tert-butyl (4-oxocyclohexyl) carbamate (91mg, 0.43mmol) in methanol (4.0mL) at room temperature was added pyrrolidine (0.43mmol) and stirred overnight. After concentration, water (20mL) was added to the resulting residue, followed by 1N hydrochloric acid (40 mL). The residue was collected and purified by high performance liquid chromatography to give the title compounds a4(37mg) and a5(25mg), total yield: 28.3 percent.

¹HNMR(400MHz,CDCl₃)for A4:δ8.95(d,1H),8.15(s,2H),7.98(s,1H),7.90(m,1H),7.64(m,1H),7.54(m,1H),7.35-7.29(m,1H),7.00-6.98(m,2H),4.51-4.50(m,1H),3.53-3.49(m,1H),2.72(s,2H),2.31(s,3H),2.21-2.18(m,2H),1.89-1.86(m,2H),1.55-1.47(m,4H),1.28(s,9H)。

MS m/z(ESI):610.0[M+1]⁺

¹HNMR(400MHz,CDCl₃)for A5:δ8.95(d,1H),8.14(s,1H),8.01(s,1H),7.97(s,1H),7.91-7.89(m,1H),7.63-7.61(m,1H),7.54(s,1H),7.35-7.33(m,1H),6.98-6.97(m,2H),4.56(m,1H),3.73(m,1H),2.84(s,2H),2.31(s,3H),2.04-1.93(m,8H),1.28(s,9H)。

MS m/z(ESI):610.0[M+1]⁺

Example A6

7- (2-methyl-5- (2- (trifluoromethyl) isonicotinamido) phenyl) -4-oxospiro [ chromane-2, 4 '-piperidine ] -1' -carboxylic acid methyl ester A6

First step of

7- (2-methyl-5- (2- (trifluoromethyl) isonicotinamido) phenyl) -4-oxospiro [ chromane-2, 4 '-piperidine ] -1' -carboxylic acid tert-butyl ester A6a

Using the synthetic route of example A1, the starting 4-hydroxycyclohexan-1-one was replaced with tert-butyl 4-oxopiperidine-1-carboxylate to give the title compound A6 a.

Second step of

N- (4-methyl-3- (4-oxospiro [ chromane-2, 4' -piperidin ] -7-yl) phenyl) -2- (trifluoromethyl) isonicotinamide hydrochloride A6b

Compound A6a (62.3mg, 0.105mmol) was dissolved in 4N hydrogen chloride in 1, 4-dioxane (4mL) at room temperature and stirred overnight. Concentration and the resulting residue was dried in vacuo to afford the title compound A6b, which was used in the next step without purification.

The third step

To a solution of compound A6b (53mg, 0.1mmol) in dichloromethane (2mL) at-78 deg.C was added triethylamine (30mg, 0.3mmol) followed by methyl chloroformate. The mixture was stirred at-78 ℃ for 1 hour. The reaction was quenched by addition of saturated sodium bicarbonate solution. It was extracted with dichloromethane, washed with saturated sodium chloride solution and dried over magnesium sulfate. Filtering, and concentrating the filtrate. The obtained residue was purified by silica gel column chromatography to give the title compound a6(34mg), 2-step yield: 61.5 percent.

¹HNMR(400MHz,CDCl₃),δ8.95(d,1H),8.26(s,1H),8.16(s,1H),7.97(d,1H),7.90(d,1H),7.64(d,1H),7.55(s,1H),7.33(d,1H),7.01-6.99(m,1H),3.95-3.90(br,2H),3.72(s,3H),3.27(br,2H),2.77(s,2H),2.31(s,3H),2.10-2.06(m,2H),1.68-1.63(m,2H)。

MS m/z(ESI):554.0[M+1]⁺

Example A7

N- (4-methyl-3- (1'- (oxetan-3-yl) -4-oxospiro [ chromane-2, 4' -piperidin ] -7-yl ] phenyl) -2- (trifluoromethyl) isonicotinamide A7

To a solution of compound A6b (42mg, 0.085mmol) and oxetan-3-one in 1, 1-dichloroethane-acetic acid (3mL-0.5mL) was added sodium triacetoxyborohydride (89mg, 0.42mmol) in portions, and stirred overnight. The mixture was neutralized with saturated sodium bicarbonate solution and extracted with dichloromethane (10mL × 3), the organic phases were combined, dried over magnesium sulfate, filtered, the filtrate was concentrated and purified to give the title compound a7(28mg), yield: and (5) 59.8%.¹HNMR(400MHz,CDCl₃),δ8.87(d,1H),8.03(s,1H),7.87-7.82(m,3H),7.51(s,1H),7.46(d,1H),7.25(d,1H),6.91(m,2H),4.61-4.53(m,4H),3.47(t,1H),2.70(s,2H),2.46-2.44(m,2H),2.26-2.21(m,2H),2.23(s,3H),2.08-2.04(m,2H),1.76-1.73(m,2H)。

MS m/z(ESI):552.0[M+1]⁺

Example A8

N- (4-methyl-3- (4-oxodispiro [ chromane-2, 1 '-cyclobutane-3', 3 "-oxetan ] -7-yl) phenyl) -2- (trifluoromethyl) isonicotinamide A8

To a solution of compound Int-A1(87mg, 0.21mmol) and 2-oxaspiro [3.3] heptan-6-one (32mg, 0.28mmol) in methanol (5mL) at room temperature was added pyrrolidine (0.28 mmol). The mixture was stirred at 65 ℃ for 15 hours. The reaction mixture was cooled to room temperature. After concentration, water (20mL) was added to the resulting residue, followed by 1N hydrochloric acid (40mL) and ethyl acetate (50 mL). The organic phase is washed with water (25 mL. times.2) and dried. The resulting residue was further purified to give the title compound A8(17mg), yield: 15.9 percent.

¹HNMR(400MHz,CDCl₃)δ8.93(d,1H),8.27(s,1H),8.16(s,1H),7.97(d,1H),7.88(d,1H),7.62(d,1H),7.53(s,1H),7.32(d,1H),6.98(d,1H),6.94(s,1H),4.74(d,4H),2.78(s,2H),2.58-2.50(m,4H),2.30(s,3H)。

MS m/z(ESI):509.0[M+1]⁺

Example A9

N- (3- (3 '-amino-4-oxospiro [ chromane-2, 1' -cyclobut ] -7-yl) -4-methylphenyl) -2- (trifluoromethyl) isonicotinamide A9

First step of

(7-bromo-4-oxospiro [ chromane-2, 1 '-cyclobut ] -3' -yl) carbamic acid tert-butyl ester A9a

To 1- (4-bromo-2-hydroxyphenyl) ethan-1-one (487mg, 2.26mmol) and (3-oxocyclo) at room temperatureButyl) carbamic acid tert-butyl ester (545mg, 2.94mmol) in methanol (10mL) pyrrolidine (3.0mmol) and

and (3) a molecular sieve. The mixture was heated to reflux with stirring for 36 hours and then cooled to room temperature. Filtered and the filtrate concentrated. The residue obtained is treated with 15mL of dilute hydrochloric acid (0.5N). Ethyl acetate (50mL) was added, washed with water (25mL × 2), and purified by silica gel column chromatography to give the title compound A9a (270mg), yield: 31.4 percent.

MS m/z(ESI):382.0[M+1]⁺

Second step of

(7- (2-methyl-5- (2- (trifluoromethyl) isonicotinamido) phenyl) -4-oxospiro [ chromane-2, 1 '-cyclobut ] -3' -yl) carbamic acid tert-butyl ester A9b

To a solution of compound Int-1(310mg, 0.75mmol), compound A9a (240mg, 0.63mmol) in dioxane-water (5mL-0.5mL) was added potassium phosphate (401mg, 1.90 mmol). The resulting turbid suspension was bubbled with nitrogen for 5 minutes, then [1,1' -bis (diphenylphosphino) ferrocene ] was added under nitrogen protection ]Palladium dichloride (Pd (dppf) Cl₂(10 mol%), the tube was sealed, and the reaction was carried out by microwave at 90 ℃ for 25 minutes. Ethyl acetate (10mL) and water (10mL) were added to dilute the mixture, the insoluble solids were removed by filtration, the ethyl acetate layer was collected, and the aqueous phase was extracted with ethyl acetate (10 mL. times.2). The organic phases are combined, washed with saturated sodium chloride solution and dried over magnesium sulfate. Filtering and concentrating. The obtained residue was purified by silica gel column chromatography with an ethyl acetate-hexane (0-60%) system to give the title compound A9b (330mg), yield: 75.7 percent.

MS m/z(ESI):582.0[M+1]⁺

The third step

Compound A9b (330mg, 0.568mmol) was dissolved in 4M hydrogen chloride in 1, 4-dioxane (5mL) and stirred at room temperature overnight. Concentration gave the title compound A9(226mg, yield: 76.9%). MS M/z (ESI) 482.0[ M +1]

Example A10

N- (3- (3 '-acrylamido-4-oxospiro [ chromane-2, 1' -cyclobut ] -7-yl) -4-methylphenyl) -2- (trifluoromethyl) isonicotinamide A10

To a solution of compound A9(65mg, 0.14mmol) in dichloromethane (2mL) was added triethylamine (44mg, 0.42mmol), followed by acryloyl chloride (15mg, 0.17mmol) at 0 deg.C under nitrogen. The mixture was stirred overnight. The reaction was quenched by the addition of sodium carbonate solution and diluted with dichloromethane. The organic layer was collected and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated sodium chloride solution and dried over magnesium sulfate. Filtration and concentration of the filtrate gave a residue which was purified by silica gel column chromatography to give the title compound a10(32mg), yield: 42.7 percent.

¹HNMR(400MHz,CDCl₃)δ8.93(s,1H),8.48(s,1H),8.19(s,1H),8.05(s,1H),7.90-7.85(m,1H),7.65(m,1H),7.53(s,1H),7.32(m,1H),7.00-6.91(m,2H),6.52-6.23(m,1H),6.17-6.05(m,1H),5.70-5.68(m,1H),4.31-4.27(m,1H),2.93(s,2H),2.80-2.77(m,2H),2.30(s,3H),2.33-2.23(m,2H)。

MS m/z(ESI):536.0[M+1]⁺

Example A11

N- (4-methyl-3- (4-oxo-3 '-propionylaminospiro [ chromane-2, 1' -cyclobut ] -7-yl) phenyl) -2- (trifluoromethyl) isonicotinamide A11

To a solution of compound A9(65mg, 0.14mmol) in dichloromethane (2mL) was added triethylamine (44mg, 0.42mmol), followed by propionyl chloride (16mg, 0.17mmol) at 0 ℃ under a nitrogen atmosphere. The mixture was stirred overnight. The reaction was quenched by the addition of sodium carbonate solution and diluted with dichloromethane. The organic layer was collected and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated sodium chloride solution and dried over magnesium sulfate. Filtration and concentration of the filtrate gave a residue which was purified by silica gel column chromatography to give the title compound a11(38mg), yield: 50.5 percent.

¹HNMR(400MHz,CDCl₃)δ8.83(m,1H),8.42(s,1H),8.16(s,1H),7.91(m,1H),7.77(m,1H),7.43(m,1H),7.24-7.21(m,1H),6.90-6.88(m,1H),6.83-6.80(m,1H),4.15-4.08(m,1H),2.81(s,2H),2.66-2.60(m,2H),2.22(s,3H),2.19-1.99(m,4H),1.06(t,3H)。

MS m/z(ESI):538.0[M+1]⁺

Example A12

N- (4-methyl-3- (4' -oxo-2, 3,5, 6-tetrahydrospiro [ pyran-4, 2' -thiochroman ] -7' -yl) phenyl) -2- (trifluoromethyl) isonicotinamide A12

First step of

2- (Benzylthio) -4-bromoxynil A12b

Phenylmethanethiol (6.2g, 49.92mmol) was added portionwise to a solution of sodium hydrogen (3.00g, 75.00mmol, 60% pure) in tetrahydrofuran (100mL) at 0 ℃ over 15 minutes, followed by slow addition of 4-bromo-2-fluoro-benzonitrile A12a (10g, 50.00mmol) and stirring at room temperature for 16 hours. The reaction was quenched by the addition of saturated ammonium chloride solution (50mL) and the mixture was extracted with ethyl acetate (100 mL). The organic phase was dried and concentrated to give crude title compound A12b (16g, 52.60 mmol).

¹H NMR(400MHz,CDCl₃):δ7.91-7.25(m,8H),4.22(s,2H)。

Second step of

1- (2- (benzylthio) -4-bromophenyl) ethan-1-one A12c

Methylmagnesium bromide (10.19g, 85.47mmol, 85mL) was added to a solution of Compound A12b (13g, 42.73mmol) in tetrahydrofuran (100mL) at 0 ℃. The reaction was stirred at room temperature overnight. The reaction was quenched by the addition of 6N hydrochloric acid (10mL) and stirred for 1 hour. The mixture was extracted with ethyl acetate (50mL), the organic phase was dried and concentrated. The obtained residue was purified by silica gel column chromatography with hexane/ethyl acetate 10/1 system to give the title compound a12c (6.5g, 20.23mmol, yield: 47.35%).

¹H NMR(400MHz,CDCl₃):δ7.65(d,1H),7.53(d,1H),7.40-7.25(m,6H),4.12(s,2H),2.56(s,3H)。

The third step

1- (4-bromo-2-mercaptophenyl) ethan-1-one A12d

A solution of boron trichloride in dichloromethane (1M, 5.60mL) was added to a solution of Compound A12c (1.2g, 3.74mmol) in dichloromethane (5mL) at room temperature. The reaction was stirred at room temperature for 1 hour and then quenched by the addition of 1N sodium hydroxide solution (10 mL). The layers were separated and the aqueous layer was acidified with 1N hydrochloric acid to a pH of less than 5. It was extracted with dichloromethane (20 mL. times.3). The organic phases were combined, dried and concentrated to give the crude title compound A12d (210mg, 908.66. mu. mol, yield: 24.32%).

¹H NMR(400MHz,CDCl₃):δ7.72(d,1H),7.49(d,1H),7.33(dd,1H),4.58(s,2H),2.61(s,3H)。

The fourth step

7' -bromo-2, 3,5, 6-tetrahydrospiro [ pyran-4, 2' -thiochroman ] -4' -one A12e

To a mixture of compound A12d (1.5g, 6.49mmol) and tetrahydropyran-4-one (1.0g, 9.99mmol) in methanol (20mL) was added pyrroline (800mg, 11.58 mmol). The solids were all dissolved and the reaction was stirred at 80 ℃ for 2 hours. TLC showed the reaction was complete. 1N hydrochloric acid (2mL) was added, stirred for 1 hour, and extracted with ethyl acetate (20 mL). The organic phase was dried and concentrated. The obtained residue was purified by silica gel column chromatography with hexane/ethyl acetate 10/1 as an eluent to give the title compound a12e (550mg, 1.76mmol, yield: 27.06%).

¹HNMR(400MHz,CDCl₃):δ7.92(d,1H),7.46(d,1H),7.31(dd,1H),3.80(dd,4H),2.95(s,2H),1.88-1.83(m,4H)。

The fifth step

A mixture of compound Int-1(100mg, 246.18. mu. mol), compound A12e (80mg, 255.42. mu. mol), [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (30mg, 36.74. mu. mol) and potassium carbonate (150mg, 1.09mmol) in water (2mL) and dioxane (8mL) was degassed and protected with nitrogen and stirred at 80 ℃ for 2 hours. The reaction mixture turned black. TLC showed the reaction was complete. The mixture was cooled and extracted with ethyl acetate (20 mL). The organic phase was dried and concentrated. The obtained residue was purified by thin layer chromatography (ethyl acetate/hexane ═ 1/2) to obtain the title compound a12(60mg, 117.06 μmol, yield: 45.83%)

¹HNMR(400MHz,CDCl₃):δ10.70(s,1H),8.99(d,1H),8.19(d,1H),8.02(d,1H),7.75(dd,1H),7.68(d,1H),7.36-7.33(m,2H),7.27(dd,1H),3.75-3.64(m,4H),3.06(s,2H),2.24(s,3H),1.85-1.81(m,4H)。

LCMS:MS m/z(ESI):513.2[M+1]

Example A13

N- (3- (4-hydroxy-2 ',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -7-yl) -4-methylphenyl) -2- (trifluoromethyl) isonicotinamide A13

To a solution of compound A1(200mg, 0.402mmol) in methanol (30mL) was added sodium borohydride (35mg, 0.836mmol), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water (40mL), and the aqueous phase was extracted with ethyl acetate (50 mL). The organic phase was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography using methanol/dichloromethane as eluent to give the title compound a13(180mg), yield: 89 percent.

¹H NMR(400MHz,CDCl₃):δ8.87(d,1H),8.22(s,1H),8.12(s,1H),7.93(d,1H),7.56(d,1H),7.45-7.47(m,2H),7.29(s,1H),6.91-6.89(m,1H),6.85(s,1H),4.93(m,1H),3.88-3.77(m,4H),2.19(s,3H),2.20-2.17(m,2H),1.96-1.93(m,2H),1.91-1.87(m,1H),1.77-1.67(m,2H)。

MS m/z(ESI):496.8[M-1]^-

Example A14

N- (4-methyl-3- (2',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -7-yl) phenyl) -2- (trifluoromethyl) isonicotinamide A14

& example A36

N- (4-methyl-3- (2',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -7-yl) phenyl) -2- (trifluoromethyl) isonicotinamide A36

First step of

7-bromo-2 ',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -4-ol A14a

To a solution of compound Int-2(900mg, 3.03mmol) in methanol (25mL) was added sodium borohydride (175mg, 4.63mmol), and the mixture was stirred at room temperature for 3 hours. The mixture was poured into water (40mL) and the aqueous phase was extracted with ethyl acetate (40 mL). The resulting residue was purified by silica gel column chromatography using n-hexane/ethyl acetate as an eluent to give the title compound a14a (700mg), yield: 77 percent.

Second step of

7-bromo-2 ',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] A14b

To a solution of compound A14a (900mg, 3.0mmol) in 1, 4-dioxane (30mL) was added p-toluenesulfonic acid (770mg, 4.47 mmol). The mixture was refluxed for 2 hours and then cooled to room temperature. Water (35mL) was added, followed by extraction with ethyl acetate (35 mL). The organic phase was dried over sodium sulfate. Filtered and the filtrate concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate to give the title compound A14b (460mg) in 54% yield.

¹H NMR(400MHz,CDCl₃):δ7.03-6.99(m,2H),6.84(d,1H),6.36-6.33(d,1H),5.62-5.60(d,1H),3.92-3.86(m,2H),3.78-3.73(m,2H),1.96-1.92(m,2H),1.80-1.73(m,2H)。

The third step

To a solution of compound A14b (60mg, 0.213mmol) in 1, 4-dioxane (10mL) was added compound Int-1(95mg, 0.233mmol), sodium carbonate (2M, 0.235mL) and [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (16mg, 0.022 mmol). Under nitrogen and stirred at 100 ℃ for 2 hours. The reaction mixture turned black. TLC monitored the reaction completion. The mixture was cooled and extracted with ethyl acetate (20 mL). The organic phase was dried and concentrated. The obtained residue was purified by thin layer chromatography (ethyl acetate/hexane ═ 1/2) to give the title compound a36(13mg, yield: 13%).

MS m/z(ESI):480.9[M+1]⁺

The fourth step

Compound A36(150mg, 0.301mmol) was dissolved in dichloromethane (25mL) and triethylsilane (300mg, 2.58mmol) was added at 0 ℃. The reaction mixture was stirred at this temperature for 30 minutes, then trifluoroacetic acid (300mg, 2.63mmol) was added. The reaction mixture was stirred at room temperature for 16 hours, then water (30mL) was added. The aqueous phase was extracted with dichloromethane (30mL) and the organic phase was dried over sodium sulfate. Filtered and the filtrate concentrated under reduced pressure. The resulting residue was purified by HPLC to give the title compound a14(50mg), yield: 34 percent.

¹H NMR(400MHz,CDCl₃):δ8.90(d,1H),8.12-8.11(m,2H),7.93-7.92(m,1H),7.58(d,1H),7.47(s,1H),7.29-7.28(m,1H),7.10(d,1H),6.85-6.81(m,2H),3.91-3.80(m,4H),2.87-2.83(m,2H),2.31(s,3H),1.90-1.87(m,2H),1.80-1.76(m,2H),1.74-1.69(m,2H)。

MS m/z(ESI):482.9[M+1]⁺

Example A15

N- (3- (4-amino-2 ',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -7-yl) -4-methylphenyl) -2- (trifluoromethyl) isonicotinamide A15

First step of

(Z) -N- (3- (4- (hydroxyimino) -2',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -7-yl) -4-methylphenyl) -2- (trifluoromethyl) isonicotinamide A15a

A solution of compound A1(300mg, 0.604mmol), hydroxylamine hydrochloride (63mg, 0.907mmol), sodium acetate (100mg, 1.22mmol) in methanol (10mL) was refluxed for 2 hours. Water (35mL) was then added, and the mixture was extracted with ethyl acetate (35 mL). The organic phase was dried over sodium sulfate. Filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using n-hexane/ethyl acetate as an eluent to give the title compound a15a (290mg), yield: 94 percent.

MS m/z(ESI):512.2[M+1]⁺

Second step tert-butyl (7- (2-methyl-5- (2- (trifluoromethyl) isonicotinamido) phenyl) -2',3',5',6' -tetrahydrospiro [ chroman-2, 4' pyran ] -4-yl) carbamate A15b

To compound A15a (280mg, 0.547mmol) in methanol (10mL) was added di-tert-butyl dicarbonate (240mg, 1.01mmol), Raney nickel (96mg, 1.64mmol), and sodium bicarbonate (93mg, 1.11 mmol). The mixture was replaced with hydrogen three times, and stirred at room temperature for 1 hour. Filtered and the filtrate concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using n-hexane/ethyl acetate as an eluent to give the title compound a15b (245mg), yield: 75 percent.

MS m/z(ESI):598.2[M+1]⁺

The third step

Compound a15b (240mg, 0.41mmol) was dissolved in trifluoroacetic acid (5mL) and stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to give the title compound a15(150mg), yield: 75 percent.

¹H NMR(400MHz,CDCl₃):δ8.93(d,1H),8.13(s,1H),7.98-7.93(m,2H),7.61(m,1H),7.46-7.44(s,2H),7.32-7.29(m,1H),6.91(d,1H),6.87(m,1H),4.67(t,1H),3.88-3.79(m,4H),3.67-3.65(m,2H),3.44(s,3H),2.13-2.01(m,2H),1.81-1.78(m,2H)。

MS m/z(ESI):495.8[M-1]^-

Example A16

(7- (2-methyl-5- (2- (trifluoromethyl) isonicotinamido) phenyl) -2',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran-4-yl) carbamic acid methyl ester A16

To a solution of compound A15(30mg, 60.3. mu. mol) in dichloromethane (5mL) was added methyl chloroformate (12mg, 127. mu. mol), followed by slow addition of triethylamine (13mg, 128. mu. mol). The mixture was stirred at room temperature for 16 hours. Water (35mL) was added, and the mixture was extracted with ethyl acetate (35 mL). The organic phase was dried over sodium sulfate. Filtered and the filtrate concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to give the title compound a16(20mg), yield: 60 percent.

¹H NMR(400MHz,CDCl₃):δ8.89(d,1H),8.11-8.08(m,2H),7.92(d,1H),7.56-7.54(m,1H),7.47(s,1H),7.32-7.29(m,2H),6.87(m,2H),5.07-5.03(m,1H),4.95-4.93(m,1H),3.93-3.90(m,1H),3.83-3.74(m,6H),2.28(s,3H),2.26-2.24(m,1H),1.87-1.78(m,5H)。

MS m/z(ESI):553.8[M-1]^-

Example A17

N- (3- (4- (dimethylamino) -2',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -7-yl) -4-methylphenyl) -2- (trifluoromethyl) isonicotinamide A17

To a solution of Compound A15(45mg, 90.4. mu. mol) in methanol (5mL), formaldehyde (90mg, 900. mu. mol) was added sodium triacetoxyborohydride (50mg, 236. mu. mol) and acetic acid (12mg, 210. mu. mol). The mixture was stirred at room temperature for 16 hours. Water (35mL) was added, and the mixture was extracted with ethyl acetate (35 mL). The organic phase was dried over sodium sulfate. Filtered and the filtrate concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give the title compound a17(23mg), yield: 48 percent.

¹H NMR(400MHz,CDCl₃):δ8.89(d,1H),8.10-8.08(m,2H),7.91(d,1H),7.60-7.57(m,2H),7.54(s,1H),7.28-7.27(m,1H),6.89-6.83(m,2H),4.06-3.98(m,2H),3.85-3.81(m,1H),3.72-3.70(m,2H),2.32(s,6H),2.30(s,3H),1.88-1.84(m,5H),1.81-1.78(m,1H)。

MS m/z(ESI):523.8[M-1]^-

Example A18

N- (3- (4- ((2-hydroxyethyl) amino) -2',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -7-yl) -4-methylphenyl) -2- (trifluoromethyl) isonicotinamide A18

To a solution of compound A15(50mg, 100.5. mu. mol) in N, N-dimethylformamide (5mL) were added 2-bromoethanol (15mg, 120. mu. mol) and potassium carbonate (30mg, 217. mu. mol). The mixture was stirred at room temperature for 16 hours. Water (35mL) was added, and the mixture was extracted with ethyl acetate (35 mL). The organic phase was dried over sodium sulfate. Filtered and the filtrate concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give the title compound a18(10mg) in 18% yield.

¹H NMR(400MHz,CDCl₃):δ8.91(d,1H),8.51(s,1H),8.18(s,1H),8.00-7.99(m,1H),7.72-7.62(m,2H),7.43(m,1H),6.92-6.89(m,2H),4.55-4.51(m,1H),3.98-3.86(m,4H),3.72-3.69(m,2H),3.02-3.01(m,2H),2.44-2.33(m,2H),2.28(s,3H),1.85-1.79(m,4H)。

MS m/z(ESI):539.8[M-1]^-

Example A19N- (3- (4- (2-hydroxyethoxy) -2',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -7-yl) -4-methylphenyl) -2- (trifluoromethyl) isonicotinamide A19

First step of

Ethyl 2- ((7-bromo-2 ',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -4-yl) oxy) acetate a19a

Sodium hydride (48mg, 2.0mmol) was added to a solution of compound A14a (300mg, 1.0mmol) in tetrahydrofuran (25mL) under ice-bath conditions. The mixture was stirred at 0 ℃ for 15 minutes, then ethyl bromoacetate (250mg,1.5mmol) was added. The mixture was stirred at room temperature for 16 hours, after which water (35mL) was added. The mixture was extracted with ethyl acetate (35 mL). The organic phase was dried over anhydrous sodium sulfate. Filtering, and concentrating the filtrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound A19a (150mg) in 39% yield.

¹H NMR(400MHz,CDCl₃):δ7.44(d,1H),7.05-7.04(m,2H),4.59-4.57(m,1H),4.24-4.20(m,4H),3.82-3.74(m,4H),2.03-1.94(m,3H),1.77-1.69(m,3H),1.31-1.28(m,3H)。

Second step of

Ethyl 2- ((7- (2-methyl-5- (2- (trifluoromethyl) isonicotinamido) phenyl-2 ',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -4-yl) oxy) acetate a19b

Compound Int-1(160mg, 0.394mmol), sodium carbonate solution (2M, 0.377mL), and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (26mg, 35.5. mu. mol) were added to a solution of compound A19a (140mg, 0.363mmol) in 1, 4-dioxane (10 mL). The mixture was blanketed with nitrogen and stirred at 100 ℃ for 2 hours. Cooled, water (35mL) was added, and the mixture was extracted with ethyl acetate (20 mL). The organic phase was dried and collected. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound A19b (136mg) in 64% yield.

MS m/z(ESI):583.2[M-1]^-

The third step

N- (3- (4- (2-hydroxyethoxy) -2',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -7-yl) -4-methylphenyl) -2- (trifluoromethyl) isonicotinamide A19

To a solution of compound A19b (136mg, 0.233mmol) in methanol (15mL) were added sodium borohydride (30mg, 0.793mmol) and calcium chloride (80mg, 0.721 mmol). The mixture was heated at 80 ℃ for 8 hours. Water (35mL) was added, followed by extraction with ethyl acetate (35 mL). The organic phase was dried over anhydrous sodium sulfate. Filtering, and concentrating the filtrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound A19(15mg) in 12% yield.

¹H NMR(400MHz,CDCl₃):δ8.85(d,1H),8.47(s,1H),8.12(s,1H),7.93-7.92(m,1H),7.59-7.54(m,2H),7.43(m,1H),7.26-7.24(m,1H),6.89-6.84(m,2H),4.70-4.67(m,1H),4.26(d,2H),3.86-3.73(m,7H),2.26(s,3H),2.08-2.07(m,2H),1.84-1.74(m,4H)。

MS m/z(ESI):540.8[M-1]^-

Example A20

N- (3- (4-acetylamino-2 ',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -7-yl) -4-methylphenyl) -2- (trifluoromethyl) isonicotinamide A20

To a solution of Compound A15(25mg, 50.25. mu. mol) in methylene chloride (5mL) were added acetic anhydride (11mg, 107.75. mu. mol) and triethylamine (15mg, 148.2. mu. mol) dropwise in this order. The mixture was stirred at room temperature for 6 hours, then water (25mL) was added. The aqueous phase was extracted with dichloromethane (25mL) and the organic phase was dried over anhydrous sodium sulfate. Filtering, and concentrating the filtrate under reduced pressure. The obtained residue was purified by high performance liquid preparative chromatography to give the title compound A20(15mg) in 40% yield.

¹H NMR(400MHz,CDCl₃):δ8.87-8.81(m,2H),8.20(s,1H),7.99(d,1H),7.64-7.59(m,1H),7.49-7.48(m,1H),7.20(d,1H),6.84-6.81(m,2H),6.03-6.01(m,1H),5.36-5.29(m,1H),3.93-3.51(m,4H),2.28(s,3H),2.22-2.10(m,1H),2.08(s,3H),1.82-1.73(m,5H)。

MS m/z(ESI):539.9[M+1]⁺

Example A21

N- (4-methyl-3- (4- (methylsulfonamido) -2',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -7-yl) phenyl) -2- (trifluoromethyl) isonicotinamide A21

To a solution of Compound A15(25mg, 50.25. mu. mol) in methylene chloride (5mL) was added dropwise methanesulfonyl chloride (10mg, 87.3. mu. mol) and triethylamine (12mg, 118.5. mu. mol) in that order. The mixture was stirred at room temperature for 6 hours, then water (25mL) was added. The aqueous phase was extracted with dichloromethane (25mL) and the organic phase was dried over anhydrous sodium sulfate. Filtering, and concentrating the filtrate under reduced pressure. The obtained residue was purified by high performance liquid preparative chromatography to give the title compound A21(15mg) in 52% yield.

¹H NMR(400MHz,CD₃OD):δ8.8.89(d,1H),8.30(s,1H),8.11(d,1H),7.63-7.55(m,3H),7.28(d,1H),6.95-6.84(m,1H),6.83(s,1H),4.77-4.73(m,1H),3.96-3.93(m,1H),3.83-3.75(m,3H),3.14(s,3H),2.38-2.34(m,1H),2.25(s,3H),1.99-1.79(m,5H)。

MS m/z(ESI):575.8[M+1]⁺

Example A22

(2- ((7- (2-methyl-5- (2- (trifluoromethyl) isonicotinamido) phenyl) -2',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran-4-yl) amino) -2-oxoethyl) carboxylic acid methyl ester A22

To a solution of compound A15(40mg, 80.4. mu. mol) and N- (methoxycarbonyl) glycine (15mg, 112.7. mu. mol) in N, N-dimethylformamide (5mL) was added 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (46mg, 121. mu. mol) and N, N-diisopropylethylamine (22mg, 170. mu. mol) at 0 ℃. The mixture was stirred at room temperature for 6 hours, then water (35mL) was added. The aqueous phase was extracted with ethyl acetate (30mL), and the organic phase was dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave a residue which was purified by high performance liquid preparative chromatography to give the title compound a22(15mg) in 30% yield.

¹H NMR(400MHz,CD₃OD):δ8.90(d,1H),8.30(s,1H),8.12(d,1H),7.64-7.59(m,2H),7.30-7.28(m,2H),6.92-6.90(m,1H),6.85(s,1H),5.36-5.32(m,1H),3.97(m,1H),3.85-3.76(m,5H),3.63(s,3H),2.25(s,3H),2.21-2.15(m,1H),1.93-1.80(m,5H)。

MS m/z(ESI):612.8[M+1]⁺

Example A23N- (4-methyl-3- (4-ureido-2 ',3',5',6' -tetrahydrospiro [ chroman-2, 4' -pyran-7-yl) phenyl) -2- (trifluoromethyl) isonicotinamide A23

Compound A15(40mg, 80.4. mu. mol) and potassium cyanate (14mg, 172. mu. mol) were dissolved in acetic acid (5mL) and stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure and purified by high performance liquid preparative chromatography to give the title compound a23(10mg) in 23% yield.

¹H NMR(400MHz,CD₃OD):δ8.90(d,1H),8.30(s,1H),8.12(d,1H),7.64-7.59(m,2H),7.30-7.25(m,2H),6.92-6.90(d,1H),6.85(s,1H),5.32-5.28(m,1H),3.97-3.96(m,1H),3.82-3.76(m,3H),2.25(s,3H),2.22-2.17(m,1H),1.88-1.81(m,5H)。

MS m/z(ESI):541.2[M+1]⁺

Example A24N- (4-methyl-3- (4-oxo-5 ',6' -dihydro-2 ' H,4' H-spiro [ chromane-2, 3' -pyran ] -7-yl) phenyl) -2- (trifluoromethyl) isonicotinamide A24

To a solution of intermediate Int-A1(51mg, 0.12mmol) and dihydro-2H-pyran-3 (4H) -one (24.6mg, 0.25mmol) in methanol (100mL) was added tetrahydropyrrole (8.5mg, 0.12mmol) at room temperature and stirred overnight. The mixture was concentrated and the resulting residue was treated with water (20mL) and hydrochloric acid (1N, 40mL), respectively. The residue was collected, washed with water (25 mL. times.2) and dried. The obtained residue was purified by high performance liquid preparative chromatography to give the title compound A24(14mg) in 23.5% yield.

¹HNMR(400MHz,CDCl₃)δ8.95(d,1H),8.15(s,1H),8.10(s,1H),7.97(m,1H),7.90(m,1H),7.70–7.60(m,1H),7.51(d,1H),7.33(m,1H),7.08–6.93(m,2H),3.99–3.81(m,2H),3.68–3.51(m,2H),2.87–2.66(m,2H),2.31(s,3H),2.18(m,1H),2.10–1.92(m,2H),1.85–1.69(m,1H)。

MS m/z(ESI):497.0[M+1]⁺

The following compounds were prepared by the methods and general procedures described above in example A24 substituting the appropriate cyclic ketone for dihydro-2H-pyran-3 (4H) -one (first step), as described in the previous schemes and examples. The desired starting materials can be purchased commercially, or obtained by working in concert as described in the literature, or synthesized by a person skilled in the art of organic synthesis from commercially available reagents using conventional reactions.

Example A29

N- (4-methyl-3- (4-morpholinyl-2 ',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -7-yl) phenyl) -2- (trifluoromethyl) isonicotinamide A29

First step 4- (7-bromo-2 ',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran-4-yl) morpholine A29a

To a solution of intermediate Int-2(600mg, 2.01mmol) and morpholine (210mg, 2.42mmol) in dry toluene was added p-toluenesulfonic acid (95mg, 0.5 mmol). The mixture was heated at 140 ℃ for 48 hours to remove the water in the Dean-Stark trap. Then, most of the toluene was removed. The residue was cooled in an ice bath and diluted with 1, 2-dichloroethane-glacial acetic acid (12mL-2 mL). Sodium triacetoxyborohydride (430mg, 4.02mmol) was added portionwise to the cooling liquid. The mixture was then stirred at room temperature for 1 hour. To the reaction mixture were added water (15mL) and dichloromethane (15 mL). The dichloromethane layer was separated and washed with water and saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate. Filtration and concentration were carried out, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane: 0-100%) to obtain the title compound A29a (36.4 mg).

Second step of

To a solution of compound A29a (36.4mg, 0.10mmol) and compound Int-1(49mg, 0.12mmol) in dioxane (2mL) was added potassium phosphate (64mg, 0.3 mmol). The resulting cloudy suspension was bubbled with nitrogen for 5 minutes, then [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (10 mol%) was added under nitrogen. The vial was sealed and microwaved at 100 ℃ for 1 hour. The reaction mixture was diluted with ethyl acetate (10mL) and water (10mL) and the insoluble solids were removed by filtration. The ethyl acetate layer was collected, and the aqueous layer was extracted with ethyl acetate (10 mL. times.2). The combined ethyl acetate layers were washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Filtering and concentrating. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane: 0-60%) to obtain the title compound A29(35 mg).

¹HNMR(400mHz,CDCl₃)δ8.93(d,1H),8.11(s,1H),7.94-7.91(m,2H),7.67(d,1H),7.57-7.54(m,2H),7.31(d,1H),6.89(d,1H),6.86(s,1H),4.06-3.97(m,2H),3.87-3.81(m,1H),3.78-3.73(m,6H),2.67-2.54(m,4H),2.32(s,3H),1.94-1.88(m,4H),1.83-1.79(m,2H)。

MS m/z(ESI):568.0[M+1]⁺

The following compounds were prepared by the methods and general procedures described above in example a29, substituting the appropriate aryl bromide for a29a (second step) as described in the previous schemes and examples. The desired starting materials can be purchased commercially, or obtained by working in concert as described in the literature, or synthesized by a person skilled in the art of organic synthesis from commercially available reagents using conventional reactions.

Example B1

N- (4-methyl-3- (1-oxo-2, 2',3',4,5',6' -hexahydro-1H-spiro [ isoquinoline-3, 4' -pyran ] -6-yl) phenyl) -2- (trifluoromethyl) isonicotinamide B1

First step of

4-bromo-2-methylbenzoic acid isopropyl ester B1B

To a solution of 4-bromo-2-methylbenzoic acid B1a (4.0g, 18.6mmol) in isopropanol (40mL) was added concentrated sulfuric acid (1.0 g). The mixture was then refluxed for 4 hours. Water (45mL) was then added. The aqueous phase was extracted with dichloromethane (45 mL. times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound B1B (4.4g) in 92% yield.

¹H NMR(400MHz,CDCl₃):δ7.78-7.76(m,1H),7.42-7.29(m,2H),5.32-5.22(m,1H),2.59(s,3H),1.39-1.38(m,6H)。

Second step of

4-bromo-2- (bromomethyl) benzoic acid isopropyl ester B1c

To a solution of compound B1B (4.0g, 15.6mmol) in acetonitrile was added N-bromosuccinimide (2.81g, 15.8mmol) and azobisisobutyronitrile (260mg, 1.58 mmol). The mixture was heated at 80 ℃ for 6 hours. The reaction mixture was cooled to room temperature, and water (45mL) was added to the reaction mixture. Ethyl acetate (45mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to give the title compound B1c (3.98g) in 76% yield.

¹H NMR(400MHz,CDCl₃):δ7.84-7.82(m,1H),7.63-7.62(m,1H),7.53-7.50(m,1H),5.32-5.30(m,1H),4.90(s,2H),1.43-1.41(m,6H)。

The third step

4- (5-bromo-2- (isopropoxycarbonyl) benzyl) tetrahydro-2H-pyran-4-carboxylic acid B1d

Lithium diisopropylamide (2M, 8.5mL, 16.2mmol) was added dropwise to a solution of tetrahydropyran-4-carboxylic acid (1.0g, 7.7mmol) in tetrahydrofuran at-10 deg.C, and the mixture was stirred at that temperature for 1 hour. The reaction was cooled to-70 ℃ and a solution of compound B1c (2.73g,8.1mmol) in tetrahydrofuran (40mL) was added dropwise. The reaction solution was slowly warmed to room temperature for 2 hours. The reaction was then quenched by the addition of saturated ammonium chloride solution (30mL) for 10 minutes. The mixture was concentrated under reduced pressure and the pH of the remaining solution was adjusted to 8 with 4N sodium hydroxide solution. The aqueous phase was washed with ether (45mL) and then adjusted to pH 3 with concentrated hydrochloric acid. Dichloromethane (45mL × 2) was added for extraction, and the combined dichloromethane layers were dried over anhydrous sodium sulfate. Anhydrous sodium sulfate solid was filtered, and the filtrate was concentrated under reduced pressure to give the title compound B1d (1.75g) in 59% yield.

MS m/z(ESI):384.8[M-1]^-

The fourth step

4-bromo-2- ((4-isocyanatotetrahydro-2H-pyran-4-yl) methyl) benzoic acid isopropyl ester B1e

To a solution of compound B1d (500mg, 1.29mmol) in toluene (15mL) were added diphenyl azidophosphate (350mg, 1.35mmol) and triethylamine (145mg, 1.43 mmol). The mixture was heated at 90 ℃ for 6 hours. The reaction was cooled to room temperature, and water (30mL) was added. The aqueous phase was extracted with ethyl acetate (30mL) and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure gave the title compound B1e (350mg) in 70% yield. MS M/z (ESI) 382.8[ M +1 ] ]⁺

The fifth step

6-bromo-2, 2',3',4,5',6' -hexahydro-1H-spiro [ isoquinoline-3, 4' -pyran ] -1-one B1f

To a solution of intermediate B1e (300mg, 0.784mmol) in toluene (20mL) was added sodium hydride (75.6mg, 3.15mmol), stirred for 5 min, followed by benzyl alcohol (170mg, 1.57 mmol). The mixture was heated at reflux for 4 h, cooled to room temperature, quenched by the addition of methanol (5mL), and concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (45mL) and washed with water (45 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to give the title compound B1f (110mg) in 47% yield.

MS m/z(ESI):296.0[M+1]

The sixth step

To a solution of compound B1f (100mg, 0.337mmol) in 1, 4-dioxane (10mL) was added intermediate Int-1(151mg, 0.371mmol), sodium carbonate solution (2M, 0.34mL) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (13mg, 0.018 mmol). The system was replaced with argon 3 times and then refluxed for 2 hours. The mixture was cooled to room temperature. The solids were filtered through celite. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to give the title compound B1(50mg) in 30% yield.

¹H NMR(400MHz,CDCl₃):δ8.91(d,1H),8.81(s,1H),8.26(s,1H),8.05-8.00(m,2H),7.76-7.74(m,1H),7.50(s,1H),7.33-7.31(m,1H),7.24-7.23(m,1H),7.18(s,1H),6.26(s,1H),3.75-3.71(m,4H),3.03(s,2H),2.26(s,3H),1.80-1.70(m,4H)。

MS m/z(ESI):496.2[M+1]

The following compounds were prepared by the methods and general procedures described above in example B1, substituting the appropriate aryl bromide for B1f (sixth step) as described in the previous schemes and examples. The desired starting materials can be purchased commercially, or obtained by working in concert as described in the literature, or synthesized by a person skilled in the art of organic synthesis from commercially available reagents using conventional reactions.

Example B7

N- (4-methyl-3- (4-oxo-2 ',3,3',4,5',6' -hexahydrospiro [ benzo [ e ] [1,3] oxazin-2, 4' -pyran ] -7-yl) phenyl) -2- (trifluoromethyl) isonicotinamide B7

First step of

7-bromo-2 ',3',5',6' -tetrahydrospiro [ benzo [ e ] [1,3] oxazine-2, 4' -pyran-4 (3H) -one B7a

To a mixed solution of 4-bromo-2-hydroxybenzamide (2.8g, 13mmol), tetrahydro-4H-pyran-4-one (2.6mL, 26mmol) and p-toluenesulfonic acid monohydrate (494mg, 2.6mmol) in 1, 4-dioxane (60mL) and toluene (100mL) was added magnesium sulfate heptahydrate (4.68g, 38.87 mmol). The mixture was refluxed overnight and LC-MS showed 80% conversion. Further tetrahydro-4H-pyran-4-one (1.2mL, 12mmol) and p-toluenesulfonic acid monohydrate (120mg, 0.24mmol) were added. The mixture was refluxed for 6 hours. Filtering, and concentrating the filtrate under reduced pressure. Ethyl acetate (300mL) was added and the organic phase was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give the objective compound B7a (3.26g, yield 84%).

MS m/z(ESI):298.0[M+1]]⁺

Second step of

To a solution of compound B7a (113mg, 0.38mmol) in dimethyl sulfoxide (3mL) were added intermediate Int-1(149mg, 0.42mmol), potassium phosphate (243mg, 1.14mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (16mg, 0.019 mmol). The system was replaced with argon 3 times and then heated at 100 ℃ for 2 hours. The mixture was cooled to room temperature and ethyl acetate (40mL) was added. The organic phase was washed with saturated sodium chloride solution (20mL) and the organic phase was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to give the title compound B7(58mg) in 31% yield.

¹H NMR(500MHz,DMSO-d₆)δ10.71(s,1H),9.00(d,1H),8.83(s,1H),8.38(d,1H),8.20(dd,1H),7.91–7.60(m,3H),7.35(d,1H),7.18–6.94(m,2H),3.75–3.88(m,2H),3.64–3.70(m,2H),2.25(s,3H),2.01–2.25(m,2H),1.76–1.91(m,2H)。MS m/z(ESI):498.0[M+1]⁺

The following compounds were prepared by the methods and general procedures described above in example B7, substituting the appropriate aryl bromide for compound B7a (second step), as described in the previous schemes and examples. The desired starting materials can be purchased commercially, or obtained by working in concert as described in the literature, or synthesized by a person skilled in the art of organic synthesis from commercially available reagents using conventional reactions.

Example B31

N- (4-methyl-3- (3-methyl-4-oxo-2 ',3,3',4,5',6' -hexahydrospiro [ benzo [ e ] [1,3] oxazin-2, 4' -pyran ] -7-yl) phenyl) -2- (trifluoromethyl) isonicotinamide B31

First step 7-bromo-3-methyl-2 ',3',5',6' -tetrahydrospiro [ benzo [ e ] [1,3] oxazine-2, 4' -pyran-4 (3H) -one B31a

To a solution of compound B7a (35mg, 0.12mmol) in N, N-dimethylformamide (2mL) was added sodium hydride (60%, 8mg, 0.24 mmol). The reaction solution was stirred at 0 ℃ for 0.5 hour. Thereafter, methyl iodide (0.20mL, 3.2mmol) was added. The mixture was stirred at room temperature for 2 hours. Ethyl acetate (25mL) was added and the organic phase was washed with saturated ammonium chloride solution. The organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane/ethyl acetate 4:6) to give the title compound B31a (39mg), which was used in the next step without purification. MS m/z(ESI):312.0[M+H]⁺

Second step of

To a solution of compound B31a (39mg, 0.125mmol) in dimethyl sulfoxide (2mL) were added intermediate Int-1(49mg, 0.14mmol), potassium phosphate (80mg, 0.38mmol) and [1,1' -bis (diphenylphosphino) ferrocene ]Palladium dichloride (5mg, 0.00625 mmol). The system was replaced with argon 3 times and then heated at 100 ℃ for 2 hours. The mixture was cooled to room temperature and ethyl acetate (40mL) was added. The organic phase was washed with saturated sodium chloride solution (20mL) and the organic phase was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to give the title compound B31(27mg) in 42% yield.¹H NMR(300MHz,DMSO-d₆)δ10.70(s,1H),9.00(d,1H),8.37(d,1H),8.11–8.28(m,1H),7.60–7.93(m,3H),7.35(d,1H),7.02–7.25(m,2H),3.60–3.93(m,4H),3.05(s,3H),2.30(s,3H),2.13–2.20(m,2H).1.93–2.01(m,2H)。

MS m/z(ESI):512.0[M+1]

The following compounds were prepared by the above-described method and general procedure described in example B31. As described in the previous schemes and examples, the methyl iodide is replaced by a suitable nucleophile, or the compound B7a is replaced by a suitable aryl bromide (first step). The desired starting materials can be purchased commercially, or obtained by working in concert as described in the literature, or synthesized by a person skilled in the art of organic synthesis from commercially available reagents using conventional reactions.

Example B35& example B36

N- (3- (4,4 '-dioxo-3, 4-dihydrospiro [ benzo [ e ] [1,3] oxazin-2, 1' -cyclohexan-7-yl) -4-methylphenyl) -2- (trifluoromethyl) isonicotinamide B35

N- (3- (4',4' -dimethoxy-4-oxo-3, 4-dihydrospiro [ benzo [ e ] [1,3] oxazin-2, 1' -cyclohexan-7-yl) -4-methylphenyl) -2- (trifluoromethyl) isonicotinamide B36

First step of

Compound B12/B13(52mg,0.11mmol) was dissolved in dichloromethane (2mL) and dess-martin oxidant (93mg,0.22mmol) was added at 0 ℃. The reaction mixture was then warmed to room temperature and stirred overnight. Dichloromethane (25mL) was added and the organic phase was washed with sodium thiosulfate solution and saturated sodium bicarbonate solution, respectively. The organic phase was concentrated under reduced pressure, and the resulting residue was purified by high performance liquid preparative chromatography to give the title compound B35(24mg, 24% yield).

¹H NMR(500MHz,DMSO-d₆)δ10.70(s,1H),9.00(d,1H),8.92(s,1H),8.38(s,1H),8.25–8.15(m,1H),7.87(d,1H),7.62–7.83(m,2H),7.36(d,1H),7.07–7.19(m,2H),2.52–2.67(m,3H),2.35–2.45(m,3H),2.29(s,3H),2.07–2.18(m,2H)。MS m/z(ESI):510.0[M+1]

Second step N- (3- (4',4' -dimethoxy-4-oxo-3, 4-dihydrospiro [ benzo [ e ] [1,3] oxazine-2, 1' -cyclohexan-7-yl) -4-methylphenyl) -2- (trifluoromethyl) isonicotinamide B36

Compound B35(19mg, 0.037mmol) was dissolved in methanol (2mL), and p-toluenesulfonic acid hydrate (1mg, 0.0037mmol) and trimethyl orthoformate (0.02mL, 0.15mmol) were added. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by high performance liquid preparative chromatography to give the title compound B36(3.8mg, yield 18.4%).

¹H NMR(500MHz,DMSO-d₆)δ10.68(s,1H),9.00(d,1H),8.73(s,1H),8.38(s,1H),8.20(d,1H),7.62–7.83(m,3H),7.35(d,1H),7.11(d,1H),7.03(d,1H),3.18(s,3H),3.10(s,3H),2.26(s,3H),1.63–1.91(m,8H)。

MS m/z(ESI):556.0[M+1]⁺

Example C1& example C2

(R) -N- (4-methyl-3- (4-oxo-2 ',4,4',5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 3' -pyran ] -8-yl) phenyl) -2- (trifluoromethyl) isonicotinamide C1

(S) -N- (4-methyl-3- (4-oxo-2 ',4,4',5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 3' -pyran ] -8-yl) -phenyl) -2- (trifluoromethyl) isonicotinamide C2

First step of

N- (4-methyl-3- (4-oxo-2 ',4',5',6' -tetrahydrospiro [ chromane-2, 3' -pyran ] -7-yl) phenyl) -2- (trifluoromethyl) isonicotinamide C1a

To a solution of intermediate Int-A1(105mg, 0.25mmol) in methanol (4mL) was added dihydro-2H-pyran-3 (4H) -one (0.03mL, 0.25mmol) and tetrahydropyrrole (0.015mL, 0.25 mmol). The reaction was heated to reflux and stirred overnight. Concentration under reduced pressure and the obtained residue were purified by high performance liquid chromatography to give the title compound C1a (112mg, yield: 90%).

MS m/z(ESI):497.2[M+H]⁺

Second step of

(Z) -N- (3- (4- (hydroxyimino) -2',4',5',6' -tetrahydrospiro [ chromane-2, 3' -pyran ] -7-yl) -4-methylphenyl) -2- (trifluoromethyl) isonicotinamide C1b

To a solution of compound C1a (105mg, 0.25mmol) in methanol were added hydroxylamine hydrochloride (19mg, 0.28mmol) and anhydrous sodium acetate (24mg, 0.30 mmol). The reaction was heated to reflux and stirred for 15 hours. The mixture was diluted with saturated sodium chloride solution (150mL) and extracted with ethyl acetate (20 mL. times.2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound C1b (107mg, yield: 92%).

MS m/z(ESI):512.1[M+H]⁺

The third step

(Z) -N- (4-methyl-3- (4- ((p-toluenesulfonyloxy) imino) -2',4',5',6' -tetrahydrospiro [ chromane-2, 3' -pyran ] -7-yl) phenyl) -2- (trifluoromethyl) isonicotinamide C1C

To a solution of compound C1b (107mg, 0.21mmol) in dichloromethane (10mL) were added triethylamine (0.05mL, 0.30mmol) and p-toluenesulfonic anhydride (76mg, 0.22 mmol). The reaction was stirred at room temperature for 20 hours. Then diluted with water (150mL) and dichloromethane (150 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane ═ 3:1) to obtain the title compound C1C (112mg, yield: 80.6%).

MS m/z(ESI):666.2[M+H]⁺

The fourth step

(S) -N- (4-methyl-3- (4-oxo-2 ',4,4',5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepine-2, 3' -pyran ] -8-yl) phenyl) -2- (trifluoromethyl) isonicotinamide C2

To a solution of compound C1C (37mg,0.056mmol) in dichloromethane (3.0mL) under argon at 0 ℃ was added aluminum trichloride (33mg,0.26 mmol). The mixture was refluxed at 40 ℃ overnight. The reaction was quenched at 0 ℃ by slow addition of water (1 mL). After that, the mixture was refluxed for another 30 minutes. Concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate 1:1, followed by 10% methanol/dichloromethane system) to give a mixture of C1 and C2. The mixture was purified by high performance liquid chromatography (acetonitrile/water) to give the title compound (11.3mg and 4.5mg, 55% total yield).

Example C1

¹H NMR(400MHz,CH3OH-d₄)δ8.92(d,1H),8.32(s,1H),8.14(d,1H),7.66(d,2H),7.33(d,1H),7.10–7.22(m,3H),3.82–3.90(m,2H),3.58–3.63(m,2H),2.57(q,2H),2.31(s,3H),2.00–2.15(m,2H),1.85–1.96(m,1H),1.65–1.71(m,1H)。

MS m/z(ESI):512.0[M+1]⁺

Example C2

¹H NMR(400MHz,CH3OH-d₄)δ8.92(d,1H),8.32(s,1H),8.14(s,1H),7.59–7.70(m,2H),7.33(d,1H),7.10–7.21(m,3H),3.79–3.90(m,2H),3.59–3.70(m,2H),2.48–2.68(m,2H),2.31(s,3H),2.00–2.18(m,2H),1.85–1.95(m,1H),1.60–1.70(m,1H)。

MS m/z(ESI):512.0[M+1]⁺

C3 and C4 (only one isomer found in the purification) were prepared using the method described previously and the general procedure described in example C1/C2, replacing dihydro-2H-pyran-3 (4H) -one with the appropriate ketone (step 1).

Example C3

N- (4-methyl-3- (4-oxo-4, 4',5,5' -tetrahydro-2 'H, 3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 3' -furan ] -8-yl) phenyl) -2- (trifluoromethyl) isonicotinamide C3

¹H NMR(400MHz,CH3OH-d₄)δ8.81(d,1H),8.20(d,1H),8.02(dd,1H),7.54(d,2H),7.21(d,1H),7.15–7.03(m,2H),7.00(d,1H),3.95–4.07(m,2H),3.90–3.95(m,1H),3.60–3.68(d,1H),2.56–2.80(m,2H),2.40–2.28(m,1H),2.19(s,3H),2.00–2.06(m,1H)。

MS m/z(ESI):498.0[M+1]⁺

Example C4

N- (4-methyl-3- (3 '-methyl-4-oxo-2', 3',4,5,5',6 '-hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -2- (trifluoromethyl) isonicotinamide C4

¹H NMR(400MHz,CH3OH-d₄)δ8.92(d,1H),8.32(s,1H),8.14(d,1H),7.60–7.70(m,2H),7.28–7.35(m,1H),7.05–7.18(m,3H),3.95–4.05(m,1H),3.78–3.90(m,1H),3.61–3.68(m,1H),3.55(d,1H),2.74–2.88(m,1H),2.50–2.60(m,1H),2.29(s,3H),1.98–2.11(m,2H),1.72–1.90(m,1H),1.09–1.18(m,3H)。

MS m/z(ESI):526.0[M+1]⁺

Example D1

N- (4-methyl-3- (5-methyl-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -6-oxo-1- (2,2, 2-trifluoroethyl) -1, 6-dihydropyridine-3-carboxamide D1

First step of

8-bromo-5-methyl-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -4(5H) -one Int-D1a

Intermediate Int-3(300mg, 961.05. mu. mol), methyl iodide (1.37g, 9.61mmol) and potassium carbonate (1.33g, 9.61mmol) were stirred in N, N-dimethylformamide (4mL) at room temperature for 10 min, and the reaction mixture was heated at 80 ℃ for 16 h. The reaction mixture was diluted with ethyl acetate (50mL) and washed with saturated sodium chloride solution (100 mL). The organic phase was concentrated, and the resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate ═ 1:1) to give the title compound Int-D1a (253mg, 775.63 μmol, yield 80.71%).

¹H NMR(400MHz,DMSO-d₆):δ7.44(d,J＝7.2Hz,1H),7.37(q,J＝8.4Hz,1H),7.30(s,1H),3.81-3.75(m,2H),3.70-3.66(m,2H),3.22(s,3H),2.47(s,2H),1.79-1.70(m,4H)。

MS m/z(ESI):326.0[M+H]⁺

Second step of

N- (4-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -6-oxo-1- (2,2, 2-trifluoroethyl) -1, 6-dihydropyridine-3-carboxamide Int-D1b

4-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (116mg, 497.61. mu. mol), intermediate Int-J18(100mg, 452.22. mu. mol), 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (283.81mg, 746.42. mu. mol) and triethylamine (151.06mg, 1.49mmol) were stirred in N, N-dimethylformamide (3mL) for 12 hours. LCMS showed reaction complete. The mixture was diluted with ethyl acetate (20mL), washed with saturated sodium chloride, dried and concentrated. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate ═ 5:1) to obtain the title compound Int-D1b (137mg, 314.05 μmol, yield 63.11%). MS M/z (ESI) 437.2[ M +1 ]]⁺

The third step

To a mixed solution of intermediate Int-D1b (110mg, 252.16. mu. mol), potassium bicarbonate (63mg, 756.48. mu. mol) and intermediate Int-D1a (82.25mg, 252.16. mu. mol) in dioxane (5 mL)/water (1mL) was added [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (20mg, 25.22. mu. mol). The reaction system was heated at 80 ℃ for 1 hour under a nitrogen atmosphere. The reaction was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with ethyl acetate (10 mL. times.3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by high performance liquid chromatography (n-hexane: ethyl acetate 1:1) to obtain the title compound D1(17mg, 30.60 μmol, yield 12.14%).

¹H NMR(400MHz,DMSO-d₆):δ10.04(s,1H),8.48(s,1H),8.09(d,1H),7.64(d,1H),7.59(s,1H),7.47(d,1H),7.28(d,1H),7.23(d,1H),7.03(s,1H),6.69(d,1H),4.96(q,2H),3.82-3.77(m,2H),3.70-3.66(m,2H),3.20(s,3H),2.50(s,2H),2.23(s,3H),1.82-1.73(m,4H)。

¹⁹F NMR(376.5MHz,DMSO-d₆):δ-69.22。

MS m/z(ESI):556.3[M+H]⁺

Using the foregoing procedure and the general procedure described in example D1, the following compounds were prepared, but replacing methyl iodide with the appropriate nucleophile (step 1), as described in the foregoing schemes and examples. The necessary starting materials are commercially available, synthesized using conventional reactions from commercially available reagents using conventional reactions, described in the literature or readily synthesized by one skilled in the art of organic synthesis without undue experimentation.

Example D6

N- (3- (5- (hydroxymethyl) -4-oxo-2 ',3',5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) -4-methylphenyl) -5- (trifluoromethyl) pyridazine-3-carboxamide D6

First step of

((8- (2-methyl-5- (5- (trifluoromethyl) pyridazin-3-carboxamido) phenyl) -4-oxo-2 ',3,3',4,5',6' -hexahydro-5H-spiro [ benzo [ b ] [1,4] oxaza-2, 4' -pyran ] -5-yl) methyl) di-tert-butyl phosphate D6a

Di-tert-butyl (chloromethyl) phosphate (93mg, 0.36mmol) was added to N- (4-methyl-3- (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] at room temperature][1,4]-2,4' -pyrane]-8-yl) phenyl) -5- (trifluoromethyl) pyridazine-3-carboxamide J3(154mg, 0.3mmol) and cesium carbonate (108mg, 0.33mmol) in DMF (3 mL). The resulting mixture was stirred at room temperature for 18 hours. Using water The mixture was diluted and extracted with EtOAc (2X 50 mL). The organic phases were combined and washed with brine. The organic phase is MgSO₄Dried, filtered and concentrated by rotary evaporator. The residue was purified by silica gel column chromatography with DCM/EtOAc as eluent to give the title compound D6a (44mg, yield: 20%). MS M/z (ESI) 735.0[ M + H ]]⁺。

Second step of

((8- (2-methyl-5- (5- (trifluoromethyl) pyridazine-3-carboxamido) phenyl) -4-oxo-2 ',3,3',4,5',6' -hexahydro-5H-spiro [ benzo [ b ] b)][1,4]Oxa-2, 4' -pyrans]-5-yl) methyl) di-tert-butylphosphate D6a (10mg, 0.014mmol) in AcOH/H₂A mixture of O (11: 1, 0.3ml) was stirred at 45 ℃ for 1 h. The crude product was purified by HPLC using 10-50% MeCN in H₂O solution + 0.1% TFA, to give the title compound D6(3mg, yield: 40.6%).

¹H NMR(400MHz，CD₃OD) δ 9.76(d, 1H), 8.66(dd, 1H), 7.83-7.75 (m, 1H), 7.76(d, 1H), 7.64(d, 1H), 7.36(d, 1H), 7.30(dd, 1H), 7.11(d, 1H), 5.29(s, 2H), 3.98(td, 2H), 3.82(dt, 2H), 2.61(s, 2H), 2.32(s, 3H), 2.00(d, 2H), 1.85(ddd, 2H). In CD ₃No-OH and amide-NH groups were observed in OD.

MS m/z(ESI):543.0[M+1]⁺.

Example E1

N- (4-methyl-3- (5-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ f ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -2- (trifluoromethyl) isonicotinamide E1

To a mixed solution of intermediate Int-1(195mg, 0.48mmol), intermediate Int-5(126mg, 0.40mmol) in dioxane-water (10mL-1.0mL), potassium phosphate (255mg,1.2mmol) was added. The resulting cloudy suspension was bubbled with nitrogen for 5 minutes, then [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (10 mol%, 32mg, 0.04mmol) was added under nitrogen. The mixture was heated at 100 ℃ for 1 hour. The reaction was cooled at room temperature, diluted with ethyl acetate (30mL) and water (10mL), and filtered to remove insoluble solids. The ethyl acetate layer was collected, and the aqueous layer was washed with ethyl acetate (40 mL. times.2). The combined ethyl acetate was washed with saturated sodium chloride solution and dried over magnesium sulfate. Filtration and concentration were carried out, and the obtained residue was purified by silica gel column chromatography (eluent n-hexane/ethyl acetate: 0-60%) to obtain the title compound E1(154 mg).

¹HNMR(400mHz,DMSO-d₆),δ10.69(s,1H),8.99(d,1H),8.43(t,1H),8.38(s,1H),7.75(d,1H),7.67(s,1H),7.66(d,1H),7.34(d,1H),7.22(d,1H),7.00(s,1H),3.84-3.79(m,2H),3.72-3.69(m,2H),3.10(d,2H),2.24(s,3H),1.80-1.76(m,2H),1.68-1.63(m,2H)。

MS m/z(ESI):512.0[M+1]⁺

Example E2

N- (4-methyl-3- (5-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ f ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) tetrahydro-2H-pyran-4-carboxamide E2

Using the synthetic route of example E1, the corresponding starting material was replaced to give compound E2.

¹HNMR(400MHz,DMSO-d₆),δ9.81(s,1H),8.34(s,1H),7.55(d,1H),7.46(s,2H),7.16-7.09(m,2H),6.87(s,1H),3.84-3.82(m,2H),3.76-3.71(m,2H),3.64-3.62(m,2H),3.30-3.28(m,2H),3.02(s,2H),2.50-2.47(m,1H),2.10(s,3H),1.71-1.68(m,2H),1.60-1.57(m,6H)。

MS m/z(ESI):451.0[M+1]⁺

Example E3

(N- (4-methyl-3- (4- (2-morpholinylethyl) -5-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ f ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -2- (trifluoromethyl) isonicotinamide E3

First step of

8-bromo-4- (2-morpholinylethyl) -2',3,3',4,5',6' -hexahydro-5H-spiro [ benzo [ f ] [1,4] oxazepin-2, 4' -pyran ] -5-one E3a

To a solution of intermediate Int-5(900mg, 2.88mmol) in N, N-dimethylformamide (40mL) was added sodium hydride (207.59mg, 8.65mmol), and the mixture was stirred at 0 ℃ for 0.5 h. Then 4- (2-chloroethyl) morpholine hydrochloride (1.73g, 11.53mmol) in N, N-dimethylformamide (10mL) and N, N-diisopropylethylamine (2.23g, 17.30mmol) were added. The mixture was heated and stirred at 100 ℃ for 12 hours. The reaction solution was poured into a saturated sodium bicarbonate solution (300mL), followed by extraction with ethyl acetate (200 mL. times.2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent methanol/ethyl acetate ═ 0:1 to 1:20, 200 to 300 mesh silica gel) to give the title compound E3a (650mg, yield 48%).

MS m/z(ESI):425.1[M+H]⁺

Second step of

To a solution of intermediate E3a (100mg, 0.23mmol) in a mixture of 1, 4-dioxane (16mL) and water (4mL) were added intermediate Int-1(143.26mg, 0.35mmol), sodium carbonate (49.85mg, 0.47mmol) and bis triphenylphosphine palladium dichloride (16.50mg, 23.51. mu. mol). The reaction system was purged with argon 5 times. The mixture was heated and stirred at 100 ℃ for 2 hours. After completion of the reaction, water (50mL) was added to dilute the reaction solution, and the resulting mixture was extracted with ethyl acetate (50 mL. times.2). The organic phase was dried, concentrated and the resulting residue was purified by silica gel column chromatography (eluent ethyl acetate/n-hexane 0:1to 3:1) to give the title compound E3(120mg, 82% yield).

¹H NMR(400MHz,CDCl₃):δ8.91(d,1H),8.27(s,1H),8.15(s,1H),7.96(d,1H),7.75(d,1H),7.61(d,1H),7.51(d,1H),7.31(d,1H),7.14(dd,1H),6.90(d,1H),3.96-3.72(m,10H),3.36(brs,2H),2.72-2.54(m,6H),2.25(s,3H),1.90-1.82(m,2H),1.74-1.67(m,2H)。

¹⁹F NMR(376.5MHz,CDCl₃):δ-68.0。

MS m/z(ESI):625.3[M+H]⁺

Using the foregoing procedure and the general procedure described in example E3, the following compounds were prepared, substituting the appropriate nucleophile for 4- (2-chloroethyl) morpholine hydrochloride (step 1), as described in the foregoing schemes and examples. The necessary starting materials are commercially available, synthesized using conventional reactions from commercially available reagents using conventional reactions, described in the literature or readily synthesized by one skilled in the art of organic synthesis without undue experimentation.

Example F1

N- (4-methyl-3- (3-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ F ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -2- (trifluoromethyl) isonicotinamide F1

First step of

4- (5-bromo-2-cyanophenoxy) tetrahydro-2H-pyran-4-carboxylic acid methyl ester F1b

Methyl 4-hydroxytetrahydro-2H-pyran-4-carboxylate F1a (1.9g, 9.60mmol) was dissolved in toluene (30mL) and replaced with argon 3 times at room temperature. Triphenylphosphine (5.05g, 19.19mmol), diethyl azodicarboxylate (3.34g, 19.19mmol) and 4-bromo-2-hydroxybenzonitrile (1.9g, 9.60mmol) were added. The reaction was heated to 100 ℃ and stirred for 3 hours. After completion of the reaction, the mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane ═ 0:1 to 3:1, 200 to 300 mesh silica gel) to give the title compound F1b (2g, yield: 61%).

Second step of

4- ((4-cyano-2 ' -methyl-5 ' - (2- (trifluoromethyl) isonicotinamido) - [1,1' -biphenyl ] -3-yl) oxy) tetrahydro-2H-pyran-4-carboxylic acid methyl ester F1c

To a mixed solution of compound F1b (2g, 5.88mmol) in 1, 4-dioxane (40mL) and water (10mL) were added compound Int-1(3.58g, 8.82mmol), sodium carbonate (1.87g, 17.64mmol) and bis (triphenylphosphine) palladium (II) dichloride (412.74mg, 587.94. mu. mol) in that order. The mixture was then degassed and replaced 5 times with argon. The mixture was heated to 100 ℃ and stirred for 3 hours. The mixture was then diluted with saturated sodium chloride solution (100mL) and extracted with ethyl acetate (100 mL. times.2). The organic phases were combined, dried and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane: 0:1 to 3:1) to obtain the title compound F1c (0.96g, yield: 30%). MS M/z (ESI) 540.2[ M + H ]⁺

The third step

Compound F1c (450mg, 0.83mmol) was dissolved in methanol (30mL), triethylamine (422.01mg) was added, followed by Raney nickel (1g, 17.04mmol), and hydrogen substitution was performed. The mixture was stirred under a hydrogen atmosphere (10 atm) at 35 ℃ overnight. After completion of the reaction, the mixture was filtered, and the filtrate was dried and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane ═ 0:1 to 2:1) to give the title compound F1(50mg, yield: 12%).

¹H NMR(400MHz,DMSO-d₆):δ10.68(s,1H),8.99(d,1H),8.37(s,1H),8.31(s,1H),8.19(d,1H),7.72(dd,1H),7.64(d,1H),7.45(d,1H),7.32(d,1H),7.16(s,1H),7.12(d,1H),4.24(d,2H),3.90-3.84(m,2H),3.80-3.75(m,2H),2.20(s,3H),2.21-2.15(m,2H),1.74(d,2H)。

MS m/z(ESI):512.2[M+H]⁺

Example F2

N- (4-methyl-3- (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] thiazepin-2, 4' -pyran ] -8-yl) phenyl) -2- (trifluoromethyl) isonicotinamide F2

First step of

(E) -7' -bromo-2, 3,5, 6-tetrahydrospiro [ pyran-4, 2' -thiochroman ] -4' -ketoxime F2a

Sodium acetate (1.65g, 20.11mmol) was added to a solution of compound A12e (2.1g, 6.70mmol) and hydroxylamine hydrochloride (1.40g, 20.11mmol) in ethanol (20 mL). The resulting reaction mixture was heated to reflux for 3 hours. After completion of the reaction, ethyl acetate and water were added. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound crude F2a (2.1g, yield: 95.5%).

MS m/z(ESI):327.9[M+H]⁺

Second step of

(E) -7' -bromo-2, 3,5, 6-tetrahydrospiro [ pyran-4, 2' -thiochroman ] -4' -one O-p-toluenesulfonyl oxime F2b

Triethylamine (1.37g, 13.59mmol) and p-toluenesulfonic anhydride (4.44g, 13.59mmol) were added to a solution of compound F2a (2.23g, 6.79mmol) in dichloromethane (20 mL). The resulting reaction mixture was stirred at room temperature overnight. After completion of the reaction, the solution was washed with water. The aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was filtered to give the title compound F2b (2.38g, yield: 72.6%).

MS m/z(ESI):482.1[M+H]⁺

The third step

8-bromo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] [1,4] thiazepine-2, 4' -pyran-4 (5H) -one F2c

A mixture of compound F2b (500mg, 1.04mmol) and polyphosphoric acid (5mL) was heated to 120 ℃ and reacted for 4 hours. After the reaction was completed, dichloromethane and water were added for extraction. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (ethyl acetate/hexane ═ 1/10) to give the title compound F2c (120mg, yield: 35.3%).

¹H NMR(400MHz,DMSO-d₆):δ9.99(s,1H),7.70(s,1H),7.76(dd,1H),7.06(d,1H),3.72-3.62(m,4H),2.39(s,2H),1.83-1.79(m,4H)。

MS m/z(ESI):328.1[M+H]⁺

The fourth step

Bis triphenylphosphine palladium dichloride (5.35mg, 7.62. mu. mol) was added to a mixture of 1, 4-dioxane (1mL) and water (0.25mL) dissolved with compound F2c (50mg, 152.33. mu. mol), compound Int-1(74.26mg, 182.80. mu. mol) and sodium carbonate (32.29mg, 304.67. mu. mol) under a nitrogen atmosphere. The mixture was heated at 100 ℃ for reaction overnight. The mixture was concentrated, and the residue was purified by silica gel column chromatography (methanol: dichloromethane ═ 1:10) to give the title compound F2(7mg, yield: 8.7%).

¹H NMR(400MHz,DMSO-d₆):δ10.68(s,1H),10.03(s,1H),9.00(d,1H),8.37(s,1H),8.20(d,1H),7.76-7.70(m,1H),7.66(s,1H),7.52-7.43(m,2H),7.33(d,1H),7.21(d,1H),3.77-3.63(m,4H),2.44(s,2H),2.24(s,3H),1.83(br,4H)。

MS m/z(ESI):528.1[M+H]⁺

Example F3

N- (3- (1, 1-dioxo-4-oxo-2 ',3',4,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] thiazepin-2, 4' -pyran ] -8-yl) -4-methylphenyl) -2- (trifluoromethyl) isonicotinamide F3

First step of

8-bromo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] [1,4] thiazepine-2, 4' -pyran ] -4(5H) -one 1, 1-dioxide F3a

To a solution of compound F2c (70mg, 213.27. mu. mol) in dichloromethane (2mL) was added m-chloroperoxybenzoic acid (92.01mg, 533.17. mu. mol). The resulting reaction mixture was stirred at room temperature overnight. After the completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane ═ 1:5) to give the title compound F3a (75mg, yield 97%).

MS m/z(ESI):357.9[M-H]^-

Second step of

To a mixture of compound F3a (75mg, 208.20. mu. mol), compound Int-1(101.49mg, 249.85. mu. mol) and sodium carbonate (44.14mg, 416.41. mu. mol) in 1, 4-dioxane (1mL) and water (0.25mL) was added bis triphenylphosphine palladium dichloride (7.31mg, 10.41. mu. mol) under a nitrogen atmosphere. The resulting reaction mixture was heated at 100 ℃ overnight. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane: 1 to dichloromethane: methanol: 60:1) to give the title compound F3(6mg, yield: 5%).

¹H NMR(400MHz,DMSO-d₆):δ10.73(s,1H),10.52(s,1H),9.00(d,1H),8.37(s,1H),8.20(d,1H),7.82(dd,1H),7.78-7.75(m,2H),7.72(d,J＝2.0Hz,1H),7.38(d,1H),7.33(d,1H),3.89-3.86(m,2H),3.62-3.56(m,2H),2.78(s,2H),2.26(s,3H),2.12-2.03(m,2H),1.77-1.73(m,2H)。

MS m/z(ESI):560.2[M+H]⁺

Example F4& example F5

N- (4-methyl-3- (4-oxo-2 ',3,3',4,5',6' -hexahydrospiro [ benzo [ b ] [1,4] dioxacycloheptatrien-2, 4' -pyran ] -8-yl) phenyl) -2- (trifluoromethyl) isonicotinamide F4

N- (3- (2',3,3',4,5',6' -hexahydrospiro [ benzo [ b ] [1,4] dioxacycloheptatriene-2, 4' -pyran ] -8-yl) -4-methylphenyl) -2- (trifluoromethyl) isonicotinamide F5

First step of

7- (5-amino-2-methylphenyl) -2',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -4-one F4a

A vial was charged with compound Int-2(1.5g, 5.0mmol), 4-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (1.75g, 7.5mmol), bis triphenylphosphine palladium dichloride (0.37g, 0.5mmol) and cesium carbonate (3.26g, 10 mmol). The cap was closed, nitrogen purged, and 1, 4-dioxane (20mL) and water (4mL) were added. The reaction was stirred at 95 ℃ for 2 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (50mL × 2). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane ═ 7:3) to give the title compound F4a (1370mg, yield 84.8%).

MS m/z(ESI):324[M+1]⁺

Second step of

8- (5-amino-2-methylphenyl) -2',3',5',6' -tetrahydrospiro [ benzo [ b ] [1,4] dioxacycloheptatriene-2, 4' -pyran ] -4(3H) -one F4b

Sodium perborate (1.51g, 9.84mmol) was added portionwise to a solution of compound F4a (1.37g, 4.24mmol) in trifluoroacetic acid (7.5 mL). The reaction mixture was stirred at room temperature for 80 minutes, and then the reaction solution was added dropwise to a precooled aqueous sodium carbonate solution with stirring to neutralize. The mixture was extracted with ethyl acetate (50 mL. times.2). The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane ═ 65:35) to give the title compound F4b (330mg, yield 23.0%).

MS m/z(ESI):340[M+1]⁺

The third step

To a solution of compound F4b (87mg, 0.26mmol), compound Int-L4a (63mg, 0.33mmol) and diisopropylethylamine (0.17mL, 0.33mmol) in DMF (2.0mL) was added 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (125mg, 0.33mmol) at room temperature. The reaction was then stirred for 3 hours. The mixture was diluted with water and extracted with ethyl acetate (30mL × 2). The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: dichloromethane ═ 3:2) to give the title compound F4(97mg, yield 72.9%).

¹H NMR(400MHz,Chloroform-d)δ8.96(d,J＝5.0Hz,1H),8.13(s,1H),7.96(d,2H),7.61(d,1H),7.57(d,1H),7.35(d,1H),7.22(d,1H),7.17(dd,1H),7.06(d,1H),3.96(td,2H),3.91–3.79(m,2H),2.78(s,2H),2.30(s,3H),2.11–1.98(m,2H),1.93–1.77(m,2H)。

MS m/z(ESI):513[M+1]⁺

The fourth step

N- (4' -hydroxy-3 ' - ((((4- (2-hydroxyethyl) tetrahydro-2H-pyran-4-yl) oxy) -6-methyl- [1,1' -biphenyl ] -3-yl) -2- (trifluoromethyl) isonicotinamide F4c

To a solution of compound F4(0.33g, 0.64mmol) in methanol (5mL) at 0 deg.C was added sodium borohydride (48mg, 1.28mmol) and water (0.5 mL). The reaction was carried out for 3 hours and at room temperature for 15 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution. Extraction was performed with ethyl acetate (30 mL. times.2). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: dichloromethane ═ 3:2) to give the title compound F4c (188mg, yield 56.9%).

MS m/z(ESI):517[M+1]⁺

The fifth step

To a mixture of compound F4c (26mg, 0.05mmol) and triphenylphosphine (13mg, 0.05mmol) in tetrahydrofuran (0.5mL) was added a solution of diethyl azodicarboxylate (9mg, 0.05mmol) in tetrahydrofuran (0.5mL) at room temperature. The reaction was stirred for 2 hours. The mixture was concentrated to dryness. The residue was purified by silica gel column chromatography (ethyl acetate: hexane ═ 3:2) to give the title compound F5(15mg, yield 60.2%).

¹H NMR(400MHz,CDCl₃):δ8.83(d,1H),8.06–8.01(m,1H),7.98(s,1H),7.85(dd,1H),7.50(dd,1H),7.36(d,1H),7.20(d,2H),6.95–6.80(m,2H),4.30–4.19(m,2H),3.77(td,2H),3.68(ddd,2H),2.19(s,3H),2.08–1.98(m,2H),1.93–1.83(m,2H),1.64(m,2H)。

MS m/z(ESI):499[M+1]⁺

Example F6

2- (difluoromethoxy) -N- (3- (4-imino-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) -4-methylphenyl) isonicotinamide F6

First step of

8-bromo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] [1,4] oxazepine-2, 4' -pyran ] -4(5H) -thione F6a

Compound Int-1(2g, 6.41mmol) was added to a solution of 2, 4-bis (4-methoxyphenyl) -1, 3-dithio-2, 4-diphospho-2, 4-thioether (Lawson's reagent, 10g, 24.72mmol) in tetrahydrofuran (50 mL). The resulting mixture was stirred at 60 ℃ for 16 hours. The mixture was diluted with ethyl acetate (300mL), and the organic phase was washed with water (100 mL. times.3), saturated sodium chloride solution (100mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with petroleum ether/dichloromethane: 1/0 to 4/1) to give the title compound F6a (1.0g, yield: 48%). MS M/z (ESI) 328.0[ M + H ]]⁺

Second step of

8-bromo-4- (methylthio) -2',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] [1,4] oxazepine-2, 4' -pyran ] F6b

To a solution of compound F6a (800mg, 2.44mmol) in dichloromethane (10mL) at 0 deg.C was added trimethyloxonium tetrafluoroborate (540mg, 3.65 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (20mL), the organic phase was separated, and the aqueous phase was extracted with dichloromethane (10 mL. times.2). The combined organic phases were washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with petroleum ether/dichloromethane ═ 4/1) to give the title compound F6b (700mg, yield: 84%).

MS m/z(ESI):342.0[M+H]⁺

The third step

8-bromo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] [1,4] oxazepine-2, 4' -pyran ] -4(5H) -imine F6c

A mixture of Compound F6b (300mg, 876.55. mu. mol) and 7M ammonia in methanol (5mL) was added to the sealed tube, heated to 120 ℃ and reacted for 16 hours. LC-MS monitored the reaction progress. The mixture was concentrated under reduced pressure and the crude product (40% pure) was used in the next step without further purification.

MS m/z(ESI):311.0[M+H]^-

The fourth step

2- (difluoromethoxy) -N- (4-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) isonicotinamide F6e

2- (7-Azabenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (700mg, 1.84mmol) was added to a solution of 2- (difluoromethoxy) isonicotinic acid Int-K21a (300mg, 1.59mmol) in N, N-dimethylformamide (5 mL). The mixture was stirred at room temperature for 10 minutes, then 4-methyl-3- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenylamine (410mg, 1.76mmol) and N, N-diisopropylethylamine (469.20mg, 3.63mmol, 0.6mL) were added. The resulting mixture was stirred at room temperature for 16 hours. The mixture was poured into water (20mL), the aqueous phase was extracted with ethyl acetate (10 mL. times.3), and the combined organic phases were washed with water (10 mL. times.3), a saturated sodium chloride solution (10 mL. times.2), and dried over anhydrous sodium sulfate. Filtration and concentration gave the title compound crude F6e (600mg, yield: 94%).

MS m/z(ESI):405.1[M+H]⁺

The fifth step

Water (4mL), sodium carbonate (70.00mg, 660.45 μmol), and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (24.00mg, 32.79 μmol) were added to a solution of Compound F6c (250mg, 321.36 μmol) in dioxane (10mL), followed by Compound F6e (300mg, 742.18 μmol). The resulting mixture was replaced with nitrogen 3 times. The mixture was heated to 80 ℃ and reacted for 1 hour. The mixture was diluted with ethyl acetate (50 mL). The organic phase was washed with water (20 mL. times.3), saturated sodium chloride solution (20 mL. times.2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/MeOH ═ 100/1 to 40/1 elution) to give the title compound F6(105mg, yield: 64%).

¹H NMR(400MHz,DMSO-d₆):δ10.52(s,1H),8.46(d,1H),7.98-7.54(m,7H),7.36-7.28(m,2H),3.75-3.69(m,2H),3.64-3.53(m,2H),3.05(s,2H),2.24(s,3H),1.82(brs,2H),1.73-1.64(m,2H),1.49-1.39(m,2H)。

¹⁹F NMR(376.5MHz,DMSO-d₆):δ-87.36。

MS m/z(ESI):509.2[M+H]⁺

Example F7

N- (4-methyl-3- (5-oxo-2 ',3,4,5,5',6 '-hexahydro-3H-spiro [ benzo [ F ] [1,4] thiazepin-2, 4' -pyran ] -8-yl) phenyl) -2- (trifluoromethyl) isonicotinamide F7

First step of

8-bromo-2 ',3,3,4,5',6 '-hexahydro-5H-spiro [ benzo [ F ] [1,4] thiazepin-2, 4' -pyran ] -5-one F7a

Sodium azide (78.87mg, 1.21mmol) was added to a solution of compound A12e (190mg, 606.62. mu. mol) in toluene (5mL) at 0 ℃ followed by dropwise addition of sulfuric acid (594.97mg, 6.07 mmol). The mixture was heated to 50 ℃ and reacted overnight. After completion of the reaction, a saturated sodium bicarbonate solution was added. Ethyl acetate and water were added. The aqueous phase was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether ═ 1/10) to give the title compound F7a (85mg, yield: 42.7%).

MS m/z(ESI):328.1[M+H]⁺

Second step of

N- (4-methyl-3- (5-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ F ] [1,4] thiazepin-2, 4' -pyran ] -8-yl) phenyl) -2- (trifluoromethyl) isonicotinamide F7

Bis triphenylphosphine palladium dichloride (8.02mg, 11.43. mu. mol), was added to a mixed solution of compound F7a (75mg, 228.50. mu. mol), compound Int-1(92.82mg, 228.50. mu. mol) and sodium carbonate (48.44mg, 457.00. mu. mol) in 1, 4-dioxane (2mL) and water (0.5mL) under a nitrogen atmosphere. The mixture was heated at 100 ℃ overnight. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol: 100:1 to 40:1) to give the title compound F7(16mg, yield: 13.2%).

¹H NMR(400MHz,DMSO-d₆):δ10.70(s,1H),9.00(d,1H),8.68-8.66(m,1H),8.37(s,1H),8.20(d,1H),7.76(dd,1H),7.70-7.64(m,2H),7.52(dd,1H),7.43(d,1H),7.35(d,1H),3.77-3.71(m,2H),3.70-3.62(m,2H),3.02(d,2H),2.24(s,3H),1.76-1.73(m,4H)。

MS m/z(ESI):528.1[M+H]⁺

Example F8

N- (3- (3-amino-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) -4-methylphenyl) -2- (trifluoromethyl) isonicotinamide F8

First step of

8-bromo-3-iodo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -4(5H) -one F8a

A solution of compound Int-3(1g, 3.20mmol) in dichloromethane (20mL) was cooled in an ice-water bath, tetramethylethylenediamine (1g, 8.61mmol) was added, trimethylsilylimidazole (1.6g, 8.00mmol) was added dropwise over 5 minutes, the light brown solution was stirred in an ice bath for 60 minutes, then iodine (1.30g, 5.13mmol) was added, and the reaction solution was stirred under an ice-water bath for further 60 minutes. The reaction was quenched with sodium thiosulfate solution and stirred for 15 minutes. The mixture was extracted with dichloromethane (20mL), and the organic layer was dried, concentrated, and the resulting residue was purified to give F8a (950mg, 2.17mmol, yield: 67.70%).

¹H NMR(400MHz,DMSO-d₆):δ10.22(s,1H),7.30(s,1H),7.21(d,1H),7.01(d,1H),4.88(s,1H),3.79-3.73(m,2H),3.67-3.63(m,1H),3.44-3.37(m,1H),1.86-1.73(m,4H)。

Second step of

3-amino-8-bromo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -4(5H) -one F8b

Compound F8a (400mg, 913.13. mu. mol) and NH₃MeOH solution (700.00mg, 41.09mmol, 6mL) was sealed and the tube was warmed to 120 deg.C and stirred overnight. To obtain a brown solution, concentrating the cooled reaction solution under reduced pressure, and collecting the residuePurification by liquid chromatography (ethyl acetate: n-hexane: 2:1) gave F8b (55mg, 168.11 μmol, yield: 18.41%).

MS m/z(ESI):327.1[M+H]⁺

The third step

A mixed reaction solution of compound F8b (45mg, 137.54. mu. mol), compound Int-1(90mg, 221.56. mu. mol), potassium carbonate (40mg, 289.86. mu. mol), and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (25mg, 30.64. mu. mol) in 1, 4-dioxane (4mL) and water (2mL) was evacuated, then nitrogen-protected, and the reaction solution was stirred for 2 hours while being warmed to 90 ℃. LC-MS detection was complete, the reaction was cooled, extracted with ethyl acetate, the organic phase was dried, concentrated, and the residue was purified by preparative high performance liquid chromatography to give F8(45mg, 85.47. mu. mol, yield: 62.14%).

¹H NMR(400MHz,DMSO-d₆):δ10.84(s,1H),10.66(s,1H),9.99(d,1H),8.37(s,1H),8.19(d,1H),7.71-7.68(m,1H),7.63(s,1H),7.29(d,1H),6.97(s,1H),6.92(s,2H),4.40(s,1H),3.74-3.58(m,4H),2.23(s,3H),1.86-1.73(m,2H),1.64(br,2H),1.43-1.33(m,2H)。

¹⁹F NMR(376.5MHz,DMSO-d₆):δ-66.44(s,3F)。

MS m/z(ESI):527.4[M+H]⁺

Example F9& example F10& example F11

(S) -N- (4-methyl-3- (4-oxo-5- (tetrahydrofuran-3-yl) -2',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -2- (trifluoromethyl) isonicotinamide F9

F9

(S) -N- (4-methyl-3- (4- ((tetrahydrofuran-3-yl) oxy) -2',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -2- (trifluoromethyl) isonicotinamide F10

N- (4-methyl-3- ((R) -4-oxo-3- ((S) -tetrahydrofuran-3-yl) -2',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -2- (trifluoromethyl) isonicotinamide F11

First step of

(S) -8-bromo-5- (tetrahydrofuran-3-yl) -2',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -4(5H) -one F9a

Cesium carbonate (1.25g,3.84mmol) and (R) -tetrahydrofuran-3-yl methanesulfonate (851.85mg,5.13mmol) were added to a mixture of compound Int-3(400mg,1.28mmol) and N, N-dimethylformamide (20mL), the reaction solution was heated to 100 ℃ and stirred for 3 hours, the reaction solution was quenched with a saturated sodium chloride solution (150mL), the resulting mixture was extracted with ethyl acetate (150mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by chromatography (ethyl acetate: N-hexane ═ 0:1 to 2:1, 200 to 300 mesh silica gel) to give the title product containing three isomers F9a, F9b, F9c (200mg, yield: 41.6%) and used directly in the next reaction.

MS m/z(ESI):382.1/384.1[M+H]⁺

Second step of

(S) -N- (4-methyl-3- (4-oxo-5- (tetrahydrofuran-3-yl) -2',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4 '-pyran ] -8-yl) phenyl) -2- (trifluoromethyl) isonicotinamide F9(S) -N- (4-methyl-3- (4- ((tetrahydrofuran-3-yl) oxy) -2',3',5',6 '-tetrahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -2- (trifluoromethyl) isonicotinamide F10.

To a solution of a mixture of the compounds F9a, F9b and F9c (200mg, 0.52mmol) obtained in the first step in 1, 4-dioxane (16mL) and water (4mL) were added Int-1(318.8mg, 0.78mmol), sodium carbonate (55.46mg, 0.52mmol) and bis (triphenylphosphine) palladium dichloride (36.7mg, 52.32. mu. mol), the reaction solution was evacuated and replaced with nitrogen three times, and the reaction solution was heated to 100 ℃ and stirred for 3 hours. The reaction was diluted with water (50mL), extracted with ethyl acetate (60mLX2), the combined organic phases dried, concentrated and the residue purified by preparative high performance liquid chromatography (basic method: acetonitrile (0.05% aqueous ammonia): water) to give the title product F11 (obtained from F9c in the first step mixture, 26 mg); f9 (obtained from F9a in the product of the first step mixture, 12mg) and F10 (obtained from F9b in the product of the first step mixture, 9.88 mg).

Compound F11

¹H NMR(400MHz,CH3OH-d₄):δ8.90(d,1H),8.29(s,1H),8.12(d,1H),7.67(d,1H),7.63(dd,1H),7.46(d,1H),7.32(d,1H),7.26(dd,1H),7.08(d,1H),4.07-3.74(m,8H),2.58(br,2H),2.28(s,3H),2.05-1.55(m,6H)。

¹⁹F NMR(376.5MHz,CH3OH-d₄):δ-68.0。

HPLC:99.552％@254nm,Rt:11.073min；99.518％@214nm,Rt:11.073min.Chiral HPLC:OD-M-D:ee:100％,Rt:3.534min；AD-M-D:ee:98.18％,Rt:4.403min；AS-M-D:ee:98.94％,Rt:3.297min；OJ-M-D:ee:98.78％,Rt:1.852min；

MS m/z(ESI):582.3[M+H]⁺,Rt:1.697min

Compound F9

¹H NMR(400MHz,CH3OH-d₄):δ8.90(d,1H),8.29(s,1H),8.12(d,1H),8.03(d,1H),7.65-7.58(m,2H),7.30(d,1H),6.99-6.92(m,2H),5.81(brs,1H),5.13(t,J＝5.2Hz,1H),4.21-4.16(m,2H),4.02-3.99(m,2H),3.96-3.86(m,2H),3.85-3.81(m,3H),3.18(s,2H),2.28(s,3H),2.21-2.18(m,4H)。

¹⁹F NMR(376.5MHz,CH3OH-d₄):δ-68.0。

HPLC:98.451％@254nm,Rt:11.546min；98.658％@214nm,Rt:11.073min.Chiral HPLC:OD-M-D:ee:98.08％,Rt:6.185min；AD-M-D:ee:100％,Rt:4.013min；AS-M-D:ee:100％,Rt:5.357min；OJ-M-D:ee:100％,Rt:2.822min；

MS m/z(ESI):582.3[M+H]⁺,Rt:1.801min

Compound F10

¹H NMR(400MHz,CH₃OH-d₄):δ8.90(d,1H),8.29(s,1H),8.12(dd,1.2Hz,1H),8.07(d,1H),7.62(d,2H),7.30(d,1H),7.00-6.93(m,2H),6.04(s,1H),5.15-5.10(m,1H),4.08-4.00(m,2H),3.94-3.88(m,2H),3.80(t,J＝5.6Hz,2H),3.75(t,2H),3.06(t,J＝5.2Hz,2H),2.39(t,J＝5.2Hz,2H),2.32-2.27(m,3H),2.25-2.20(m,3H)。

¹⁹F NMR(376.5MHz,CH₃OH-d₄):δ-68.0。

HPLC:98.166％@254nm,Rt:11.546min；98.670％@214nm,Rt:10.806min.Chiral HPLC:OD-M-D:ee:98.40％,Rt:8.268min；AD-M-D:ee:100％,Rt:4.359min；AS-M-D:ee:100％,Rt:5.140min；OJ-M-D:ee:96.74％,Rt:4.894min；

MS m/z(ESI):582.3[M+H]⁺,Rt:1.782min

Example F12

N- (3- (2',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) -4-methylphenyl) -2- (trifluoromethyl) isonicotinamide F12

First step of

8-bromo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepine-2, 4' -pyran ] F12a

A solution of compound Int-3a (150mg, 0.482mmol) in dichloromethane (3mL) was added dropwise a solution of diisobutylaluminum hydride in dichloromethane (1.0M in CH) at 0 deg.C under argon₂Cl₂2.8mL, 2.8mmol), stirring at 0 ℃ for 30 minutes, and allowing the reaction to warm to room temperature and stirring overnight. The solvent was partially removed by concentration under reduced pressure, and the residual solution (. about.2 mL) was purified by silica gel column chromatography to give the title product F12a (65mg), yield: 45.4 percent.

MS m/z(ESI):298.0[M+1]⁺

Second step of

Compound F12a (15mg,0.05mmol) was added to a solution of intermediate Int-1(21mg,0.052mmol), potassium phosphate (32mg,0.15mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (2mg,0.0025mmol) in dimethylsulfoxide (1mL), the reaction system was evacuated, nitrogen was replaced three times, and the reaction solution was heated to 100 ℃ and stirred for 1 hour. The reaction was cooled to room temperature, ethyl acetate (40mL) was added, the organic phase was washed with saturated sodium chloride solution (20mL), the organic solvent was removed by concentration under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to give the title product F12(2.3mg), yield: 9.3 percent.

¹H NMR(400MHz,Chloroform-d)δ8.93(d,1H),8.14(s,1H),8.02(s,1H),7.61(d,1H),7.42(s,1H),7.16(d,1H),6.89(s,1H),6.69-6.75(m,2H),3.75-3.89(m,2H),3.53-3.69(m,2H),3.11-3.20(m,2H),2.19(s,3H),1.75-1.88(m,4H),1.55-1.65(m,2H)。

MS m/z(ESI):498.0[M+1]⁺

Example F13

N- (4-methyl-3- (5-methyl-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -2- (trifluoromethyl) isonicotinamide F13

First step of

8-bromo-5-methyl-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] F13a

Sodium hydrogen (60%, 9mg, 0.225mmol) was added to a solution of compound F12a (32mg, 0.108mmol) in N, N-dimethylformamide (3mL) at 0 ℃ under an argon atmosphere, and stirred at 0 ℃ for 20 minutes, methyl iodide (0.02mL, 0.32mmol) was added dropwise, the reaction solution was warmed to room temperature, and stirred for 1.5 hours. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give F13a, which was used in the next reaction without purification.

MS m/z(ESI):312.0[M+1]⁺

Second step of

The intermediate Int-1(44mg, 0.11mmol), potassium phosphate (69mg, 0.33mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (5mg, 0.006mmol) are added into a dimethylsulfoxide (1mL) solution of the compound F13a (about 0.108mmol) obtained in the first step, the reaction system is vacuumized and replaced by argon gas for three times, and the reaction solution is heated to 100 ℃ and stirred for 1 hour. The reaction was cooled to room temperature, ethyl acetate (40mL) was added, the organic phase was washed with saturated sodium chloride solution (20mL), and the organic phase was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to give the title product F12(8.5mg) in two-step yield: 15.4 percent.

¹H NMR(400MHz,Chloroform-d)δ8.94(d,1H),8.14(s,1H),7.96(d,1H),7.42-7.61(m,2H),7.30(d,1H),6.90(d,1H),6.73-6.89(m,2H),3.79-3.90(m,2H),3.60-3.70(m,2H),3.11-3.20(m,2H),2.80(s,3H),2.17(s,3H),1.75-1.90(m,4H),1.52-1.63(m,2H)。

MS m/z(ESI):512.0[M+1]⁺

Example F14

N- (3- (5- (2-hydroxyethyl) -2',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) -4-methylphenyl) -2- (trifluoromethyl) isonicotinamide F14

First step of

8-bromo-5- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -2',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -4(5H) -one F14a

Sodium hydrogen (60%, 30mg, 1.5mmol) was added to a solution of compound Int-3(153mg, 0.50mmol) in N, N-dimethylformamide (2mL) at 0 ℃ under an argon atmosphere, and stirred at 0 ℃ for 30 minutes, 2- (tert-butyldimethylsilyloxy) ethylbromide compound (0.40mL, 1.50mmol) was slowly added dropwise, the reaction was warmed to room temperature, and stirred overnight. The reaction solution was quenched with a saturated ammonium chloride solution, extracted with ethyl acetate (60mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography eluting with n-hexane/ethyl acetate to give the title product F14a (217mg, yield: 93.9%).

MS m/z(ESI):470.0[M+1]⁺

Second step of

8-bromo-5- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -2',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepine-2, 4' -pyran ] F14b

Tetramethyldisiloxane (TMDS, 0.12mL, 0.895mmol) was added to a solution of Compound F14a (100mg, 0.213mmol) and triruthenium dodecacarbonyl (14mg, 0.022mmol) in dry toluene (4mL) under nitrogen, the reaction solution was stirred for 10 minutes at room temperature, then heated to 60 ℃ and stirred overnight. The reaction was quenched with 4N hydrogen chloride in 1, 4-dioxane (0.2 mL). The reaction was concentrated under reduced pressure, ethyl acetate (50mL) was added, the organic phase was washed with saturated sodium bicarbonate solution, the organic phase was concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give crude F14b (containing TMDS), which was used in the next reaction without purification.

MS m/z(ESI):456.0[M+1]⁺

The third step

2- (8-bromo-2 ',3,3',4,5',6' -hexahydro-5H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -5-yl) ethan-1-ol F14c

The crude compound F14b (. about.0.213 mmol) obtained in the second step was dissolved in tetrahydrofuran (3mL), tetra-n-butylammonium fluoride (1.0M in tetrahydrofuran, 0.43mL, 0.43mmol) was added, and the reaction was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography using n-hexane/ethyl acetate to give the title compound F14c (31mg, two-step yield: 42.7%).

MS m/z(ESI):342.0[M+1]⁺

The fourth step

Compound F14c (13mg, 0.038mmol) was added to a solution of intermediate Int-1(16mg, 0.039mmol), potassium phosphate (24mg, 0.12mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (2mg, 0.00244mmol) in dimethylsulfoxide (1mL), the reaction was evacuated, replaced with argon three times, and the reaction was heated to 100 ℃ and stirred for 1 hour. The reaction was cooled to room temperature, ethyl acetate (40mL) was added, the organic phase was washed with saturated sodium chloride solution (20mL), and the organic phase was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to give the title product F14(1.85mg), yield: 9.0 percent.

¹H NMR(400MHz,CH₃OH-d₄)δ8.92(s,1H),8.32(s,1H),8.14(s,1H),7.60(d,2H),7.29(d,1H),6.99(d,2H),6.89(s,1H),3.95(t,2H),3.71-3.85(m,4H),3.42-3.51(m,2H),3.38-3.46(m,2H),2.29(s,3H),1.91-2.01(m,4H),1.65-1.76(m,2H)。

MS m/z(ESI):542.0[M+1]⁺

Example F15

N- (3- (2',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ F ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) -4-methylphenyl) -2- (trifluoromethyl) isonicotinamide F15

First step 8-bromo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ F ] [1,4] oxazepine-2, 4' -pyran ] F15a A borane tetrahydrofuran solution (1.0M, 3.0mL, 3.0mmol) was added dropwise to a solution of compound Int-5(193mg, 0.621mmol) in tetrahydrofuran (3mL) at 0 deg.C under argon shield, and the reaction was allowed to warm to room temperature slowly, then warmed to reflux, and stirred overnight. The reaction solution was cooled to 0 ℃ and methanol (2mL) was carefully added dropwise, followed by addition of hydrogen chloride solution (10%, 3mL), the reaction solution was stirred at room temperature for 20 minutes, ethyl acetate (60mL) was added, the organic phase was washed with a saturated sodium bicarbonate solution, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography and purified by eluting with a methanol/dichloromethane system to give the title product F15a (65mg, yield: 35.3%).

MS m/z(ESI):298.0[M+1]⁺

Second step of

Compound F15a (21mg, 0.071mmol) in dimethylsulfoxide (1mL) was added intermediate Int-1(29mg, 0.075mmol), potassium phosphate (45mg, 0.23mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (3mg, 0.004mmol), the reaction was evacuated and replaced with argon three times, and the reaction was heated to 100 ℃ and stirred for 1 hour. The reaction was cooled to room temperature, ethyl acetate (40mL) was added, the organic phase was washed with saturated sodium chloride solution (20mL), and the organic phase was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to give the title product F15(24.2mg), yield: 55.8 percent.

¹H NMR(400MHz,CH₃OH-d₄)δ8.93(d,1H),8.31(s,1H),8.13(d,1H),7.73(s,1H),7.56-7.67(m,1H),7.51(d,1H),7.35(d,1H),7.28(s,1H),7.23(d,1H),4.45(s,2H),3.95(t,2H),3.81(d,2H),3.52(s,2H),2.27(s,3H),1.75-1.92(m,4H)。

MS m/z(ESI):498.0[M+1]⁺

Example F16

N- (4-methyl-3- (4-methyl-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ F ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -2- (trifluoromethyl) isonicotinamide F16

A solution of compound F15(10mg, 0.016mmol) in methanol (1mL) was cooled to 0 ℃, an aqueous formaldehyde solution (37%, 0.1mL, 1.23mmol), acetic acid (0.1mL) and sodium borohydride acetate (40mg, 0.19mmol) were added, and the reaction mixture was stirred at room temperature for 4 hours. Water (2mL) was added and the crude product was purified by preparative high performance liquid chromatography to give the title product F16(1.65mg, yield: 20.2%).

¹H NMR(400MHz,CH3OH-d₄)δ8.93(d,1H),8.31(s,1H),8.13(d,1H),7.72(s,1H),7.62(d,1H),7.50(d,1H),7.35(d,1H),7.15-7.31(m,2H),4.48(s,2H),3.75-3.99(m,4H),3.51-3.67(m,2H),3.05(s,3H),2.27(s,3H),1.78-1.90(m,4H)。

MS m/z(ESI):512.0[M+1]⁺

Example F17

N- (3- (4- (2-hydroxyethyl) -2',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ F ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) -4-methylphenyl) -2- (trifluoromethyl) isonicotinamide F17

First step of

2- (8-bromo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ F ] [1,4] oxazepin-2, 4' -pyran ] -4(5H) -yl) ethan-1-ol F17a

To a solution of compound F15a (7mg, 0.024mmol) in N, N-dimethylformamide (1mL) at 0 ℃ under argon was added NaH (60%, 6mg, 0.15mmol), and the mixture was stirred at 0 ℃ for 20 minutes. 2-Bromoethanol (0.01mL, 0.14mmol) was added, and then the mixture was allowed to return to room temperature, stirred at room temperature for 2 hours, heated to 60 ℃ and reacted overnight. Quench with saturated ammonium chloride solution, extract with ethyl acetate (30mL), dry the organic phase over anhydrous sodium sulfate, filter to remove solids, and concentrate the filtrate under reduced pressure. The crude product F17a was obtained and used in the next step without purification.

MS m/z(ESI):342.0[M+1]⁺

Second step of

Compound F17a (0.024 mmol) obtained above was added dimethyl sulfoxide (1mL), intermediate Int-1(10mg, 0.025mmol), potassium phosphate (16mg, 0.076mmol), and 1, 1-bis (diphenylphosphino) ferrocene dichloropalladium (2mg, 0.003 mmol). The mixture was replaced with argon 3 times and heated at 100 ℃ for 1 hour. The mixture was cooled to room temperature and ethyl acetate (40mL) was added. The organic phase was washed with saturated sodium chloride solution (20mL) and the organic solvent was concentrated under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography and prepared by high performance liquid chromatography in two steps in 9.2% yield to give the title compound F17(1.2 mg).

¹H NMR(400MHz,CH₃OH-d₄)δ8.92(d,1H),8.32(s,1H),8.14(s,1H),7.66(d,1H),7.61(s,1H),7.40-7.19(m,2H),7.07(s,1H),7.02(d,1H),3.89(t,2H),3.69-3.85(m,6H),2.88-2.93(m,2H),2.71-2.81(m,2H),2.26(s,3H),1.65-1.92(m,4H)。

MS m/z(ESI):542.0[M+1]⁺

Example G1

N- (3- (6-fluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) -4-methylphenyl) -2- (trifluoromethyl) isonicotinamide G1

First step of

3-bromo-5-fluorophenylacetate G1b

A solution of 3-bromo-5-fluorophenol G1a (20G, 104.71mmol) in dichloromethane (200mL) was added N, N-diisopropylethylamine (20.30G, 157.07mmol) and acetyl chloride (8.9mL, 125.64mmol) at 0 ℃ under nitrogen, and stirred at 25 ℃ overnight. After the reaction was completed, water was added to quench. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (n-hexane: ethyl acetate: 100:1 to 50:1) to obtain the title compound G1b (23.3G, yield 95%).

¹H NMR(400MHz,CDCl₃):δ7.17-7.12(m,1H),7.10(dd,1H),6.84(dt,1H),2.30(s,3H)。

MS m/z(ESI):233.2[M+H]⁺

Second step of

1- (4-bromo-2-fluoro-6-hydroxyphenyl) ethan-1-one G1c

To a solution of compound G1b (23.2G, 99.56mmol) in dichloromethane (200mL) at 0 ℃ under nitrogen was added aluminum trichloride (39.84G, 298.67mmol) in portions. The reaction mixture was concentrated to a thick, heated to 140 ℃ and reacted for 3 hours. After completion of the reaction, the reaction was partitioned between ethyl acetate and water at 0 ℃, and the organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by silica gel column chromatography (n-hexane: ethyl acetate: 20:1 to 5:1) to obtain the title compound G1c (10G, yield 43.1%).¹H NMR(400MHz,CDCl₃):δ12.89(s,1H),6.99(t,1H),6.82(dd,1H),2.67(d,3H)。

The third step

7-bromo-5-fluoro-2 ',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -4-one G1d

Pyrrolidine (805.70mg, 11.33mmol) was added to a solution of compound G1c (2.64G, 11.33mmol) in ethanol (26mL) at 0 ℃ and stirred for 20 min. Then, tetrahydropyran-4-one (1.13g, 11.33mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated, and the resulting crude product was purified by silica gel column chromatography (n-hexane: ethyl acetate 10:1) to obtain the title compound G1d (2.1G, yield 60.5%).

¹H NMR(400MHz,CDCl₃):δ7.09-7.06(m,1H),6.91(dd,J＝10.2Hz,1.6Hz,1H),3.83-3.79(m,4H),2.75(s,2H),2.01-1.94(m,2H),1.85-1.75(m,2H)。

MS m/z(ESI):315.0[M+H]⁺

The fourth step

(E) -7-bromo-5-fluoro-2 ',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -4-ketoxime G1e

To a solution of compound G1d (460mg, 1.46mmol) in ethanol (10mL) were added hydroxylamine hydrochloride (304.37mg, 4.38mmol) and sodium acetate (359.29mg, 4.38mmol), and the mixture was refluxed for 3 hours. After completion of the reaction, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, the organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude title compound G1e (442 mg).

LCMS:MS m/z(ESI):330[M+H]⁺

The fifth step

(E) -7-bromo-5-fluoro-2 ',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -4-one O-toluenesulfonyl oxime G1f

Triethylamine (91.95mg, 908.68. mu. mol) and p-toluenesulfonic anhydride (593.17mg, 1.82mmol) were added to a solution of compound G1e (300mg, 908.68. mu. mol) in dichloromethane (8mL) at 0 ℃ and reacted at room temperature for 4 hours. Washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude title compound G1f (440mg, crude) which was used in the next step without purification.

LCMS:MS m/z(ESI):484.1[M+H]⁺

The sixth step

8-bromo-6-fluoro-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -4(5H) -one G1G

To a solution of compound G1f (440mg, 908.46. mu. mol) in dichloromethane (10mL) at 0 ℃ was added aluminum trichloride (483.30mg, 3.63mmol), and the mixture was stirred at room temperature overnight. After completion of the reaction, it was quenched with a saturated sodium bicarbonate solution, the reaction mixture was adjusted to pH <5, extracted with dichloromethane, the organic phase was dried and concentrated, and the resulting crude product was purified by silica gel column chromatography (n-hexane: ethyl acetate ═ 1:5) to give the title compound G1G (140mg, yield 46.7%).

¹H NMR(400MHz,CDCl₃):δ7.13(dd,1H),7.08(brs,1H),7.04-7.02(m,1H),3.93-3.81(m,4H),2.62(s,2H),2.01-1.95(m,2H),1.89-1.79(m,2H)。

MS m/z(ESI):330.0[M+H]⁺

Seventh step

To a solution of compound G1G (65mg, 208.23. mu. mol), compound Int-1(93.04mg, 229.05. mu. mol) and sodium carbonate (43.81mg, 416.45. mu. mol) in 1, 4-dioxane (1mL) and water (0.25mL) was added bis triphenylphosphine palladium dichloride (7.31mg, 10.41. mu. mol) under nitrogen, the reaction mixture was sealed and heated to 100 ℃ overnight. After completion of the reaction, insoluble solids were removed by filtration, and the filtrate was concentrated. Purification by flash column chromatography (methanol: dichloromethane ═ 1:30) gave the crude product (35mg), which was further purified to give the title compound G1(7mg, yield 6.6%).

¹H NMR(400MHz,DMSO-d₆):δ10.68(s,1H),9.79(s,1H),9.00(d,1H),8.37(s,1H),8.20(d,1H),7.73(dd,1H),7.66(d,1H),7.33(d,1H),7.13(dd,1H),6.91(s,1H),3.82-3.76(m,2H),3.71-3.66(m,2H),2.55(s,2H),2.25(s,3H),1.86-1.72(m,4H)。MS m/z(ESI):530.2[M+H]⁺

Example G2

N- (3- (9-fluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) -4-methylphenyl) -2- (trifluoromethyl) isonicotinamide G2

First step of

3-bromo-2-fluorophenylacetate G2b

To a solution of 3-bromo-2-fluoro-phenol G2a (10G, 52.36mmol) in dichloromethane (100mL) was added triethylamine (14.5mL, 104.32mmol) and acetyl chloride (5.5mL, 77.07mmol) dropwise, and the reaction was stirred at 15 ℃ for 3 hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane (100mL), washed with water (50mL × 2) and saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution system: petroleum ether: ethyl acetate ═ 10:1) to give the title product G2b (12G, yield: 98.4%).

¹H NMR(400MHz,CDCl₃):δ7.45-7.41(m,1H),7.12-7.00(m,2H),2.34(s,3H)。

Second step of

1- (4-bromo-3-fluoro-2-hydroxyphenyl) ethan-1-one G2c

Aluminum trichloride (3.4G, 25.75mmol) was added in portions to a solution of compound G2b (2G, 8.58mmol) in dichloromethane (20mL) at 0 deg.C, the reaction solution was stirred at 0 deg.C for 10 minutes, the reaction solution was concentrated under reduced pressure, and the residue was stirred at 140 deg.C for 3 hours. The reaction solution was cooled to 80 ℃ and then ice (20g) and 10% hydrogen chloride solution (10mL) were added. The reaction solution was extracted with ethyl acetate (20mL X3), the combined organic phases were washed with a saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution system: petroleum ether: ethyl acetate ═ 5:1) to give the title product G2c (1.4G, yield: 70%).

¹H NMR(400MHz,CDCl₃):δ12.45(s,1H),7.40(dd,1H),7.08(dd,1H),2.64(s,3H)。

MS m/z(ESI):233.0[M+H]⁺

The third step

7-bromo-8-fluoro-2 ',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -4-one G2d

Pyrrolidine (658mg, 9.25mmol) was added to a solution of compound G2c (1.2G, 5.15mmol, 8056-005) in ethanol (15mL), the resulting yellow solution was stirred at 0 ℃ for 20 minutes, tetrahydropyran-4-one (770mg, 7.69mmol) was added, and the reaction solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution system: petroleum ether: ethyl acetate: 3:1) to obtain the title product G2d (1.2G, yield 74%). ¹H NMR(400MHz,CDCl₃):δ7.52(dd,1H),7.17(dd,1H),3.91-3.85(m,2H),3.82-3.77(m,2H),2.77(s,2H),2.03-1.98(m,2H),1.85-1.74(m,2H)。

MS m/z(ESI):315.0[M+H]⁺

The fourth step

(E) -7-bromo-8-fluoro-2 ',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -4-ketoxime G2e

To a solution of compound G2d (1.2G, 5.15mmol) in ethanol (20mL) were added sodium acetate (2.0G, 7.52mmol) and hydroxylamine hydrochloride (530mg, 7.63mmol), and the reaction mixture was heated to 90 ℃ and stirred for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50mL), washed with water (20mL × 3) and a saturated sodium chloride solution (20mL), dried, concentrated, and purified by silica gel column chromatography (elution system: petroleum ether: ethyl acetate: 4:1 to 2:1) to obtain the title product G2e (0.9G, yield: 72%).

MS m/z(ESI):333.0[M+H]⁺

The fifth step (E) -7-bromo-8-fluoro-2 ',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -4-one O-p-toluenesulfonyl oxime G2f

Triethylamine (827.54mg, 8.18mmol) and p-toluenesulfonic anhydride (1.33G, 4.09mmol) were added to a solution of compound G2e (0.9G, 2.7mmol) in dichloromethane (20mL), and the reaction was stirred at room temperature for 30 minutes. The reaction solution was diluted with dichloromethane (100mL), washed with water (30mL × 3) and saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (elution system: petroleum ether: ethyl acetate ═ 5:1) to give the title product G2f (1.15G, yield: 87%).

1H NMR(400MHz,CDCl₃):δ7.91(d,2H),7.43-7.35(m,3H),7.07(dd,1H),3.83-3.72(m,4H),2.91(s,2H),2.45(s,3H),1.83-1.76(m,2H),1.75-1.64(m,2H)。

The sixth step

8-bromo-9-fluoro-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -4(5H) -one G2G

To a solution of compound G2f (0.6G, 1.24mmol) in dichloromethane (20mL) at 0 ℃ was added aluminum trichloride (660.73mg, 4.96mmol) in portions, and the reaction solution was stirred at room temperature for 3 hours. The reaction was completed by LC-MS detection, the reaction was quenched with saturated sodium bicarbonate solution, adjusted to pH 2 with 1N hydrogen chloride solution, the organic phase was separated, the aqueous phase was extracted with dichloromethane (10mL X3), the combined organic phases were washed with saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution system: petroleum ether: ethyl acetate ═ 2:1) to give the title product G2G (270mg, yield: 66%).

¹H NMR(400MHz,DMSO-d₆):δ9.99(s,1H),7.43(dd,1H),6.83(dd,1H),3.78-3.70(m,4H),2.56(s,2H),1.81-1.77(m,4H)。

MS m/z(ESI):330.1[M+H]⁺

Seventh step

To a solution of intermediate G2G (250mg, 757.23. mu. mol) in dioxane (4mL) under nitrogen was added water (2mL), potassium carbonate (160.00mg, 1.51mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (55.00mg, 75.17. mu. mol) and intermediate Int-1(431.25mg, 1.06 mmol). The reaction mixture was stirred at 90 ℃ for 4 hours. LC-MS showed the reaction was complete. The reaction mixture was diluted with ethyl acetate (50 mL). The organic phase was washed with water (20 mL. times.2) and saturated sodium chloride solution. Drying, filtering and concentrating. The obtained residue was purified by silica gel column chromatography (eluent dichloromethane: methanol ═ 30:1) to obtain the title compound G2(110mg, yield 27%).

¹H NMR(400MHz,DMSO-d₆):δ10.71(s,1H),10.01(s,1H),8.99(d,1H),8.37(s,1H),8.19(d,1H),7.73(d,1H),7.68(s,1H),7.35(d,1H),7.08(t,1H),6.95(d,1H),3.79-3.70(m,4H),2.59(s,2H),2.13(s,3H),1.81(br,4H)。

¹⁹F NMR(376.5MHz,DMSO-d₆):δ-66.47(s,3F),-132.08(s,1F)。

MS m/z(ESI):530.2[M+H]⁺

Example G3

N- (3- (7-fluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) -4-methylphenyl) -2- (trifluoromethyl) isonicotinamide G3

First step of

3-bromo-4-fluorophenylacetate G3b

To a solution of 3-bromo-4-fluorophenol G3a (20G, 104.71mmol) in dichloromethane (300mL) were added triethylamine (13.75G, 136.13mmol) and acetyl chloride (11.76G, 115.18 mmol). The mixture was stirred at 15 ℃ for 3 hours. After completion of the reaction, the mixture was diluted with dichloromethane (200mL), the organic phase was washed with water (100mL × 2) and saturated sodium chloride solution (100mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give the title compound G3b (24G, 102.99mmol, yield: 98.35%).

¹H NMR(400MHz,CDCl₃):δ7.33(dd,1H),7.15-7.10(m,1H),7.05-7.00(m,1H),2.29(s,3H)。

Second step of

1- (4-bromo-5-fluoro-2-hydroxyphenyl) ethan-1-one G3c

To a solution of compound G3b (22G, 94.41mmol) in dichloromethane (200mL) was added aluminum trichloride (68.38G, 283.22mmol) in portions at 0 ℃. The mixture was stirred at 0 ℃ for 10 minutes, then the mixture was concentrated, heated at 150 ℃ and stirred for 3 hours. Cooled to 80 ℃ and ice (200g) and 10% hydrochloric acid (100mL) were added. The mixture was extracted with ethyl acetate (200 mL. times.3). The organic phases were combined, washed with saturated sodium chloride solution (200mL), and the collected organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give the title compound G3c (19G, 81.53mmol, yield 86.36%).

¹H NMR(400MHz,CDCl₃):δ12.03(s,1H),7.47(d,1H),7.24(d,1H),2.62(s,3H)。

The third step

7-bromo-6-fluoro-2 ',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -4-one G3d

Pyrrolidine (5.48G, 77.24mmol) was added to a solution of compound G3c (15G, 64.37mmol) in ethanol (75mL) and the resulting yellow solution was stirred at 0 deg.CAfter stirring for 20 minutes, tetrahydropyran-4-one (9.67g, 96.55mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 3:1) to give the title compound G3d (19.9G, 63.15mmol, yield 98.10%).¹H NMR(400MHz,CDCl₃):δ7.59(d,1H),7.30(d,1H),3.84-3.78(m,4H),2.74(s,2H),2.00-1.96(m,2H),1.83-1.75(m,2H)。

The fourth step

(E) -7-bromo-6-fluoro-2 ',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -4-ketoxime G3e

To a solution of compound G3d (17.9G, 56.80mmol) in ethanol (130mL) were added potassium carbonate (12.54G, 90.88mmol) and hydroxylamine hydrochloride (7.90G, 113.60mmol), and the mixture was heated at 90 ℃ for 3 hours. After completion of the reaction, the mixture was concentrated, and the residue was dissolved with ethyl acetate (500mL), washed with water (200 mL. times.3) and saturated sodium chloride solution (200mL), dried and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 4:1 to 2:1) to give the title compound G3e (16G, 48.46mmol, yield 85.32%).

MS m/z(ESI):332.0[M+H]⁺

The fifth step

(E) -7-bromo-6-fluoro-2 ',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -4-one-O-tosyloxime G3f

To a solution of compound G3e (16.8G, 50.89mmol) in dichloromethane (168mL) were added triethylamine (7.71G, 76.33mmol), 4-dimethylaminopyridine (620.81mg, 5.09mmol) and p-toluenesulfonic anhydride (19.93G, 61.06mmol), respectively. The mixture was stirred at room temperature for 30 minutes. The reaction solution was extracted with dichloromethane (500mL), washed with water (300 mL. times.2) and saturated sodium chloride solution (300mL), and the collected organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give the title compound G3f (23G, 47.49mmol, yield 93.32%).

MS m/z(ESI):486.0[M+H]⁺

The sixth step

8-bromo-7-fluoro-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -4(5H) -one G3G

To a solution of compound G3f (1.60G, 4.85mmol) in dichloromethane (60mL) was added aluminum trichloride (3.88G, 29.08mmol) in portions at 0 ℃ and stirred at room temperature for 3 hours. LC-MS detects the completion of the reaction. The reaction was quenched by addition of saturated sodium bicarbonate solution and adjusted to pH 2 by addition of 1N hydrochloric acid. The organic phase was separated, the aqueous phase was extracted with dichloromethane (30 mL. times.3), the organic layers were combined, washed with saturated sodium chloride solution (60mL), dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 2:1) to give the title compound G3G (230mg, 696.65 μmol, yield 14.37%).

MS m/z(ESI):330.0[M+H]⁺

Seventh step

Compound Int-1(147.64mg, 363.47. mu. mol), compound G3G (100mg, 302.89. mu. mol) and sodium carbonate (96.32mg, 908.68. mu. mol) were added sequentially to a mixed solution of 1, 4-dioxane (10mL) and water (2mL), followed by bis-triphenylphosphine palladium dichloride (49.60mg, 60.58. mu. mol) under nitrogen. The mixture was sealed and heated to 100 ℃ overnight. After completion of the reaction, insoluble solids were filtered and the filtrate was concentrated. The filtrate was concentrated to dryness and the crude product was purified by flash column chromatography (methanol: dichloromethane ═ 1:30) to give crude product (15mg) which was purified to give the title compound G3(3.8mg, 7.18 μmol, yield 2.37%).

¹H NMR(400MHz,CDCl₃):δ8.91-8.86(m,1H),8.36-8.32(m,1H),8.09-8.02(m,1H),7.93-7.76(m,2H),7.53-7.45(m,1H),7.28-7.25(m,1H),7.19-7.14(m,1H),6.93-6.74(m,2H),3.88-3.74(m,4H),2.58-2.54(m,2H),2.16-1.95(m,3H),1.96-1.89(m,2H),1.80-1.73(m,2H)。

MS m/z(ESI):530.3[M+H]⁺

Example G4

N- (3- (6-amino-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) -4-methylphenyl) -2- (difluoromethoxy) isonicotinamide G4

First step of

8-bromo 6-nitro-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -4(5H) -one G4a

Potassium nitrate (33mg, 320.35. mu. mol) was added to a solution of compound Int-1 in concentrated sulfuric acid (2mL) at 0 ℃. The mixture was stirred at 0 ℃ for 0.5 h. The mixture was filtered, the filter cake was washed with water, and the filter cake was dried to give the title compound G4a (89mg, 249.19. mu. mol, yield 77.79%).

MS m/z(ESI):357.2[M+1]⁺

Second step of

6-amino-8-bromo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -4(5H) -one G4b

After heating to 90 ℃ a mixture of compound G4a (560mg, 1.57mmol) and iron powder (1.75G, 31.36mmol) in methanol (20mL) was added dropwise hydrochloric acid (816.67mg, 7.84mmol, 35% purity) and stirred at 90 ℃ for 2 h. The mixture was cooled to room temperature and diluted with water. The mixture was extracted with ethyl acetate (10mL × 2), and the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was prepared by thin layer chromatography (ethyl acetate) to give the title compound G4b (64mg, 195.62 μmol, yield 12.48%). MS M/z (ESI) 327.0[ M +1 ]]⁺

The third step

Compound G4b (40mg, 123.00. mu. mol), Cs₂CO₃(120.30mg, 369.00. mu. mol) and compound F6e (60.00mg, 148.44. mu. mol) were added successively to a mixed solution of 1, 4-dioxane (3mL) and water (0.5mL), followed by addition of 1, 1-bis (diphenylphosphino) ferrocene dichloropalladium (40mg, 400.00mmol) under nitrogen, and the reaction was stirred with heating at 80 ℃ for 1 hour. Cold Cool to room temperature and quench with water (30 mL). The mixture was extracted with ethyl acetate (10mL × 3), and the organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the crude product by high performance liquid chromatography gave the title compound G4(13mg, 24.88. mu. mol, yield 20.23%).

¹H NMR(400MHz,DMSO-d₆):δ10.49(brs,1H),9.60(brs,1H),8.46(d,1H),7.74(t,J＝29.6Hz,1H),7.72(d,1H),7.55(s,1H),7.30(d,1H),6.55(s,1H),6.43(s,1H),4.47(brs,2H),3.73-3.63(m,4H),2.50(s,2H),2.09(s,3H),1.79-1.66(m,4H)。

¹⁹F NMR(376.5MHz,DMSO-d₆):δ-87.35。

MS m/z(ESI):525.3[M+H]⁺

Example G5

N- (4-fluoro-3- (7-fluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -2- (trifluoromethyl) isonicotinamide G5

First step of

N- (3-bromo-4-fluorophenyl) -2- (trifluoromethyl) pyridine-4-carboxamide G5b

2- (trifluoromethyl) Isonicotinic acid Int-L4a (5g, 26.16mmol) in N, N-dimethylformamide (30mL) was added 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (11.94g, 31.40mmol), stirred for 20 min, then 3-bromo-4-fluoroaniline (5.47g, 28.78mmol) and N, N-diisopropylethylamine (6.75g, 52.33mmol) were added and stirred at 30 ℃ for 2 h. The reaction solution was poured into water (60mL) and extracted with ethyl acetate (50 mL. times.3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified by silica gel column chromatography (dichloromethane: ethyl acetate ═ 20:1) to give the title compound G5b (5.5G, 15.15mmol, yield 57.89%).

¹H NMR(400MHz,CDCl₃):δ8.92(d,1H),8.08(s,1H),8.04(s,1H),7.95-7.90(m,2H),7.56-7.51(m,1H),7.15(t,1H)。

MS m/z(ESI):363.0[M+H]⁺

Second step of

N- [ 4-fluoro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] -2- (trifluoromethyl) pyridine-4-carboxamide G5c

To a solution of compound G5b (600mg, 1.65mmol) and pinacol diborate (630mg, 2.48mmol) in 1, 4-dioxane (10mL) were added 1, 1-bis (diphenylphosphino) ferrocene palladium dichloride (120.91mg, 165.24. mu. mol) and potassium acetate (324mg, 3.30mmol), and the reaction was stirred at 90 ℃ for 16 hours with nitrogen substitution. The mixture was diluted with water (50mL), extracted with ethyl acetate (40 mL. times.3), and the organic phases were combined, washed with saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (n-hexane: ethyl acetate ═ 5:1) to give the title compound G5c (600mg, 1.66mmol, yield 88.0%).

MS m/z(ESI):411.1[M+H]⁺

The third step

To a solution of compound G3G (130mg, 393.76. mu. mol) in 1, 4-dioxane (10mL) was added water (2mL), sodium carbonate (125.22mg, 1.18mmol) and 1, 1-bis (diphenylphosphino) ferrocene dichloropalladium (64.47mg, 78.75. mu. mol) in that order, followed by compound G5c (191.94mg, 472.51. mu. mol) and stirred at 90 ℃ for 4 hours under nitrogen. The completion of the reaction was monitored by LC-MS. The mixture was extracted with ethyl acetate (50mL), the organic phases were washed with water (20 mL. times.2) and saturated sodium chloride solution (20mL), the organic phases were combined, washed with anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified by silica gel column chromatography (dichloromethane: methanol ═ 30:1) to give the title compound G5(33mg, 61.86 μmol, yield 15.71%).

¹H NMR(400MHz,CDCl₃):δ8.88(br,1H),8.05(s,1H),7.88(br,1H),7.87(br,2H),7.67-7.60(m,2H),7.05(d,1H),6.79(d,1H),3.89-3.75(m,4H),2.51(s,2H),1.96-1.92(m,2H),1.80-1.74(m,2H)。

MS m/z(ESI):534.2[M+H]⁺

Example G6

N- (3- (6-methoxy-5-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ f ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) -4-methylphenyl-2- (trifluoromethyl) isonicotinamide G6

First step of

1- (4-bromo-2, 6-dimethoxyphenyl) ethanone G6b

A solution of 1-bromo-3, 5-methoxybenzene G6a (6.5G, 30.0mmol) in dichloromethane (50mL) was added dropwise to a solution of aluminum trichloride (4.8G, 35.6mmol) in dichloromethane (50mL) at 0 deg.C, stirred at room temperature for 16 hours, and quenched with water (50mL) at 0 deg.C. The aqueous phase was extracted with dichloromethane (50mL) and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (n-hexane/ethyl acetate eluent) to give the title compound G6b (2.5G) in 32% yield.

¹H NMR(400MHz,CDCl₃):δ6.72(s,2H),3.80(s,6H),2.45(s,3H)。

Second step of

1- (4-bromo-2-hydroxy-6-methoxyphenyl) ethanone G6c

Compound G6b (1.64G, 6.33mmol) was dissolved in dichloromethane (20mL), cooled to-30 deg.C, boron tribromide (6.98mL, 6.98mmol, 1M in DCM) was added slowly and stirred at-30 deg.C for 3 h. Quench at 0 deg.C with slow water (45 mL). The aqueous phase was extracted with dichloromethane (50mL) and the organic phase was dried over anhydrous sodium sulfate. Filtration and concentration gave the crude product which was purified by silica gel column chromatography (n-hexane/ethyl acetate eluent system) to give the title compound G6c (1.45G) in 93% yield.

MS m/z(ESI):245.0[M+1]⁺

The third step

7-bromo-5-methoxy-2 ',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -4-one G6d

Pyrrolidine (60mg, 0.61mmol) was added to a solution of compound G6c (1.4G, 5.71mmol) and tetrahydro-4H-pyran-4-one (0.58G, 5.79mmol) in methanol (30mL) at 0 deg.C, slowly warmed to room temperature, and stirred for 24H. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate (50mL), 1N hydrochloric acid (30mL) was added, and the mixture was stirred for 30 minutes. The organic phase was washed with water and saturated sodium chloride solution and dried over anhydrous sodium sulfate. Filtration and concentration gave the crude product which was purified by silica gel column chromatography (n-hexane/ethyl acetate eluent system) to give the title compound G6d (1.46G) in 78% yield.

MS m/z(ESI):327.0[M+1]⁺

The fourth step

(Z) -7-bromo-5-methoxy-2 ',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -4-ketoxime G6e

Compound G6d (0.75G, 2.29mmol), hydroxylamine hydrochloride (0.25G, 3.60mmol) and sodium acetate (0.375G, 4.57mmol) were added successively to a methanol (20mL) solution, and the reaction was refluxed for 2 hours. Cool to room temperature and add water (35 mL). The aqueous phase was extracted with ethyl acetate (50mL), and the organic phase was collected and dried over anhydrous sodium sulfate. Filtration and concentration gave the crude title compound, G6e (750mg), in 95% yield.

MS m/z(ESI):342.0[M+1]⁺

The fifth step

8-bromo-6-methoxy-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ f ] [1,4] oxazepin-2, 4' -pyran ] -5(4H) -one G6f

To a solution of compound G6e (250mg, 0.73mmol) in toluene (25mL) was added polyphosphoric acid (1.0G, 3.65mmol), the reaction was refluxed for 12 hours, and cooled to room temperature. Water (35mL) was added, the aqueous phase was extracted with ethyl acetate (35mL), and the organic phase was collected, washed successively with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Filtration and concentration gave the crude product which was purified by silica gel column chromatography (n-hexane/ethyl acetate eluent system) to give the title compound G6f (120mg) in 48% yield.

MS m/z(ESI):342.0[M+1]⁺

The sixth step

N- (3- (6-methoxy-5-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ f ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) -4-methylphenyl) -2- (trifluoromethyl) isonicotinamide G6

To a solution of compound G6f (80mg, 0.233mmol) in 1, 4-dioxane (15mL) were added, followed by intermediate Int-1(100mg, 0.246mmol), sodium carbonate solution (2M, 0.236mL) and 1, 1-bis (diphenylphosphino) ferrocene dichloropalladium (17mg, 0.023mmol), replaced 3 times with argon, and refluxed for 2 hours. The mixture was cooled to room temperature and the solids were removed by filtration through celite. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol elution system) to give the title compound G6(50mg) in 39% yield.

¹H NMR(400MHz,CDCl₃):δ10.04(s,1H),8.81(d,1H),8.32(s,1H),8.09(d,1H),7.95(d,1H),7.38(s,1H),7.28-7.23(m,2H),6.59(s,1H),6.48(s,1H),3.92-3.89(m,2H),3.87-3.80(m,2H),3.77(s,3H),3.09(d,2H),2.23(s,3H),1.85-1.82(m,2H),1.61-1.55(m,2H)。

MS m/z(ESI):542.2[M+1]⁺

Example G7

N- (4-fluoro-3- (9-fluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -2- (trifluoromethyl) isonicotinamide G7

To a solution of compound G2G (150mg, 454.34. mu. mol) in 1, 4-dioxane (3mL) were added water (1mL), sodium carbonate (96.31mg, 908.68. mu. mol), and 1, 1-bis (diphenylphosphino) ferrocene dichloropalladium (33.26mg, 45.43. mu. mol), followed by compound G5c (186.36mg, 454.34. mu. mol), nitrogen substitution 3 times, and heating at 80 ℃ for 4 hours. After completion of the reaction, the mixture was extracted with ethyl acetate (50mL), and the organic phase was washed with water (20 mL. times.3) and saturated sodium chloride solution (20 mL. times.2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 4:1 to 2:1) to give the title compound G7(47mg, yield 19%).

¹H NMR(400MHz,DMSO-d₆):δ10.82(s,1H),10.05(s,1H),9.01(d,1H),8.37(s,1H),8.20(d,1H),7.90-7.85(m,2H),7.39(t,1H),7.21(t,1H),6.98(d,1H),3.82-3.70(m,4H),2.60(s,2H),1.83-1.81(m,4H)。

¹⁹F NMR(376.5MHz,DMSO-d₆):δ-66.47(s,3F),-119.50(d,1F),-131.60(d,1F)。MS m/z(ESI):534.0[M+H]⁺

Example H1

N- (4-fluoro-3- (5-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ f ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -2- (trifluoromethyl) isonicotinamide H1

To a mixture of compound Int-5(200mg, 640.70. mu. mol) and compound G5c (394.19mg, 961.05. mu. mol) in 1, 4-dioxane (2mL) and water (0.4mL) were added 1, 1-bis (diphenylphosphino) ferrocene palladium dichloride (46.84mg, 64.07. mu. mol) and sodium bicarbonate (107.65mg, 1.28mmol), and the reaction was stirred at 90 ℃ for 2 hours. The mixture was poured into water (30mL) and the aqueous phase was extracted with ethyl acetate (20 mL. times.3). The organic phases were collected, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was prepared by high performance liquid chromatography to give the title compound H1(109mg, 211.46 μmol, yield 33.01%).

¹H NMR(400MHz,DMSO-d6):δ10.82(s,1H),9.02(d,1H),8.47-8.44(m,1H),8.38(s,1H),8.22(d,1H),7.95(d,1H),7.86(d,1H),7.71(d,1H),7.43-7.37(m,2H),7.19(s,1H),3.85-3.79(m,2H),3.74-3.70(m,2H),3.10(d,2H),1.81-1.76(m,2H),1.66-1.63(m,2H)。

¹⁹F NMR(376.5MHz,DMSO-d6):δ-66.46,-122.42。

MS m/z(ESI):516.3[M+H]⁺

Example H2

N- (4-fluoro-3- (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -2- (trifluoromethyl) isonicotinamide H2

Potassium carbonate (101.10mg, 731.52. mu. mol) was added to a mixture of compound G5b (200mg, 487.68. mu. mol), compound Int-4(210.22mg, 585.22. mu. mol) and bis (diphenylphosphino) ferrocene dichloropalladium (II) (71.30mg, 97.54. mu. mol) in 1, 4-dioxane (4mL), and the reaction was stirred at 100 ℃ for 16 hours. The completion of the reaction was monitored by TLC (n-hexane: ethyl acetate ═ 1: 1). The mixture was diluted with water (40mL) and dichloromethane (40mL), the organic phases were collected, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography (n-hexane: ethyl acetate ═ 1:1) to give the title compound H2(65mg, 126.10 μmol, yield 25.86%).

¹H NMR(400MHz,DMSO-d₆):δ10.79(s,1H),9.89(s,1H),9.01(d,1H),8.38(s,1H),8.21(d,1H),7.92(dd,1H),7.84-7.80(m,1H),7.39-7.33(m,2H),7.23(s,1H),7.15(d,1H),3.83-3.78(m,2H),3.72-3.69(m,2H),2.51(s,2H),1.86-1.82(m,2H),1.79-1.75(m,2H)。

MS m/z(ESI):516.2[M+1]⁺

Example H3

2- (difluoromethoxy) -N- (4-fluoro-3- (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) isonicotinamide H3

First step of

8- (5-amino-2-fluorophenyl) -2',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -4(5H) -one H3a

Compound Int-1(150.00mg, 417.57. mu. mol), 3-bromo-4-fluoro-aniline (79.34mg, 417.57. mu. mol) and sodium carbonate (88.52mg, 835.13. mu. mol) in a mixture of 1, 4-dioxane (1mL) and water (0.25mL) was added bis triphenylphosphine palladium dichloride (14.65mg, 20.88. mu. mol), under nitrogen, and heated at 100 ℃ overnight. After completion of the reaction, the solvent was removed in vacuo, and the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane ═ 1:5) to give the title compound H3a (110mg, yield 77%).

MS m/z(ESI):343.1[M+H]⁺

Second step of

To a solution of 2- (difluoromethoxy) pyridine-4-carboxylic acid (53.03mg, 280.40. mu. mol) in N, N-dimethylformamide (5mL) were added N, N ' -diisopropylethylamine (45.30mg, 350.50. mu. mol) and 2- (7-azabenzotriazole) -N, N, N ', N ' -tetramethyluronium hexafluorophosphate (106.62mg, 280.40. mu. mol), stirred for 0.5H, then compound H3a (80mg, 233.67. mu. mol) was added, and stirred at room temperature overnight. After the reaction was completed, water and ethyl acetate were added for extraction. The aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The crude product was purified by silica gel column chromatography (methanol: dichloromethane ═ 1:100) to give the title compound H3(43mg, yield 36%).

¹H NMR(400MHz,DMSO-d₆):δ10.62(s,1H),9.87(s,1H),8.48(d,1H),7.92-7.90(m,1H),7.79-7.77(m,2H),7.77-7.72(m,1H),7.59(d,1H),7.40-7.29(m,2H),7.22(s,1H),7.15(d,1H),3.83-3.78(m,2H),3.72-3.69(m,2H),2.52(s,2H),1.86-1.83(m,2H),1.79-1.73(m,2H)。

MS m/z(ESI):514.3[M+H]⁺

The following compounds were prepared by the methods and general procedures described above in examples H1, H2, H3, substituted with the appropriate aryl carboxylic acid, aryl bromide, or aryl pinacol boronate ester intermediates, as described in the previous schemes and examples. The necessary starting materials can be purchased commercially, or obtained by working up as described in the literature, or synthesized by a person skilled in the art of organic synthesis from commercially available reagents using conventional reactions.

Example H48

N- (4- (difluoromethyl) -3- (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -6- (trifluoromethyl) pyridazine-3-carboxamide H48

First step of

2-bromo-4-nitrobenzoic acid H48b

BH is reacted at 0 ℃ under an argon atmosphere for 0.5 h₃THF (1N, 8mL) was added to a solution of compound H48a (1g, 4.06mmol) in THF (5 mL). The mixture was stirred at 50 ℃ for 5 hours. The resulting mixture was poured into NH₄Cl (20mL), extracted with EtOAc (10 mL. times.3). The organic solution was washed with brine (20 mL. times.2) and Na₂SO₄Dried and concentrated. The residue was purified by silica gel chromatography (EtOAc/hexane ═ 1/10) to give the desired product H48b (600mg, yield: 63.6%).

¹H NMR(400MHz,DMSO-d₆):δ8.38(d,1H),8.29(dd,1H),7.80(d,1H),5.80(t,1H),4.59(d,2H).

Second step of

8- (2- (hydroxymethyl) -5-nitrophenyl) -2',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -4(5H) -one H48c

Pd(dppf)Cl₂(122mg, 167. mu. mol) and Na₂CO₃(354mg, 3.34mmol) was added to a solution of Int-4(600mg, 1.67mmol) and H48b (465mg, 2.00mmol) in 1, 4-dioxane (6mL) and water (1.2 mL). The mixture was stirred at 100 ℃ for 5 h. The mixture was then poured into water (15mL) and the aqueous phase extracted with EtOAc (10 mL. times.3). The organic phase is passed through Na₂SO₄Dried, filtered and concentrated. The residue was purified by silica gel chromatography (EtOAc/hexane: 1/4) to give the desired product H48c (330mg, yield: 51.4%).

LCMS:MS m/z(ESI):385.0[M+H]⁺

The third step

4-Nitro-2- (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) benzaldehyde H48d

At room temperature, adding MnO₂(452.4mg, 5.20mmol) CH to H48c (200mg, 520, 3. mu. mol)₂Cl₂(2mL) in solution. The mixture was stirred at room temperature overnight. The reaction mixture was filtered and the filter cake was washed with CH₂Cl₂And (6) washing. The filtrate was concentrated to give the objective product H48d (181mg, yield: 90.5%).

LCMS:MS m/z(ESI):383.0[M+H]⁺

The fourth step

8- (2- (difluoromethyl) -5-nitrophenyl) -2',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -4(5H) -one H48e

DAST (539.01mg, 2.35mmol) was added to H48d (180mg, 470.75. mu. mol) in CH₂Cl₂(2mL) in solution. The mixture was stirred at room temperature for 14 hours. The resulting mixture was poured into water (3mL) and extracted with EtOAc (5 mL. times.2). The organic solution was washed with brine (5 mL. times.2) and Na₂SO₄Dried and concentrated. The residue was purified by HPLC to give the target H48e (47mg, 24.7% yield). LCMS MS M/z (ESI) 405.0[ M + H ]]⁺

The fifth step

8- (5-amino-2- (difluoromethyl) phenyl) -2',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -4(5H) -one H48f

Pd/C (8mg, 65.87. mu. mol) was added to a solution of H48e (40mg, 98.92. mu. mol) in MeOH (2 mL). The mixture was stirred at room temperature for 5 hours. The mixture was filtered and the filter cake was washed with MeOH (5 mL). The filtrate was concentrated, and the residue was purified by HPLC to give the objective product H48f (15mg, 40.07. mu. mol, yield: 40.50%).

The sixth step

Mixing H48f (25.34mg, 67.67. mu. mol), HATU (51.46mg, 135. mu. mol)35 μmol) and DIPEA (17.49mg, 135.35 μmol) were added to a mixture of 6- (trifluoromethyl) pyridazine-3-carboxylic acid (13mg, 67.67 μmol) in THF (2 mL). The mixture was stirred at room temperature for 2 h. The resulting mixture was poured into water (4mL) and extracted with EtOAc (5 mL. times.2). The organic solution was washed with brine (5 mL. times.2) and Na₂SO₄Dried and concentrated. The residue was purified by preparative HPLC to give the objective product H48(15mg, yield: 40.4% yield).

¹H NMR(400MHz,DMSO)δ11.53(s,1H),9.86(s,1H),8.60-8.53(m,2H),8.15(d,1H),8.05(s,1H),7.77(d,1H),7.14(s,2H),7.07(s,1H),6.82(t,1H),3.82-3.69(m,4H),2.51(s,2H),1.85-1.72(m,4H).

LCMS:MS m/z(ESI):549.1[M+H]⁺.

Example 49

6- (Difluoromethoxy) -N- [3- [ 4-oxo-5- (Trideuteromethyl) ] spiro [3H-1, 5-oxazepine-2, 4' -tetrahydropyran ]

-8-yl ] phenyl ] pyridine-3-carboxamide H49

First step of

1- (methyl-d)₃) -4-Nitrophenyl H49b

Will (t-Bu)₂MePPdG₂(7mg, 24.09. mu. mol) and t-BuOK (108mg, 963.58. mu. mol) were added to a mixture of 4,4,5, 5-tetramethyl-2- (4-nitrophenyl) -1,3, 2-dioxaborane H49a (200mg, 802.99. mu. mol) in tert-amyl alcohol (3.5 mL). Under the protection of argon, then the CD is put at room temperature₃I (232.80mg, 1.61mmol) was added to the mixture. The mixture was stirred at 65 ℃ for 18 h. The mixture was poured into water (3mL) and the aqueous phase was treated with Et ₂O (3 mL. times.3) extraction. The organic phase is then washed with Na₂SO₄Dried, filtered and concentrated. The residue was purified by silica gel chromatography (hexane) to give H49b (56mg, yield: 49.8%).

¹H NMR(400MHz,DMSO):8.12(d,2H),7.32(d,2H).

Second step of

2-bromo-1- (methyl-d)₃) -4-Nitrophenyl H49c

1, 3-dibromo-5, 5-dimethylhydantoin (2.45g, 8.56mmol) and methanesulfonic acid (2.74g, 28.54mmol) were added to CHCl in H49b (2.0g, 14.27mmol)₃(45 mL). The mixture was stirred at 65 ℃ for 6 h. The mixture was poured into water (5mL) and the aqueous phase was washed with CH₂Cl₂(10 mL. times.3). The organic phase was washed with brine (5 mL. times.2) and Na₂SO₄Drying, filtration and concentration gave crude H49c (2.3g, 73.58% yield), which was used without further purification.

The third step

3-bromo-4- (methyl-d)₃) Phenylamine H49d

Reacting NH₄Cl (5.72g, 105.0mmol) and Fe (2.94g, 52.5mmol) were added to a solution of H49c (2.3g, 10.50mmol) in EtOH (25 mL). The mixture was stirred at 95 ℃ for 6 h. The mixture was filtered and the filter cake was washed with EtOAc (40 mL). The organic phase was then washed with brine (20 mL. times.2) and Na₂SO₄Dried, filtered and concentrated. The residue was purified by silica gel chromatography (EtOAc/hexane ═ 1/10) to give H49d (1.9g, yield: 95.7%).

The fourth step

8- [ 5-amino-2- (trideuteromethyl) phenyl ] spiro [3, 5-dihydro-1, 5-oxazepine-2, 4' -tetrahydropyran ] -4-one H49e

In N₂Next, Int-4(125mg, 349.08. mu. mol), H49d (60mg, 317.35. mu. mol), Cs were added at 105 ℃ to₂CO₃(310mg, 952.04. mu. mol) and Pd (dppf) Cl₂(52mg, 63.47. mu. mol) in 1mL of water) and dioxane (5mL) for 4 hours. The reaction mixture was cooled to room temperature. Water (100mL) was added, and the mixture was extracted with EtOAc (100 mL. times.3). The organic phases were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated by rotary evaporator. The residue was purified by silica gel Chromatography (CH)₂Cl₂MeOH: 15: 1) to give H49e (95mg, yield: 87.68%). LCMS MS M/z (ESI) 342.2[ M + H ]]⁺

The fifth step

6- (difluoromethoxy) -N- [3- [ 4-oxo-5- (Trideuteromethyl) ] spiro [3H-1, 5-oxazepine-2, 4' -tetrahydropyran ] -8-yl ] phenyl ] pyridine-3-carboxamide H49

HATU (55mg, 145.41. mu. mol) was added to a solution of 6- (difluoromethoxy) nicotinic acid (25mg, 132.19. mu. mol), H49e (45mg, 132.19. mu. mol) and DIEA (51mg, 396.58. mu. mol) in DMF (1mL) at room temperature. The resulting solution was then stirred at room temperature for 4 hours. Water (50mL) was added, and the mixture was extracted with EtOAc (50 mL. times.3). The organic phases were combined and washed with anhydrous Na ₂SO₄Dried, filtered and concentrated by rotary evaporator. The residue was purified by preparative HPLC to give the objective product H49(45mg, yield: 66.42%).¹H NMR(400MHz,DMSO-d₆):δ10.38(s,1H),9.81(s,1H),8.82(s,1H),8.45-8.40(m,1H),7.81(t,1H),7.70-7.63(m,2H),7.31-7.23(m,2H),7.13-7.10(m,2H),7.03(s,1H),3.82-3.67(m,4H),2.54(s,2H),1.85-1.74(m,4H).

¹⁹F NMR(376.5MHz,DMSO):δ-87.78.

LCMS:MS m/z(ESI):513.2[M+H]⁺.

Examples H50 and H51 were prepared using the methods previously described and the general method described in example H49, but with the appropriate aryl carboxylic acid substituted in step 5 as described in the previous schemes and examples. The necessary starting materials are commercially available, synthesized using conventional reactions from commercially available reagents using conventional reactions, readily described in the literature or by those skilled in the art of organic synthesis, without undue experimentation.

Example H50

N- (4- (methyl-d)₃) -3- (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazepine-2, 4' -pyrans]-8-yl) phenyl) -5- (trifluoromethyl) pyridazine-3-carboxamide H50

¹H NMR(400MHz,DMSO-d₆):δ11.26(s,1H),9.97(d,1H),9.82(s,1H),8.58(d,1H),7.88(d,2H),7.33(d,1H),7.22–7.07(m,2H),7.06(d,1H),3.91–3.60(m,4H),2.53(s,2H),1.95–1.66(m,4H).

LCMS:MS m/z(ESI):516.2[M+H]⁺.

Example H51

N- (4- (methyl-d)₃) -3- (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazepine-2, 4' -pyrans]-8-yl (phenyl) -6- (trifluoromethoxy) nicotinamide H51

¹H NMR(400MHz,DMSO-d₆)δ10.47(s,1H),9.82(s,1H),8.90(d,1H),8.51(dd,1H),7.80–7.60(m,2H),7.47(d,1H),7.30(d,1H),7.19–6.94(m,3H),3.95–3.64(m,4H),2.54(s,2H),1.93–1.62(m,4H).

LCMS:MS m/z(ESI):531.2[M+H]⁺.

Example J1

N- (4-methyl-3- (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -2- (trifluoromethyl) isonicotinamide J1

Potassium phosphate (7.07g, 33.3mmol) was added to a mixed solution of compound Int-1(5.18g, 12.7mmol) and compound Int-3(3.46g, 11.1mmol) in 1, 4-dioxane-water (50mL-5.0 mL). The nitrogen was replaced twice. 1, 1-bis (diphenylphosphino) ferrocene dichloropalladium (10 mol%, 906mg, 1.11mmol) was added under nitrogen protection and heated at 90 ℃ for 1.5 hours. The reaction was cooled to room temperature, diluted with ethyl acetate (100mL) and water (40mL), and filtered to remove insoluble solids. The ethyl acetate layer was collected, and the aqueous phase was extracted with ethyl acetate (100 mL. times.2). The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a crude product The product was purified by silica gel column chromatography (ethyl acetate: n-hexane: 0 to 60%) to give the title compound J1(4.68g) in 82.7% yield.¹HNMR(400MHz,CD₃OD),δ8.92(d,1H),8.32(s,1H),8.14(d,1H),7.66(s,1H),7.64(d,1H),7.33(d,1H),7.15(s,2H),7.10(s,1H),3.98(t,2H),3.84-3.82(m,2H),2.60(s,2H),2.30(s,3H),2.03-2.00(m,2H),1.89-1.84(m,2H)。

MS m/z(ESI):512.0[M+1]⁺

Example J2

N- (4-methyl-3- (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -2- (trifluoromethyl) piperidine-4-carboxamide J2

Compound J1(44mg, 0.086mmol) was dissolved in the mixed solvent ethanol-tetrahydrofuran (6mL-1mL) and Pd/C (10 mol%) was added under nitrogen. The reaction solution was replaced with hydrogen twice and reacted overnight under hydrogen atmosphere at room temperature. After the reaction was completed, hydrogen was replaced twice. The mixture was filtered through a layer of silica gel, washed with ethyl acetate (40mL), and the filtrate was concentrated to give crude J2(38.4mg, 86% yield) as the title compound.

¹HNMR(400MHz,DMSO-d₆),δ9.83(s,1H),9.72(s,1H),7.42(s,2H),7.12(d,1H),7.00(s,2H),6.91(s,1H),3.75-3.72(m,2H),3.70-3.63(m,2H),3.25-3.19(m,1H),3.00-2.97(m,1H),2.53-2.50(m,3H),2.10(s,3H),1.81-1.70(m,6H),1.40-1.38(m,2H),1.17(s,1H)。

MS m/z(ESI):518.0[M+1]⁺

Example J3

N- (4-methyl-3- (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -5- (trifluoromethyl) pyridazine-3-carboxamide J3

First step of

8- (5-amino-2-methylphenyl) -2',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -4(5H) -one J3a

To a solution of compound Int-3(1.5g, 4.81mmol) in 1, 4-dioxane (20mL) were added water (10mL), sodium carbonate (1.02g, 9.61mmol), 1-bis (diphenylphosphino) ferrocene palladium dichloride (350.00mg, 478.14. mu. mol) and 4-methyl-3- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -aniline (1.34g, 5.77mmol), and the reaction was stirred at 90 ℃ for 4 hours under nitrogen. The reaction was cooled and extracted with ethyl acetate (30mL), the organic phase was collected, washed with water (10mL × 3) and saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting crude product was purified by silica gel column chromatography (dichloromethane: methanol ═ 30:1) to give the title compound J3a (1.6g, yield 98%).

¹H NMR(400MHz,CDCl₃):δ7.64(s,1H),7.08-7.01(m,4H),6.64(dd,1H),6.58(d,1H),3.95-3.92(m,2H),3.85-3.77(m,2H),3.62(brs,2H),2.59(s,2H),2.15(s,3H),2.04-2.00(m,2H),1.87-1.79(m,2H)。

MS m/z(ESI):339.1[M+H]⁺

Second step of

Compound J3a (140mg, 413.71. mu. mol), 5- (trifluoromethyl) pyridazine-3-carboxylic acid (70mg, 64.48. mu. mol), 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (235.96mg, 620.57. mu. mol) and triethylamine (125.59mg, 1.24mmol) were added to N, N-dimethylformamide (5mL), respectively, and the mixture was stirred at room temperature for 12 hours. The completion of the reaction was monitored by LC-MS. Extraction with ethyl acetate (20mL), collection of the organic phase, washing with saturated sodium chloride solution, drying and concentration gave crude product which was prepared by thin layer chromatography (ethyl acetate) to give the title compound J3(93mg, 181.47. mu. mol, yield 43.86%).

¹H NMR(400MHz,DMSO-d₆):δ11.26(s,1H),9.96(d,1H),9.82(s,1H),8.57(d,1H),7.88(d,1H),7.86(s,1H),7.31(d,1H),7.17-7.09(m,2H),7.05(d,1H),3.81-3.78(m,2H),3.72-3.68(m,2H),2.50(s,2H),2.25(s,3H),1.87-1.74(m,4H)。

¹⁹F NMR(376.5MHz,DMSO-d₆):δ-63.08。

MS m/z(ESI):513.2[M+H]

The following compounds were prepared by the methods and general procedures described above in the syntheses of examples J1 and J3, substituting the appropriate aryl carboxylic acid in the amide coupling reaction and the appropriate aryl pinacol boronic ester intermediate in the Suzuki coupling reaction, as described in the previous schemes and examples. The necessary starting materials can be purchased commercially, or obtained by working up as described in the literature, or synthesized by a person skilled in the art of organic synthesis from commercially available reagents using conventional reactions.

Example K1

1- (2-fluoro-4-methyl-5- (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -3- (2- (trifluoromethyl) pyridin-4-yl) urea K1

First step of

Phenyl (5-bromo-2-fluoro-4-methylphenyl) carbamate K1a

A solution of 5-bromo-2-fluoro-4-methylaniline Int-K20f (1.0g, 4.90mmol) and pyridine (426.44mg, 5.39mmol) in dichloromethane (20mL) was cooled to 0 deg.C and phenyl chloroformate (844.07mg, 5.39mmol) was added dropwise. The reaction was stirred at room temperature for 4 h, then diluted with dichloromethane (100mL), the mixture was washed with saturated ammonium chloride solution (30mL), saturated sodium chloride solution (30mL), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title product, crude K1a (1.6 g).

MS m/z(ESI):324.2[M+H]⁺

Second step of

1- (5-bromo-2-fluoro-4-methylphenyl) -3- (2- (trifluoromethyl) pyridin-4-yl) urea K1b

Compound K1a (324mg, 1.0mmol), 2- (trifluoromethyl) pyridin-4-ylamine Int-K20a (194.45mg, 1.20mmol) and 4-dimethylaminopyridine (122mg, 1.0mmol) were added to N, N-dimethylformamide (5mL) and the mixture was heated to 100 ℃ for 30 min. The reaction solution was diluted with water (40mL), the mixture was extracted with ethyl acetate (50mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (20mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated, and the resulting residue was purified by silica gel column chromatography (elution system: petroleum ether: ethyl acetate: 1/10-1/2) to give the title product K1b (310mg, yield: 79.1%).

MS m/z(ESI):392.1[M+1]⁺

The third step

To a solution of compound K1b (200mg, 510.01. mu. mol) in 1, 4-dioxane (4mL) was added water (2mL) and sodium carbonate (108.11mg, 1.02mmol), followed by the addition of compound Int-4(220mg, 612.43. mu. mol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (37.33mg, 51.00. mu. mol), nitrogen substitution was carried out three times, and the reaction mixture was heated to 80 ℃ and stirred for 4 hours. The reaction solution was diluted with ethyl acetate (40mL), the organic phase was washed with water (20mL × 2) and a saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution system: dichloromethane: methanol ═ 40:1) to give the title product K1(68mg, yield: 24%).

¹H NMR(400MHz,DMSO-d₆):δ9.81(d,2H),8.84(s,1H),8.53(d,1H),8.06(d,1H),7.90(d,1H),7.52(dd,1H),7.23(d,1H),7.12-7.06(m,2H),7.00(s,1H),3.83-3.74(m,2H),3.70-3.66(m,2H),2.50(s,2H),2.20(s,3H),1.87-1.69(m,4H)。

¹⁹F NMR(377MHz,DMSO-d₆):δ-66.93(s,3F),-130.87(s,1F)。

MS m/z(ESI):545.0[M+H]⁺

Example K2

N- (4-methyl-3- (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -2- (trifluoromethyl) pyridine-4-sulfonamide K2

First step of

4- (benzylthio) -2- (trifluoromethyl) pyridine K2b

To a solution of 4-chloro-2- (trifluoromethyl) pyridine K2a (500mg, 2.75mmol) in 1, 4-dioxane (3mL) were added N, N-diisopropylethylamine (712mg, 5.51mmol),4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene (162mg, 279.98. mu. mol) and dibenzylideneacetone dipalladium (Pd) ₂(dba)₃128mg, 139.78. mu. mol), then phenylmethylthiol (600mg, 4.83mmol) was added, nitrogen gas was substituted three times, and the reaction mixture was heated to 100 ℃ and stirred for 1 hour. The reaction mixture was diluted with methanol (30mL), insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution system: petroleum ether: ethyl acetate: 10:1) to give the title product K2b (700mg,yield: 94%).

¹H NMR(400MHz,CDCl₃)δ8.46(d,1H),7.49(d,2H),7.43-7.26(m,3H),7.26-7.11(m,2H),4.26(s,2H)。

Second step of

2- (trifluoromethyl) pyridine-4-sulfonyl chloride K2c

To a solution of compound K2b (300mg, 1.11mmol) in acetic acid (8mL) were added water (3mL) and N-chlorosuccinimide (885mg, 6.63mmol), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was diluted with water (30mL), concentrated under reduced pressure to remove the organic solvent, the aqueous solution was basified with saturated sodium carbonate solution, extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product K2c (350mg), which was directly subjected to the next reaction without purification.

The third step

N- (3-bromo-4-methylphenyl) -2- (trifluoromethyl) pyridine-4-sulfonamide K2d

Compound K2c (350mg, 1.43mmol) in dichloromethane (5mL) was added pyridine (225.44mg, 2.85mmol) and 3-bromo-4-methylaniline Int-J10c (265.13mg, 1.43mmol) and the reaction was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution system: petroleum ether: ethyl acetate: 6:1) to obtain the title product K2d (350mg, yield: 62%).

MS m/z(ESI):394.8[M+H]⁺

The fourth step

To a solution of compound K2d (150mg, 379.56. mu. mol) in 1, 4-dioxane (3mL) was added water (1.5mL) and sodium carbonate (80mg, 754.80. mu. mol), 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (30mg, 40.98. mu. mol), followed by compound Int-4(165mg, 461.86. mu. mol), the reaction was replaced with nitrogen gas three times, and the reaction was heated to 80 ℃ and stirred for 4 hours. The reaction solution was diluted with ethyl acetate (50mL), the organic phase was washed with water (20 mL. times.3) and a saturated sodium chloride solution (20 mL. times.2) in succession, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative high performance liquid chromatography to give the title product K2(32mg, yield: 15%).

¹H NMR(400MHz,DMSO-d₆):δ9.79(s,1H),9.00(d,1H),8.02(s,1H),7.95(d,1H),7.16(d,1H),7.05(d,1H),7.01-6.91(m,2H),6.84(dd,2H),3.82-3.73(m,2H),3.72-3.65(m,2H),2.48(s,2H),2.12(s,3H),1.81-1.67(m,4H)。

¹⁹F NMR(376.5MHz,DMSO-d₆):δ-66.84(s,3F)。

MS m/z(ESI):548.1[M+H]⁺

Example K3

8- (2-methyl-5- ((8- (trifluoromethyl) quinazolin-4-yl) amino) phenyl) -2',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -4(5H) -one K3

First step of

8- (trifluoromethyl) quinazoline-4-ol K3b

2-amino-3- (trifluoromethyl) benzoic acid K3a (5.40g, 26.32mmol) and formamide (15mL) were heated to 150 ℃ with stirring for 45 minutes and then to 175 ℃ with stirring for 70 minutes. The reaction was cooled to room temperature, then diluted with water (100mL), the reaction was filtered, the filter cake was rinsed with water (50mL), the filter cake was collected and dried under vacuum to give the title product K3b (2.0g, yield: 35.48%).

MS m/z(ESI):215.2[M+1]⁺

Second step of

4-chloro-8- (trifluoromethyl) quinazoline K3c

A mixture of compound K3b (800mg, 3.74mmol) and phosphorus oxychloride (15.2mL) was warmed to 100 ℃ and stirred for 4 hours. The reaction solution was poured into ice water (100mL), extracted with ethyl acetate (200mL), and the organic phase was washed with 2N sodium carbonate solution (80 mL. times.2) and saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product K3c (500mg, yield: 57.5%).

MS m/z(ESI):233.0[M+1]⁺

The third step

A mixture of compound J3a (200mg, 0.591mmol) and compound Int-K3c (222mg,0.954mmol) in isopropanol (10mL) was heated to 80 deg.C and stirred for 5 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution system: petroleum ether: ethyl acetate: 10/1-1/1) to give the title product K3(100mg, yield: 19.6%).

¹H NMR(400MHz,DMSO-d₆):δ10.06(s,1H),9.82(s,1H),8.85(d,1H),8.68(s,1H),8.25(d,1H),7.82(dd,1H),7.78-7.74(m,1H),7.68(d,1H),7.33(d,1H),7.16-7.06(m,3H),3.81-3.77(m,2H),3.72-3.68(m,2H),2.50(s,2H),2.27(s,3H),1.86-1.75(m,4H)。

MS m/z(ESI):535.2[M+1]

Example K4

4-methyl-3- (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) -N- (2- (trifluoromethyl) pyridin-4-yl) benzamide K4

First step of

4-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -N- (2- (trifluoromethyl) pyridin-4-yl) benzamide K4a

Under nitrogen, a catalytic amount of N, N-dimethylformamide and oxalyl chloride (1.26g, 9.92mmol) was added dropwise to a solution of compound Int-L4e (2g, 7.63mmol) in dichloromethane (20mL) at 0 ℃. The reaction solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methylene chloride (10mL), and the resulting solution was added dropwise to a solution of 2- (trifluoromethyl) pyridin-4-amine Int-K22a (1.24g, 7.63mmol) and triethylamine (0.93g, 9.16mmol) in methylene chloride (10mL) at 0 ℃ and the reaction mixture was stirred at room temperature overnight. The reaction solution was washed with water and a saturated sodium chloride solution, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/n-hexane: 1/5) to give the title product K4a (840mg, yield: 27%).

¹H NMR(400MHz,CDCl₃):δ8.63(d,1H),8.40-8.38(m,1H),8.18(d,1H),8.05(d,1H),7.92-7.86(m,2H),7.32(d,1H),2.62(s,3H),1.38(s,12H)。

MS m/z(ESI):407.2[M+H]⁺

Second step of

Under nitrogen protection, [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (11mg, 0.016mmol) was added to a mixture of compound Int-3(100mg, 0.32mmol,8057-009), compound K4a (144mg, 0.35mmol) and sodium carbonate (68mg, 0.64mmol) in 1, 4-dioxane/water (1mL/0.25mL), and the reaction was heated to 100 ℃ and stirred overnight. After the completion of the reaction, the solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-hexane: 1/2) to give the title product K4(58mg, yield: 35%).

¹H NMR(400MHz,DMSO-d₆):δ10.86(s,1H),9.85(s,1H),8.67(d,1H),8.31(d,1H),8.08(dd,1H),7.93-7.90(m,2H),7.51(d,1H),7.19(dd,1H),7.14-7.11(m,2H),3.83-3.77(m,2H),3.71-3.67(m,2H),2.34(s,3H),1.86-1.71(m,4H)。

MS m/z(ESI):512.2[M+H]⁺

Example K5

8- (2-methyl-5- ((6- (trifluoromethyl) -1H-benzo [ d ] imidazol-2-yl) amino) phenyl) -2',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] [1,4] oxazepine-2, 4' -pyran ] -4(5H) -one K5

First step of

2-bromo-4-isothiocyanato-1-methylbenzene K5a

3-bromo-4-methylaniline Int-J10c (2g, 10.75mmol) was added to a solution of thiophosgene (2.05g, 16.12mmol) in dichloromethane (20mL) at 0 deg.C, triethylamine (1.30g, 12.90mmol) was added, and the mixture was stirred at 0 deg.C for 1 hour. The reaction mixture was diluted with dichloromethane (30mL) and the mixture was washed with saturated sodium chloride solution (50 mL). The organic phase was collected, dried, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-hexane ═ 1/5) to give the title product K5a (2g, 8.77mmol, yield: 81.56%).

¹H NMR(400MHz,DMSO-d₆):δ7.42(d,1H),7.20(d,1H),7.07(dd,1H),2.39(s,3H)。

Second step of

1- (2-amino-4- (trifluoromethyl) phenyl) -3- (3-bromo-4-methylphenyl) thiourea K5b

To a mixed solution of compound K5a (447.38mg, 1.96mmol) in N, N-dimethylformamide (6mL) at 0 ℃ were added 4- (trifluoromethyl) benzene-1, 2-diamine (380mg, 2.16mmol) and triethylamine (595.38mg, 5.88mmol), and the reaction mixture was heated to 25 ℃ and stirred for 15 hours. The completion of the reaction was detected by thin layer chromatography (ethyl acetate/n-hexane: 1/1), and the reaction solution was diluted with water (30mL), followed by extraction with ethyl acetate (10mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title product K5b (403mg, 996.91. mu. mol, yield: 50.83%).

The third step

N- (3-bromo-4-methylphenyl) -5- (trifluoromethyl) -1H-benzo [ d ] imidazol-2-amine K5c

Compound K5b (403mg, 996.91. mu. mol) and ferric trichloride (29mg, 99.69. mu. mol) were added to a solution of N, N-dimethylformamide (5mL), and the mixture was stirred at 80 ℃ for 4 hours. The reaction liquid turns black, and LC-MS detects that the reaction is complete. The reaction solution was cooled, diluted with ethyl acetate (20mL), the mixture was washed with a saturated sodium chloride solution (20mL × 2), the organic phase was collected, dried, concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/n-hexane ═ 1/10) to give the title product K5c (170mg, 456.77 μmol, yield: 45.82%).

MS m/z(ESI):370.0[M+1]⁺

The fourth step

Compound K5c (53.08mg, 147.78. mu. mol), compound Int-4(50mg, 134.34. mu. mol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (7.91mg, 13.43. mu. mol) and cesium carbonate (131.39mg, 403.03. mu. mol) were added to a mixture of 1, 4-dioxane (3mL) and water (0.5mL), the mixture was purged with nitrogen and the reaction mixture was stirred at 100 ℃ for 2 hours. The reaction liquid turns black, and the LC-MS detection reaction is good. The reaction solution was cooled and extracted with ethyl acetate (20mL), and the organic phase was collected, dried, and concentrated. The residue was purified by thin layer chromatography (ethyl acetate/n-hexane: 1/2) to give the title product (6mg, 11.44 μmol, yield: 8.51%).

¹H NMR(400MHz,DMSO-d₆):δ11.81-11.60(m,1H),9.95(brs,1H),9.81(s,1H),7.68(dd,1H),7.62(brs,1H),7.60-7.57(m,1H),7.42(brs,1H),7.30(d,1H),7.25(d,1H),7.16-7.10(m,2H),7.05(d,1H),3.84-3.79(m,2H),3.72-3.68(m,2H),2.54(s,2H),2.21(s,3H),1.82-1.65(m,4H)。

¹⁹F NMR(376.5MHz,DMSO-d₆):δ-58.40。

MS m/z(ESI):523.2[M+H]⁺

Example K6

N- (4-methyl-3- (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -7- (trifluoromethyl) -2, 3-dihydro-4H-benzo [ b ] [1,4] oxazine-4-carboxamide K6

First step of

7- (trifluoromethyl) -2H-benzo [ b ] [1,4] oxazin-3 (4H) -one K6b

Sodium bicarbonate (1.42g, 16.94mmol) was added to a solution of 2-amino-5- (trifluoromethyl) phenol K6a (1g,5.65mmol) in ethylene glycol dimethyl ether (5mL), followed by dropwise addition of 2-chloroacetyl chloride (956.47mg, 8.47mmol) at 0 deg.C and stirring of the reaction solution at room temperature for 1 hour. The reaction was then heated to 80 ℃ and stirred overnight. After completion of the reaction, the reaction mixture was extracted with ethyl acetate and water, the organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (ethyl acetate/n-hexane ═ 10:1) to obtain the title product K6b (870mg, yield: 70.9%).

MS m/z(ESI):216.0[M-H]^-

Second step of

7- (trifluoromethyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine K6c

Borane (9.2g, 9.22mmol, 1M in tetrahydrofuran) was added to a solution of compound K6b (870mg, 4.01mmol) in tetrahydrofuran (10mL) at 0 ℃ under nitrogen, and the reaction was heated to 80 ℃ and stirred for 2 hours. After completion of the reaction, methanol was added, the reaction liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane ═ 20:1) to give the title product K6c (681mg, yield: 83.6%)

MS m/z(ESI):204.1[M+H]⁺

The third step

N- (3-bromo-4-methylphenyl) -7- (trifluoromethyl) -2, 3-dihydro-4H-benzo [ b ] [1,4] oxazine-4-carboxamide K6d

To a solution of 3-bromo-4-methylaniline Int-J10c (400mg, 2.15mmol) in dichloromethane (15mL) was added 4-nitrophenyl chloroformate (476.69mg, 2.36mmol) and pyridine (238.09mg, 3.01mmol), the reaction was stirred at room temperature for 3 hours, then N, N-diisopropylethylamine (333.44mg, 2.58mmol) and a solution of compound K6c (436.79mg, 2.15mmol) in dichloromethane were added, and the reaction was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane: 5:1) to give the title product K6d (560mg, yield: 62.4%).

MS m/z(ESI):415.1[M+H]⁺

The fourth step

To a mixture solution of compound K6d (130mg, 361.89. mu. mol), compound Int-4(100.66mg, 241.26. mu. mol), sodium carbonate (51.14mg, 482.52. mu. mol) in 1, 4-dioxane (1mL) and water (0.25mL) was added [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (16.93mg, 24.13. mu. mol) under nitrogen, and the reaction solution was heated to 70 ℃ for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane ═ 2:1) to give the title product K6(47mg, yield: 34.2%).

¹H NMR(400MHz,DMSO-d₆):δ9.79(s,1H),9.27(s,1H),7.75(d,1H),7.42(d,1H),7.38(s,1H),7.23-7.19(m,3H),7.09(s,2H),6.99(s,1H),4.31(brs,2H),3.88(brs,2H),3.79(t,2H),3.71-3.67(m,2H),2.49(brs,2H),2.20(s,3H),1.85-1.71(m,4H)。

MS m/z(ESI):568.2[M+1]⁺

Example K7& example K8

N- (4-methyl-3- (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -2- (trifluoromethyl) isonicotinamidine K7

N- (4-methyl-3- (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -2- (trifluoromethyl) isonicotinic acid methyl ester K8

First step of

N- (3-iodo-4-methylphenyl) -2- (trifluoromethyl) isonicotinamide K7a

2- (7-Azobenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (6.57g, 17.27mmol) was added to a solution of 2- (trifluoromethyl) isonicotinic acid Int-L4a (3g,15.70mmol) in N, N-dimethylformamide (30mL), the reaction solution was stirred at room temperature for 20 minutes, then 3-iodo-4-methylaniline Int-K27a (4.02g, 17.27mmol) and N, N-diisopropylethylamine (4.06g, 31.40mmol) were added and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was poured into water (300mL), extracted with ethyl acetate (80 mL. times.3), the organic phases were combined, washed with water (80 mL. times.3) and a saturated sodium chloride solution (80 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product K7a (6g, yield: 94%) which was directly subjected to the next reaction without purification.

MS m/z(ESI):407.0[M+H]⁺

Second step of

N- (3-iodo-4-methylphenyl) -2- (trifluoromethyl) pyridine-4-thiocarboxamide K7b

To a mixture of 2, 4-bis (4-methoxyphenyl) -1, 3-dithio-2, 4-diphospho-2, 4-thioether (lawson's reagent, 9g, 22.25mmol) in tetrahydrofuran (80mL) was added compound K7a (3g, 7.39mmol), and the reaction mixture was heated to 60 ℃ and stirred for 16 hours. The reaction solution was poured into water (200mL), extracted with ethyl acetate (80mL × 3), the organic phases were combined, washed with saturated sodium chloride (80mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20/1) to give the title product K7b (2.4g, yield: 77%).

MS m/z(ESI):422.9[M+H]⁺

The third step

N- (3-iodo-4-methylphenyl) -2- (trifluoromethyl) pyridine-4-imidazoic acid thiomethyl ester K7c

Trimethyloxonium tetrafluoroborate (650mg, 4.39mmol) was added to a solution of Compound K7b (1.4g, 3.32mmol) in dichloromethane (30mL) at 0 ℃ and stirred at room temperature for 1 hour. The reaction solution was quenched with water, the organic phase was separated, the aqueous phase was extracted with dichloromethane (10mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20/1) to give the title product K7c (650mg, yield: 45%).

MS m/z(ESI):436.9[M+H]⁺

The fourth step

N- (3-iodo-4-methylphenyl) -2- (trifluoromethyl) isonicotinamidine K7d

N- (3-iodo-4-methylphenyl) -2- (trifluoromethyl) isonicotinic acid methyl ester K7e

A solution of compound K7c (350mg, 802.32. mu. mol) in 7M methanolic ammonia (5mL) was heated to 120 ℃ in a sealed tube for 16 hours, and the reaction solution was concentrated under reduced pressure to give the title products K7d and K7e (250mg, total yield: 75%) which were directly subjected to the next reaction without purification.

The fifth step

The compounds K7d and K7e (250mg, 0.62mmol) obtained in the above step were dissolved in 1, 4-dioxane (4mL), then water (2mL, Drech), sodium carbonate (100mg, 943.49. mu. mol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (40mg, 54.64. mu. mol) was added, then the compound Int-4(300mg, 0.84mmol) was added, replaced with nitrogen 3 times, warmed to 80 ℃ and stirred for 1 hour. The reaction solution was diluted with ethyl acetate (50mL), the organic phase was washed with water (20mL × 2) and saturated sodium chloride (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane: methanol: 100:1-40:1) to give the title product K7(31mg, yield: 26%, prepared from K7 d) and K8(34mg, yield: 27%, prepared from K7 e)

Example K7¹H NMR(400MHz,DMSO-d₆):δ9.78(s,1H),8.88(d,1H),8.39(s,1H),8.23(d,1H),7.26(d,1H),7.15(dd,1H),7.08-7.06(m,2H),6.84-6.80(m,3H),6.74(d,1H),3.83-3.77(m,2H),3.71-3.67(m,2H),2.50(s,2H),2.23(s,3H),1.85-1.70(m,4H)。

¹⁹F NMR(376.5MHz,DMSO-d₆):δ-66.46(s,3F)。

MS m/z(ESI):511.2[M+H]⁺

Example K8¹H NMR(400MHz,DMSO-d₆):δ9.76(s,1H),8.78(d,1H),7.75(s,1H),7.59(d,1H),7.12(d,1H),7.01(d,1H),6.89(dd,1H),6.76(d,1H),6.68(dd,1H),6.56(d,1H),3.95(s,3H),3.79-3.66(m,4H),2.45(s,2H),2.12(s,3H),1.81-1.71(m,4H)。

¹⁹F NMR(376.5MHz,DMSO-d₆):δ-66.89(s,3F)。

MS m/z(ESI):526.2[M+H]⁺

The following compounds were prepared using the general procedure described in the procedures of example K1 and example K2, substituted with the appropriate aryl bromide, aryl boronic acid ester intermediate as described in the previous schemes and examples. The necessary starting materials can be purchased commercially, or obtained by working up as described in the literature, or synthesized by a person skilled in the art of organic synthesis from commercially available reagents using conventional reactions.

Example L1

8- (2-methyl-5- (5- (2- (trifluoromethyl) pyridin-4-yl) -4H-1,2, 4-triazol-3-yl) phenyl) -2',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] [1,4] oxazepine-2, 4' -pyran ] -4(5H) -one L1

First step of

2- (2- (trifluoromethyl) isonicotinyl) hydrazine-1-carboxylic acid tert-butyl ester L1b

A mixture of 2- (trifluoromethyl) isonicotinic acid Int-L4a (5.00g, 26.16mmol), tert-butyl carbazate (5.18g, 39.25mmol), 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (14.92g, 39.25mmol), N, N-diisopropylethylamine (6.75g, 52.33mmol) in dichloromethane (150mL) was stirred at room temperature for 18 hours. The reaction solution was washed with water and a saturated sodium chloride solution in this order, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution system: petroleum ether: ethyl acetate: 20:1-10:1) to give the title product L1b (7.0g, yield: 87.6%).

MS m/z(ESI):306.1[M+1]⁺

Second step of

2- (trifluoromethyl) isonicotinyl hydrazide dihydrochloride L1c

To a solution of the compound L1b (7.0g, 22.93mmol, 8051-001) in 1, 4-dioxane (80mL) was added dropwise a solution of hydrogen chloride/1, 4-dioxane (4.0M, 100 mL). The reaction mixture was stirred at 30 ℃ for 18 hours. The reaction mixture was concentrated under reduced pressure to give the title product L1c (5.7g, yield: 88.4%).

MS m/z(ESI):206.1[M+1]⁺.

The third step

4- (5- (3-bromo-4-methylphenyl) -4H-1,2, 4-triazol-3-yl) -2- (trifluoromethyl) pyridine L1d

A mixture of compound L1c (1.13g, 4.08mmol), 3-bromo-4-methyl-benzonitrile Int-L5c (400mg, 2.04mmol) and potassium carbonate (2.25g, 16.32mmol) in n-butanol (20mL) was reacted at 150 ℃ for 1 hour in a microwave. The reaction mixture was diluted with ethyl acetate (100mL), washed with water (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution system: petroleum ether/ethyl acetate 20/1-3/1) to give the title product L1d (0.40g, yield: 61.2%).

MS m/z(ESI):383.0[M+1]⁺

The fourth step

4- (5- (4-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4H-1,2, 4-triazol-3-yl) -2- (trifluoromethyl) pyridine L1e

A solution of compound L1d (1.2g, 3.13mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (150mg, 3.13mmol), pinacol diboron (1.60g, 6.30mmol) and potassium acetate (850mg, 8.67mmol) in dimethylsulfoxide (50mL) was replaced with nitrogen three times. The reaction mixture was heated to 100 ℃ and stirred for 18 hours. Water (200mL) was added to the reaction mixture, and extraction was performed with ethyl acetate (150 mL. times.3), and the organic phases were combined, washed with a saturated sodium chloride solution (100 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution system: petroleum ether/ethyl acetate 1/10-1/2) to give the title product L1e (750mg, yield: 55.7%).

¹H NMR(400MHz,DMSO-d₆):14.99(brs,1H),δ8.92(d,1H),8.37(s,2H),8.32(d,1H),8.07(dd,1H),7.38(d,1H),2.55(s,3H),1.36(s,12H)。

MS m/z(ESI):430.2[M+1]⁺

The fifth step

Compound Int-3(100mg, 0.32mmol), compound L1c (206.74mg, 0.48mmol), sodium carbonate (101.86mg, 961.05 μmol) in a mixture of 1, 4-dioxane (16mL) and water (4mL) were added bis (triphenylphosphine) palladium dichloride (23mg, 32 μmol), and the reaction was stirred and heated to 100 ℃ under nitrogen for 16 hours. The reaction solution was cooled and diluted with saturated sodium chloride solution (80mL), the mixture was extracted with ethyl acetate (80mL × 2), the organic phases were combined, dried, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution system: petroleum ether: ethyl acetate ═ 0:1-3:1) to give the title product L1(80mg, yield: 47%).

¹H NMR(400MHz,CH₃OH-d₄):δ8.82(d,1H),8.46(s,1H),8.32(d,1H),7.97-7.94(m,2H),7.49(d,1H),7.24-7.17(m,2H),7.14(d,1H),3.96-3.94(m,2H),3.82-3.80(m,2H),2.60(s,2H),2.36(s,3H),2.01(d,2H),1.90-1.82(m,2H)。

¹⁹F NMR(376.5MHz,CH₃OH-d₄):δ-69.5。

MS m/z(ESI):536.2[M+H]⁺

Example L2

8- (2-methyl-5- (5- (2- (trifluoromethyl) pyridin-4-yl) -1,3, 4-thiadiazol-2-yl) phenyl) -2',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] [1,4] oxazepine-2, 4' -pyran ] -4(5H) -one L2

First step of

N' - (3-iodo-4-methylbenzoyl) -2- (trifluoromethyl) isonicotinyl hydrazide L2a

To a solution of 3-iodo-4-methylbenzoic acid Int-L4d (2.62g, 10.00mmol) and oxalyl chloride (2.54g, 20.00mmol) in dichloromethane (50mL) was added N, N-dimethylformamide (0.1 mL). The reaction mixture was stirred at room temperature for 3 hours, and the reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (20mL), and the resulting solution was added dropwise to a solution of compound L1c (2.78g, 10.00mmol) and pyridine (1.61mL, 20mmol) in methylene chloride (50mL) at 0 ℃ and the reaction mixture was allowed to warm and react for 18 hours. The reaction mixture was diluted with dichloromethane (100mL), washed successively with a saturated aqueous ammonium chloride solution (40mL) and a saturated sodium chloride solution (300mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution system: petroleum ether/ethyl acetate 5/1-1/1) to give the title product L2a (2.50g, yield: 55.7%).

MS m/z(ESI):450.0[M+1]⁺

Second step of

2- (3-iodo-4-methylphenyl) -5- (2- (trifluoromethyl) pyridin-4-yl) -1,3, 4-thiadiazoles L2b

A solution of compound L2a (800mg, 1.78mmol) and 2, 4-bis (4-methoxyphenyl) -1, 3-dithio-2, 4-diphospho-2, 4-thioether (Lawson's reagent, 719.56mg, 1.78mmol) in tetrahydrofuran (20mL) was stirred and heated to 60 ℃ for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution system: petroleum ether: ethyl acetate: 5/1-1/1) to give the title product L2b (500mg, yield: 62.7%). MS M/z (ESI) 448.1[ M +1 ]]⁺

The third step

To a solution of compound L2b (100mg, 223.61. mu. mol) in 1, 4-dioxane (4mL) were added water (2mL) and sodium carbonate (60mg, 447.21. mu. mol), and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (15mg, 20.49. mu. mol) and compound Int-4(96.39mg, 268.33. mu. mol) were added, the reaction solution was replaced with nitrogen 3 times, and the reaction solution was heated to 80 ℃ and stirred for reaction for 4 hours. The reaction mixture was diluted with ethyl acetate (40mL), washed with water (20 mL. times.2) and a saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution system: dichloromethane/methanol-70/1) to give the title product L2(43mg, yield: 35%).

¹H NMR(400MHz,DMSO-d₆):δ9.85(s,1H),9.00(d,1H),8.40(s,1H),8.31(d,1H),7.96(d,1H),7.87(d,1H),7.56(d,1H),7.21-7.19(m,1H),7.15-7.12(m,2H),3.84-3.78(m,2H),3.72-3.67(m,2H),2.50(s,2H),2.34(s,3H),1.88-1.72(m,4H)。

¹⁹F NMR(377MHz,DMSO-d₆):δ-66.68。

MS m/z(ESI):553.0[M+H]⁺

The following compounds were prepared using the general procedure described in the procedures of example L1 and example L2, substituted with the appropriate aryl bromide, aryl boronic acid ester intermediate as described in the previous schemes and examples.

The necessary starting materials can be purchased commercially, or obtained by working up as described in the literature, or synthesized by a person skilled in the art of organic synthesis from commercially available reagents using conventional reactions.

Test example:

biological evaluation

cRAF kinase Activity inhibition assay

The ability of a compound to inhibit cRAF kinase activity was tested in vitro using a time-resolved fluorescence resonance energy transfer (TR-FRET) assay, and assayed according to kit instructions. Briefly, human recombinant cRAF protein kinase (BPS Bioscience, catalog No. 40008) was first diluted to 0.027 ng/. mu.l using 1-fold kinase buffer a (Life Tech, catalog No. PV6135, 5-fold original concentration, diluted 1-fold with water); fluorescein-labeled MAP2K1(Life Tech, catalog number PV4812) was diluted to 0.5 μ M; ATP (Life Tech, Cat # PV3227) was diluted to 20. mu.M; then, 2.5. mu.l of each of the diluted reagents was added to the 384-well plate(PerkinElmer, ProxiPlate-384Plus, Cat. No. 6008280) and mixed well; add 2.5 μ l of the compound after gradient dilution to the above mixture (blank for the same volume of dilution without compound); then, 10. mu.l of 400-fold diluted LanthaScreen Tb-pMAP2K1(pSer217/221) antibody (Life Tech, Cat. No. PV4817) was added and incubated at room temperature for 1 hour. Data were read on PHERAStar FSX, percent inhibition of kinase activity by compound was calculated (blank 0% inhibition, no kinase control 100% inhibition), dose response curves were generated using GraphPad Prism software, and median Inhibitory Concentration (IC) was calculated by non-linear regression analysis ₅₀)。

BRAF^WTInhibition of kinase Activity

Detection of compound vs BRAF in vitro using time-resolved fluorescence resonance energy transfer (TR-FRET) assay^WTThe inhibitory capacity of kinase activity was determined according to the kit instructions. Briefly, human recombinant BRAF was first diluted 1-fold with 1-fold kinase buffer a (Life Tech, catalog No. PV6135, 5-fold original concentration, 1-fold diluted with water)^WTProtein kinase (BPS Bioscience, catalog number 40065) diluted to 0.027 ng/. mu.l; fluorescein-labeled MAP2K1(Life Tech, catalog number PV4812) was diluted to 0.5 μ M; ATP (Life Tech, Cat # PV3227) was diluted to 20. mu.M; then 2.5. mu.l of each of the above diluted reagents was added to a 384 well plate (Perkinelmer, ProxiPlate-384Plus, Cat. No. 6008280) and mixed well; add 2.5 μ l of the compound after gradient dilution to the above mixture (blank for the same volume of dilution without compound); then, 10. mu.l of 400-fold diluted LanthaScreen Tb-pMAP2K1(pSer217/221) antibody (Life Tech, Cat. No. PV4817) was added and incubated at room temperature for 1 hour. Data were read on PHERAStar FSX, percent inhibition of kinase activity by compound was calculated (blank 0% inhibition, no kinase control 100% inhibition), dose response curves were generated using GraphPad Prism software, and median Inhibitory Concentration (IC) was calculated by non-linear regression analysis ₅₀)。

BRAF^V600EInhibition of kinase Activity

Detection of compound pairs in vitro using time-resolved fluorescence resonance energy transfer (TR-FRET) assayBRAF^V600EThe inhibitory capacity of kinase activity was determined according to the kit instructions. Briefly, human recombinant BRAFV600E protein kinase (BPS Bioscience, catalog No. 40533) was first diluted to 0.027 ng/. mu.l using 1-fold kinase buffer a (Life Tech, catalog No. PV6135, 5-fold original concentration, diluted 1-fold with water); fluorescein-labeled MAP2K1(Life Tech, catalog number PV4812) was diluted to 0.5 μ M; ATP (Life Tech, Cat # PV3227) was diluted to 20. mu.M; then 2.5. mu.l of each of the above diluted reagents was added to a 384 well plate (Perkinelmer, ProxiPlate-384Plus, Cat. No. 6008280) and mixed well; add 2.5 μ l of the compound after gradient dilution to the above mixture (blank for the same volume of dilution without compound); then, 10. mu.l of 400-fold diluted LanthaScreen Tb-pMAP2K1(pSer217/221) antibody (Life Tech, Cat. No. PV4817) was added and incubated at room temperature for 1 hour. Data were read on PHERAStar FSX, percent inhibition of kinase activity by compound was calculated (blank 0% inhibition, no kinase control 100% inhibition), dose response curves were generated using GraphPad Prism software, and median Inhibitory Concentration (IC) was calculated by non-linear regression analysis ₅₀)。

Claims

1. A compound of the general formula (I),

wherein:

is a single bond or a double bond;

P is selected from CR⁴R⁵、C(O)、NR⁶O, S and S (O)₂；

X、YAnd Z is the same or different and is each independently selected from CR⁷R⁸、CR⁷、C(O)、C(NH)、S(O)₂、NR⁹N, O and S;

G¹selected from O, S, C (O), C (O) NH, NR¹⁰、CR¹¹R¹²And S (O)₂；

M is N or CR¹³；

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

ring B is selected from phenyl, pyridyl, thiazolyl, thienyl and pyridonyl;

l is selected from a bond,

R⁰are the same OR different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, -C (O) OR¹⁴Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, arylAnd heteroaryl are each independently optionally substituted with one or more substituents selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R¹are the same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, -C (O) NR¹⁵R¹⁶、-S(O)₂R¹⁸Oxo, NR¹⁵R¹⁶、S-R¹⁸、C(O)R¹⁸Cycloalkyl, -O-cycloalkyl, heterocyclyl, -O-heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R⁶、R⁹and R¹⁰Are the same OR different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, an amino group, a cycloalkyl group, a heterocyclic group, C (O) OR ¹⁴、C(O)R¹⁸Aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, C (O) OR¹⁴、NR¹⁵R¹⁶、NR¹⁵C(O)OR¹⁴、R¹⁹Cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R¹³Selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups,Cycloalkyl, heterocyclyl, aryl and heteroaryl;

k is 0 or 1;

s is 0, 1 or 2;

t is 0, 1 or 2;

q is 0, 1, 2, 3 or 4;

n is 0, 1, 2 or 3;

m is 0, 1, 2, 3 or 4.

2. The compound of claim 1, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof,

wherein:

l is selected from a bond,

R²The same or different, and each is independently selected from the group consisting of hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups, wherein the alkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl groups, alkoxy groups, halogens, haloalkyl groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups.

3. The compound according to claim 1 or 2, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein

Is selected from

G¹、P、X、Y、Z、W¹、W²、W³、R⁰S, t and q are as defined in claim 1 or 2.

4. A compound according to claims 1 to 3, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein W is ¹、W²And W³Are the same or different and are each independently CR³，R³As defined in claim 1 or 2.

5. The compound according to any one of claims 1 to 4, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, which is a compound represented by general formula (II) or general formula (III), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof,

wherein:

G¹p, X, Y, Z, L, M, ring B, ring A, R⁰、R¹、R²S, t, q, n and m are as defined in claim 1 or 2.

6. The compound according to any one of claims 1 to 4, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein

Selected from:

preferably selected from

G¹、R⁰、R⁷、R⁸、R⁹And q is as defined in claim 1 or 2.

7. The compound according to any one of claims 1 to 6, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein

Is selected from

Preferably, the first and second electrodes are formed of a metal,

is selected from

R²And n is as defined in claim 1 or 2.

8. The compound according to any one of claims 1 to 7, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein

Is selected from

R²And n is as defined in claim 1 or 2.

9. The compound of any one of claims 1 to 5, 7 and 8, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein P is selected from O, S, NH, N (OH), S (O) ₂And CH₂(ii) a Preferably O.

10. The compound according to any one of claims 1 to 5 and 7 to 9, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein X is CR⁷R⁸Or C (O); y and Z are the same or different and are each independently selected from CR⁷R⁸、C(O)、C(NH)、S(O)₂、NR⁹O and S.

11. The compound according to any one of claims 1 and 3 to 10, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein L is selected from the group consisting of a bond, -NH-, a pharmaceutically acceptable salt, solvate, or prodrug thereof,

Preferably, it is

12. The compound according to any one of claims 1 to 7 and 9 to 11, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, which is a compound represented by general formula (IVG), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof,

Wherein:

R⁰、R¹、R²、R⁷、R⁸、R⁹、R¹³Ring A, m and q are as defined in claim 1 or 2.

13. The compound according to any one of claims 1 to 11, or a tautomer, cis or trans isomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, which is a compound represented by general formula (IV), general formula (V), or general formula (VI), or a tautomer, cis or trans isomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof,

wherein R is^2aSelected from the group consisting of hydrogen atoms, halogens, alkyl groups, deuterated alkyl groups, alkoxy groups, halogenated alkyl groups, halogenated alkoxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, wherein the alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl groups, alkoxy groups, halogen groups, halogenated alkyl groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups; preferably, R ^2aSelected from the group consisting of hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, wherein said alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl groups, alkoxy groups, halogens, haloalkyl groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups; r⁰、R¹、R²、R⁷、R⁸、R⁹、G¹Ring a, n, m and q are as defined in claim 1 or 2.

14. The compound of any one of claims 1 to 13, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein ring a is selected from the group consisting of 3-to 10-membered cycloalkyl, 3-to 10-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 14-membered heteroaryl; preferably, ring a is selected from 3-to 10-membered heterocyclyl, 6-to 10-membered aryl and 5-to 14-membered heteroaryl.

15. The compound according to any one of claims 1 to 14, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein

Is selected from

R¹And m is as defined in claim 1 or 2.

16. The compound according to any one of claims 1 to 11 and 13 to 15, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein G is¹Is O.

17. The compound according to any one of claims 1 to 16, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R is⁰Is a hydrogen atom or an alkyl group.

18. The compound according to any one of claims 1 to 17, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R is¹Are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, cyano, -C (O) NR¹⁵R¹⁶、-S(O)₂R¹⁸Oxo, NR ¹⁵R¹⁶、S-R¹⁸、C(O)R¹⁸Cycloalkyl, -O-cycloalkyl, heterocyclyl, -O-heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy and hydroxyalkyl; r¹⁵、R¹⁶And R¹⁸As defined in claim 1; preferably, R¹Are the same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, cycloalkyl, -O-cycloalkyl, heterocyclyl and-O-heterocyclyl.

19. The compound according to any one of claims 1 to 18, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R is²The same or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl group, deuterated alkyl group, oxo group, haloalkyl group, alkoxy group, haloalkoxy group, cyano group and hydroxyalkyl group(ii) a Preferably, R²Are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a cyano group and a hydroxyalkyl group.

20. The compound according to any one of claims 1 to 19, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R is⁷And R⁸Are the same OR different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, -C (O) OR¹⁴、-NR¹⁵R¹⁶、-NR¹⁵C(O)OR¹⁴、-OR¹⁷、-NR¹⁵C(O)R¹⁸Cycloalkyl, heterocyclyl, aryl and heteroaryl; r¹⁴～R¹⁸As defined in claim 1.

21. The compound according to any one of claims 1 to 20, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R is⁹Selected from the group consisting of hydrogen atoms, alkyl groups and hydroxyalkyl groups, wherein said alkyl groups are optionally substituted by groups selected from the group consisting of alkoxy, halogen, hydroxy, hydroxyalkyl and-NR¹⁵R¹⁶Is substituted with one or more substituents of (1); r¹⁵And R¹⁶As defined in claim 1.

22. The compound according to any one of claims 1 to 21, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, selected from the group consisting of:

23. The compound according to any one of claims 1 to 22, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, selected from the group consisting of:

24. a process for the preparation of a compound of formula (I) according to claim 1 or 2, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, which process comprises

wherein:

R^xis halogen; preferably Br;

R^gis composed of

Ring A, ring B, M, L, R⁰、R¹、R²、W¹、W²、W³、P、X、Y、Z、G¹S, t, k, q, n and m are as defined in claim 1 or 2.

25. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 23, or a tautomer, cis or trans isomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

26. Use of a compound of general formula (I) according to any one of claims 1 to 23 or a tautomer, cis or trans isomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition according to claim 25 in the manufacture of a medicament for the inhibition of RAF.

27. Use of a compound of general formula (I) according to any one of claims 1 to 23 or a tautomer, cis or trans isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition according to claim 25, for the manufacture of a medicament for the treatment of a RAF mediated disease or disorder; preferably, the RAF mediated disease or disorder is cancer.

28. The use of claim 27, wherein the cancer is selected from the group consisting of lymphoma, leukemia, breast cancer, lung cancer, prostate cancer, ovarian cancer, liver cancer, melanoma, rhabdomyosarcoma, synovial sarcoma, mesothelioma, cervical cancer, colon cancer, rectal cancer, stomach cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, bone cancer, kidney cancer, bladder cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, glioma, glioblastoma, head and neck cancer, and myeloma; lymphoma, leukemia, breast cancer, lung cancer, prostate cancer, ovarian cancer, liver cancer, melanoma, rhabdomyosarcoma, synovial sarcoma, and mesothelioma are preferred.