CN114149423A

CN114149423A - Tetrahydropyridopyrimidine diketone derivative, preparation method and medical application thereof

Info

Publication number: CN114149423A
Application number: CN202111041349.6A
Authority: CN
Inventors: 张晓敏; 胡伟民; 马殿强; 张婷; 贺峰; 陶维康
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2020-09-08
Filing date: 2021-09-07
Publication date: 2022-03-08
Anticipated expiration: 2041-09-07
Also published as: CN114149423B

Abstract

The disclosure relates to tetrahydropyridopyrimidinedione derivatives, a preparation method thereof and application thereof in medicines. Specifically, the disclosure relates to tetrahydropyridopyrimidinedione derivatives represented by general formula (IM) and preparation thereofA preparation method, a pharmaceutical composition containing the derivative and application of the derivative as a therapeutic agent, in particular application of the derivative as a Myosin (Myosin) inhibitor and application of the derivative in medicines for treating Hypertrophic Cardiomyopathy (HCM) or heart diseases with pathophysiological characteristics related to the HCM.

Description

Tetrahydropyridopyrimidine diketone derivative, preparation method and medical application thereof

Technical Field

The disclosure belongs to the field of medicines, and relates to a tetrahydropyridopyrimidinedione derivative, a preparation method thereof and application thereof in medicines. In particular, the disclosure relates to tetrahydropyridopyrimidinedione derivatives represented by general formula (IM), methods for preparing the same, pharmaceutical compositions containing the same, and uses thereof as Myosin (Myosin) inhibitors and in drugs for treating Hypertrophic Cardiomyopathy (HCM) or heart diseases having pathophysiological characteristics related to HCM.

Background

Hypertrophic Cardiomyopathy (HCM) is a dominant hereditary myocardial disease associated with genetic mutations. The global incidence is about 0.2%, which is the most important cause of sudden death in younger age 35 years (Tuohy, CV.et al., Eur J Heart Fail,22,2020, 228-. Clinically, it is characterized by the asymmetrical hypertrophy of left ventricular wall, frequent invasion and ventricular septum, small ventricular cavity, obstruction of left ventricular blood filling, and decreased ventricular diastolic compliance. The disease is classified into obstructive and non-obstructive hypertrophic cardiomyopathy according to the presence or absence of obstruction in the left ventricular outflow tract. At present, beta-blockers and calcium channel blockers are mostly adopted for clinically treating hypertrophic cardiomyopathy to reduce cardiac contraction and relieve symptoms. However, these treatments are all palliative and not root-cause. HCM progression to late stages can only be followed by heart transplantation (Ramaraj, r. cardio Rev,16,2008, 172-. Therefore, it is very urgent to find a treatment method aiming at the pathogenesis source of HCM.

The present study found that 70% of HCM patients are caused by mutations in the sarcomere gene. Multiple site mutations are found in 5-7% of patients. More than about 70 pathogenic mutations have been identified, but most of these have family specificity, with only a few hot spots identified, such as the MYH 7R 403Q and R453C mutations (Frey, N.et al, Nat Rev Cardiol,9,2011, 91-100; Sabater-Molina, M.et al, Clin Genet,93,2018, 3-14). Research aiming at the pathogenic probability of gene mutation finds that MYH7 gene mutation patients account for about 30%. MYH7 causes early onset of disease and more severe myocardial hypertrophy compared to other sarcomere genes. Myosin is a constituent unit of the thick myofilaments of myofibrils and plays an important role in muscle movement. The molecular shape is like bean sprout, and is composed of two heavy chains and a plurality of light chains. The myosin head combines with actin to form a transverse bridge, so that the ATPase activity of myosin is greatly improved, ATP hydrolysis reaction is catalyzed, energy is generated to promote the transverse bridge to slide, and muscle contraction is carried out. The results of the study showed that the mutation in the MYH7 gene resulted in an increase in myosin ATPase activity, a decrease in myosin super-delayed State (SRX) ratio, and an increase in the transverse bridge between myosin and actin, leading to cardiac contractile dysfunction (Green, EM.et al, Science,351,2016, 617-. Myosin is therefore an important target for the treatment of hypertrophic cardiomyopathy.

Patent applications for myosin inhibitors have been disclosed including WO2014205223a1, WO2014205234a1, WO2019028360a1, WO2020092208a1 and CN110698415A, among others.

Disclosure of Invention

The purpose of the present disclosure is to provide a compound represented by the general formula (IM), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

R^xis alkyl or

Wherein said alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy and hydroxyalkyl;

R^yis a hydrogen atom or a halogen;

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

l is selected from the group consisting of a bond, (CH)₂)_r、C(O)、NH、NR⁰Oxygen atom and sulfur atom;

R⁰selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

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

each R is¹The same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

each R is²The same or different and each is independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkylHaloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, COR⁴、C(O)OR⁵、S(O)_tR⁶、S(O)_tNR⁷R⁸And C (O) NR⁷R⁸；

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

each R is³Are the same OR different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, amino, nitro, hydroxy, hydroxyalkyl, and C (O) OR⁵；

R⁴Selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy and hydroxyalkyl;

R⁵selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

R⁶selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, hydroxyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

R⁷and R⁸Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a cycloalkylalkyl group, a heterocyclic group, a heterocyclylalkyl group, an aryl group, and a heteroaryl group; or R⁷And R⁸Together with the nitrogen atom to which they are attached form a heterocyclyl group, which heterocyclyl group is optionally substituted by one or more substituents selected from the group consisting of halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

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

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

r is 0, 1,2, 3, 4, 5 or 6;

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

t is 0, 1 or 2.

In some preferred embodiments of the present disclosure, the compound of formula (IM), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is^yIs a hydrogen atom or a fluorine atom; preferably, R^yIs a fluorine atom.

IN some preferred embodiments of the present disclosure, the compound represented by the general formula (IM), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (IN), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring A, ring C, L, R¹、R²、R^xS and m are as defined in formula (IM).

IN some preferred embodiments of the present disclosure, the compound represented by the general formula (IM), the general formula (IN), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (IN-1), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring A, ring C, L, R¹、R²、R^xS and m are as defined in formula (IM).

IN some preferred embodiments of the present disclosure, the compound of formula (IM), formula (IN-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is^xIs C_1-6Alkyl or

Preferably, R^xIs isopropyl or

Wherein, ring B, R³And n is as defined in formula (IM).

IN some preferred embodiments of the present disclosure, the compound represented by formula (IM), formula (IN), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by formula (I), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

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

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

each R is¹The same or different and each is independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, halogenAlkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

each R is²The same or different, and each is independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, COR⁴、C(O)OR⁵、S(O)_tR⁶、S(O)_tNR⁷R⁸And C (O) NR⁷R⁸；

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

R⁷and R⁸Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a cycloalkylalkyl group, a heterocyclic group, a heterocyclylalkyl group, an aryl group, and a heteroaryl group; or R⁷And R⁸Together with the nitrogen atom to which they are attached form a heterocyclic group, said heterocyclic group being optionally selected from halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloSubstituted with one or more substituents selected from the group consisting of alkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

m is 0, 1,2, 3, 4, 5;

n is 0, 1,2, 3, 4, 5, 6;

r is 0, 1,2, 3, 4, 5, 6;

s is 0, 1,2, 3, 4, 5, 6; and is

t is 0, 1,2.

IN some preferred embodiments of the present disclosure, the compound represented by formula (IM), formula (IN-1), formula (I), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by formula (I-1), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring A, ring B, ring C, L, R¹To R³S, m and n are as defined in formula (IM).

IN some preferred embodiments of the present disclosure, the compound of formula (IM), formula (IN-1), formula (I-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring a is selected from the group consisting of 3-to 8-membered cycloalkyl, 3-to 12-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 10-membered heteroaryl; preferably, ring a is phenyl or pyridyl.

IN some preferred embodiments of the present disclosure, the compound of formula (IM), formula (IN), formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (II), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

W¹to W⁵One is a carbon atom, and the remaining four are the same or different and are each independently a carbon atom or a nitrogen atom;

ring B, ring C, L, R¹To R³S, m and n are as defined in formula (IM).

IN some preferred embodiments of the present disclosure, the compound of formula (IM), formula (IN-1), formula (I-1), formula (II), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (II-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring B, ring C, L, R¹To R³S, m and n are as defined in formula (IM).

IN some preferred embodiments of the present disclosure, the compound of formula (IM), formula (IN-1), formula (I-1), formula (II-1), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from the group consisting of 3-to 8-membered cycloalkyl, 3-to 12-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 10-membered heteroaryl; preferably, ring B is a 5 or 6 membered heterocyclyl; more preferably, ring B is tetrahydropyranyl.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II-1), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from the group consisting of 3-to 8-membered cycloalkyl, 3-to 12-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 10-membered heteroaryl; preferably, ring B is tetrahydropyranyl.

IN some preferred embodiments of the present disclosure, the compound of formula (IM), formula (IN-1), formula (I-1), formula (II-1), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring C is selected from the group consisting of 3-to 8-membered cycloalkyl, 3-to 12-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 10-membered heteroaryl; preferably, ring C is selected from 3 to 6 membered cycloalkyl, 3 to 6 membered heterocyclyl and 5 or 6 membered heteroaryl; more preferably, ring C is selected from cyclopropyl, pyridyl, tetrahydrofuranyl and tetrahydropyranyl.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II-1), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring C is selected from the group consisting of 3-to 8-membered cycloalkyl, 3-to 12-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 10-membered heteroaryl; preferably, ring C is a 3 to 6 membered cycloalkyl or 5 or 6 membered heteroaryl; more preferably, ring C is cyclopropyl or pyridyl.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II-1), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring C is selected from the group consisting of 3-to 8-membered cycloalkyl, 3-to 12-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 10-membered heteroaryl; preferably, ring C is a 3 to 8 membered cycloalkyl group.

IN some preferred embodiments of the present disclosure, the compound of formula (IM), formula (IN-1), formula (I-1), formula (II-1), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R is R¹Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl and C_1-6A haloalkyl group; preferably, each R¹Are the same or different and are each independently selected from the group consisting of a hydrogen atom, a methyl group and a trifluoromethyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II-1), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R is R¹Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl and C_1-6A haloalkyl group; preferably, each R¹The same or different, and each independently is a hydrogen atom or a trifluoromethyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II-1), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R is R¹Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C_1-6An alkyl group.

IN some preferred embodiments of the present disclosure, the compound of formula (IM), formula (IN-1), formula (I-1), formula (II-1), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R is R²Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkyl and C_1-6A haloalkoxy group; preferably, each R²Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl and C_1-6A haloalkyl group; more preferably, each R²Are the same or different and are each independently a hydrogen atom or a fluorine atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II-1), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R is R²Are the same or different and are each independently a hydrogen atom or a fluorine atom.

IN some preferred embodiments of the present disclosure, the compound of formula (IM), formula (IN-1), formula (I-1), formula (II-1), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is R³Is a hydrogen atom.

IN some preferred embodiments of the present disclosure, the compound represented by formula (IM), formula (IN-1), formula (I-1), formula (II-1), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L is a chemical bond or an oxygen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II-1), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L is a bond.

IN some preferred embodiments of the present disclosure, the compound of formula (IM), formula (IN-1), formula (I-1), formula (II-1), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein W is¹To W⁵One isCarbon atoms, the remaining four being the same or different and each independently being a carbon atom or a nitrogen atom; preferably, W¹To W⁵Is a carbon atom or W¹、W²、W⁴And W⁵Is a carbon atom and W³Is a nitrogen atom; more preferably, W¹To W⁵Is a carbon atom.

IN some preferred embodiments of the present disclosure, the compound of formula (IM), formula (IN-1), formula (I-1), formula (II-1), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein

Is composed of

Is composed of

W¹To W⁵One is a carbon atom and the remaining four are the same or different and are each independently a carbon atom or a nitrogen atom, wherein ring C, L, R¹、R²S and m are as defined in formula (IM); preferably, it is

Wherein the ring C, L, R¹、R²S andm is as defined in formula (IM); more preferably from

In some preferred embodiments of the present disclosure, the compound of formula (II), formula (II-1), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein

Is composed of

Wherein the ring C, L, R¹、R²S and m are as defined in formula (II); preferably selected from

IN some preferred embodiments of the present disclosure, the compound of formula (IM), formula (IN-1), formula (I-1), formula (II-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein s is 0, 1, or 2; preferably, s is 0 or 1.

IN some preferred embodiments of the present disclosure, the compound of formula (IM), formula (IN-1), formula (I-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2; preferably, m is 0 or 1.

In some preferred embodiments of the present disclosure, the compound of formula (II), formula (II-1), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein m is 4.

IN some preferred embodiments of the present disclosure, the compound of formula (IM), formula (IN-1), formula (I-1), formula (II-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2; preferably, n is 0 or 1; more preferably, n is 0.

IN some preferred embodiments of the present disclosure, the compound of formula (IM), formula (IN-1), formula (I-1), formula (II-1), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is R¹Selected from halogen, C_1-6Alkyl and C_1-6A haloalkyl group; and s is 0, 1 or 2.

IN some preferred embodiments of the present disclosure, the compound of formula (IM), formula (IN-1), formula (I-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R is R²Are the same or different and are each independently selected from halogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkyl and C_1-6A haloalkoxy group; and m is 0 or 1.

In some preferred embodiments of the present disclosure, the compound of formula (II), formula (II-1), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R is²Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkyl and C_1-6HaloalkoxyA group; and m is 4.

In some preferred embodiments of the present disclosure, the compound of formula (IM), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is^xIs C_1-6Alkyl or

R^yIs a hydrogen atom or a halogen; ring a is 6-to 10-membered aryl or 5-to 10-membered heteroaryl; ring B is a 3-to 12-membered heterocyclyl; ring C is selected from 3-to 8-membered cycloalkyl, 3-to 12-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 10-membered heteroaryl; l is a bond or an oxygen atom; each R is¹Are the same or different and are each independently selected from halogen, C_1-6Alkyl and C_1-6A haloalkyl group; each R is²Are the same or different and are each independently selected from halogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkyl and C_1-6A haloalkoxy group; s is 0, 1 or 2; m is 0 or 1; n is 0.

IN some preferred embodiments of the present disclosure, the compound of formula (IN), formula (IN-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is^xIs C_1-6Alkyl or

Ring a is 6-to 10-membered aryl or 5-to 10-membered heteroaryl; ring B is a 3-to 12-membered heterocyclyl; ring C is selected from 3-to 8-membered cycloalkyl, 3-to 12-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 10-membered heteroaryl; l is a bond or an oxygen atom; each R is¹Are the same or different and are each independently selected from halogen, C_1-6Alkyl and C_1-6A haloalkyl group; each R is²Are the same or different and are each independently selected from halogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkyl and C_1-6Halogenated alkoxy(ii) a s is 0, 1 or 2; m is 0 or 1; n is 0.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (I-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring a is 6-to 10-membered aryl or 5-to 10-membered heteroaryl; ring B is a 3-to 12-membered heterocyclyl; ring C is selected from 3-to 8-membered cycloalkyl, 3-to 12-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 10-membered heteroaryl; l is a bond or an oxygen atom; each R is¹Are the same or different and are each independently selected from halogen, C_1-6Alkyl and C_1-6A haloalkyl group; each R is²Are the same or different and are each independently selected from halogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkyl and C_1-6A haloalkoxy group; s is 0, 1 or 2; m is 0 or 1; n is 0.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (I-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring a is a 6-to 10-membered aryl group; ring B is a 5 or 6 membered heteroA cyclic group; ring C is a 3 to 6 membered cycloalkyl or 5 or 6 membered heteroaryl; l is a bond or an oxygen atom; each R is¹Are the same or different and are each independently selected from halogen, C_1-6Alkyl and C_1-6A haloalkyl group; each R is²Are the same or different and are each independently selected from halogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkyl and C_1-6A haloalkoxy group; s is 0, 1 or 2; m is 0 or 1; n is 0.

In some preferred embodiments of the present disclosure, the compound of formula (II), formula (II-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein W is¹To W⁵Is a carbon atom; ring B is a 5 or 6 membered heterocyclyl; ring C is selected from 3 to 6 membered cycloalkyl, 3 to 6 membered heterocyclyl and 5 or 6 membered heteroaryl; l is a bond or an oxygen atom; each R is¹Are the same or different and are each independently selected from halogen, C_1-6Alkyl and C_1-6A haloalkyl group; each R is²Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkyl and C_1-6A haloalkoxy group; s is 0, 1 or 2; m is 4; n is 0.

In some preferred embodiments of the present disclosure, the compound of formula (II), formula (II-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein W is¹To W⁵Is a carbon atom; ring B is a 5 or 6 membered heterocyclyl; ring C is a 3 to 6 membered cycloalkyl or 5 or 6 membered heteroaryl; l is a bond or an oxygen atom; each R is¹Are the same or different and are each independently selected from halogen, C_1-6Alkyl and C_1-6A haloalkyl group; each R is²Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkyl and C_1-6A haloalkoxy group; s is 0, 1 or 2; m is 4; n is 0.

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

another aspect of the present disclosure relates to a compound of formula (IMA), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

x is selected from chlorine atom, bromine atom and iodine atom; preferably, X is a bromine atom;

ring A, R²、R^x、R^yAnd m is as defined in formula (IM).

Another aspect of the present disclosure relates to a compound of formula (INA), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring A, R²、R^xAnd m is as defined IN formula (IN).

Another aspect of the present disclosure relates to a compound represented by the general formula (INA-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring A, R²、R^xAnd m is as defined IN the general formula (IN-1).

Another aspect of the present disclosure relates to a compound of formula (IA), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring A, ring B, R²、R³M and n are as defined in formula (I).

Another aspect of the present disclosure relates to a compound represented by general formula (IA-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring A, ring B, R²、R³M and n are as defined in the general formula (I-1).

Another aspect of the disclosure relates to a compound of formula (IIA), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring B, R²、R³、W¹To W⁵M and n are as defined in formula (II).

Another aspect of the present disclosure relates to a compound of formula (IIA-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring B, R²、R³、W¹To W⁵M and n are as defined in the general formula (II-1).

Typical compounds of the present disclosure include, but are not limited to:

another aspect of the present disclosure relates to a compound represented by the general formula (IMB), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring A, ring C, L, R¹、R²、R^x、R^yS and m are as defined in formula (IM).

Another aspect of the present disclosure relates to a compound of formula (INB), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring A, ring C, L, R¹、R²、R^xS and m are as defined IN formula (IN).

Another aspect of the present disclosure relates to a compound represented by the general formula (INB-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring A, ring C, L, R¹、R²、R^xS and m are as IN the formula (IN-1)And (4) defining.

Another aspect of the present disclosure relates to a compound of formula (IB), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring A, ring B, ring C, L, R¹To R³S, m and n are as defined in formula (I).

Another aspect of the present disclosure relates to a compound represented by the general formula (IB-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring A, ring B, ring C, L, R¹To R³S, m and n are as defined in the general formula (I-1).

Another aspect of the present disclosure relates to a compound of formula (IIB), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring B, ring C, L, R¹To R³S, m and n are as defined in formula (II).

Another aspect of the present disclosure relates to a compound represented by the general formula (IIB-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring B, ring C, L, R¹To R³S, m and n are as defined in the general formula (II-1).

The compound shown in the general formula (IMB), the general formula (INB-1), the general formula (IB-1), the general formula (IIB) and the general formula (IIB-1) or the tautomer, the racemate, the enantiomer, the diastereoisomer or the mixture form or the pharmaceutically acceptable salt form thereof, wherein the pharmaceutically acceptable salt is hydrochloride. Typical compounds of the present disclosure include, but are not limited to:

another aspect of the present disclosure relates to a method of preparing a compound of formula (IM), or a tautomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

carrying out Suzuki coupling reaction on the compound of the general formula (IMA) or a tautomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof or a pharmaceutically acceptable salt thereof and the compound of the general formula (V) to obtain the compound of the general formula (IM) or the tautomer, the racemate, the enantiomer, the diastereomer or a mixture form thereof or a pharmaceutically acceptable salt thereof;

wherein:

l is a chemical bond;

y is

R is a hydrogen atom or an alkyl group;

ring A, ring C, R¹、R²、R^x、R^yS and m are as defined in formula (IM).

Another aspect of the present disclosure relates to a method of preparing a compound represented by the general formula (IN), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

carrying out Suzuki coupling reaction on the compound of the general formula (INA) or a tautomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof or a pharmaceutically acceptable salt thereof and the compound of the general formula (V) to obtain the compound of the general formula (IN) or the tautomer, the racemate, the enantiomer, the diastereomer or a mixture form thereof or a pharmaceutically acceptable salt thereof;

wherein:

l is a chemical bond;

y is

R is a hydrogen atom or an alkyl group;

ring A, ring C, R¹、R²、R^xS and m are as defined IN formula (IN).

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (IN-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

carrying out Suzuki coupling reaction on the compound of the general formula (INA-1) or a tautomer, a racemate, an enantiomer, a diastereomer or a mixture thereof or a pharmaceutically acceptable salt thereof and the compound of the general formula (V) to obtain the compound of the general formula (IN-1) or the tautomer, the racemate, the enantiomer, the diastereomer or the mixture thereof or the pharmaceutically acceptable salt thereof;

wherein:

l is a chemical bond;

y is

R is a hydrogen atom or an alkyl group;

ring A, ring C, R¹、R²、R^xS and m are as defined IN the general formula (IN-1).

Another aspect of the present disclosure relates to a method of preparing a compound of formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

carrying out Suzuki coupling reaction on the compound of the general formula (IA) or a tautomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof or a pharmaceutically acceptable salt thereof and the compound of the general formula (V) to obtain the compound of the general formula (I) or the tautomer, the racemate, the enantiomer, the diastereomer or a mixture form thereof or a pharmaceutically acceptable salt thereof;

wherein:

l is a chemical bond;

y is

R is a hydrogen atom or an alkyl group;

ring A, ring B, ring C, R¹To R³S, m and n are as defined in formula (I).

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (I-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

carrying out Suzuki coupling reaction on the compound of the general formula (IA-1) or a tautomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof or a pharmaceutically acceptable salt thereof and the compound of the general formula (V) to obtain the compound of the general formula (I-1) or the tautomer, the racemate, the enantiomer, the diastereomer or a mixture form thereof or a pharmaceutically acceptable salt thereof;

wherein:

l is a chemical bond;

y is

R is a hydrogen atom or an alkyl group;

ring A, ring B, ring C, R¹To R³S, m and n are as defined in the general formula (I-1).

Another aspect of the present disclosure relates to a method of preparing a compound of formula (II), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

carrying out Suzuki coupling reaction on the compound of the general formula (IIA) or a tautomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof or a pharmaceutically acceptable salt thereof and the compound of the general formula (V) to obtain the compound of the general formula (II) or the tautomer, the racemate, the enantiomer, the diastereomer or a mixture form thereof or a pharmaceutically acceptable salt thereof;

wherein:

l is a chemical bond;

y is

R is a hydrogen atom or an alkyl group;

ring B, ring C, R¹To R³、W¹To W⁵S, m and n are as defined in formula (II).

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (II-1), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

carrying out Suzuki coupling reaction on the compound of the general formula (IIA-1) or a tautomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof or a pharmaceutically acceptable salt thereof and the compound of the general formula (V) to obtain the compound of the general formula (II-1) or the tautomer, the racemate, the enantiomer, the diastereomer or a mixture form thereof or a pharmaceutically acceptable salt thereof;

wherein:

l is a chemical bond;

y is

R is a hydrogen atom or an alkyl group;

ring B, ring C, R¹To R³、W¹To W⁵S, m and n are as defined in the general formula (II-1).

Another aspect of the present disclosure relates to a method of treating a compound of formula (IM), or a tautomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

a compound of the general formula (IMB) or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof (preferably hydrochloride) is subjected to a ring formation reaction to obtain a compound of the general formula (IM) or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or pharmaceutically acceptable salt thereof;

wherein:

ring A, ring C, L, R¹、R²、R^x、R^yS and m are as defined in formula (IM).

Another aspect of the present disclosure relates to a method of treating a compound of formula (IN), or a tautomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

a compound of the general formula (INB) or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof (preferably hydrochloride) is subjected to a cyclization reaction to obtain a compound of the general formula (IN) or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or pharmaceutically acceptable salt thereof;

wherein:

ring A, ring C, L, R¹、R²、R^xS and m are as defined IN formula (IN).

Another aspect of the present disclosure relates to a method of preparing a compound represented by the general formula (IN-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

a compound of the general formula (INB-1) or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof (preferably hydrochloride) is subjected to a cyclization reaction to obtain a compound of the general formula (IN-1) or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof;

wherein:

ring A, ring C, L, R¹、R²、R^xS and m are as defined IN the general formula (IN-1).

a compound of the general formula (IB) or a tautomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof (preferably hydrochloride) thereof is subjected to a ring formation reaction to obtain the compound of the general formula (I) or the tautomer, the racemate, the enantiomer, the diastereomer or a mixture thereof, or the pharmaceutically acceptable salt thereof;

wherein:

ring A, ring B, ring C, L, R¹To R³S, m and n are as defined in formula (I).

a compound of the general formula (IB-1) or a tautomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof (preferably hydrochloride) is subjected to a cyclization reaction to obtain the compound of the general formula (I-1) or the tautomer, the racemate, the enantiomer, the diastereomer or a mixture thereof, or the pharmaceutically acceptable salt thereof;

wherein:

a compound of the general formula (IIB) or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof (preferably hydrochloride) is subjected to a cyclization reaction to obtain a compound of the general formula (II) or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or pharmaceutically acceptable salt thereof;

wherein:

ring B, ring C, L, R¹To R³S, m and n are as defined in formula (II).

a compound of the general formula (IIB-1) or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof (preferably hydrochloride) is subjected to a cyclization reaction to obtain a compound of the general formula (II-1) or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof;

wherein:

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of formula (IM), formula (IN-1), formula (I-1), formula (II-1) and a compound of table a or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

The disclosure further relates to the use of a compound of formula (IM), formula (IN-1), formula (I-1), formula (II-1) and the compound of Table A or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, IN the manufacture of a medicament for the manufacture of a Myosin (Myosin) inhibitor.

The present disclosure further relates to the use of a compound of formula (IM), formula (IN-1), formula (I-1), formula (II-1) and a compound of table a or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt or pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment of a disease or disorder selected from the group consisting of diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, Hypertrophic Cardiomyopathy (HCM), nonallergic hypertrophic cardiomyopathy (nHCM), obstructive hypertrophic cardiomyopathy (oHCM), normal ejection fraction heart failure (HFpEF), intermediate ejection fraction ref heart failure (hfm), Valve disease, aortic stenosis, inflammatory cardiomyopathy, love endocarditis, myocardial endocardial fibrosis, invasive cardiomyopathy, hemochromatosis, fabry's disease, glycogen storage disease, congenital heart disease, french tetragon, left ventricular hypertrophy, refractory angina, and chagas disease; preferably selected from ischemic heart disease, restrictive cardiomyopathy, Hypertrophic Cardiomyopathy (HCM), non-obstructive hypertrophic cardiomyopathy (nHCM), obstructive hypertrophic cardiomyopathy (oHCM), inflammatory cardiomyopathy, invasive cardiomyopathy, congenital heart disease, and left ventricular hypertrophy; more preferably Hypertrophic Cardiomyopathy (HCM).

The present disclosure further relates to the use of a compound of formula (IM), formula (IN-1), formula (I-1), formula (II-1) and a compound of table a or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same IN the preparation of a medicament for the treatment of a disease or condition mediated by Myosin selected from diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, Hypertrophic Cardiomyopathy (HCM), non-obstructive hypertrophic cardiomyopathy (nHCM), obstructive cardiomyopathy (oHCM), normal ejection fraction heart failure (HFpEF), intermediate ejection fraction heart failure (HFmREF), valve disease, aortic stenosis, inflammatory disease, liener endocarditis, myocardial endocardial fibrosis cardiomyopathy, myocardial infarction, Invasive cardiomyopathy, hemochromatosis, fabry's disease, glycogen storage disease, congenital heart disease, falo tetrad, left ventricular hypertrophy, refractory angina pectoris, and chagas disease; preferably selected from ischemic heart disease, restrictive cardiomyopathy, Hypertrophic Cardiomyopathy (HCM), non-obstructive hypertrophic cardiomyopathy (nHCM), obstructive hypertrophic cardiomyopathy (oHCM), inflammatory cardiomyopathy, invasive cardiomyopathy, congenital heart disease, and left ventricular hypertrophy; more preferably Hypertrophic Cardiomyopathy (HCM).

The present disclosure further relates to a method of inhibiting Myosin (Myosin) comprising administering to a patient IN need thereof an effective inhibiting amount of a compound of formula (IM), formula (IN-1), formula (I-1), formula (II-1) and a compound of table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a method of treating a disease or condition selected from the group consisting of diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, Hypertrophic Cardiomyopathy (HCM), non-obstructive hypertrophic cardiomyopathy (nHCM), obstructive hypertrophic cardiomyopathy (oHCM), normal ejection fraction heart failure (HFpEF), intermediate ejection fraction heart failure (HFmREF), valve disease, aortic stenosis, inflammatory disease, liener endocarditis myocarditis, or a pharmaceutical composition comprising the same, comprising administering to a patient IN need thereof a therapeutically effective amount of a compound of formula (IM), formula (IN-1), formula (I-1), formula (II-1), and a compound of table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, Myocardial endocardial fibrosis, invasive cardiomyopathy, hemochromatosis, fabry's disease, glycogen storage disease, congenital heart disease, falo tetrad, left ventricular hypertrophy, refractory angina pectoris, and chagas disease; preferably selected from ischemic heart disease, restrictive cardiomyopathy, Hypertrophic Cardiomyopathy (HCM), non-obstructive hypertrophic cardiomyopathy (nHCM), obstructive hypertrophic cardiomyopathy (oHCM), inflammatory cardiomyopathy, invasive cardiomyopathy, congenital heart disease, and left ventricular hypertrophy; more preferably Hypertrophic Cardiomyopathy (HCM).

The present disclosure further relates to a method of treating a disease or condition mediated by Myosin, comprising administering to a patient IN need thereof a therapeutically effective amount of a compound of formula (IM), formula (IN-1), formula (I-1), formula (II-1), and a compound of formula (II-1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, selected from the group consisting of diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, Hypertrophic Cardiomyopathy (HCM), non-obstructive hypertrophic cardiomyopathy (nHCM), obstructive hypertrophic cardiomyopathy (oHCM), normal ejection fraction heart failure (HFpEF), intermediate ejection fraction heart failure (hfmmm), ref valve disease, aortic stenosis, inflammatory cardiomyopathy, Love endocarditis, myocardial endocardial fibrosis, invasive cardiomyopathy, hemochromatosis, fabry's disease, glycogen storage disease, congenital heart disease, Fallo tetrad, left ventricular hypertrophy, refractory angina and Chagas disease; preferably selected from ischemic heart disease, restrictive cardiomyopathy, Hypertrophic Cardiomyopathy (HCM), non-obstructive hypertrophic cardiomyopathy (nHCM), obstructive hypertrophic cardiomyopathy (oHCM), inflammatory cardiomyopathy, invasive cardiomyopathy, congenital heart disease, and left ventricular hypertrophy; more preferably Hypertrophic Cardiomyopathy (HCM).

The present disclosure further relates to compounds of formula (IM), formula (IN-1), formula (I-1), formula (II-1) and the compounds of table a or tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as a medicament.

The present disclosure further relates to compounds of formula (IM), formula (IN-1), formula (I-1), formula (II-1) and the compounds of table a or tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as Myosin (Myosin) inhibitors.

The present disclosure further relates to a compound of formula (IM), formula (IN-1), formula (I-1), formula (II-1) and a compound of table a or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use IN treating a disease or disorder selected from the group consisting of diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, Hypertrophic Cardiomyopathy (HCM), non-obstructive hypertrophic cardiomyopathy (nHCM), obstructive hypertrophic cardiomyopathy (oHCM), normal ejection fraction heart failure (HFpEF), intermediate ejection fraction heart failure (ref), valvular disease, heart failure, heart attack, heart disease, Aortic valve stenosis, inflammatory cardiomyopathy, love endocarditis, myocardial endocardial fibrosis, invasive cardiomyopathy, hemochromatosis, fabry's disease, glycogen storage disease, congenital heart disease, french tetragon, left ventricular hypertrophy, refractory angina pectoris, and chagas' disease; preferably selected from ischemic heart disease, restrictive cardiomyopathy, Hypertrophic Cardiomyopathy (HCM), non-obstructive hypertrophic cardiomyopathy (nHCM), obstructive hypertrophic cardiomyopathy (oHCM), inflammatory cardiomyopathy, invasive cardiomyopathy, congenital heart disease, and left ventricular hypertrophy; more preferably Hypertrophic Cardiomyopathy (HCM).

The present disclosure further relates to a compound of formula (IM), formula (IN-1), formula (I-1), formula (II-1), and a compound of table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use IN treating a disease or disorder mediated by Myosin, selected from diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, Hypertrophic Cardiomyopathy (HCM), non-obstructive cardiomyopathy (nHCM), obstructive hypertrophic cardiomyopathy (oHCM), normal ejection fraction heart failure (HFpEF), intermediate ejection fraction heart failure (HFmREF), valve disease, aortic stenosis, inflammatory disease, liener endocarditis, myocardial endocardial fibrotic cardiomyopathy, myocardial infarction, and other, myocardial infarction, invasive cardiomyopathy, hemochromatosis, fabry's disease, glycogen storage disease, congenital heart disease, falo tetrad, left ventricular hypertrophy, refractory angina pectoris, and chagas disease; preferably selected from ischemic heart disease, restrictive cardiomyopathy, Hypertrophic Cardiomyopathy (HCM), non-obstructive hypertrophic cardiomyopathy (nHCM), obstructive hypertrophic cardiomyopathy (oHCM), inflammatory cardiomyopathy, invasive cardiomyopathy, congenital heart disease, and left ventricular hypertrophy; more preferably Hypertrophic Cardiomyopathy (HCM).

The compounds of the general formula (IM), general formula (IN-1), general formula (I-1), general formula (II-1) and the compounds of Table A or tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, of the present disclosure can alter the natural history of HCM and other diseases, not just the alleviation of symptoms. The mechanisms that confer clinical benefit to HCM patients may be extended to patients with other forms of heart disease that share similar pathophysiology with or without significant genetic influence. For example, effective treatment of HCM by improving ventricular relaxation during diastole may also be effective for a wider range of populations characterized by diastolic dysfunction.

The compounds represented by the general formula (IM), the general formula (IN-1), the general formula (I-1), the general formula (II) and the general formula (II-1) of the present disclosure, as well as the compounds of the table A or tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, can specifically target the root cause of a disease or act on other downstream pathways. Accordingly, the compounds of the general formula (I) of the present disclosure, or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, may confer benefits to patients suffering from diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, or restrictive cardiomyopathy.

The compounds of formula (IM), formula (IN-1), formula (I-1), formula (II-1) and the compounds of table a or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same of the present disclosure may also promote beneficial ventricular remodeling of left ventricular hypertrophy due to volume or pressure overload; such as chronic mitral regurgitation, chronic aortic stenosis, or chronic systemic hypertension; the compounds or pharmaceutically acceptable salts thereof are combined with therapies aimed at correcting or reducing the main causes of volume or pressure overload (valve repair/replacement, effective antihypertensive therapy). By reducing left ventricular filling pressure, the compounds may reduce the risk of pulmonary edema and respiratory failure. Reducing or eliminating functional mitral regurgitation and/or reducing left atrial pressure may reduce the risk of sudden or persistent atrial fibrillation, and it reduces the concomitant risk of arterial thromboembolic complications, including but not limited to cerebral arterial embolic stroke. Reducing or eliminating dynamic and/or static left ventricular outflow tract obstructions may reduce the likelihood of the need for interval ablation therapy (surgical or percutaneous) and the attendant risks of its short-term and long-term complications.

The compounds of formula (IM), formula (IN-1), formula (I-1), formula (II-1) and the compounds of table a or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same of the present disclosure may reduce the severity of chronic ischemic conditions associated with HCM and thereby reduce the risk of Sudden Cardiac Death (SCD) or its equivalent IN patients with implantable cardioverter-defibrillators (frequent and/or repeated ICD discharges) and/or the need for potentially toxic antiarrhythmic drugs.

The compounds of formula (IM), formula (IN-1), formula (I-1), formula (II-1) and the compounds of table a or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, of the present disclosure may be valuable IN reducing or eliminating the need for concomitant medications with their attendant potential toxicity, drug-drug interactions, and/or side effects.

The compounds shown IN the general formula (IM), the general formula (IN-1), the general formula (I-1), the general formula (II) and the general formula (II-1) of the disclosure, as well as the compounds shown IN the table A, or tautomers, racemes, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, can reduce interstitial myocardial fibrosis and/or slow the progression of left ventricular hypertrophy, prevent or reverse left ventricular hypertrophy.

The active compounds may be formulated in a form suitable for administration by any suitable route, using one or more pharmaceutically acceptable carriers to formulate compositions of the disclosure by conventional methods. Thus, the active compounds of the present disclosure may be formulated in a variety of dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or insufflation. The compounds of the present disclosure may also be formulated in sustained release dosage forms, such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.

The dosage of the compound or composition used in the treatment methods of the present disclosure 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, the active compound is preferably in unit dosage form, or in such a way that the patient can self-administer it in a single dose. The unit dose of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled liquid, powder, granule, lozenge, suppository, reconstituted powder, or liquid. A suitable unit dose may be 0.1 to 1000 mg.

The pharmaceutical compositions of the present disclosure may contain, in addition to the active compound, one or more excipients 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.

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.

Dispersible powders and granules of the compounds of the present disclosure can be administered by the addition of water to prepare an aqueous suspension. These pharmaceutical compositions may be prepared by mixing the active ingredient with dispersing or wetting agents, suspending agents, or one or more preservatives.

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 mode of treatment, daily dose, or type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Description of the terms

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 carbon atoms (i.e., C)_1-12Alkyl), more preferably alkyl (i.e., C) having 1 to 6 carbon atoms (e.g., 1,2, 3, 4, 5, and 6)_1-6Alkyl groups). Non-limiting examples include: methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1-dimethylpropyl group, 1, 2-dimethylpropyl group, 2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1, 2-trimethylpropyl group, 1-dimethylbutyl group, 1, 2-dimethylbutyl group, 2-dimethylbutyl group, 1, 3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2, 3-dimethylbutyl group, n-heptyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 2-methylpentyl group, 3-methylhexyl group, 4-methylhexyl group, 2-dimethylpropyl group, 2-pentyl group, 2-methylpropyl group, 2-methyl-pentyl group, 3-pentyl group, 2-methyl-pentyl group, 2-pentyl group, and 3-pentyl group, 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-methylhexyl-3-ethylpentyl group, n-nonyl group, 2-methyl-2-ethylhexyl group, 2-methyl-3-ethylhexyl group, 2-diethylpentyl group, n-decyl group, 3-diethylhexyl group, 2-diethylhexyl group, various branched isomers thereof and the like. Most preferred is a lower alkyl group 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. Alkyl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, with the substituents preferably being selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkylene" refers to a saturated straight or branched aliphatic hydrocarbon radical, which is a residue 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 radical containing from 1 to 20 carbon atoms, preferably an alkylene radical containing from 1 to 12 carbon atoms (i.e., C)_1-12Alkylene) groups, more preferably alkylene groups (i.e., C) having 1 to 6 carbon atoms (e.g., 1,2, 3, 4, 5, and 6)_1-6Alkylene). 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, it may be any that may be usedSubstituted at the point of attachment, the substituents are preferably selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclylalkoxy, cycloalkylthio, heterocyclylthio, and oxo.

The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl radicals (i.e. C) containing from 2 to 12, for example 2,3, 4, 5,6,7,8, 9, 10, 11 and 12, carbon atoms are preferred_2-12Alkenyl), more preferably alkenyl having 2 to 6 carbon atoms (i.e., C)_2-6Alkenyl). The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl (i.e., C) groups containing 2 to 12 (e.g., 2,3, 4, 5,6,7,8, 9, 10, 11, and 12) carbon atoms are preferred_2-12Alkynyl), more preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C)_2-6Alkynyl). Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably selected from one or more of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

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 (i.e., 3 to 12 membered cycloalkyl groups), preferably 3 to 8 carbon atoms (e.g., 3, 4, 5,6,7, and 8) (i.e., 3 to 8 membered cycloalkyl groups), more preferably 3 to 6 carbon atoms (i.e., 3 to 6 membered cycloalkyl groups). 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 spirocycloalkyl, fused ring alkyl, 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 single rings, which may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). Spirocycloalkyl groups are classified as mono-or polyspirocycloalkyl (e.g., a bispyridyl cycloalkyl group), preferably mono-and bispyridyl, depending on the number of spiro atoms shared between rings. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/4-membered, 6-membered/5-membered or 6-membered/6-membered spirocycloalkyl. 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, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be divided into polycyclic fused-ring alkyls such as bicyclic, tricyclic, tetracyclic, etc., 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/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicycloalkyl. 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, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic, etc. polycyclic bridged cycloalkyl groups according to the number of constituent rings, preferably bicyclic, tricyclic, or tetracyclic bridged cycloalkyl groups, and more preferably bicyclic or tricyclic bridged cycloalkyl groups. Non-limiting examples of bridged cycloalkyl groups include:

the cycloalkyl ring includes a cycloalkyl ring (including monocyclic, spiro, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring as described above, wherein the rings attached to the parent structure are cycloalkyl, non-limiting examples of which include

Etc.; preference is given to

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, with the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkoxy" refers to-O- (alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic substituent comprising from 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form a sulfoxide or sulfone), but does not include the ring portion 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 1-4 (e.g., 1,2, 3 and 4) are heteroatoms (i.e., 3-to 12-membered heterocyclyl); more preferably 3 to 8 ring atoms (e.g., 3, 4, 5,6,7, and 8), wherein 1-3 are heteroatoms (e.g., 1,2, and 3) (i.e., 3-to 8-membered heterocyclyl); more preferably 3 to 6 ring atoms, of which 1-3 are heteroatoms (i.e. 3 to 6 membered heterocyclyl); most preferably 5 or 6 ring atoms, of which 1 to 3 are heteroatoms (i.e. a 5 or 6 membered heterocyclyl group). Non-limiting examples of monocyclic heterocyclic groups include: pyrrolidinyl, tetrahydropyranyl, 1, 2.3.6-tetrahydropyridinyl, 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 which shares a single atom (referred to as the spiro atom) between single rings, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), with the remaining ring atoms being carbon. It may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). Spiro heterocyclic groups are classified into a mono-spiro heterocyclic group or a multi-spiro heterocyclic group (e.g., a bis-spiro heterocyclic group), preferably a mono-spiro heterocyclic group and a bis-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered or 6-membered/6-membered mono spiroheterocyclyl. 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, one or more of the rings may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e. to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic, etc. polycyclic fused heterocyclic groups according to the number of constituting 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/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/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 not directly attached, which may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic, etc. polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic, or tetracyclic bridged heterocyclic groups, and more preferably bicyclic or tricyclic bridged heterocyclic groups. Non-limiting examples of bridged heterocyclic groups include:

the heterocyclyl ring includes a heterocyclyl (including monocyclic, spiroheterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring as described above, 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 substituted or unsubstituted and when substituted may be substituted at any available point of attachment, the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (fused polycyclic is a ring sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably a 6 to 10 membered aryl group, such as phenyl and naphthyl. Such aryl rings include those wherein the aryl ring as described above 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:

aryl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, with the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms (e.g., 1,2, 3, and 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Preferably 5 to 10 membered heteroaryl (e.g. 5,6,7,8, 9 or 10 membered), more preferably 5 or 6 membered heteroaryl, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:

heteroaryl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, with the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The above-mentioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups have a residue derived from the parent ring atom by removal of one hydrogen atom, or a residue 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 "amino protecting group" is intended to protect an amino group with a group that can be easily removed in order to keep the amino group unchanged when the rest of the molecule is subjected to a reaction. Non-limiting examples include: (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, t-butoxycarbonyl, acetyl, benzyl, allyl, and p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy or nitro.

The term "hydroxyl-protecting group" is a suitable group for hydroxyl protection known in the art, see the literature ("Protective Groups in Organic Synthesis", 5)^Th Ed.T.W.Greene&P.g.m.wuts). By way of example, preferably the hydroxyl protecting group is selected from (C)_1-10Alkyl or aryl)₃Silane groups (e.g., triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, etc.); c_1-10Alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C_1-6Alkoxy-substituted C_1-6Alkyl or phenyl substituted C_1-6Alkyl, most preferably C_1-4Alkoxy-substituted C_1-4Alkyl (e.g., methyl, t-butyl, benzyl, methoxymethyl (MOM), ethoxyethyl, etc.); (C)_1-10Alkyl or aryl) acyl (for example: formyl, acetyl, benzoyl, p-nitrobenzoyl, and the like); (C)_1-6Alkyl or C_6-10Aryl) sulfonyl; or (C)_1-6Alkoxy or C_6-10Aryloxy) carbonyl; an allyl group; 2-Tetrahydropyranyl (THP).

The term "cycloalkyloxy" refers to cycloalkyl-O-wherein cycloalkyl is as defined above.

The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

The term "aryloxy" refers to aryl-O-wherein aryl is as defined above.

The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.

The term "alkylthio" refers to an alkyl-S-group wherein alkyl is as defined above.

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

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

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

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

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

The term "hydroxy" refers to-OH.

The term "mercapto" refers to-SH.

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

The term "cyano" refers to — CN.

The term "nitro" means-NO₂。

The term "oxo" or "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.

The compounds of the present disclosure may also comprise isotopic derivatives thereof. The term "isotopic derivative" refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms. For example, having the structure of the present disclosure except that "deuterium" or "tritium" is substituted for hydrogen, or¹⁸F-fluorine labeling: (¹⁸Isotope of F) instead of fluorine, or with¹¹C-、¹³C-or¹⁴C-enriched carbon (C¹¹C-、¹³C-or¹⁴C-carbon labeling;¹¹C-、¹³c-or¹⁴C-isotopes) instead of carbon atoms are within the scope of the present disclosure. Such compounds are useful as analytical tools or probes in, for example, biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. The disclosure also includes various deuterated forms of the compounds. Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom. The person skilled in the art is able to synthesize the deuterated forms of the compounds with reference to the relevant literature. Commercially available deuterated starting materials can be used in preparing the deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated boranes, trideuteroborane in tetrahydrofuran, deuterated lithium aluminum hydrides, deuterated iodoethanes, and deuterated iodomethanes, among others. Deuterations can generally retain activity comparable to non-deuterated compounds and can achieve better metabolic stability when deuterated at certain specific sites, thereby achieving certain therapeutic advantages.

In the chemical structure of the compounds described in the present disclosure, a bond

Denotes an unspecified configuration, i.e. a bond if a chiral isomer is present in the chemical structure

Can be that

Or

Or at the same time contain

And

two configurations. In the chemical structure of the compounds described in the present disclosure, a bond

The configuration is not specified, i.e., either the Z configuration or the E configuration, or both configurations are contemplated.

"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 1 to 6, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. Those skilled in the art are able to ascertain (by experiment or theory) without undue effort, substitutions that are possible or impossible. 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 disclosed compounds which are safe and effective for use in a mammalian body and which possess the requisite biological activity. Salts may be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate group with an appropriate base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.

The term "solvate" as used herein refers to a physical association of a compound of the present disclosure with one or more, preferably 1-3, solvent molecules, whether organic or inorganic. The physical bonding includes hydrogen bonding. In some cases, for example, when one or more, preferably 1-3, solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be isolated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

By "prodrug" is meant a compound that can be converted in vivo under physiological conditions, for example, by hydrolysis in blood, to yield the active parent compound.

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

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

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

Synthesis of the Compounds of the disclosure

In order to achieve the purpose of the present disclosure, the present disclosure adopts the following technical solutions:

scheme one

The preparation method of the compound shown in the general formula (IM) or the tautomer, the racemate, the enantiomer, the diastereoisomer or the mixture form thereof or the pharmaceutically acceptable salt thereof comprises the following steps:

a compound of the general formula (IMA) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, with a compound of the general formula (V) in the presence of a metal catalyst under basic conditions to give a compound of the general formula (IM) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

wherein:

l is a chemical bond;

y is

R is a hydrogen atom or an alkyl group;

ring A, ring C, R¹、R²、R^x、R^yS and m are as defined in formula (IM).

Scheme two

The preparation method of the compound shown IN the general formula (IN) or the tautomer, the racemate, the enantiomer, the diastereoisomer or the mixture form thereof or the pharmaceutically acceptable salt thereof comprises the following steps:

carrying out Suzuki coupling reaction on a compound of a general formula (INA) or a tautomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof or a pharmaceutically acceptable salt thereof and a compound of a general formula (V) IN the presence of a metal catalyst under basic conditions to obtain a compound of a general formula (IN) or a tautomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof or a pharmaceutically acceptable salt thereof;

wherein:

l is a chemical bond;

y is

R is a hydrogen atom or an alkyl group;

ring A, ring C, R¹、R²、R^xS and m are as defined IN formula (IN).

Scheme three

The preparation method of the compound shown IN the general formula (IN-1) or the tautomer, the racemate, the enantiomer, the diastereomer or the mixture thereof or the pharmaceutically acceptable salt thereof comprises the following steps:

carrying out Suzuki coupling reaction on a compound of a general formula (INA-1) or a tautomer, a racemate, an enantiomer, a diastereomer or a mixture thereof or a pharmaceutically acceptable salt thereof and a compound of a general formula (V) IN the presence of a metal catalyst under basic conditions to obtain a compound of a general formula (IN-1) or a tautomer, a racemate, an enantiomer, a diastereomer or a mixture thereof or a pharmaceutically acceptable salt thereof;

wherein:

l is a chemical bond;

y is

R is a hydrogen atom or an alkyl group;

Scheme four

The preparation method of the compound shown in the general formula (I) or the tautomer, the racemate, the enantiomer, the diastereoisomer or the mixture form or the pharmaceutically acceptable salt form comprises the following steps:

carrying out Suzuki coupling reaction on a compound of a general formula (IA) or a tautomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof or a pharmaceutically acceptable salt thereof and a compound of a general formula (V) in the presence of a metal catalyst under basic conditions to obtain a compound of a general formula (I) or a tautomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof or a pharmaceutically acceptable salt thereof;

wherein:

l is a chemical bond;

y is

R is a hydrogen atom or an alkyl group;

ring A, ring B, ring C, R¹To R³S, m and n are as defined in formula (I).

Scheme five

A process for producing a compound represented by the general formula (I-1) of the present disclosure, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which comprises:

carrying out Suzuki coupling reaction on a compound of a general formula (IA-1) or a tautomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof or a pharmaceutically acceptable salt thereof and a compound of a general formula (V) in the presence of a metal catalyst under basic conditions to obtain a compound of a general formula (I-1) or a tautomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof or a pharmaceutically acceptable salt thereof;

wherein:

l is a chemical bond;

y is

R is a hydrogen atom or an alkyl group;

Scheme six

A compound of the general formula (II) of the present disclosure, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereofA process for the preparation of a pharmaceutically acceptable salt, which process comprises:

carrying out Suzuki coupling reaction on a compound of a general formula (IIA) or a tautomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof or a pharmaceutically acceptable salt thereof and a compound of a general formula (V) in the presence of a metal catalyst under basic conditions to obtain a compound of a general formula (II) or a tautomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof or a pharmaceutically acceptable salt thereof;

wherein:

l is a chemical bond;

y is

R is a hydrogen atom or an alkyl group;

Scheme seven

A process for preparing a compound of the general formula (II-1) of the present disclosure, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the process comprising:

carrying out Suzuki coupling reaction on the compound of the general formula (IIA-1) or a tautomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof or a pharmaceutically acceptable salt thereof and the compound of the general formula (V) in the presence of a metal catalyst under basic conditions to obtain the compound of the general formula (II-1) or the tautomer, the racemate, the enantiomer, the diastereomer or a mixture form thereof or a pharmaceutically acceptable salt thereof;

wherein:

l is a chemical bond;

y is

R is a hydrogen atom or an alkyl group;

Scheme eight

The method for preparing the compound shown in the general formula (IM) or the tautomer, the racemate, the enantiomer, the diastereoisomer or the mixture form thereof or the pharmaceutically acceptable salt thereof comprises the following steps:

performing a cyclization reaction on the compound of the general formula (IMB) or a tautomer, a racemate, an enantiomer, a diastereoisomer or a mixture form thereof, or a pharmaceutically acceptable salt (preferably hydrochloride) thereof in microwave to obtain the compound of the general formula (IM) or the tautomer, the racemate, the enantiomer, the diastereoisomer or a mixture form thereof, or the pharmaceutically acceptable salt thereof;

wherein:

ring A, ring C, L, R¹、R²、R^x、R^yS and m are as defined in formula (IM).

Scheme nine

The method for preparing the compound shown IN the general formula (IN) or the tautomer, the racemate, the enantiomer, the diastereoisomer or the mixture form thereof or the pharmaceutically acceptable salt thereof comprises the following steps:

performing a cyclization reaction on the compound of the general formula (INB) or a tautomer, a racemate, an enantiomer, a diastereoisomer or a mixture form thereof, or a pharmaceutically acceptable salt (preferably hydrochloride) thereof IN microwave to obtain the compound of the general formula (IN) or the tautomer, the racemate, the enantiomer, the diastereoisomer or a mixture form thereof, or the pharmaceutically acceptable salt thereof;

wherein:

ring A, ring C, L, R¹、R²、R^xS and m are as defined IN formula (IN).

Scheme ten

The method for preparing the compound shown IN the general formula (IN-1) or the tautomer, the racemate, the enantiomer, the diastereomer or the mixture thereof or the pharmaceutically acceptable salt thereof comprises the following steps:

performing a cyclization reaction on the compound of the general formula (INB-1) or a tautomer, a racemate, an enantiomer, a diastereoisomer or a mixture form thereof, or a pharmaceutically acceptable salt (preferably hydrochloride) thereof IN microwave to obtain the compound of the general formula (IN-1) or the tautomer, the racemate, the enantiomer, the diastereoisomer or a mixture form thereof, or the pharmaceutically acceptable salt thereof;

wherein:

Scheme eleven

A process for the preparation of a compound of the general formula (I) of the present disclosure, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

performing a cyclization reaction on the compound of the general formula (IB) or a tautomer, a racemate, an enantiomer, a diastereoisomer or a mixture form thereof, or a pharmaceutically acceptable salt (preferably hydrochloride) thereof in microwave to obtain the compound of the general formula (I) or the tautomer, the racemate, the enantiomer, the diastereoisomer or a mixture form thereof, or the pharmaceutically acceptable salt thereof;

wherein:

ring A, ring B, ring C, L, R¹To R³S, m and n are as defined in formula (I).

Scheme twelve

performing cyclization reaction on the compound of the general formula (IB-1) or a tautomer, a racemate, an enantiomer, a diastereoisomer or a mixture form thereof, or a pharmaceutically acceptable salt (preferably hydrochloride) thereof in microwave to obtain the compound of the general formula (I-1) or the tautomer, the racemate, the enantiomer, the diastereoisomer or a mixture form thereof, or the pharmaceutically acceptable salt thereof;

wherein:

Scheme thirteen

A process for the preparation of a compound of the general formula (II) of the present disclosure, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

performing a cyclization reaction on a compound of the general formula (IIB) or a tautomer, a racemate, an enantiomer, a diastereomer or a mixture thereof or a pharmaceutically acceptable salt thereof (preferably hydrochloride) in microwave to obtain a compound of the general formula (II) or a tautomer, a racemate, an enantiomer, a diastereomer or a mixture thereof or a pharmaceutically acceptable salt thereof;

wherein:

ring B, ring C, L, R¹To R³S, m and n are as defined in formula (II).

Scheme fourteen

performing cyclization reaction on the compound of the general formula (IIB-1) or a tautomer, a racemate, an enantiomer, a diastereoisomer or a mixture form thereof or a pharmaceutically acceptable salt (preferably hydrochloride) thereof in microwave to obtain the compound of the general formula (II-1) or the tautomer, the racemate, the enantiomer, the diastereoisomer or a mixture form thereof or a pharmaceutically acceptable salt thereof;

wherein:

ring B, ring C, L, R¹To R³S, m and n are as defined in formula (II-1)And (4) defining.

In the above reaction, the metal catalyst includes a metal palladium complex catalyst or a combination of a palladium-containing catalyst and a ligand. The metal palladium complex catalyst includes, but is not limited to, tetrakistriphenylphosphine palladium, bis (dibenzylideneacetone) palladium, chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium, [1,1 '-bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex, 1' -bis (dibenzylideneacetone) dichloropalladium or tris (dibenzylideneacetone) dipalladium. The palladium-containing catalyst includes, but is not limited to, palladium/carbon, palladium dichloride, palladium acetate, preferably palladium acetate; the ligand includes but is not limited to triphenylphosphine, tricyclohexylphosphine, tri-n-butylphosphine, trimethoxy phosphine, etc.; tricyclohexylphosphine is preferred.

In the above reaction, the base includes organic bases including but not limited to triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, and inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide; potassium phosphate is preferred.

The above reaction is preferably carried out in a solvent, including but not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, N-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, N-hexane, dimethyl sulfoxide, 1, 4-dioxane, water, N-dimethylformamide, N-dimethylacetamide, 1, 2-dibromoethane, and mixtures thereof.

The reaction temperature of the microwave reaction is 110-140 ℃, and preferably 120 ℃.

The reaction time of the microwave reaction is 0.5 to 4 hours; preferably 1-2 hours; more preferably 1 or 1.5 hours.

Detailed Description

The present disclosure is further described below with reference to examples, but these examples do not limit the scope of the present disclosure.

Examples

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 a Bruker AVANCE-400 nuclear magnetic instrument or Bruker AVANCE NEO 500M in deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated chloroform (CDCl)₃) Deuterated methanol (CD)₃OD), internal standard Tetramethylsilane (TMS).

MS was measured using an Agilent 1200/1290DAD-6110/6120Quadrupole MS LC MS (manufacturer: Agilent, MS model: 6110/6120Quadrupole MS), waters ACQuity UPLC (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultrate 3000-Q active (manufacturer: THERMO, MS model: THERMO Q active).

High Performance Liquid Chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 HPLC.

Chiral HPLC analytical determination using Agilent 1260DAD liquid chromatograph.

High Performance liquid preparation A preparative chromatograph was used from Waters 2767, Waters 2767-SQ Detector 2, Shimadzu LC-20AP and Gilson-281.

Chiral preparation was performed using Shimadzu LC-20AP preparative chromatograph.

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

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.

Average inhibition rate of kinase and IC₅₀The values were determined with a NovoStar microplate reader (BMG, Germany).

Known starting materials of the present disclosure may be synthesized using 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, nephelo Chemical science and technology (Accela ChemBio Inc), dare 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: n-hexane/ethyl acetate system, B: the volume ratio of the solvent in the dichloromethane/methanol system is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.

Example 1

(6S,7S) -7- (5-cyclopropyl-2-fluorophenyl) -6-fluoro-3- (tetrahydro-2H-pyran-4-yl) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidine-2, 4(1H,3H) -dione 1

First step of

(2R,3S) -3- (5-bromo-2-fluorophenyl) -3- ((R) -1, 1-dimethylethylenesulfonamido) -2-fluoropropionic acid Ethyl ester 1c

(R, E) -N- (5-bromo-2-fluorobenzylidene) -2-methylpropane-2-sulfinamide 1a (8.6g, 28.2mmol, prepared by a method known in the literature "J.Med.chem, 2019,62, 9618-. Cooled to-70 ℃ and 1M lithium bis (trimethylsilyl) amide in tetrahydrofuran (42.3mL, 42.3mmol, Shanghai Tantake Technology Co., Ltd.) was added dropwise. The reaction was stirred at-70 ℃ for 3 hours under nitrogen. The reaction was quenched by addition of 1N HCl at-20 ℃. Saturated ammonium chloride solution (80mL) was added and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (80 mL. times.2), and the organic phases were combined and washed with saturated sodium chloride solution (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 1c (6.9g, yield: 59.5%).

MS m/z(ESI):412.0[M+1]。

Second step of

(2R,3S) -3- (5-bromo-2-fluorophenyl) -3- ((R) -1, 1-dimethylethylenesulfonamido) -2-fluoropropionic acid 1d

Compound 1c (1.0g, 2.4mmol) was dissolved in tetrahydrofuran (9mL) and 1N sodium hydroxide solution (4.8mL, 4.8mmol) was added. The reaction was stirred for 4 hours. Water (20mL) was added to dilute the solution, and the solution was washed with ethyl acetate (10 mL. times.2). The aqueous phase was adjusted to pH 5 with saturated aqueous citric acid. Concentrating under reduced pressure, and purifying by high performance liquid chromatography (SharpSil T-C18, 5 μm,30mm x 150mm, elution system: H)₂O (0.1% trifluoroacetic acid), acetonitrile from 25% (v/v) to 95% (v/v) in 18 minutes, detection wavelength 214&254nm) to yield the title product 1d (500.0mg, yield: 53.7%).

MS m/z(ESI):384.0[M+1]。

The third step

(R) -N- ((1S,2R) -1- (5-bromo-2-fluorophenyl) -2-fluoro-3-oxo-3- (2,4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) propyl) -2-methylpropane-2-sulfinamide 1f

Compound 1d (400.0mg, 1.1mmol), 1- (tetrahydro-2H-pyran-4-yl) pyrimidine-2, 4,6(1H,3H,5H) -trione 1e (332.1mg, 1.6mmol, prepared using methods well known for the synthesis of compounds 2-3 on page 50 of the document "WO 2020092208a 1") and 2- (7-azabenzotriazole) -N, N' -tetramethylurea hexafluorophosphate (596.6mg, 1.6mmol, shanghai co ltd, shao) were dissolved in N, N-dimethylformamide (7 mL). Diisopropylethylamine (3.1g, 16.6mmol, Shanghai Tantake Techno Co., Ltd.) was added at 0 ℃ and stirred at room temperature for 16 hours. The reaction was quenched by the addition of saturated sodium bicarbonate solution (20mL) and extracted with ethyl acetate (50 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title product, crude 1f (1.4g), which was used in the next step without purification.

MS m/z(ESI):578.0[M+1]。

The fourth step

(R) -N- ((1S,2R) -1- (5-bromo-2-fluorophenyl) -2-fluoro-3- (2,4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) propyl) -2-methylpropane-2-sulfinamide 1g

The crude compound 1f (700.0mg, 1.2mmol) was dissolved in acetic acid (7 mL). Sodium cyanoborohydride (191.0mg, 3.0mmol, Shaoshima technologies Shanghai, Inc.) was added under ice bath. The reaction was stirred at room temperature for 1 hour. Ice water (20mL) was added, and extraction was performed with ethyl acetate (20 mL. times.3). The organic phases were combined and washed with saturated sodium chloride solution (10 mL. times.2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title product 1g of crude product (700.0mg) which was used in the next step without purification.

MS m/z(ESI):564.0[M+1]。

The fifth step

5- ((2S,3S) -3-amino-3- (5-bromo-2-fluorophenyl) -2-fluoropropyl) -1- (tetrahydro-2H-pyran-4-yl) pyrimidine-2, 4,6(1H,3H,5H) -trione hydrochloride 1H

1g of crude compound (700.0mg, 1.2mmol) was dissolved in ethanol (7 mL). Thionyl chloride (142.8mg, 1.2mmol, Shanghai Kagaku Kogyo Co., Ltd.) was added thereto at 0 ℃. Stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure to give the title product as a 1h crude product (620.0mg) which was used in the next step without further purification.

MS m/z(ESI):460.0[M+1]。

The sixth step

(6S,7S) -7- (5-bromo-2-fluorophenyl) -6-fluoro-3- (tetrahydro-2H-pyran-4-yl) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidine-2, 4- (1H,3H) -dione 1i

Compound 1h crude (620mg, 1.3mmol) was suspended in acetonitrile (9 mL). The reaction was carried out at 120 ℃ for 1 hour by microwave. Concentration under reduced pressure and purification of the resulting residue by silica gel column chromatography with eluent system B gave the title product 1i (200.0mg, yield from compound 1 d: 86.2%).

MS m/z(ESI):441.9[M+1]。

Seventh step

Compound 1i (160.0mg, 0.36mmol), cyclopropylboronic acid 1j (94.0g, 1.1mmol, Shaoyuan Shanghai science, Inc.), tricyclohexylphosphine (40.3mg, 0.15mmol, Shaoyuan Shanghai science, Inc.) and potassium phosphate (233.2mg, 1.1mmol, Beijing Bailingwei science, Inc.) were dissolved in toluene (5mL) and water (1 mL). Palladium acetate (16.0mg, 0.07mmol, Ikay technologies, Inc. of Beijing) was added. The nitrogen was replaced three times. The reaction was stirred at 100 ℃ for 16 hours under nitrogen. Concentrating under reduced pressure, and purifying by high performance liquid chromatography (SharpSil T-C18, 5 μm,30mm x 150mm, elution system: H)₂O (0.1% trifluoroacetic acid), acetonitrile rising from 30% (v/v) to 95% (v/v) in 23 minutes, detection wavelength 214&254nm) to give the title product 1(18.0mg, yield: 12.4%).

MS m/z(ESI):404.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ10.22(s,1H),7.19-6.99(m,3H),6.46(s,1H),5.10-4.83(m,3H),3.91(dd,2H),3.33-3.30(m,2H),2.73-2.49(m,4H),1.97-1.92(m,1H),1.39(d,2H),0.95(dd,2H),0.67-0.55(m,2H)。

Example 2

(6S,7S) -6-fluoro-7- (2-fluoro-5- ((6- (trifluoromethyl) pyridin-3-yl) oxy) phenyl) -3- (tetrahydro-2H-pyran-4-yl) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidine-2, 4(1H,3H) -dione 2

First step of

2-fluoro-5- ((6- (trifluoromethyl) pyridin-3-yl) oxy) benzaldehyde 2c

2-fluoro-5-hydroxybenzaldehyde 2a (500mg, 3.57mmol, adamas) and 5-fluoro-2- (trifluoromethyl) pyridine 2b (1.2g, 7.27mmol, adamas) were dissolved in N, N-dimethylformamide (10mL), and potassium carbonate (1.0g, 7.25mmol) was added and reacted at 110 ℃ for 0.5 hour. Water (50mL) was added, extraction was performed with ethyl acetate (20 mL. times.2), the organic phases were combined, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 2c (300mg, yield: 29.5%).

MS m/z(ESI):285.8[M+1]。

Second step of

(R) -N- (2-fluoro-5- ((6- (trifluoromethyl) pyridin-3-yl) oxy) benzylidene) -2-methylpropane-2-sulfinamide 2e

Compound 2c (300mg, 1.05mmol) and (R) -2-methylpropane-2-sulfinamide 2d (130mg, 1.07mmol, adamas) were dissolved in dichloromethane (5mL), cesium carbonate (410mg, 1.26mmol) was added, and stirring was carried out at room temperature for 16 hours. Filtration and concentration gave the crude title product 2e (400mg, yield: 97.9%).

MS m/z(ESI):388.9[M+1]。

The third step

(2R,3S) -3- (((R) -tert-butylsulfinyl) amino) -2-fluoro-3- (2-fluoro-5- ((6- (trifluoromethyl) pyridin-3-yl) oxy) phenyl) propanoic acid ethyl ester 2f

Compound 2e (350mg, 1.12mmol), compound 1b (180mg, 1.70mmol, Shanghai Tantake Technique, Inc.) and N, N, N ', N' -tetramethylethylenediamine (0.3mL, Shanghai Aladdin Biotech, Inc.) were dissolved in anhydrous tetrahydrofuran (5.0 mL). Cooled to-78 deg.C, and a 1M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (1.7mL, 1.7mmol, Shanghai Tantake Technology Co., Ltd.) was added dropwise. Stirring at-78 deg.C for 3 hr under nitrogen protection. The reaction was quenched by addition of 1N hydrochloric acid at-20 ℃. Saturated ammonium chloride solution (20mL) was added and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (100mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 2f (320mg, yield: 68.3%).

MS m/z(ESI):494.8[M+1]。

The fourth step

(2R,3S) -3- (((R) -tert-butylsulfinyl) amino) -2-fluoro-3- (2-fluoro-5- ((6- (trifluoromethyl) pyridin-3-yl) oxy) phenyl) propanoic acid 2g

Compound 2f (250mg, 0.506mmol) was dissolved in tetrahydrofuran (3.0mL) and 1N aqueous sodium hydroxide (1.0mL, 1.0mmol) was added at 0 ℃. Stirred at room temperature for 2 hours. The pH was adjusted to 5 with saturated aqueous citric acid. Concentrating under reduced pressure, and purifying by high performance liquid chromatography (SharpSil T-C18, 5 μm,30mm x 150mm, elution system: H)₂O (0.1% trifluoroacetic acid), acetonitrile rising from 10% (v/v) to 90% (v/v) within 18 minutes, detection wavelength 214&254nm) to obtain 2g of the title product (180mg, yield: 76.3%).

MS m/z(ESI):466.8[M+1]。

The fifth step

(R) -N- ((1S,2R) -2-fluoro-1- (2-fluoro-5- ((6- (trifluoromethyl) pyridin-3-yl) oxy) phenyl) -3-oxo-3- (2,4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) propyl) -2-methylpropane-2-sulfinamide 2H

Compound 2g (180mg, 0.386mmol), compound 1e (120mg, 0.565mmol) and 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (220mg, 0.579mmol) were dissolved in N, N-dimethylformamide (3.0 mL). Diisopropylethylamine (150mg, 1.16mmol) was added at 0 ℃ and stirred at room temperature for 16 hours. Quenched by addition of saturated sodium bicarbonate solution (20mL) and extracted with ethyl acetate (10 mL. times.3). The organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave the title product as a 2h crude product (260mg, 101.2%) which was used in the next step without further purification.

MS m/z(ESI):661.0[M+1]。

The sixth step

(R) -N- ((1S,2S) -2-fluoro-1- (2-fluoro-5- ((6- (trifluoromethyl) pyridin-3-yl) oxy) phenyl) -3- (2,4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) propyl) -2-methylpropane-2-sulfinamide 2i

Compound 2h (250mg, 0.378mmol) was dissolved in acetic acid (3.0 mL). Sodium cyanoborohydride (60.0mg, 0.952mmol) was added under ice bath. The reaction was stirred at room temperature for 1 hour. Ice water (20mL) was added, and extraction was performed with ethyl acetate (20 mL. times.3). The organic phases were combined, washed with saturated sodium chloride solution (10mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title product, crude 2i (240mg, 98.1%), which was used in the next step without purification.

MS m/z(ESI):647.0[M+1]。

Seventh step

5- ((2S,3S) -3-amino-2-fluoro-3- (2-fluoro-5- ((6- (trifluoromethyl) pyridin-3-yl) oxy) phenyl) propyl) -1- (tetrahydro-2H-pyran-4-yl) pyrimidine-2, 4,6(1H,3H,5H) -trione hydrochloride 2j

Compound 2i (240mg, 0.371mmol) was dissolved in ethanol (3.0mL) and thionyl chloride (50.0mg, 0.420mmol) was added at 0 ℃. Stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure to give the title product 2j crude (200mg, 93.1%) which was used in the next step without purification.

MS m/z(ESI):542.8[M+1]。

Eighth step

The crude compound 2j (200mg, 1.3mmol) was suspended in acetonitrile (3.0 mL). The reaction was carried out at 120 ℃ for 1 hour by microwave. Concentrating under reduced pressure, and purifying by high performance liquid chromatography (Boston Phlex C18, 5 μm,30 mm. about.150 mm, elution system: H)₂O (10mmol ammonium bicarbonate), acetonitrile, from 38% (v/v) to 95% (v/v) in 18 minutes, detection wavelength 214&254nm) to yield the title product 2(100mg, 51.7%). MS M/z (ESI) 525.0[ M +1]]。

¹H NMR(500MHz,DMSO-d₆)δ10.31(s,1H),8.53(d,1H),7.92(d,1H),7.54(m,1H),7.42(m,1H),7.31(m,1H),7.22(m,1H),6.49(s,1H),5.13(m 1H),5.00(m 1H),4.85(m 1H),3.91-3.89(m 2H),3.31-3.29(m 2H),2.76-2.55(m,4H),1.39-1.35(m,2H)。

Example 3

(6S,7S) -6-fluoro-7- (2-fluoro-5- ((6-methylpyridin-3-yl) oxy) phenyl) -3- (tetrahydro-2H-pyran-4-yl) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidine-2, 4(1H,3H) -dione 3

First step of

2-fluoro-5- ((6-methylpyridin-3-yl) oxy) benzaldehyde 3c

6-methylpyridin-3-ol 3a (1.0g, 9.16mmol, Shanghai Biao pharmaceutical science and technology Co., Ltd.) and (4-fluoro-3-formylphenyl) boronic acid 3b (2.0g, 11.9mmol, Shanghai Han chemical science and technology Co., Ltd.) were dissolved in dichloromethane (10mL), pyridine (1.5g, 18.8mmol, adamas), triethylamine (1.9g, 18.8mmol, adamas), anhydrous copper acetate (3.4g, 18.8mmol, Shanghai Biao pharmaceutical science and technology Co., Ltd.) were added and reacted at room temperature for 24 hours. Filtration and concentration under reduced pressure, and purification of the resulting residue by silica gel column chromatography with eluent system A gave the title product 3c (650mg, yield: 30.7%).

MS m/z(ESI):231.9[M+1]。

Second step of

(R) -N- (2-fluoro-5- ((6-methylpyridin-3-yl) oxy) benzylidene) -2-methylpropane-2-sulfinamide 3d

Compound 3c (650mg, 2.81mmol) and compound 2d (345mg, 2.84mmol) were dissolved in dichloromethane (10mL), cesium carbonate (1.1g, 3.37mmol) was added, and the mixture was stirred at room temperature for 16 hours. Filtration and concentration gave the title product as crude 3d (940mg, yield: 100%).

MS m/z(ESI):334.9[M+1]。

The third step

(2R,3S) -3- (((R) -tert-butylsulfinyl) amino) -2-fluoro-3- (2-fluoro-5- ((6-methylpyridin-3-yl) oxy) phenyl) propanoic acid ethyl ester 3e

Compound 3d (340mg, 1.02mmol), compound 1b (170mg, 1.60mmol) and N, N, N ', N' -tetramethylethylenediamine (0.3mL, Shanghai Aladdin Biotech Co., Ltd.) were dissolved in anhydrous tetrahydrofuran (5.0 mL). Cooled to-78 deg.C, and a 1M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (1.6mL, 1.6mmol, Shanghai Tantake Technology Co., Ltd.) was added dropwise. Stirring at-78 deg.C for 1 hr under nitrogen protection. The reaction was quenched by addition of 1N hydrochloric acid at-20 ℃. Saturated ammonium chloride solution (20mL) was added and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (100mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 3e (400mg, yield: 89.3%).

MS m/z(ESI):440.9[M+1]。

The fourth step

(2R,3S) -3- (((R) -tert-butylsulfinyl) amino) -2-fluoro-3- (2-fluoro-5- ((6-methylpyridin-3-yl) oxy) phenyl) propanoic acid 3f

Compound 3e (400mg, 0.908mmol) was dissolved in tetrahydrofuran (5.0mL) and 1N sodium hydroxide solution (2.0mL, 2.0mmol) was added at 0 ℃. Stirred at room temperature for 2 hours. The pH was adjusted to 5 with saturated aqueous citric acid. Concentrating under reduced pressure, and purifying by high performance liquid chromatography (SharpSil T-C18, 5 μm,30mm x 150mm, elution system: H)₂O (0.1% trifluoroacetic acid), acetonitrile rising from 10% (v/v) to 90% (v/v) within 18 minutes, detection wavelength 214&254nm) to give the title product 3f (280mg, yield: 74.7%).

MS m/z(ESI):412.9[M+1]。

The fifth step

(R) -N- ((1S,2R) -2-fluoro-1- (2-fluoro-5- ((6-methylpyridin-3-yl) oxy) phenyl) -3-oxo-3- (2,4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) propyl) -2-methylpropane-2-sulfinamide 3g

Compound 3f (280mg, 0.679mmol), compound 1e (210mg, 0.990mmol) and 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (390mg, 1.03mmol) were dissolved in N, N-dimethylformamide (5.0 mL). Diisopropylethylamine (370mg, 2.86mmol) was added at 0 ℃ and stirred at room temperature for 16 hours. Quenched by addition of saturated sodium bicarbonate solution (20mL) and extracted with ethyl acetate (10 mL. times.3). The organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave the title product as 3g of crude product (420mg, 102%) which was used in the next step without further purification.

MS m/z(ESI):607.1[M+1]。

The sixth step

(R) -N- ((1S,2S) -2-fluoro-1- (2-fluoro-5- ((6-methylpyridin-3-yl) oxy) phenyl) -3- (2,4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) propyl) -2-methylpropane-2-sulfinamide 3H

3g (400mg, 0.659mmol) of the compound was dissolved in acetic acid (4.0 mL). Sodium cyanoborohydride (110mg, 1.75mmol) was added under ice bath. The reaction was stirred at room temperature for 1 hour. Ice water (20mL) was added, and extraction was performed with ethyl acetate (20 mL. times.3). The organic phases were combined, washed with saturated sodium chloride solution (10mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title product as a 3h crude product (400mg, 102.4%) which was used in the next step without purification.

MS m/z(ESI):593.1[M+1]。

Seventh step

5- ((2S,3S) -3-amino-2-fluoro-3- (2-fluoro-5- ((6-methylpyridin-3-yl) oxy) phenyl) propyl) -1- (tetrahydro-2H-pyran-4-yl) pyrimidine-2, 4,6(1H,3H,5H) -trione hydrochloride 3i

Compound 3h (390mg, 0.658mmol) was dissolved in ethanol (5.0mL) and thionyl chloride (100mg, 0.840mmol) was added at 0 ℃. Stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure to give the title product, crude 3i (350mg, 101.3%), which was used in the next step without purification.

MS m/z(ESI):489.1[M+1]。

Eighth step

Crude Compound 3i (350mg, 0.666 mmo)l) was suspended in acetonitrile (7.0 mL). The reaction was carried out at 120 ℃ for 1 hour by microwave. Concentrating under reduced pressure, and purifying by high performance liquid chromatography (Boston Phlex C18, 5 μm,30 mm. about.150 mm, elution system: H)₂O (10mmol ammonium bicarbonate), acetonitrile, from 33% (v/v) to 90% (v/v) in 20 minutes, detection wavelength 214&254nm) to yield the title product 3(90mg, 28.7%).

MS m/z(ESI):471.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ10.34(s,1H),8.23(d,1H),7.36-7.28(m,3H),7.10(m,1H),7.04(m,1H),6.49(s,1H),5.09(m,1H),4.95(m,1H),4.85(m,1H),3.92-3.89(m,2H),3.31-3.29(m,2H),2.74-2.55(m,4H),2.46(s,3H),1.39-1.36(m,2H)。

Example 4

(R) -7- (2-fluoro-5- ((6-methylpyridin-3-yl) oxy) phenyl) -3- (tetrahydro-2H-pyran-4-yl) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidine-2, 4(1H,3H) -dione 4

First step of

(S) -N- (2-fluoro-5- ((6-methylpyridin-3-yl) oxy) benzylidene) -2-methylpropane-2-sulfinamide 4b

Compound 3c (310mg, 1.34mmol) and (S) -2-methylpropane-2-sulfinamide 4a (140mg, 1.40mmol, from Shanghai Biao pharmaceutical science Co., Ltd.) were dissolved in dichloromethane (5.0mL), and cesium carbonate (530mg, 1.62mmol) was added and stirred at room temperature for 16 hours. Filtration and concentration under reduced pressure, and purification of the resulting residue by silica gel column chromatography with eluent system A gave the title product 4b (430mg, yield: 95.9%).

MS m/z(ESI):335.0[M+1]。

Second step of

(R) -3- ((S) -1, 1-Dimethylethylsulfonamido) -3- (2-fluoro-5- ((6-methylpyridin-3-yl) oxy) phenyl) propanoic acid Ethyl ester 4d

Activated zinc powder (150mg,2.29mmol) was suspended in anhydrous tetrahydrofuran (3.0mL), and a solution of compound 4b (250mg, 0.747mmol) and ethyl bromoacetate 4c (380mg, 2.28mmol, Shaoshima technologies (Shanghai) Co., Ltd.) in anhydrous tetrahydrofuran (3.0mL) was added under a nitrogen atmosphere. The reaction was carried out at 70 ℃ for 1 hour. Filtration and concentration under reduced pressure, and purification of the resulting residue by silica gel column chromatography with eluent system A gave the title product 4d (270mg, yield: 85.4%).

MS m/z(ESI):423.1[M+1]。

The third step

(R) -3- ((S) -1, 1-Dimethylethylsulfonamido) -3- (2-fluoro-5- ((6-methylpyridin-3-yl) oxy) phenyl) propanoic acid 4e

Compound 4d (270mg, 0.639mmol) was dissolved in tetrahydrofuran (5.0mL), and 1N aqueous sodium hydroxide (1.3mL, 1.3mmol) was added at 0 ℃. Stirred at room temperature for 2 hours. The pH was adjusted to 5 with saturated aqueous citric acid. Concentrating under reduced pressure, and purifying by high performance liquid chromatography (SharpSil T-C18, 5 μm,30mm x 150mm, elution system: H)₂O (0.1% trifluoroacetic acid), acetonitrile rising from 10% (v/v) to 90% (v/v) within 18 minutes, detection wavelength 214&254nm) to give the title product 4e (160mg, yield: 63.4%).

MS m/z(ESI):394.9[M+1]。

The fourth step

(S) -N- ((1R) -1- (2-fluoro-5- ((6-methylpyridin-3-yl) oxy) phenyl) -3-oxo-3- (2,4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) propyl) -2-methylpropane-2-sulfinamide 4f

Compound 4e (160mg, 0.406mmol), compound 1e (130mg, 0.613mmol) and 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (230mg, 0.605mmol) were dissolved in N, N-dimethylformamide (2.0 mL). Diisopropylethylamine (160mg, 1.24mmol) was added at 0 ℃ and stirred at room temperature for 16 hours. Quenched by addition of saturated sodium bicarbonate solution (20mL) and extracted with ethyl acetate (10 mL. times.3). The organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave the title product, crude 4f (240mg, 100.5%) which was used in the next step without purification.

MS m/z(ESI):589.1[M+1]。

The fifth step

(S) -N- ((1R) -1- (2-fluoro-5- ((6-methylpyridin-3-yl) oxy) phenyl) -3- (2,4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) propyl) -2-methylpropane-2-sulfinamide 4g

Compound 4f (240mg, 0.407mmol) was dissolved in acetic acid (3.0 mL). Sodium cyanoborohydride (65mg, 1.03mmol) was added under ice bath. The reaction was stirred at room temperature for 1 hour. Ice water (20mL) was added, and extraction was performed with ethyl acetate (15 mL. times.2). The organic phases were combined, washed with saturated sodium chloride solution (10mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title product 4g of crude product (240mg, 102.4%) which was used in the next step without purification.

MS m/z(ESI):575.2[M+1]。

The sixth step

5- ((R) -3-amino-3- (2-fluoro-5- ((6-methylpyridin-3-yl) oxy) phenyl) propyl) -1- (tetrahydro-2H-pyran-4-yl) pyrimidine-2, 4,6(1H,3H,5H) -trione hydrochloride 4H

Compound 4g (240mg, 0.417mmol) was dissolved in ethanol (3.0mL) and thionyl chloride (60mg, 0.504mmol) was added at 0 ℃. Stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure to give the title product as a 4h crude (200mg, 94.5%) which was used in the next step without purification.

MS m/z(ESI):471.1[M+1]。

Seventh step

The crude compound 4h (200mg, 0.394mmol) was suspended in acetonitrile (3.0 mL). The reaction was carried out at 120 ℃ for 1 hour by microwave. Concentrating under reduced pressure, and purifying by high performance liquid chromatography (Boston Phlex C18, 5 μm,30 mm. about.150 mm, elution system: H)₂O (10mmol ammonium bicarbonate), acetonitrile, from 35% (v/v) to 95% (v/v) in 20 minutes, detection wavelength 214&254nm) to yield the title product 4(30mg, 16.8%).

MS m/z(ESI):453.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ10.16(s,1H),8.20(d,1H),7.32-7.24(m,3H),6.99(m,1H),6.88(m,1H),6.39(s,1H),4.87-4.80(m,2H),3.92-3.89(m,2H),3.32-3.29(m,2H),2.63-2.55(m,2H),2.45(s,3H),2.29(m,1H),2.02-1.93(m,2H),1.79(m,1H),1.39-1.35(m,2H)。

Example 5

(6S,7S) -6-fluoro-7- (2-fluoro-5- (((S) -tetrahydrofuran-3-yl) oxy) phenyl) -3- (tetrahydro-2H-pyran-4-yl) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidine-2, 4(1H,3H) -dione 5

First step of

(S) -2-fluoro-5- ((tetrahydrofuran-3-yl) oxy) benzaldehyde 5b

Compound 3b (10g, 59.5mmol, shanghai han hong chemical science co., ltd.) and (S) -tetrahydrofuran-3-ol 5a (15.8g, 179mmol, shanghai science co., ltd.) were dissolved in dichloromethane (100mL), pyridine (10g, 126mmol, adamas), triethylamine (13g, 129mmol), anhydrous copper acetate (22g, 121mmol, shanghai bi medicine science co., ltd.) were added and reacted at room temperature for 24 hours. Filtration and concentration under reduced pressure, and purification of the resulting residue by silica gel column chromatography with eluent system A gave the title product 5b (1.0g, yield: 7.99%).

MS m/z(ESI):211.0[M+1]。

Second step of

(R) -N- (2-fluoro-5- (((S) -tetrahydrofuran-3-yl) oxy) benzylidene) -2-methylpropane-2-sulfinamide 5c

Compound 5b (1.0g, 4.76mmol) and compound 2d (580mg, 4.78mmol, adamas) were dissolved in dichloromethane (20mL), cesium carbonate (1.9g, 5.83mmol) was added, and the mixture was stirred at room temperature for 16 hours. Filtration, concentration and purification of the resulting residue by column chromatography on silica gel with eluent system A gave the title product 5c (1.4g, yield: 93.9%).

MS m/z(ESI):313.9[M+1]。

The third step

(2R,3S) -3- (((R) -tert-butylsulfinyl) amino) -2-fluoro-3- (2-fluoro-5- (((S) -tetrahydrofuran-3-yl) oxy) phenyl) propanoic acid ethyl ester 5d

Compound 5c (1.3g, 4.15mmol), compound 1b (690mg, 6.50mmol, Shanghai Tantake Technique, Inc.) and N, N, N ', N' -tetramethylethylenediamine (1.3mL, Shanghai Aladdin Biotech, Inc.) were dissolved in anhydrous tetrahydrofuran (10 mL). Cooled to-78 deg.C, and a 1M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (6.5mL, 6.5mmol, Shanghai Tantake Technology Co., Ltd.) was added dropwise. Stirring at-78 deg.C for 1 hr under nitrogen protection. The reaction was quenched by addition of 2N hydrochloric acid at-20 ℃. Saturated ammonium chloride solution (40mL) was added and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (30 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (100mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 5d (1.2g, yield: 68.9%).

MS m/z(ESI):419.9[M+1]。

The fourth step

(2R,3S) -3- (((R) -tert-butylsulfinyl) amino) -2-fluoro-3- (2-fluoro-5- (((S) -tetrahydrofuran-3-yl) oxy) phenyl) propanoic acid 5e

Compound 5d (1.2g, 2.86mmol) was dissolved in tetrahydrofuran (15.0mL) and 1N aqueous sodium hydroxide (6.0mL, 6.0mmol) was added at 0 ℃. Stirred at room temperature for 2 hours. The pH was adjusted to 5 with saturated aqueous citric acid. Concentrating under reduced pressure, and purifying by high performance liquid chromatography (SharpSil T-C18, 5 μm,30mm x 150mm, elution system: H)₂O (0.1% trifluoroacetic acid), acetonitrile rising from 10% (v/v) to 90% (v/v) within 18 minutes, detection wavelength 214&254nm) to give the title product 5e (900mg, yield: 80.3%).

MS m/z(ESI):391.9[M+1]。

The fifth step

(R) -N- ((1S,2R) -2-fluoro-1- (2-fluoro-5- (((S) -tetrahydrofuran-3-yl) oxy) phenyl) -3-oxo-3- (2,4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) propyl) -2-methylpropane-2-sulfinamide 5f

Compound 5e (900mg, 2.30mmol), compound 1e (730mg, 3.44mmol) and 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (1.3g, 3.42mmol) were dissolved in N, N-dimethylformamide (10.0 mL). Diisopropylethylamine (900mg, 6.96mmol) was added at 0 ℃ and stirred at room temperature for 16 hours. Quenched by addition of saturated sodium bicarbonate solution (50mL) and extracted with ethyl acetate (30 mL. times.3). The organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave the title product, crude 5f (1.4g, 104%) which was used in the next step without purification.

MS m/z(ESI):585.9[M+1]。

The sixth step

(R) -N- ((1S,2S) -2-fluoro-1- (2-fluoro-5- (((S) -tetrahydrofuran-3-yl) oxy) phenyl) -3- (2,4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) propyl) -2-methylpropane-2-sulfinamide 5g

Compound 5f (1.4g, 2.39mmol) was dissolved in acetic acid (15 mL). Sodium cyanoborohydride (380mg, 6.03mmol) was added under ice bath. The reaction was stirred at room temperature for 1 hour. Ice water (50mL) was added, and extraction was performed with ethyl acetate (50 mL. times.2). The organic phases were combined, washed with saturated sodium chloride solution (50mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title product 5g of crude product (1.4g, 102%) which was used in the next step without purification. MS M/z (ESI) 572.1[ M +1 ].

Seventh step

5- ((2S,3S) -3-amino-2-fluoro-3- (2-fluoro-5- (((S) -tetrahydrofuran-3-yl) oxy) phenyl) propyl) -1- (tetrahydro-2H-pyran-4-yl) pyrimidine-2, 4,6(1H,3H,5H) -trione hydrochloride 5H

Compound 5g (1.3g, 2.27mmol) was dissolved in ethanol (15mL) and thionyl chloride (320mg, 2.69mmol) was added at 0 ℃. Stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure to give the title product as a 5h crude (1.1g, 96.0%) which was used in the next step without further purification.

MS m/z(ESI):468.1[M+1]。

Eighth step

Compound 5h crude (1.1g, 2.18mmol) was suspended in acetonitrile: (acetonitrile)15 mL). The reaction was carried out at 120 ℃ for 1 hour by microwave. Concentrating under reduced pressure, and purifying by high performance liquid chromatography (Boston Phlex C18, 5 μm,30 mm. about.150 mm, elution system: H)₂O (10mmol ammonium bicarbonate), acetonitrile from 30% (v/v) to 90% (v/v) in 20 minutes, detection wavelength 214&254nm) to yield the title product 5(560mg, 57.1%).

MS m/z(ESI):450.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ10.28(s,1H),7.20(d,1H),6.97(m,1H),6.89(m,1H),6.49(s,1H),5.09(m,1H),4.98-4.86(m,3H),3.93-3.87(m,2H),3.83-3.80(m,2H),3.78-3.74(m,2H),3.31-3.29(m,2H),2.74-2.57(m,4H),2.20(m,1H),1.93(m,1H),1.42-1.38(m,2H)。

Example 6

(6S,7S) -6-fluoro-7- (2-fluoro-5- (((R) -tetrahydrofuran-3-yl) oxy) phenyl) -3- (tetrahydro-2H-pyran-4-yl) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidine-2, 4(1H,3H) -dione 6

First step of

(R) -2-fluoro-5- ((tetrahydrofuran-3-yl) oxy) benzaldehyde 6b

Compound 3b (10g, 59.5mmol, Shanghai Han hong chemical science and technology Co., Ltd.) and (R) -tetrahydrofuran-3-ol 6a (10g, 113mmol, Shanghai Biao medical science and technology Co., Ltd.) were dissolved in dichloromethane (100mL), pyridine (10g, 126mmol, adamas), triethylamine (13g, 129mmol), anhydrous copper acetate (23g, 127mmol, Shanghai Biao medical science and technology Co., Ltd.) were added, and the reaction was carried out at room temperature for 24 hours. Filtration and concentration under reduced pressure, and purification of the resulting residue by silica gel column chromatography with eluent system A gave the title product 6b (1.9g, yield: 15.2%).

MS m/z(ESI):211.0[M+1]。

Second step of

(R) -N- (2-fluoro-5- (((R) -tetrahydrofuran-3-yl) oxy) benzylidene) -2-methylpropane-2-sulfinamide 6c

Compound 6b (1.9g, 9.04mmol) and compound 2d (1.1g, 9.08mmol, adamas) were dissolved in dichloromethane (30mL), cesium carbonate (3.6g, 11.4mmol) was added, and the mixture was stirred at room temperature for 16 hours. Filtration, concentration and purification of the resulting residue by column chromatography on silica gel with eluent system A gave the crude title product 6c (2.8g, yield: 98.8%).

MS m/z(ESI):313.9[M+1]。

The third step

(2R,3S) -3- (((R) -tert-butylsulfinyl) amino) -2-fluoro-3- (2-fluoro-5- (((R) -tetrahydrofuran-3-yl) oxy) phenyl) propanoic acid ethyl ester 6d

Compound 6c (1.5g, 4.79mmol), compound 1b (760mg, 7.16mmol, Shanghai Tantake Techno technology Co., Ltd.) and N, N, N ', N' -tetramethylethylenediamine (1.5mL, Shanghai Aladdin Biotech Co., Ltd.) were dissolved in anhydrous tetrahydrofuran (15 mL). Cooled to-78 deg.C, and a 1M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (7.2mL, 7.2mmol, Shanghai Tantake Technology Co., Ltd.) was added dropwise. Stirring at-78 deg.C for 1 hr under nitrogen protection. The reaction was quenched by addition of 1N hydrochloric acid at-20 ℃. Saturated ammonium chloride solution (40mL) was added and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (30 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (100mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 6d (1.3g, yield: 64.7%).

MS m/z(ESI):419.9[M+1]。

The fourth step

(2R,3S) -3- (((R) -tert-butylsulfinyl) amino) -2-fluoro-3- (2-fluoro-5- (((R) -tetrahydrofuran-3-yl) oxy) phenyl) propanoic acid 6e

Compound 6d (1.3g, 3.10mmol) was dissolved in tetrahydrofuran (15.0mL) and 1N aqueous sodium hydroxide (6.2mL, 6.2mmol) was added at 0 ℃. Stirred at room temperature for 2 hours. The pH was adjusted to 5 with saturated aqueous citric acid. Concentrating under reduced pressure, and purifying by high performance liquid chromatography (SharpSil T-C18, 5 μm,30mm x 150mm, elution system: H)₂O (0.1% trifluoroacetic acid), acetonitrile rising from 10% (v/v) to 90% (v/v) within 18 minutes, detection wavelength 214&254nm) to give the title product 6e (830mg, yield: 68.4%).

MS m/z(ESI):391.9[M+1]。

The fifth step

(R) -N- ((1S,2R) -2-fluoro-1- (2-fluoro-5- (((R) -tetrahydrofuran-3-yl) oxy) phenyl) -3-oxo-3- (2,4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) propyl) -2-methylpropane-2-sulfinamide 6f

Compound 6e (820mg, 2.09mmol), compound 1e (690mg, 3.11mmol) and 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (1.2g, 3.16mmol) were dissolved in N, N-dimethylformamide (10.0 mL). Diisopropylethylamine (820mg, 6.34mmol) was added at 0 ℃ and stirred at room temperature for 16 hours. Quenched by addition of saturated sodium bicarbonate solution (50mL) and extracted with ethyl acetate (30 mL. times.3). The organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave the title product, crude 6f (1.3g, 106%) which was used in the next step without purification.

MS m/z(ESI):585.9[M+1]。

The sixth step

(R) -N- ((1S,2S) -2-fluoro-1- (2-fluoro-5- (((R) -tetrahydrofuran-3-yl) oxy) phenyl) -3- (2,4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) propyl) -2-methylpropane-2-sulfinamide 6g

Compound 6f (1.2g, 2.05mmol) was dissolved in acetic acid (15 mL). Sodium cyanoborohydride (320mg, 5.08mmol) was added under ice bath. The reaction was stirred at room temperature for 1 hour. Ice water (50mL) was added, and extraction was performed with ethyl acetate (50 mL. times.2). The organic phases were combined, washed with saturated sodium chloride solution (50mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title product 6g of crude product (1.2g, 102%) which was used in the next step without purification. MS M/z (ESI) 572.1[ M +1 ].

Seventh step

5- ((2S,3S) -3-amino-2-fluoro-3- (2-fluoro-5- (((R) -tetrahydrofuran-3-yl) oxy) phenyl) propyl) -1- (tetrahydro-2H-pyran-4-yl) pyrimidine-2, 4,6(1H,3H,5H) -trione hydrochloride 6H

6g (1.2g, 2.10mmol) of the compound was dissolved in ethanol (15mL) and thionyl chloride (300mg, 2.52mmol) was added thereto at 0 ℃. Stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure to give the title product as 6h crude (1.1g, 104%) which was used in the next step without purification.

MS m/z(ESI):468.1[M+1]。

Eighth step

The crude compound 6h (1.0g, 1.98mmol) was suspended in acetonitrile (15 mL). The reaction was carried out at 120 ℃ for 1 hour by microwave. Concentrating under reduced pressure, and purifying by high performance liquid chromatography (Boston Phlex C18, 5 μm,30 mm. about.150 mm, elution system: H)₂O (10mmol ammonium bicarbonate), acetonitrile from 30% (v/v) to 90% (v/v) in 20 minutes, detection wavelength 214&254nm) to yield the title product 6(420mg, 47.1%).

MS m/z(ESI):450.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ10.31(s,1H),7.21(d,1H),6.97(m,1H),6.88(m,1H),6.51(s,1H),5.09(m,1H),4.98-4.86(m,3H),3.93-3.90(m,2H),3.87-3.81(m,2H),3.78-3.73(m,2H),3.32-3.30(m,2H),2.74-2.57(m,4H),2.22(m,1H),1.97(m,1H),1.41-1.38(m,2H)。

Example 7

(6S,7S) -7- (5-cyclopropyl-2-fluorophenyl) -6-fluoro-3-isopropyl-5, 6,7, 8-tetrahydropyrido [2,3-d ] pyrimidine-2, 4(1H,3H) -dione 7

First step of

(2R,3S) -3- (5-cyclopropyl-2-fluorophenyl) -3- ((R) -1, 1-dimethylethylsulfonamido) -2-fluoropropanoic acid 7a

Compound 1d (500.0mg, 1.3mmol), compound 1j (335.9g, 3.9mmol, Shaoshima Tech, Shanghai Co., Ltd.) and potassium phosphate (551.8mg, 2.6mmol, Beijing Bailingwei Tech Co., Ltd.) were dissolved in dioxane (20mL) and water (4 mL). 1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (106.5mg, 0.13mmol, Shanghai Tantake Techno Co., Ltd.) was added. The nitrogen was replaced three times. The reaction was stirred at 100 ℃ for 16 hours under nitrogen. Concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with eluent system B to give crude title product 7a (480 mg).

MS m/z(ESI):344.0[M-1]。

Second step of

(R) -N- ((1S,2R) -1- (5-cyclopropyl-2-fluorophenyl) -2-fluoro-3- (1-isopropyl-2, 4, 6-trioxohexahydropyrimidin-5-yl) -3-oxopropyl) -2-methylpropane-2-sulfinamide 7c

Compound 7a (480.0mg, 1.4mmol), 1-isopropylpyrimidine-2, 4,6(1H,3H,5H) -trione 7b (354.8mg, 2.1mmol, prepared as disclosed in patent application WO2014205223A1, page 28, example 1.3), and 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (792.2mg, 2.1mmol, Shao Yuan Shanghai Co., Ltd.) were dissolved in N, N-dimethylformamide (8 mL). Diisopropylethylamine (538.9mg, 4.2mmol) was added at 0 ℃ and stirred at room temperature for 16 hours. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate (20mL), extracted with ethyl acetate (30 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave the title product, 7c, as crude product (1.3g), which was used in the next step without further purification.

MS m/z(ESI):498.1[M+1]。

The third step

(R) -N- ((1S,2R) -1- (5-cyclopropyl-2-fluorophenyl) -2-fluoro-3- (1-isopropyl-2, 4, 6-trioxohexahydropyrimidin-5-yl) propyl) -2-methylpropane-2-sulfinamide 7d

The crude compound 7c (1.3g, 2.5mmol) was dissolved in acetic acid (13 mL). Sodium cyanoborohydride (478.7mg, 7.6mmol) was added under ice bath. The reaction was stirred at room temperature for 1 hour. The reaction was quenched by addition of ice water (30mL), extracted with ethyl acetate (20 mL. times.3), and the organic phases were combined and washed with saturated sodium chloride solution (10 mL. times.2). Dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title product 7d as crude product (1.2g) which was used in the next step without further purification.

MS m/z(ESI):484.1[M+1]。

The fourth step

5- ((2S,3S) -3-amino-3- (5-cyclopropyl-2-fluorophenyl) -2-fluoropropyl) -1-isopropylpyrimidine-2, 4,6(1H,3H,5H) -trione hydrochloride 7e

The crude compound 7d (1.2g, 2.5mmol) was dissolved in ethanol (13 mL). Thionyl chloride (363.3mg, 3.1mmol, Shanghai Kagaku Kogyo Co., Ltd.) was added thereto at 0 ℃. The reaction was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure to give the title product, crude 7e (1.0g), which was used in the next step without purification.

MS m/z(ESI):380.1[M+1]。

The fifth step

The crude compound 7e (1.0g, 2.5mmol) was suspended in acetonitrile (20 mL). The reaction was carried out at 120 ℃ for 1.5 hours by microwave. Concentrating under reduced pressure, and purifying by high performance liquid chromatography (Boston Phlex Prep C185 μm 30 x 150mm, elution system: H₂O(10mmol NH₄HCO₃) Acetonitrile, acetonitrile from 40% (v/v) to 60% (v/v) within 15 minutes, detection wavelength 214&254nm) to give the title product 7(52.0mg, yield: 5.6%).

MS m/z(ESI):362.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ10.06(s,1H),7.15-7.05(m,3H),6.41(s,1H),5.10-4.99(m,2H),4.91(d,1H),2.73-2.54(m,2H),1.95(m,1H),1.34(d,6H),0.95(d,2H),0.69-0.53(m,2H)。

Example 8

(6S,7S) -7- (4-cyclopropyl-2-fluorophenyl) -6-fluoro-3- (tetrahydro-2H-pyran-4-yl) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidine-2, 4(1H,3H) -dione 8

First step of

(R) -N- (4-bromo-2-fluorobenzylidene) -2-methylpropane-2-sulfinamide 8b

4-Bromobenzaldehyde 8a (10.0g, 49.3mmol, Shanghai Bigdi pharmaceutical science Co., Ltd.) and compound 2d (6.3g, 51.7mmol, Shanghai Tantake Tech Co., Ltd.) were dissolved in dichloromethane (80 mL). Cesium carbonate (19.3g, 59.4mmol) was added and the reaction stirred for 16 h. The reaction was filtered and the filtrate was concentrated under reduced pressure to give the title product, crude 8b (15g), which was used in the next step without purification.

MS m/z(ESI):305.9[M+1]。

Second step of

(2R,3S) -3- (4-bromo-2-fluorophenyl) -3- ((R) -1, 1-dimethylethylsulfonamido amino) -2-fluoropropionic acid ethyl ester 8c

Crude 8b (15.0g, 49.0mmol), compound 1b (7.8g, 73.5mmol, Shanghai Tantake Technique, Inc.) and N, N, N ', N' -tetramethylethylenediamine (11.4g, 98.1mmol, Shanghai Aladdin Biotech, Inc.) were dissolved in anhydrous tetrahydrofuran (150 mL). Cooled to-70 ℃ and a 1M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (73.5mL, 73.5mmol, Shanghai Tantake Technology Co., Ltd.) was added dropwise. The reaction was stirred at-70 ℃ for 3 hours under nitrogen. The reaction was quenched by addition of 1N hydrochloric acid at-20 ℃. Saturated ammonium chloride solution (100mL) was added and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (100 mL. times.2), and the organic phases were combined and washed with saturated sodium chloride solution (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 8c (12.6g, yield: 62.4%).

MS m/z(ESI):412.0[M+1]。

The third step

(2R,3S) -3- (4-bromo-2-fluorophenyl) -3- ((R) -1, 1-dimethylethylsulfonamido) -2-fluoropropanoic acid 8d

Compound 8c (2.0g, 4.9mmol) was dissolved in tetrahydrofuran (18mL) and 1N sodium hydroxide solution (10mL, 10mmol) was added. The reaction was stirred for 4 hours. Diluting with water (20mL), and adding ethyl acetateEster (10 mL. times.2) wash. The aqueous phase was adjusted to pH 5 with saturated aqueous citric acid. Concentrating under reduced pressure, and purifying by high performance liquid chromatography (SharpSil T-C18, 5 μm,30mm x 150mm, elution system: H)₂O (0.1% trifluoroacetic acid), acetonitrile rising from 30% (v/v) to 95% (v/v) within 18 minutes, detection wavelength 214&254nm) to yield the title product 8d (1.0mg, yield: 53.7%).

MS m/z(ESI):384.0[M+1]。

The fourth step

(R) -N- ((1S,2R) -1- (4-bromo-2-fluorophenyl) -2-fluoro-3-oxo-3- (2,4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) propyl) -2-methylpropane-2-sulfinamide 8e

Compound 8d (1.0g, 2.6mmol), compound 1e (828.5mg, 3.9mmol) and 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (1.5g, 3.9mmol, Shaoshima Shanghai Co., Ltd.) were dissolved in N, N-dimethylformamide (15 mL). Diisopropylethylamine (1.0g, 7.8mmol, Shanghai Tantake Techno Co., Ltd.) was added at 0 ℃ and stirred at room temperature for 16 hours. The reaction was quenched by the addition of saturated sodium bicarbonate solution (30mL) and extracted with ethyl acetate (50 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title product, crude 8e (3.6g), which was used in the next step without purification.

MS m/z(ESI):578.0[M+1]。

The fifth step

(R) -N- ((1S,2R) -1- (4-bromo-2-fluorophenyl) -2-fluoro-3- (2,4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) propyl) -2-methylpropane-2-sulfinamide 8f

The crude compound 8e (3.6g, 6.2mmol) was dissolved in acetic acid (30 mL). Sodium cyanoborohydride (980.3mg, 15.6mmol, Shaoshima technologies Shanghai, Inc.) was added under ice bath. The reaction was stirred at room temperature for 1 hour. Ice water (50mL) was added, and extraction was performed with ethyl acetate (80 mL. times.3). The organic phases were combined and washed with saturated sodium chloride solution (30 mL. times.2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title product, crude 8f (2.8g), which was used in the next step without purification.

MS m/z(ESI):564.0[M+1]。

The sixth step

5- ((2S,3S) -3-amino-3- (4-bromo-2-fluorophenyl) -2-fluoropropyl) -1- (tetrahydro-2H-pyran-4-yl) pyrimidine-2, 4,6(1H,3H,5H) -trione hydrochloride 8g

The crude compound 8f (560.0mg, 1.0mmol) was dissolved in ethanol (5 mL). Thionyl chloride (141.7mg, 1.2mmol, Shanghai Kagaku Kogyo Co., Ltd.) was added at 0 ℃. Stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give 8g of the title product as a crude product (480.0mg), which was used in the next step without purification.

MS m/z(ESI):460.0[M+1]。

Seventh step

(6S,7S) -7- (4-bromo-2-fluorophenyl) -6-fluoro-3- (tetrahydro-2H-pyran-4-yl) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidine-2, 4- (1H,3H) -dione 8H

Compound 8g crude (480.0mg, 1.0mmol) was suspended in acetonitrile (6 mL). The reaction was carried out at 120 ℃ for 1 hour by microwave. Concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 8h (210.0mg, yield starting from compound 8 d: 90.2%).

MS m/z(ESI):441.9[M+1]。

Eighth step

Compound 8h (170.0mg, 0.38mmol), Compound 1j (66.1g, 0.8mmol, Shao Yuan technology Shanghai, Inc.), tricyclohexylphosphine (64.6mg, 0.23mmol, Shao Yuan technology Shanghai, Inc.) and potassium phosphate (163.0mg, 0.8mmol, Beijing Bailingwei technology Inc.) were dissolved in toluene (15mL) and water (3 mL). Palladium acetate (25.9mg, 0.12mmol, Ikay technologies, Inc. of Beijing) was added. The nitrogen was replaced three times. The reaction was stirred at 100 ℃ for 16 hours under nitrogen. Concentrating under reduced pressure, and purifying by high performance liquid chromatography (Welch Ultimate XB-C18, 5 μm,30mm × 150mm, elution system: H₂O (0.1% trifluoroacetic acid), acetonitrile from 30% (v/v) to 95% (v/v) in 12.1 min, detection wavelength 214&254nm) to give the title product 8(7.0mg, yield: 4.5%).

MS m/z(ESI):403.9[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ10.27(s,1H),7.26(t,1H),7.00(d,1H),6.95(d,1H),6.42(s,1H),5.04(d,1H),4.91-4.83(m,2H),3.91(d,2H),3.35-3.30(m,2H),2.73-2.53(m,4H),1.99-1.92(m,1H),1.39(t,2H),1.00-0.96(m,2H),0.73-0.70(m,2H)。

Example 9

(6S,7S) -6-fluoro-7- (2-fluoro-5- ((tetrahydro-2H-pyran-4-yl) oxy) phenyl) -3- (tetrahydro-2H-pyran-4-yl) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidine-2, 4(1H,3H) -dione 9

First step of

4- (3-bromo-4-fluorophenoxy) tetrahydro-2H-pyran 9c

3-bromo-4-fluorophenol 9a (1.0g, 5.24mmol, Shaoyuan technologies (Shanghai) Co., Ltd.) and tetrahydro-2H-pyran-4-yl methanesulfonate 9b (1.2g, 6.66mmol, prepared by a method known in the literature "US 20100210674A1, page 7-8, example 8") were dissolved in N, N-dimethylformamide (10mL), and potassium carbonate (1.1g, 7.97mmol) was added to react at 90 ℃ for 16 hours. Water (50mL) was added, extraction was performed with ethyl acetate (20 mL. times.2), the organic phases were combined, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 9c (850mg, yield: 59.0%).

¹H NMR(500MHz,CDCl3-d)δ7.13(m,1H),7.05(m,1H),6.85(m,1H),4.40(m,1H),4.01-3.97(m,2H),3.61-3.57(m,2H),2.04-1.99(m,2H),1.82-1.75(m,2H)。

Second step of

2-fluoro-5- ((tetrahydro-2H-pyran-4-yl) oxy) benzaldehyde 9d

Compound 9c (850mg, 3.09mmol) was dissolved in anhydrous tetrahydrofuran (10mL), and a solution of n-butyllithium in n-hexane (1.6mL, 4.00mmol,2.5M) was added dropwise at 70 ℃ and stirred at 70 ℃ for 0.5 hour. N, N-dimethylformamide (300mg,4.10mmol) was added dropwise at-70 ℃ and stirred at-70 ℃ for 1 hour. Quenched with saturated aqueous ammonium chloride (20mL), extracted with ethyl acetate (20 mL. times.2), and concentrated to give the title product, crude 9d (690mg, yield: 99.6%). MS M/z (ESI) 225.1[ M +1 ].

The third step

(R) -N- (2-fluoro-5- ((tetrahydro-2H-pyran-4-yl) oxy) benzylidene) -2-methylpropane-2-sulfinamide 9e

Compound 9d (690mg, 3.08mmol) and compound 2d (380mg, 3.13mmol, Shanghai Biao pharmaceutical science Co., Ltd.) were dissolved in dichloromethane (10mL), and cesium carbonate (1.2g, 3.68mmol) was added and stirred at room temperature for 16 hours. Filtration and concentration under reduced pressure, and purification of the resulting residue by silica gel column chromatography with eluent system A gave the title product 9e (640mg, yield: 63.5%).

MS m/z(ESI):328.1[M+1]。

The fourth step

(2R,3S) -3- (((R) -tert-butylsulfinyl) amino) -2-fluoro-3- (2-fluoro-5- ((tetrahydro-2H-pyran-4-yl) oxy) phenyl) propanoic acid ethyl ester 9f

Compound 9e (300mg, 0.916mmol), compound 1b (150mg, 1.41mmol, Shanghai Tantake Technique, Inc.) and N, N, N ', N' -tetramethylethylenediamine (0.3mL, Shanghai Aladdin Biotech, Inc.) were dissolved in anhydrous tetrahydrofuran (5.0 mL). Cooled to-78 deg.C, and a 1M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (1.4mL, 1.4mmol, Shanghai Tantake Technology Co., Ltd.) was added dropwise. Stirring at-78 deg.C for 3 hr under nitrogen protection. The reaction was quenched by addition of 1N hydrochloric acid at-20 ℃. Saturated ammonium chloride solution (20mL) was added and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (70mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 9f (320mg, yield: 80.5%).

MS m/z(ESI):434.1[M+1]。

The fifth step

(2R,3S) -3- (((R) -tert-butylsulfinyl) amino) -2-fluoro-3- (2-fluoro-5- ((tetrahydro-2H-pyran-4-yl) oxy) phenyl) propanoic acid 9g

Compound 9f (320mg, 0.738mmol) was dissolved in tetrahydrofuran (4.0mL) and 1N aqueous sodium hydroxide (1.5mL, 1.5mmol) was added at 0 ℃. Stirred at room temperature for 1 hour. The pH was adjusted to 5 with saturated aqueous citric acid. Concentrating under reduced pressure, and purifying by high performance liquid chromatography (SharpSil T-C18, 5 μm,30mm x 150mm, elution system: H)₂O (0.1% trifluoroacetic acid), acetonitrile rising from 10% (v/v) to 90% (v/v) within 20 minutes, detection wavelength 214&254nm) to obtain 9g of the title product (140mg, yield: 46.8%).

MS m/z(ESI):405.9[M+1]。

The sixth step

(R) -N- ((1S,2R) -2-fluoro-1- (2-fluoro-5- ((tetrahydro-2H-pyran-4-yl) oxy) phenyl) -3-oxo-3- (2,4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) propyl) -2-methylpropane-2-sulfinamide 9H

Compound 9g (140mg, 0.345mmol), compound 1e (110mg, 0.518mmol and 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (200mg, 0.526mmol) were dissolved in N, N-dimethylformamide (3.0mL) at 0 deg.C, diisopropylethylamine (140mg, 1.08mmol) was added, stirred at room temperature for 16 hours, quenched by addition of saturated sodium bicarbonate solution (20mL), extracted with ethyl acetate (10 mL. times.3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title product 9h crude (210mg, 101.4%) which was used in the next step without purification.

MS m/z(ESI):600.1[M+1]。

Seventh step

(R) -N- ((1S,2S) -2-fluoro-1- (2-fluoro-5- ((tetrahydro-2H-pyran-4-yl) oxy) phenyl) -3- (2,4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) propyl) -2-methylpropane-2-sulfinamide 9i

Compound 9h (210mg, 0.350mmol) was dissolved in acetic acid (2.0 mL). Sodium cyanoborohydride (55.0mg, 0.873mmol) was added under ice bath. The reaction was stirred at room temperature for 1 hour. Ice water (20mL) was added, and extraction was performed with ethyl acetate (10 mL. times.3). The organic phases were combined, washed with saturated sodium chloride solution (10mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title product, crude 9i (210mg, 102.4%), which was used in the next step without purification.

MS m/z(ESI):586.1[M+1]。

Eighth step

5- ((2S,3S) -3-amino-2-fluoro-3- (2-fluoro-5- ((tetrahydro-2H-pyran-4-yl) oxy) phenyl) propyl) -1- (tetrahydro-2H-pyran-4-yl) pyrimidine-2, 4,6(1H,3H,5H) -trione hydrochloride 9j

Compound 9i (210mg, 0.358mmol) was dissolved in ethanol (2.0mL) and thionyl chloride (50.0mg, 0.420mmol) was added at 0 ℃. Stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure to give the title product 9j crude (180mg, 96.9%) which was used in the next step without purification.

MS m/z(ESI):482.1[M+1]。

The ninth step

Crude compound 9j (180mg, 0.347mmol) was suspended in acetonitrile (4.0 mL). The reaction was carried out at 120 ℃ for 1 hour by microwave. Concentrating under reduced pressure, and purifying by high performance liquid chromatography (Boston Phlex C18, 5 μm,30 mm. about.150 mm, elution system: H)₂O (10mmol ammonium bicarbonate), acetonitrile, from 35% (v/v) to 95% (v/v) in 19 minutes, detection wavelength 214&254nm) to yield the title product 9(70mg, 43.4%).

MS m/z(ESI):464.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ10.43(s,1H),7.18(d,1H),7.02(m,1H),5.94(m,1H),6.64(s,1H),5.08(m,1H),4.92-4.84(m,2H),4.49(m 1H),3.93-3.89(m,2H),3.86-3.82(m,2H),3.49-3.44(m,2H),3.35-3.32(m,2H),2.74-2.56(m,4H),1.98-1.93(m,2H),1.61-1.53(m,2H),1.39-1.37(m,2H)。

Biological evaluation

The present disclosure is further described and explained below in conjunction with test examples, but these examples are not meant to limit the scope of the present disclosure.

Test example 1 the inhibitory effect of the compounds of the disclosure on myosin ATPase enzyme activity.

The following methods were used to determine the inhibitory effect of the compounds of the present disclosure on myosin ATPase enzyme activity, and the experimental methods are summarized below:

first, experimental material and instrument

1. Actin (Cardiac Actin) (Cytoskeleton, AD99)

2. Myosin S1(Myosin Motor Protein S1 Fragment) (Cytoskeleton, CS-MYS03)

3.ATP(Sigma，A7699-1G)

4.UltraPure^TM 1M Tris-HCI Buffer，pH 7.5(Thermo，15567027)

5.CytoPhosTM Phosphate Assay Biochem Kit(Cytoskeleton，BK054)

6. Magnesium chloride solution (Sigma, 68475-100ML-F)

7. Potassium chloride solution (Sigma, 60142-100ML-F)

8.EGTA(Sigma，E3889-100G)

9.96 well plate (Corning 3697)

U type bottom 96-well plate (Corning, 3795)

11. Enzyme mark instrument (BMG, PHERAStar)

12. Constant temperature incubator (Shanghai Boxun, SPX-100B-Z)

Second, the experimental procedure

mu.M actin 1.61. mu.M, 10.07. mu.M myosin S mixed with different concentrations of small molecule compounds (first concentration 100. mu.M, 3-fold gradient dilution 9 concentrations) were incubated at 37 ℃ for 1 hour, followed by addition of 120. mu.M ATP and incubation at 37 ℃ for 2 hours. Finally, the detection solution (70. mu.L/well) from the Cytophos Phosphate Assay Biochem Kit was added to each well and incubated for 10min at room temperature. Reading OD value of 650nM wavelength with enzyme labeling instrument, calculating Pi value according to standard curve, processing data with GraphPad software, drawing inhibition curve according to each concentration of compound and corresponding inhibition rate, and calculating the concentration of compound when the inhibition rate reaches 50%, i.e. IC₅₀The value is obtained. The results are detailed in table 1.

TABLE 1 inhibitory Activity of the disclosed Compounds on myosin ATPase enzyme

Example numbering	IC₅₀(μM)
		1	0.40
2	0.80
		3	0.82
4	0.06
		5	0.24
6	0.30
		7	0.28
8	6.05
		9	0.39

And (4) conclusion: the compounds of the present disclosure have inhibitory effects on myosin ATPase enzyme.

Claims

1. A compound of formula (IM), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

R^xis alkyl or

R^yis a hydrogen atom or a halogen;

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

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

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

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

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

r is 0, 1,2, 3, 4, 5 or 6;

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

t is 0, 1 or 2.

2. The compound of the general formula (IM) according to claim 1, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (IN), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring A, ring C, L, R¹To R²、R^xS and m are as defined in claim 1.

3. The compound represented by the general formula (IM) according to claim 1 or2, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IN-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring A, ring C, L, R¹、R²、R^xS and m are as defined in claim 1.

4. A compound of general formula (IM) according to any one of claims 1 to 3, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R^xIs C_1-6Alkyl or

Wherein, ring B, R³And n is as followsAs defined in claim 1.

5. The compound of the general formula (IM) according to any one of claims 1,2, 4, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring A, ring B, ring C, L, R¹To R³S, m and n are as defined in claim 1.

6. The compound represented by the general formula (IM) according to any one of claims 1 to 5, which is a compound represented by the general formula (I-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring A, ring B, ring C, L, R¹To R³S, m and n are as defined in claim 1.

7. A compound of general formula (IM) according to any one of claims 1 to 6, or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring a is selected from the group consisting of 3-to 8-membered cycloalkyl, 3-to 12-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 10-membered heteroaryl; preferably, ring a is phenyl or pyridyl.

8. The compound of the general formula (IM) according to any one of claims 1,2, 4, 5, 7, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (II), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring B, ring C, L, R¹To R³S, m and n are as defined in claim 1.

9. The compound represented by the general formula (IM) according to any one of claims 1 to 8, which is a compound represented by the general formula (II-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring B, ring C, L, R¹To R³S, m and n are as defined in claim 1As defined.

10. A compound of general formula (IM) according to any one of claims 1 to 9, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from the group consisting of 3-to 8-membered cycloalkyl, 3-to 12-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 10-membered heteroaryl; preferably, ring B is a 5 or 6 membered heterocyclyl; more preferably, ring B is tetrahydropyranyl.

11. A compound of general formula (IM) according to any one of claims 1 to 10, or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring C is selected from the group consisting of 3-to 8-membered cycloalkyl, 3-to 12-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 10-membered heteroaryl; preferably, ring C is selected from 3 to 6 membered cycloalkyl, 3 to 6 membered heterocyclyl and 5 or 6 membered heteroaryl; more preferably, ring C is selected from cyclopropyl, pyridyl, tetrahydrofuranyl and tetrahydropyranyl.

12. The compound of general formula (IM) according to any one of claims 1 to 11, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R is¹Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl and C_1-6A haloalkyl group.

13. The compound of general formula (IM) according to any one of claims 1 to 12, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R is²Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkyl and C_1-6A haloalkoxy group.

14. The compound of general formula (IM) according to any one of claims 1 to 13, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R³Is a hydrogen atom.

15. The compound of general formula (IM) according to any one of claims 1 to 14, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L is a chemical bond or an oxygen atom.

16. A compound of general formula (IM) according to any one of claims 1 to 15, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

17. a compound of formula (IMA), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring A, R²、R^x、R^yAnd m is as defined in claim 1.

18. A compound of formula (IMA) according to claim 17, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

19. a compound of formula (IMB), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring A, ring C, L, R¹、R²、R^x、R^yS and m are as defined in claim 1.

20. A compound of formula (IMB) according to claim 19, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

21. a process for the preparation of a compound of formula (IM), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

wherein:

l is a chemical bond;

y is

R is a hydrogen atom or an alkyl group;

ring A, ring C, R¹、R²、R^x、R^yS and m are as defined in claim 1.

22. A process for the preparation of a compound of formula (IM), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

wherein:

ring A, ring C, L, R¹、R²、R^x、R^yS and m are as defined in claim 1.

23. A pharmaceutical composition comprising a compound of general formula (IM) according to any one of claims 1 to 16 or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

24. Use of a compound of general formula (IM) according to any one of claims 1 to 16 or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23, for the preparation of a medicament for the treatment of a Myosin (Myosin) inhibitor.

25. Use of a compound of general formula (IM) according to any one of claims 1 to 16 or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23, for the manufacture of a medicament for the treatment of a disease or disorder selected from the group consisting of diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, Hypertrophic Cardiomyopathy (HCM), nonallergic hypertrophic cardiomyopathy (nHCM), obstructive hypertrophic cardiomyopathy (oHCM), normal ejection fraction heart failure (HFpEF), intermediate ejection fraction heart failure (HFmREF), valve disease, aortic stenosis, inflammatory cardiomyopathy, love endocarditis, myocardial endocarditis fibrosis, invasive cardiomyopathy, Hemochromatosis, fabry's disease, glycogen storage disease, congenital heart disease, falo tetrad, left ventricular hypertrophy, refractory angina and chagas disease; preferably selected from ischemic heart disease, restrictive cardiomyopathy, Hypertrophic Cardiomyopathy (HCM), non-obstructive hypertrophic cardiomyopathy (nHCM), obstructive hypertrophic cardiomyopathy (oHCM), inflammatory cardiomyopathy, invasive cardiomyopathy, congenital heart disease, and left ventricular hypertrophy; more preferably Hypertrophic Cardiomyopathy (HCM).