CN114149423B

CN114149423B - Tetrahydropyridopyrimidinedione derivative, preparation method thereof and application thereof in medicine

Info

Publication number: CN114149423B
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: 2023-12-12
Anticipated expiration: 2041-09-07
Also published as: CN114149423A

Abstract

The present disclosure relates to tetrahydropyridopyrimidine dione derivatives, methods of preparation and their use in medicine. In particular, the present disclosure relates to tetrahydropyridopyrimidine dione derivatives of general formula (IM), methods for their preparation and pharmaceutical compositions containing them, and their use as therapeutic agents, in particular as Myosin (Myosin) inhibitors and in medicaments for the treatment of Hypertrophic Cardiomyopathy (HCM) or heart diseases with pathophysiological characteristics associated with HCM.

Description

Tetrahydropyridopyrimidinedione derivative, preparation method thereof and application thereof in medicine

Technical Field

The present disclosure relates to a tetrahydropyridopyrimidine dione derivative, a preparation method thereof and application thereof in medicine, and belongs to the field of medicine. In particular, the present disclosure relates to tetrahydropyridopyrimidine dione derivatives represented by general formula (IM), a process for their preparation and pharmaceutical compositions containing them, as well as their use as Myosin (Myosin) inhibitors and in medicaments for the treatment of Hypertrophic Cardiomyopathy (HCM) or heart diseases having pathophysiological characteristics associated with HCM.

Background

Hypertrophic Cardiomyopathy (HCM) is a dominant inherited cardiomyopathy associated with gene mutations. Global morbidity is about 0.2% and is the most important cause of sudden death in young people under 35 years of age (Tuohy, cv.et al., eur J Heart fat, 22,2020,228-240). Clinically, the characteristics are that the left ventricle wall is asymmetrically hypertrophic, is frequently invaded and is frequently separated, the inner cavity of the ventricle is reduced, the left ventricle blood filling is blocked, and the compliance of the ventricular diastole is reduced. The left ventricular outflow tract is classified into obstructive and non-obstructive hypertrophic cardiomyopathy according to the presence or absence of obstruction. Currently, beta-blockers and calcium channel blockers are mostly used clinically for treating hypertrophic cardiomyopathy to reduce heart contraction and relieve symptoms. However, these treatments are both palliative and not palliative. HCM progresses to late stages for heart transplantation only (Ramaraj, r.cardiol Rev,16,2008,172-180). Thus, it is urgent to find a therapeutic method for the root cause of HCM.

The existing study found that 70% of HCM patients are caused by the mutation of sarcomere protein gene. Wherein a plurality of 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 being identified, such as MYH 7R 403Q and R453C mutations (Frey, n.et al., nat Rev Cardiol,9,2011,91-100; sabter-Molina, m.et al., clin Genet,93,2018,3-14). Studies on the probability of causing gene mutation have found that about 30% of patients with MYH7 gene mutation are involved. MYH7 causes early onset of disease and more severe myocardial hypertrophy compared to other sarcomere genes. Myosin is a constituent unit of myofibrillar crude muscle filaments and plays an important role in muscle movement. The molecular shape of the light chain is like bean sprout, and the light chain consists of two heavy chains and a plurality of light chains. The head of myosin is combined with actin to form transverse bridge, so that the ATPase activity of myosin is greatly raised, and the ATP hydrolysis reaction is catalyzed to produce energy to promote the transverse bridge to slide and to contract muscle. The results of the study showed that mutations in the MYH7 gene resulted in increased myosin atpase activity, decreased myosin super-delayed State (SRX) ratio, increased cross-bridges between myosin and actin, and resulted in abnormal systolic function (Green, em.et al., science,351,2016,617-621;Sommese,RF.et al, proc Natl Acad Sci U S A,110,2013,12607-12612). Thus, myosin is an important target for the treatment of hypertrophic cardiomyopathy.

Patent applications for which myosin inhibitors have been disclosed include WO2014205223A1, WO2014205234A1, WO2019028360A1, WO2020092208A1, and CN110698415A, among others.

Disclosure of Invention

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

wherein:

R ^x is alkyl orWherein the alkyl group is optionally substituted with one or more substituents selected from halogen, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy and hydroxyalkyl;

R ^y is a hydrogen atom or a halogen;

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

l is selected from chemical bonds, (CH) ₂ ) _r 、C(O)、NH、NR ⁰ Oxygen and sulfur atoms;

R ⁰ selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups;

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

each R is ¹ The same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

Each R is ² The same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, COR ⁴ 、C(O)OR ⁵ 、S(O) _t R ⁶ 、S(O) _t NR ⁷ R ⁸ And C (O) NR ⁷ R ⁸ ；

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

each R is ³ Identical 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) OR ⁵ ；

R ⁴ Selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, cycloalkyl groups, heterocyclyl groups, and aryl groupsRadicals and heteroaryl radicals; wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is 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;

R ⁵ selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups;

R ⁶ selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ⁷ And R is ⁸ The same or different and are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, and heteroaryl; or R is ⁷ And R is ⁸ Together with the nitrogen atom to which they are attached, form a heterocyclic group, which is optionally substituted with one or more substituents selected from halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, 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 also provided with

t is 0, 1 or 2.

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

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

Wherein:

ring a, ring C, L, R ¹ 、R ² 、R ^x S and m are as defined in the general formula (IM).

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

wherein:

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 ^x Is C _1-6 Alkyl orPreferably, R ^x Is isopropyl or +.>Wherein the ringB、R ³ And n is as defined in formula (IM).

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

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

each R is ³ Identical or different and each independentlySelected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, amino, nitro, hydroxy, hydroxyalkyl, and C (O) OR ⁵ ；

R ⁴ Selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is 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;

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 also provided with

t is 0, 1, 2.

IN some preferred embodiments of the present disclosure, the compound of formula (IM), formula (IN-1), formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of 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, R ¹ To R ³ S, 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 pyridinyl.

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:

W ¹ to W ⁵ One of which 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, R ¹ To R ³ S, 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, R ¹ To R ³ S, 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, 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.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II-1), 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 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, diastereomer, or 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, pyridinyl, 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, diastereomer, or 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 pyridinyl.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II-1), or a tautomer, racemate, enantiomer, diastereomer, or 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.

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 each R ¹ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; preferably, each R ¹ 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 general formula (I), general formula (I-1), general formula (II), general formula(II-1) a compound of formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R ¹ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; preferably, each R ¹ The same or different and are each independently 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, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R ¹ Identical or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An 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, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R ² Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Haloalkoxy groups; preferably, each R ² Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; more preferably, each R ² 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, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R ² The same or different and are each independently a hydrogen atom or a fluorine atom.

In some of the best of the present disclosureIN alternative embodiments, 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 R ³ Is a hydrogen 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, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L is a 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, diastereomer, or 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, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein W ¹ To W ⁵ One of which is a carbon atom and the remaining four are the same or different and are each independently a carbon atom or a nitrogen atom; preferably, W ¹ To W ⁵ Is a carbon atom or W ¹ 、W ² 、W ⁴ And W is ⁵ Is a carbon atom and W ³ Is a nitrogen atom; more preferably, W ¹ To W ⁵ Is 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, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Is->

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, whereinIs thatW ¹ To W ⁵ One of which 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, R ¹ 、R ² S and m are as defined in formula (IM); preferably +.> Wherein ring C, L, R ¹ 、R ² S and m are as defined in formula (IM); more preferably selected from

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, whereinIs thatWherein ring C, L, R ¹ 、R ² S 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, diastereomer, or 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 compounds of formula (IM), formula (IN-1) A compound of the general formula (I), the general formula (I-1), the general formula (II-1), or a tautomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ Selected from halogen, C _1-6 Alkyl and C _1-6 A 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 ² Identical or different and are each independently selected from halogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Haloalkoxy groups; 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, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R ² Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Haloalkoxy groups; and m is 4.

In some preferred embodiments of the present disclosure, the compound of formula (IM), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^x Is C _1-6 Alkyl orR ^y Is a hydrogen atom or a halogen; ring a is a 6 to 10 membered aryl or a 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 of which isR ¹ Identical or different and are each independently selected from halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; each R is ² Identical or different and are each independently selected from halogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Haloalkoxy groups; 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 ^x Is C _1-6 Alkyl orRing a is a 6 to 10 membered aryl or a 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 is ¹ Identical or different and are each independently selected from halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; each R is ² Identical or different and are each independently selected from halogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Haloalkoxy groups; 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 or a 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 is ¹ Identical or different and are each independently selected from halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; each R is ² Identical or different and each independentlySelected from halogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Haloalkoxy groups; 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 or a 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 is ¹ Identical or different and are each independently selected from halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; each R is ² Identical or different and are each independently selected from halogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Haloalkoxy groups; 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; ring B is a 5 or 6 membered heterocyclyl; ring C is 3 to 6 membered cycloalkyl or 5 or 6 membered heteroaryl; l is a bond or an oxygen atom; each R is ¹ Identical or different and are each independently selected from halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; each R is ² Identical or different and are each independently selected from halogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Haloalkoxy groups; 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 thereof An isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein W ¹ To W ⁵ Is 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 is ¹ Identical or different and are each independently selected from halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; each R is ² Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Haloalkoxy groups; 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 ¹ To W ⁵ Is a carbon atom; ring B is a 5 or 6 membered heterocyclyl; ring C is 3 to 6 membered cycloalkyl or 5 or 6 membered heteroaryl; l is a bond or an oxygen atom; each R is ¹ Identical or different and are each independently selected from halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; each R is ² Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Haloalkoxy groups; 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:

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another aspect of the present disclosure relates to a compound represented by the general 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, R ² 、R ^x 、R ^y And m is as defined in formula (IM).

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

wherein:

ring A, R ² 、R ^x And m is as defined IN formula (IN).

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

wherein:

Ring A, R ² 、R ^x And m is as defined IN formula (IN-1).

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

wherein:

ring a, ring B, R ² 、R ³ M 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, R ² 、R ³ M and n are as defined in formula (I-1).

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

/>

wherein:

ring B, R ² 、R ³ 、W ¹ To W ⁵ M and n are as defined in formula (II).

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

Wherein:

ring B, R ² 、R ³ 、W ¹ To W ⁵ M and n are as defined in the general formula (II-1).

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

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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, R ¹ 、R ² 、R ^x 、R ^y S and m are as defined in the general formula (IM).

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

wherein:

ring a, ring C, L, R ¹ 、R ² 、R ^x S and m are as defined IN formula (IN).

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

wherein:

ring a, ring C, L, R ¹ 、R ² 、R ^x S and m are as defined IN the general formula (IN-1).

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

Wherein:

ring a, ring B, ring C, L, R ¹ To R ³ S, m and n are as defined in formula (I).

Another aspect of the present disclosure relates to a compound of 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, R ¹ To R ³ S, m and n are as defined in formula (I-1).

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

wherein:

ring B, ring C, L, R ¹ To R ³ S, m and n are as defined in formula (II).

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

wherein:

Ring B, ring C, L, R ¹ To R ³ S, m and n are as defined in the general formula (II-1).

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

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

a compound of the general formula (IMA) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is subjected to Suzuki coupling reaction with a compound of the general formula (V) to obtain 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 bond;

Y is

R is a hydrogen atom or an alkyl group;

ring a, ring C, R ¹ 、R ² 、R ^x 、R ^y S and m are as defined in the general formula (IM).

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

a compound of the general formula (INA) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is subjected to Suzuki coupling reaction with a compound of the general formula (V) to obtain a compound of the general formula (IN) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

wherein:

l is a bond;

y is

R is a hydrogen atom or an alkyl group;

ring a, ring C, R ¹ 、R ² 、R ^x S and m are as defined IN formula (IN).

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

A 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 a compound of the general formula (V) undergo a Suzuki coupling reaction to obtain a compound of the 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 bond;

y is

R is a hydrogen atom or an alkyl group;

ring a, ring C, R ¹ 、R ² 、R ^x S 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:

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

Wherein:

l is a bond;

y is

R is a hydrogen atom or an alkyl group;

ring a, ring B, ring C, R ¹ To R ³ S, 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 general formula (I-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

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

wherein:

l is a bond;

y is

R is a hydrogen atom or an alkyl group;

ring a, ring B, ring C, R ¹ To R ³ S, m and n are as defined in 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, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

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

wherein:

l is a bond;

y is

R is a hydrogen atom or an alkyl group;

ring B, ring C, R ¹ To R ³ 、W ¹ To W ⁵ S, 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 general formula (II-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

carrying out Suzuki coupling reaction on a compound shown as a general formula (IIA-1) or a tautomer, a racemate, an enantiomer, a diastereoisomer or a mixture of the enantiomers or pharmaceutically acceptable salts of the compounds, and obtaining a compound shown as a general formula (II-1) or a tautomer, a racemate, an enantiomer, a diastereoisomer or a mixture of the enantiomers or pharmaceutically acceptable salts of the compounds;

Wherein:

l is a bond;

y is

R is a hydrogen atom or an alkyl group;

ring B, ring C, R ¹ To R ³ 、W ¹ To W ⁵ S, m and n are as defined in the general formula (II-1).

a compound of the general formula (IMB) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, preferably hydrochloride, undergoes a ring-forming reaction 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:

A compound of formula (INB) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, preferably hydrochloride, is cyclized to give a compound of formula (IN) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

wherein:

ring a, ring C, L, R ¹ 、R ² 、R ^x S and m are as defined IN formula (IN).

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

a compound of formula (INB-1) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt (preferably hydrochloride) thereof, undergoes a ring-forming reaction to give a compound of formula (IN-1) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

wherein:

a compound of formula (IB) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof (preferably hydrochloride salt) undergoes a ring-forming reaction to give a compound of formula (I) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

wherein:

a compound of formula (IB-1) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof (preferably hydrochloride salt) undergoes a ring-forming reaction to give a compound of formula (I-1) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

Wherein:

a compound of formula (IIB) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, preferably hydrochloride, undergoes a ring-forming reaction to give a compound of formula (II) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

wherein:

ring B, ring C, L, R ¹ To R ³ S, m and n are as defined in formula (II).

A compound of formula (IIB-1) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt (preferably hydrochloride) thereof, undergoes a cyclization reaction to give a compound of 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, of the present disclosure, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

The present disclosure further relates to the use of a 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, or a pharmaceutical composition comprising the same, IN the preparation of a medicament for 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), 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 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), ejection fraction intermediate heart failure (HFmREF), valve disease, aortic valve stenosis, inflammatory cardiomyopathy, lux endocarditis, myocardial fibrosis, invasive cardiomyopathy, bruxism, storage, dyscrasia, left-hand hemorrhoea, asbestic hemorrhoea, and right-ventricular hyperpigmentation; preferably selected from ischemic heart disease, limited 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), formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, IN the manufacture of a medicament for treating a disease or disorder mediated by Myosin selected from diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic Cardiomyopathy (HCM), non-obstructive hypertrophic cardiomyopathy (nHCM), obstructive hypertrophic cardiomyopathy (oHCM), normal ejection fraction heart failure (HFpEF), ejection fraction intermediate heart failure (HFmREF), a disease, aortic valve stenosis, inflammatory cardiomyopathy, lux endocarditis, myocardial endocardial fibrosis, invasive cardiomyopathy, hemochromatosis, fabricism, glycogen storage disease, heart disease, congenital heart disease, fabrician, left ventricular dysphoria, and right ventricular angina; preferably selected from ischemic heart disease, limited 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 disorder selected from diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic Cardiomyopathy (HCM), non-obstructive hypertrophic cardiomyopathy (nHCM), obstructive hypertrophic cardiomyopathy (oHCM), normal ejection fraction heart failure (HFpEF), ejection fraction median heart failure (HFmREF), diseases, aortic stenosis, inflammatory cardiomyopathy, lux endocarditis, myocardial endocardial fibrosis, invasive cardiomyopathy, hemochromatosis, fabry's disease, glycogen storage disease, heart disease, left-hand disease, right-hand ventricular disease, and right-hand ventricular disease, comprising administering to a patient IN need thereof a therapeutically effective amount of a compound of formula (IM), formula (IN-1), formula (I), formula (II), or a pharmaceutically acceptable salt thereof; preferably selected from ischemic heart disease, limited 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 disorder 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 table a 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, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic Cardiomyopathy (HCM), non-obstructive cardiomyopathy (nHCM), obstructive hypertrophic cardiomyopathy (oHCM), normal ejection fraction heart failure (HFpEF), intermediate value heart failure (HFmREF), a valve disease, a valve stenosis, an inflammatory cardiomyopathy, a lux endocarditis, a cardiomyopathy, an invasive cardiomyopathy, a valvular disease, a fabricism, a glycogen storage disease, a storage method, a heart condition, a right ventricular condition, a congenital heart disease, a left-of the heart disease, and a right ventricular condition; preferably selected from ischemic heart disease, limited 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 tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

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 as a Myosin (Myosin) inhibitor.

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 tautomer thereof, racemate, enantiomer, diastereomer, or mixture form thereof, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use IN treating a disease or disorder 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 hypertrophic cardiomyopathy (oHCM), normal ejection fraction heart failure (HFpEF), ejection fraction intermediate heart failure (hfm), valve disease, aortic valve stenosis, inflammatory cardiomyopathy, lux endocarditis, myocardial endocardia fibrosis, invasive cardiomyopathy, hemopathy, brucellosis, storage disorder, leigh's disease, asbestic heart disease, and ventricular dyspareunia; preferably selected from ischemic heart disease, limited 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 the group consisting of diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic Cardiomyopathy (HCM), non-obstructive hypertrophic cardiomyopathy (nHCM), obstructive hypertrophic cardiomyopathy (oHCM), normal ejection fraction heart failure (HFpEF), ejection fraction intermediate heart failure (HFmREF), valve disease, aortic valve stenosis, inflammatory cardiomyopathy, lux endocarditis, myocardial endocardial fibrosis, invasive cardiomyopathy, hemochromatosis, fabry disease, glycogen storage disease, congenital heart disease, fabry-perot, left-side disease, dyscrasia, and right ventricular angina; preferably selected from ischemic heart disease, limited 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 formula (IM), formula (IN-1), formula (I-1), formula (II-1) and the compounds of table a or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, of the present disclosure may alter the natural history of HCM and other diseases, rather than merely alleviate symptoms. The mechanism by which clinical benefit is imparted to HCM patients can be extended to patients with other forms of heart disease that together have similar pathophysiology, with or without the influence of significant genetic factors. For example, effective treatment of HCM by improving ventricular diastole during diastole may also be effective for a broader population characterized by diastolic dysfunction.

The compounds of general formula (IM), general formula (IN-1), general formula (I-1), general formula (II-1) and the compounds of table a or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, of the present disclosure may specifically target the root cause of the disorder or act on other downstream pathways. Thus, a compound of formula (I) of the present disclosure, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, may confer a benefit to a patient suffering from diastolic heart failure with a retained ejection fraction, ischemic heart disease, angina, 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 alleviating the main cause of volume or pressure overload (valve repair/replacement, effective antihypertensive therapies). By lowering 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 permanent 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 obstruction may reduce the likelihood of requiring intermittent ablative treatment (surgical or percutaneous) and the attendant risks of short-term and long-term complications thereof.

The compounds of general formula (IM), general formula (IN-1), general formula (I-1), general formula (II-1) and the table a compounds 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 equivalent diseases thereof IN patients with implantable cardioverter-defibrillators (frequent and/or repeated ICD discharges) and/or reduce 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 drugs (with their attendant potential toxicity, drug-drug interactions and/or side effects).

The compounds of formula (IM), formula (IN-1), formula (I-1), formula (II-1) and the compounds of table a or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, of the present disclosure may reduce interstitial myocardial fibrosis and/or slow the progression of left ventricular hypertrophy, prevent or reverse left ventricular hypertrophy.

The active compounds can be formulated in a form suitable for administration by any suitable route, using one or more pharmaceutically acceptable carriers by conventional methods to formulate the compositions of the present disclosure. Accordingly, 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) administration, 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, troches or syrups.

The dosage of the compound or composition used in the disclosed methods of treatment 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 guideline, the active compounds are preferably administered in unit doses, or in a manner whereby the patient can self-administer a single dose. The unit dosage of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled lotion, powder, granule, lozenge, suppository, reconstituted powder or liquid formulation. Suitable unit doses may be in the range 0.1 to 1000mg.

The pharmaceutical compositions of the present disclosure may contain, in addition to the active compound, one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, and the like. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of the 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 to 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 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. The aqueous suspension may also contain one or more preservatives, one or more colorants, one or more flavoring agents and one or more sweeteners.

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

The pharmaceutical compositions of the present disclosure may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and 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 sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, which is prepared by injecting a liquid or microemulsion into the blood stream of a patient by topical mass injection. Alternatively, it may be desirable to administer the solutions and microemulsions in a manner that maintains a constant circulating concentration of the compounds of the present disclosure. To maintain this constant concentration, a continuous intravenous delivery device may be used. An example of such a device is a Deltec CADD-PLUS. TM.5400 model intravenous pump.

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

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

The compounds of the present disclosure may be administered by adding water to prepare water-suspended dispersible powders and granules. These pharmaceutical compositions may be prepared by mixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.

As is well known to those skilled in the art, the amount of drug administered depends on a variety of factors, including, but not limited to, the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, optimal treatment regimens such as the mode of treatment, daily use, or the type of pharmaceutically acceptable salt can be validated against conventional treatment regimens.

Description of the terms

Unless stated to the contrary, the 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 from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 12 carbon atoms (i.e., C _1-12 Alkyl groups), more preferably alkyl groups (i.e., C) containing 1 to 6 carbon atoms (e.g., 1,2, 3, 4, 5, and 6) _1-6 Alkyl). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. Most preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atom, 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 chain aliphatic hydrocarbon group which is a residue derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkylene group containing from 1 to 12 carbon atoms (i.e., C _1-12 Alkylene groups), more preferably alkylene groups (i.e., C) containing 1 to 6 carbon atoms (e.g., 1,2, 3, 4, 5, and 6) _1-6 An alkylene group). Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH) ₂ (-), 1-ethylene (-CH (CH) ₃ ) (-), 1, 2-ethylene (-CH) ₂ CH ₂ ) -, 1-propylene (-CH (CH) ₂ CH ₃ ) (-), 1, 2-propylene (-CH) ₂ CH(CH ₃ ) (-), 1, 3-propylene (-CH) ₂ CH ₂ CH ₂ (-), 1, 4-butylene (-CH) ₂ CH ₂ CH ₂ CH ₂ (-), etc. The alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents preferably being 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, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.

The term "alkenyl" refers to an alkyl compound having at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl groups (i.e., C) containing from 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms are preferred _2-12 Alkenyl), more preferably alkenyl having 2 to 6 carbon atoms (i.eC _2-6 Alkenyl). Alkenyl 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 "alkynyl" refers to an alkyl compound having at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl groups (i.e., C) containing from 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms are preferred _2-12 Alkynyl groups), more preferably alkynyl groups containing 2 to 6 carbon atoms (i.e. C _2-6 Alkynyl). 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 containing from 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), preferably containing from 3 to 8 carbon atoms (e.g., 3, 4, 5, 6, 7, and 8) (i.e., 3 to 8 membered cycloalkyl), more preferably containing from 3 to 6 carbon atoms (i.e., 3 to 6 membered cycloalkyl). 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, monocyclic, polycyclic group sharing one carbon atom (referred to as the spiro atom) between the monocyclic rings, which may contain one or more double bonds. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). The spirocycloalkyl groups are classified into single spirocycloalkyl groups or multiple spirocycloalkyl groups (e.g., double spirocycloalkyl groups) according to the number of common spiro atoms between rings, with single spirocycloalkyl groups and double spirocycloalkyl groups being preferred. 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 monocyclocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

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

the term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms that are not directly attached, which may contain one or more double bonds. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). Polycyclic cycloalkyl groups which can be classified into bicyclic, tricyclic, tetracyclic and the like according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyl groups, more preferably bicyclic or tricyclic bridged cycloalkyl groups. Non-limiting examples of bridged cycloalkyl groups include:

The cycloalkyl ring includes cycloalkyl groups (including monocyclic, spiro, fused and bridged rings) fused to aryl groups as described above,Heteroaryl or heterocycloalkyl rings, wherein the ring attached to the parent structure is cycloalkyl, non-limiting examples includeEtc.; preferably->

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, they 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 "alkoxy" refers to-O- (alkyl) wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of a D atom, 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 monocyclic or polycyclic cyclic substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which sulfur may optionally be oxo (i.e., form sulfoxides or sulfones), but excluding the ring portions of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferably from 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, of which 1 to 4 (e.g., 1,2, 3, and 4) are heteroatoms (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 is a heteroatom (e.g., 1,2, and 3) (i.e., 3 to 8 membered heterocyclyl); more preferably 3 to 6 ring atoms, 1-3 of which are heteroatoms (i.e., 3 to 6 membered heterocyclyl); most preferably contain 5 or 6 ring atoms, 1-3 of which are heteroatoms (i.e., 5 or 6 membered heterocyclyl). Non-limiting examples of monocyclic heterocyclyl groups include: pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a 5 to 20 membered, polycyclic heterocyclic group having a single ring sharing one atom (referred to as the spiro atom) therebetween, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which sulfur may optionally be oxo (i.e., form a sulfoxide or sulfone), the remaining ring atoms being carbon. Which may contain one or more double bonds. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). The spiroheterocyclyl groups are classified into single spiroheterocyclyl groups or multiple spiroheterocyclyl groups (e.g., double spiroheterocyclyl groups) according to the number of common spiro atoms between rings, with single and double spiroheterocyclyl groups being preferred. 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 single spiro heterocyclyl. Non-limiting examples of spiroheterocyclyl 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 which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form sulfoxides or sulfones), and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). The number of constituent rings may be classified into a polycyclic fused heterocyclic group such as a bicyclic ring, a tricyclic ring, a tetracyclic ring, etc., preferably a bicyclic ring or a tricyclic ring, more preferably a 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 bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:

the term "bridged heterocyclyl" refers to a 5 to 14 membered, polycyclic heterocyclic group in which any two rings share two atoms which are not directly connected, 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., form sulfoxides or sulfones), the remaining ring atoms being carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). Polycyclic bridged heterocyclic groups which can be classified into bicyclic, tricyclic, tetracyclic and the like according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic bridged heterocyclic groups, more preferably bicyclic or tricyclic bridged heterocyclic groups. Non-limiting examples of bridged heterocyclyl groups include:

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

etc.

The heterocyclic group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably 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 being 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. The aryl ring includes aryl rings fused to heteroaryl, heterocyclyl, or cycloalkyl rings as described above, 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, they 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 "heteroaryl" refers to heteroaromatic systems containing 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 a 5-to 10-membered heteroaryl (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably a 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 heteroaryl condensed onto an aryl, heterocyclyl, or cycloalkyl ring as described above, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

heteroaryl groups may be substituted or unsubstituted, and when substituted, they 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 cycloalkyl, heterocyclyl, aryl and heteroaryl groups mentioned above have residues derived from the removal of one hydrogen atom from the parent ring atom, or residues derived from the removal of two hydrogen atoms from the same or two different ring atoms of the parent, i.e. "divalent cycloalkyl", "divalent heterocyclyl", "arylene", "heteroarylene".

The term "amino protecting group" is intended to mean an amino group that is protected by an easily removable group in order to keep the amino group unchanged when the reaction is carried out at other positions of the molecule. Non-limiting examples include: (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, t-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy or nitro.

The term "hydroxy protecting group" is a suitable group for hydroxy protection known in the art, see literature ("Protective Groups in Organic Synthesis", 5) ^Th Ed.T.W.Greene&P.g.m.wuts). As an example, preferably, the hydroxyl protecting group is selected from (C _1-10 Alkyl or aryl radicals ₃ Silyl groups (e.g., triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, etc.); c (C) _1-10 Alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C _1-6 Alkoxy substituted C _1-6 Alkyl-or phenyl-substituted C _1-6 Alkyl, most preferably C _1-4 Alkoxy substituted C _1-4 Alkyl (e.g., methyl, t-butyl, benzyl, methoxymethyl (MOM), ethoxyethyl, etc.); (C) _1-10 Alkyl or aryl) acyl (e.g.: formyl, acetyl, benzoyl, p-nitrobenzoyl, and the like); (C) _1-6 Alkyl or C _6-10 Aryl) sulfonyl; may also be (C) _1-6 Alkoxy or C _6-10 Aryloxy) carbonyl; an allyl group; 2-Tetrahydropyranyl (THP).

The term "cycloalkyloxy" refers to a cycloalkyl-O-group, 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-, 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-NH ₂ 。

The term "cyano" refers to-CN.

The term "nitro" refers to-NO ₂ 。

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, cycloalkyl are as defined above.

The compounds of the present disclosure may also include isotopic derivatives thereof. The term "isotopically-enriched 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 hydrogenOr use ¹⁸ F-fluorine labeling [ ] ¹⁸ F isotope) instead of fluorine, or with ¹¹ C-、 ¹³ C-or ¹⁴ C-enriched carbon ¹¹ C-、 ¹³ C-or ¹⁴ C-carbon labeling; ¹¹ C-、 ¹³ c-or ¹⁴ C-isotopes) are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays, or as diagnostic imaging tracers in vivo for diseases, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. The present disclosure also includes various deuterated forms of the compounds. Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. Those skilled in the art are able to refer to the relevant literature for the synthesis of deuterated forms of the compounds. Commercially available deuterated starting materials may be used in preparing the deuterated form of the compound or they may be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, tridentate borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like. Deuterated compounds generally retain activity comparable to non-deuterated compounds and may achieve better metabolic stability when deuterated at certain specific sites, thus achieving certain therapeutic advantages.

In the chemical structure of the compounds of the present disclosure, the bondIndicating the unspecified configuration, i.e.the bond +.>Can be +.>Or->Or at the same time contain->And->Two configurations. In the chemical structure of the compound of the present disclosure, the bond +.>The configuration is not specified, i.e., either the Z configuration or the E configuration, or both configurations are included.

"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 group" means that an alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

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

"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.

By "pharmaceutically acceptable salts" is meant salts of the compounds of the present disclosure which are safe and effective when used in a mammal, and which possess the desired biological activity. Salts may be prepared separately during the final isolation and purification of the compounds, or by reacting the appropriate groups 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 and 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 intended effect. 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, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.

The term "solvate" as used herein refers to a physical combination of a compound of the present disclosure with one or more, preferably 1-3, solvent molecules, whether organic or inorganic. The physical bond includes a hydrogen bond. In some cases, for example, when one or more, preferably 1-3, solvent molecules are incorporated into the crystalline solid lattice, 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.

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

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 are effective for the intended use.

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

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

Methods of synthesizing compounds of the present disclosure

In order to accomplish the purpose of the present disclosure, the present disclosure adopts the following technical scheme:

scheme one

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, according to the present disclosure, comprising the steps of:

a compound of the general formula (IMA) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is subjected to Suzuki coupling reaction with a compound of the general formula (V) in the presence of a metal catalyst under basic conditions to obtain 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 bond;

y is

R is a hydrogen atom or an alkyl group;

Scheme II

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

a compound of formula (INA) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is subjected to Suzuki coupling reaction with a compound of formula (V) IN the presence of a metal catalyst under basic conditions to obtain a compound of formula (IN) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

wherein:

l is a bond;

y is

R is a hydrogen atom or an alkyl group;

ring a, ring C, R ¹ 、R ² 、R ^x S and m are as defined IN formula (IN).

Scheme III

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

/>

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

wherein:

l is a bond;

y is

R is a hydrogen atom or an alkyl group;

Scheme IV

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

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

Wherein:

l is a bond;

y is

R is a hydrogen atom or an alkyl group;

ring a, ring B, ring C, R ¹ To R ³ S, m and n are as defined in formula (I).

Scheme five

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

/>

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

wherein:

l is a bond;

y is

R is a hydrogen atom or an alkyl group;

Scheme six

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

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

wherein:

l is a bond;

y is

R is a hydrogen atom or an alkyl group;

Scheme seven

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

/>

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

Wherein:

l is a bond;

y is

R is a hydrogen atom or an alkyl group;

Scheme eight

A method of the present disclosure for the compounds of formula (IM), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

a compound of the general formula (IMB) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, preferably hydrochloride, undergoes a cyclization in microwaves 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:

Scheme nine

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

A compound of formula (INB) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof (preferably hydrochloride salt) undergoes a cyclization reaction IN microwaves to give a compound of formula (IN) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

wherein:

ring a, ring C, L, R ¹ 、R ² 、R ^x S and m are as defined IN formula (IN).

Scheme ten

A method of the present disclosure for the preparation of a compound of formula (IN-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

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, undergoes a cyclization IN the microwave to give a compound of the general formula (IN-1) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

wherein:

Scheme eleven

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

a compound of formula (IB) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof (preferably hydrochloride salt) undergoes a cyclization reaction in microwaves to give a compound of formula (I) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

wherein:

Scheme twelve

a compound of formula (IB-1) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof (preferably hydrochloride salt) undergoes a cyclization reaction in microwaves to give a compound of formula (I-1) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

Wherein:

Scheme thirteen

a compound of formula (IIB) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof (preferably hydrochloride salt) undergoes a cyclization reaction in microwaves to give a compound of formula (II) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

wherein:

ring B, ring C, L, R ¹ To R ³ S, m and n are as defined in formula (II).

Scheme fourteen

/>

A compound of formula (IIB-1) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof (preferably hydrochloride salt) undergoes a cyclization reaction in microwaves to give a compound of formula (II-1) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

wherein:

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, tetrakis triphenylphosphine 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 ] palladium dichloride dichloromethane complex, 1' -bis (dibenzylphosphine) ferrocene palladium dichloride or tris (dibenzylideneacetone) palladium. The palladium-containing catalyst includes, but is not limited to, palladium on carbon, palladium dichloride, palladium acetate, preferably palladium acetate; such ligands include, but are not limited to, triphenylphosphine, tricyclohexylphosphine, tri-n-butylphosphine, trimethoxyphosphine, and the like; 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, methylene chloride, 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 above-mentioned microwave reaction is 110 to 140℃and preferably 120 ℃.

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

Detailed Description

The present disclosure is further described below in conjunction with the examples, which are not intended to 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 ^-6 Units of (ppm) are given. NMR was performed using a Bruker AVANCE-400 nuclear magnetic resonance apparatusOr Bruker AVANCE NEO M, the measuring solvent is deuterated dimethyl sulfoxide (DMSO-d ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard is Tetramethylsilane (TMS).

MS was measured using an Agilent 1200/1290DAD-6110/6120 Quadragole MS liquid chromatography-mass spectrometry (manufacturer: agilent, MS model: 6110/6120 Quadragole MS), waters ACQuity UPLC (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q active (manufacturer: THERMO, MS model: THERMO Q Exactive).

High Performance Liquid Chromatography (HPLC) analysis used Agilent HPLC 1200DAD, agilent HPLC 1200VWD, and Waters HPLC e2695-2489 high performance liquid chromatography.

Chiral HPLC analysis was determined using an Agilent 1260DAD liquid chromatograph.

High performance liquid chromatography was performed using Waters 2767, waters 2767-SQ detector 2, shimadzu LC-20AP and Gilson-281 preparative chromatographs.

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

The CombiFlash flash rapid prep instrument used CombiFlash Rf200 (teldyne ISCO).

The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the 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.

The silica gel column chromatography generally uses 200-300 mesh silica gel of yellow sea of the tobacco stand as a carrier.

Average inhibition rate of kinase and IC ₅₀ The values were measured using a NovoStar microplate reader (BMG, germany).

Known starting materials of the present disclosure may be synthesized using or following methods known in the art, or may be purchased from ABCR GmbH & co.kg, acros Organics, aldrich Chemical Company, shaog chemical technology (Accela ChemBio Inc), dary chemicals, and the like.

The examples are not particularly described, and the reaction can be carried out under an argon atmosphere or a nitrogen atmosphere.

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

The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L volume.

The pressure hydrogenation reaction uses a Parr 3916 model EKX hydrogenometer and a clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenometer.

The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times.

The microwave reaction used was a CEM Discover-S908860 type microwave reactor.

The examples are not specifically described, and the solution refers to an aqueous solution.

The reaction temperature is room temperature and is 20-30 deg.c without specific explanation in the examples.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), the developing reagent used for the reaction, the system of eluent for column chromatography employed for purifying the compound and the developing reagent system of thin layer chromatography included: a: n-hexane/ethyl acetate system, B: the volume ratio of the methylene dichloride to the methanol is adjusted according to the polarity of the compound, and small amounts of alkaline 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

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

(R, E) -N- (5-bromo-2-fluorobenzylidene) -2-methylpropane-2-sulfinamide 1a (8.6 g,28.2mmol, prepared using the method known from the literature "J.Med. Chem,2019,62,9618-9641"), ethyl 2-fluoroacetate 1b (4.5 g,42.3mmol, shanghai-Teartan technologies Co., ltd.) and N, N, N ', N' -tetramethyl ethylenediamine (6.6 g,56.4mmol, shanghai-Albumin Biochemical technologies Co., ltd.) were dissolved in anhydrous tetrahydrofuran (90 mL). Cooled to-70℃and 1M lithium bis (trimethylsilyl) amide in tetrahydrofuran (42.3 mL,42.3mmol, shanghai Technophore Co., ltd.) was added dropwise. The reaction was stirred at-70℃for 3 hours under nitrogen protection. The reaction was quenched by addition of 1N HCl at-20 ℃. A saturated ammonium chloride solution (80 mL) was added and the organic phase separated. The aqueous phase was extracted with ethyl acetate (80 mL. Times.2), 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 (6.9 g, yield: 59.5%).

MS m/z(ESI):412.0[M+1]。

Second step

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

Compound 1c (1.0 g,2.4 mmol) was dissolved in tetrahydrofuran (9 mL) and 1N sodium hydroxide solution (4.8 mL,4.8 mmol) was added. The reaction was stirred for 4 hours. Water (20 mL) was added for dilution and the mixture 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, purifying with high performance liquid chromatography (Sharpsil T-C18,5 μm,30 mm. Times.150 mm, eluting system: H) ₂ O (0.1% trifluoroacetic acid), acetonitrile was increased from 25% (v/v) to 95% (v/v) in 18 minutes, and the detection wavelength was 214&254 nm) to give the title product 1d (500.0 mg, yield: 53.7%).

MS m/z(ESI):384.0[M+1]。

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-methylpropan-2-sulfinamide 1f

Compound 1d (400.0 mg,1.1 mmol), 1- (tetrahydro-2H-pyran-4-yl) pyrimidine-2, 4,6 (1H, 3H, 5H) -trione 1e (332.1 mg,1.6mmol, prepared by the well-known method for the synthesis of Compound 2-3 on page 50 of document "WO2020092208A 1") and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (596.6 mg,1.6mmol, shaoshao-technical Shanghai Co., ltd.) were dissolved in N, N-dimethylformamide (7 mL). Diisopropylethylamine (3.1 g,16.6mmol, shanghai taitan technologies 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 (20 mL) and extracted with ethyl acetate (50 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude title product 1f (1.4 g), which was used in the next step without purification.

MS m/z(ESI):578.0[M+1]。

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-methylpropan-2-sulfinamide 1g

The crude compound 1f (700.0 mg,1.2 mmol) was dissolved in acetic acid (7 mL). Sodium cyanoborohydride (191.0 mg,3.0mmol, shaoshan technology Shanghai Co., ltd.) was added under ice bath. The reaction was stirred at room temperature for 1 hour. Ice water (20 mL) was added thereto, 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×2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1g of the title product as a crude product (700.0 mg), which was used in the next step without purification.

MS m/z(ESI):564.0[M+1]。

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 (700.0 mg,1.2 mmol) was dissolved in ethanol (7 mL). Thionyl chloride (142.8 mg,1.2mmol, shanghai chemical Co., ltd.) was added at 0deg.C. Stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give the title product as a 1-h crude product (620.0 mg), which was used in the next step without purification.

MS m/z(ESI):460.0[M+1]。

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

The crude compound 1h (620 mg,1.3 mmol) was suspended in acetonitrile (9 mL). The reaction was carried out for 1 hour at 120℃with microwaves. The residue obtained was purified by silica gel column chromatography with eluent system B to give the title product 1i (200.0 mg, yield: 86.2% based on compound 1 d).

MS m/z(ESI):441.9[M+1]。

Seventh step

Compound 1i (160.0 mg,0.36 mmol), cyclopropylboronic acid 1j (94.0 g,1.1mmol, shaoshan, inc.), tricyclohexylphosphine (40.3 mg,0.15mmol, shaoshan, inc.) and potassium phosphate (233.2 mg,1.1mmol, beijing carboline technologies Co., ltd.) were dissolved in toluene (5 mL) and water (1 mL). Palladium acetate (16.0 mg,0.07mmol, beijing enoki technologies Co., ltd.) was added. The nitrogen was replaced three times. The reaction was stirred at 100℃for 16 hours under nitrogen protection. Concentrating under reduced pressure, purifying with high performance liquid chromatography (Sharpsil T-C18,5 μm,30 mm. Times.150 mm, eluting system: H) ₂ O (0.1% trifluoroacetic acid), acetonitrile was increased from 30% (v/v) to 95% (v/v) in 23 minutes, and the detection wavelength was 214&254 nm) to give the title product 1 (18.0 mg, yield: 12.4%).

MS m/z(ESI):404.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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

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

2-fluoro-5-hydroxybenzaldehyde 2a (500 mg,3.57mmol, adamas) and 5-fluoro-2- (trifluoromethyl) pyridine 2b (1.2 g,7.27mmol, adamas) were dissolved in N, N-dimethylformamide (10 mL), and potassium carbonate (1.0 g,7.25 mmol) was added to react at 110℃for 0.5 hours. Water (50 mL) was added, extracted 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 (300 mg, yield: 29.5%).

MS m/z(ESI):285.8[M+1]。

Second step

(R) -N- (2-fluoro-5- ((6- (trifluoromethyl) pyridin-3-yl) oxy) benza-no) -2-methylpropan-2-sulfinamide 2e

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

MS m/z(ESI):388.9[M+1]。

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 (350 mg,1.12 mmol), compound 1b (180 mg,1.70mmol, shanghai Taitan technologies Co., ltd.) and N, N, N ', N' -tetramethyl ethylenediamine (0.3 mL, shanghai Ala Biochemical technologies Co., ltd.) were dissolved in anhydrous tetrahydrofuran (5.0 mL). Cooled to-78 ℃, 1M lithium bis (trimethylsilyl) amide in tetrahydrofuran (1.7 ml,1.7mmol, shanghai tai technology co., ltd.) was added dropwise. Stirring for 3 hours at-78 ℃ under the protection of nitrogen. The reaction was quenched by addition of 1N hydrochloric acid at-20 ℃. Saturated ammonium chloride solution (20 mL) was added and the organic phase separated. The aqueous phase was extracted with ethyl acetate (20 mL. Times.2), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), 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 (320 mg, yield: 68.3%).

MS m/z(ESI):494.8[M+1]。

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

MS m/z(ESI):466.8[M+1]。

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-methylpropan-2-sulfinamide 2H

2g (180 mg, 0.383 mmol) of compound 1e (120 mg, 0.560 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (220 mg,0.579 mmol) were dissolved in N, N-dimethylformamide (3.0 mL). Diisopropylethylamine (150 mg,1.16 mmol) was added thereto at 0℃and stirred at room temperature for 16 hours. Saturated sodium bicarbonate solution (20 mL) was added and quenched 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 crude 2h (260 mg, 101.2%) which was used in the next step without purification.

MS m/z(ESI):661.0[M+1]。

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-methylpropan-2-sulfinamide 2i

Compound 2h (250 mg,0.378 mmol) was dissolved in acetic acid (3.0 mL). Sodium cyanoborohydride (60.0 mg,0.952 mmol) was added under ice-bath. The reaction was stirred at room temperature for 1 hour. Ice water (20 mL) was added thereto, and extraction was performed with ethyl acetate (20 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (10 ml×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude title product 2i (240 mg, 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 (240 mg,0.371 mmol) was dissolved in ethanol (3.0 mL) and thionyl chloride (50.0 mg,0.420 mmol) was added at 0deg.C. Stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give crude title product 2j (200 mg, 93.1%), which was used in the next step without purification.

MS m/z(ESI):542.8[M+1]。

Eighth step

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

¹ H NMR(500MHz,DMSO-d ₆ )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

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

6-methylpyridin-3-ol 3a (1.0 g,9.16mmol, shanghai Bifide medical science Co., ltd.) and (4-fluoro-3-formylphenyl) boronic acid 3b (2.0 g,11.9mmol, shanghai Hongshi chemical science Co., ltd.) were dissolved in dichloromethane (10 mL), pyridine (1.5 g,18.8mmol, adamas), triethylamine (1.9 g,18.8mmol, adamas), anhydrous copper acetate (3.4 g,18.8mmol, shanghai Bifide medical science Co., ltd.) were added and reacted at room temperature for 24 hours. The residue obtained was purified by silica gel column chromatography with eluent system A, filtered, concentrated under reduced pressure to give the title product 3c (650 mg, yield: 30.7%).

MS m/z(ESI):231.9[M+1]。

Second step

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

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

MS m/z(ESI):334.9[M+1]。

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 (340 mg,1.02 mmol), compound 1b (170 mg,1.60 mmol) and N, N, N ', N' -tetramethyl ethylenediamine (0.3 mL, shanghai Ala Biochemical technologies Co., ltd.) were dissolved in anhydrous tetrahydrofuran (5.0 mL). Cooled to-78 ℃, 1M lithium bis (trimethylsilyl) amide in tetrahydrofuran (1.6 ml,1.6mmol, shanghai tai technology co., ltd.) was added dropwise. Stirring for 1 hour at-78 ℃ under nitrogen protection. The reaction was quenched by addition of 1N hydrochloric acid at-20 ℃. Saturated ammonium chloride solution (20 mL) was added and the organic phase separated. The aqueous phase was extracted with ethyl acetate (20 mL. Times.2), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), 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 (400 mg, yield: 89.3%).

MS m/z(ESI):440.9[M+1]。

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 (400 mg, 0.258 mmol) was dissolved in tetrahydrofuran (5.0 mL) and 1N sodium hydroxide solution (2.0 mL,2.0 mmol) was added at 0deg.C. Stirred at room temperature for 2 hours. The pH was adjusted to 5 with saturated aqueous citric acid. Concentrating under reduced pressure, purifying with high performance liquid chromatography (Sharpsil T-C18,5 μm,30 mm. Times.150 mm, eluting system: H) ₂ O (0.1% trifluoroacetic acid), acetonitrile was increased from 10% (v/v) to 90% (v/v) in 18 minutes, and the detection wavelength was 214&254 nm) to give the title product 3f (280 mg, yield: 74.7%).

MS m/z(ESI):412.9[M+1]。

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-methylpropan-2-sulfinamide 3g

Compound 3f (280 mg,0.679 mmol), compound 1e (210 mg,0.990 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (390 mg,1.03 mmol) were dissolved in N, N-dimethylformamide (5.0 mL). Diisopropylethylamine (370 mg,2.86 mmol) was added thereto at 0℃and stirred at room temperature for 16 hours. Saturated sodium bicarbonate solution (20 mL) was added and quenched 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 3g of the title product as crude (420 mg, 102%) which was used in the next step without purification.

MS m/z(ESI):607.1[M+1]。

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-methylpropan-2-sulfinamide 3H

Compound 3g (400 mg,0.659 mmol) was dissolved in acetic acid (4.0 mL). Sodium cyanoborohydride (110 mg,1.75 mmol) was added under ice bath. The reaction was stirred at room temperature for 1 hour. Ice water (20 mL) was added thereto, and extraction was performed with ethyl acetate (20 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (10 ml×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title product as a crude product (400 mg, 102.4%) for 3h, 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 (390 mg, 0.618 mmol) was dissolved in ethanol (5.0 mL) and thionyl chloride (100 mg,0.840 mmol) was added at 0deg.C. Stirring at room temperature for 1 hour. The reaction was concentrated under reduced pressure to give crude title product 3i (350 mg, 101.3%), which was used in the next step without purification.

MS m/z(ESI):489.1[M+1]。

Eighth step

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

MS m/z(ESI):471.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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

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

Compound 3c (310 mg,1.34 mmol) and (S) -2-methylpropane-2-sulfinamide 4a (140 mg,1.40mmol, shanghai Bi-pharmaceutical technologies Co., ltd.) were dissolved in dichloromethane (5.0 mL), cesium carbonate (530 mg,1.62 mmol) was added, and stirred at room temperature for 16 hours. The residue obtained was purified by silica gel column chromatography with eluent system A, followed by filtration, concentration under reduced pressure, to give the title product 4b (430 mg, yield: 95.9%).

MS m/z(ESI):335.0[M+1]。

Second step

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

Activated zinc powder (150 mg,2.29 mmol) was suspended in anhydrous tetrahydrofuran (3.0 mL), and a solution of compound 4b (250 mg,0.747 mmol) and ethyl bromoacetate 4c (380 mg,2.28mmol, shao Yuan technology (Shanghai) Co., ltd.) in anhydrous tetrahydrofuran (3.0 mL) was added under nitrogen. The reaction was carried out at 70℃for 1 hour. The residue obtained was purified by silica gel column chromatography with eluent system A, filtered, concentrated under reduced pressure to give the title product 4d (270 mg, yield: 85.4%).

MS m/z(ESI):423.1[M+1]。

Third step

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

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

MS m/z(ESI):394.9[M+1]。

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-methylpropan-2-sulfinamide 4f

Compound 4e (160 mg,0.406 mmol), compound 1e (130 mg,0.613 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (230 mg,0.605 mmol) were dissolved in N, N-dimethylformamide (2.0 mL). Diisopropylethylamine (160 mg,1.24 mmol) was added thereto at 0℃and stirred at room temperature for 16 hours. Saturated sodium bicarbonate solution (20 mL) was added and quenched 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 crude title product 4f (240 mg, 100.5%) which was used in the next step without purification.

MS m/z(ESI):589.1[M+1]。

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-methylpropan-2-sulfinamide 4g

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

MS m/z(ESI):575.2[M+1]。

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

MS m/z(ESI):471.1[M+1]。

Seventh step

Crude compound 4h (200 mg, 0.390 mmol) was suspended in acetonitrile (3.0 mL). The reaction was carried out for 1 hour at 120℃with microwaves. Concentrating under reduced pressure, purifying with high performance liquid chromatography (Boston Phlex C18,5 μm,30 mm. Times.150 mm, eluting system: H) ₂ O (10 mmol ammonium bicarbonate), acetonitrile rise from 35% (v/v) to 95% (v/v) in 20 minutes, detection wavelength 214&254 nm) to give the title product 4 (30 mg, 16.8%).

MS m/z(ESI):453.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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

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

Compound 3b (10 g,59.5mmol, shanghai Han chemical Co., ltd.) and (S) -tetrahydrofuran-3-ol 5a (15.8 g, 178 mmol, shaoshan Techno (Shanghai Co., ltd.) were dissolved in dichloromethane (100 mL), pyridine (10 g,126mmol, adamas), triethylamine (13 g,129 mmol), anhydrous copper acetate (22 g,121mmol, shanghai Pichia pharmaceutical Co., ltd.) were added, and reacted at room temperature for 24 hours. The residue obtained was purified by silica gel column chromatography with eluent system A, followed by filtration, concentration under reduced pressure, to give the title product 5b (1.0 g, yield: 7.99%).

MS m/z(ESI):211.0[M+1]。

Second step

(R) -N- (2-fluoro-5- (((S) -tetrahydrofuran-3-yl) oxy) benza-ylene) -2-methylpropan-2-sulfinamide 5c

Compound 5b (1.0 g,4.76 mmol) and compound 2d (580 mg,4.78mmol, adamas) were dissolved in dichloromethane (20 mL), cesium carbonate (1.9 g,5.83 mmol) was added, and stirred at room temperature for 16 hours. The residue obtained was purified by filtration, concentration and column chromatography on silica gel using an eluent system A to give the title product 5c (1.4 g, yield: 93.9%).

MS m/z(ESI):313.9[M+1]。

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 (1.3 g,4.15 mmol), compound 1b (460 mg,6.50mmol, shanghai Tectam technologies Co., ltd.) and N, N, N ', N' -tetramethyl ethylenediamine (1.3 mL, shanghai Ala Biochemical technologies Co., ltd.) were dissolved in anhydrous tetrahydrofuran (10 mL). Cooled to-78 ℃, 1M lithium bis (trimethylsilyl) amide in tetrahydrofuran (6.5 ml,6.5mmol, shanghai taitant technologies Co., ltd.) was added dropwise. Stirring for 1 hour at-78 ℃ under nitrogen protection. The reaction was quenched by addition of 2N hydrochloric acid at-20 ℃. A saturated ammonium chloride solution (40 mL) was added and the organic phase separated. The aqueous phase was extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), 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 (1.2 g, yield: 68.9%).

MS m/z(ESI):419.9[M+1]。

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

MS m/z(ESI):391.9[M+1]。

Fifth step

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

Compound 5e (900 mg,2.30 mmol), compound 1e (730 mg,3.44 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (1.3 g,3.42 mmol) were dissolved in N, N-dimethylformamide (10.0 mL). Diisopropylethylamine (900 mg,6.96 mmol) was added thereto at 0℃and stirred at room temperature for 16 hours. Saturated sodium bicarbonate solution (50 mL) was added and quenched 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 crude title product 5f (1.4 g, 104%) which was used in the next step without purification.

MS m/z(ESI):585.9[M+1]。

Sixth step

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

Compound 5f (1.4 g,2.39 mmol) was dissolved in acetic acid (15 mL). Sodium cyanoborohydride (380 mg,6.03 mmol) was added under ice-bath. The reaction was stirred at room temperature for 1 hour. Ice water (50 mL) was added thereto, and extraction was performed with ethyl acetate (50 mL. Times.2). The organic phases were combined, washed with saturated sodium chloride solution (50 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 5g of the title product as crude (1.4 g, 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) -tetrahydrofurane-3-yl) oxy) phenyl) propyl) -1- (tetrahydro-2H-pyran-4-yl) pyrimidine-2, 4,6 (1H, 3H, 5H) -trione hydrochloride for 5H

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

MS m/z(ESI):468.1[M+1]。

Eighth step

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

MS m/z(ESI):450.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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

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

Compound 3b (10 g,59.5mmol, shanghai Han dynasty chemical technology Co., ltd.) and (R) -tetrahydrofuran-3-ol 6a (10 g,113mmol, shanghai Pichia pharmaceutical technology Co., ltd.) were dissolved in dichloromethane (100 mL), pyridine (10 g,126mmol, adamas), triethylamine (13 g,129 mmol), anhydrous copper acetate (23 g,127mmol, shanghai Pichia pharmaceutical technology Co., ltd.) were added, and reacted at room temperature for 24 hours. The residue obtained was purified by silica gel column chromatography with eluent system A, followed by filtration, concentration under reduced pressure, to give the title product 6b (1.9 g, yield: 15.2%).

MS m/z(ESI):211.0[M+1]。

Second step

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

Compound 6b (1.9 g,9.04 mmol) and compound 2d (1.1 g,9.08mmol, adamas) were dissolved in dichloromethane (30 mL), cesium carbonate (3.6 g,11.4 mmol) was added and stirred at room temperature for 16 hours. The residue obtained was purified by filtration, concentration and column chromatography on silica gel using an eluent system A to give the crude product 6c (2.8 g, yield: 98.8%).

MS m/z(ESI):313.9[M+1]。

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 (1.5 g,4.79 mmol), compound 1b (760 mg,7.16mmol, shanghai Tectam technologies Co., ltd.) and N, N, N ', N' -tetramethyl ethylenediamine (1.5 mL, shanghai Ala Biochemical technologies Co., ltd.) were dissolved in anhydrous tetrahydrofuran (15 mL). Cooled to-78 ℃, 1M lithium bis (trimethylsilyl) amide in tetrahydrofuran (7.2 ml,7.2mmol, shanghai taitant technologies Co., ltd.) was added dropwise. Stirring for 1 hour at-78 ℃ under nitrogen protection. The reaction was quenched by addition of 1N hydrochloric acid at-20 ℃. A saturated ammonium chloride solution (40 mL) was added and the organic phase separated. The aqueous phase was extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), 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 (1.3 g, yield: 64.7%).

MS m/z(ESI):419.9[M+1]。

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

MS m/z(ESI):391.9[M+1]。

Fifth step

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

Compound 6e (630 mg,2.09 mmol), compound 1e (460 mg,3.11 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (1.2 g,3.16 mmol) were dissolved in N, N-dimethylformamide (10.0 mL). Diisopropylethylamine (820 mg,6.34 mmol) was added thereto at 0℃and stirred at room temperature for 16 hours. Saturated sodium bicarbonate solution (50 mL) was added and quenched 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 crude title product 6f (1.3 g, 106%) which was used in the next step without purification.

MS m/z(ESI):585.9[M+1]。

Sixth step

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

Compound 6f (1.2 g,2.05 mmol) was dissolved in acetic acid (15 mL). Sodium cyanoborohydride (320 mg,5.08 mmol) was added under ice bath. The reaction was stirred at room temperature for 1 hour. Ice water (50 mL) was added thereto, and extraction was performed with ethyl acetate (50 mL. Times.2). The organic phases were combined, washed with saturated sodium chloride solution (50 mL. Times.2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 6g of the title product as crude (1.2 g, 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) -tetrahydrofurane-3-yl) oxy) phenyl) propyl) -1- (tetrahydro-2H-pyran-4-yl) pyrimidine-2, 4,6 (1H, 3H, 5H) -trione hydrochloride 6H

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

MS m/z(ESI):468.1[M+1]。

Eighth step

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

MS m/z(ESI):450.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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

(2R, 3S) -3- (5-cyclopropyl-2-fluorophenyl) -3- ((R) -1, 1-dimethylethylsulfinamido) -2-fluoropropionic acid 7a

Compound 1d (500.0 mg,1.3 mmol), compound 1j (335.9 g,3.9mmol, shaoshan technologies Co., ltd.) and potassium phosphate (551.8 mg,2.6mmol, beijing carboline technologies Co., ltd.) were dissolved in dioxane (20 mL) and water (4 mL). 1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (106.5 mg,0.13mmol, shanghai Taitan technologies Co., ltd.) was added. The nitrogen was replaced three times. The reaction was stirred at 100℃for 16 hours under nitrogen protection. The residue was concentrated under reduced pressure and 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

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

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

MS m/z(ESI):498.1[M+1]。

Third step

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

The crude compound 7c (1.3 g,2.5 mmol) was dissolved in acetic acid (13 mL). Sodium cyanoborohydride (478.7 mg,7.6 mmol) was added under ice-bath. The reaction was stirred at room temperature for 1 hour. The reaction was quenched with ice water (30 mL), 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 crude title product 7d (1.2 g), which was used in the next step without purification.

MS m/z(ESI):484.1[M+1]。

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 (1.2 g,2.5 mmol) was dissolved in ethanol (13 mL). Thionyl chloride (363.3 mg,3.1mmol, shanghai chemical Co., ltd.) was added at 0deg.C. The reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give crude title product 7e (1.0 g), which was used in the next step without purification.

MS m/z(ESI):380.1[M+1]。

Fifth step

Crude compound 7e (1.0 g,2.5 mmol) was suspended in acetonitrile (20 mL). The reaction was carried out for 1.5 hours at 120℃with microwaves. Concentrating under reduced pressure, purifying with high performance liquid chromatography (Boston Phlex Prep C, 5 μm 30 x 150mm, eluting system: H) ₂ O(10mmol NH ₄ HCO ₃ ) Acetonitrile, acetonitrile was increased from 40% (v/v) to 60% (v/v) in 15 minutes, detection wavelength 214&254 nm) to give the title product 7 (52.0 mg, yield: 5.6%).

MS m/z(ESI):362.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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

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

4-bromobenzaldehyde 8a (10.0 g,49.3mmol, shanghai Bi-pharmaceutical technologies Co., ltd.) and Compound 2d (6.3 g,51.7mmol, shanghai Taitan technologies Co., ltd.) were dissolved in dichloromethane (80 mL). Cesium carbonate (19.3 g,59.4 mmol) was added and the reaction stirred for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 8b (15 g), which was used in the next step without purification.

MS m/z(ESI):305.9[M+1]。

Second step

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

Crude 8b (15.0 g,49.0 mmol), compound 1b (7.8 g,73.5mmol, shanghai Techno Co., ltd.) and N, N, N ', N' -tetramethyl ethylenediamine (11.4 g,98.1mmol, shanghai Ala Techno Co., ltd.) were dissolved in anhydrous tetrahydrofuran (150 mL). Cooled to-70℃and 1M lithium bis (trimethylsilyl) amide in tetrahydrofuran (73.5 mL,73.5mmol, shanghai Technophore Co., ltd.) was added dropwise. The reaction was stirred at-70℃for 3 hours under nitrogen protection. The reaction was quenched by addition of 1N hydrochloric acid at-20 ℃. Saturated ammonium chloride solution (100 mL) was added and the organic phase separated. The aqueous phase was extracted with ethyl acetate (100 mL. Times.2), 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 (12.6 g, yield: 62.4%).

MS m/z(ESI):412.0[M+1]。

Third step

(2R, 3S) -3- (4-bromo-2-fluorophenyl) -3- ((R) -1, 1-dimethylethylsulfinamido) -2-fluoropropionic acid 8d

Compound 8c (2.0 g,4.9 mmol) was dissolved in tetrahydrofuran (18 mL) and 1N sodium hydroxide solution (10 mL,10 mmol) was added. The reaction was stirred for 4 hours. Water (20 mL) was added for dilution and the mixture 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, purifying with high performance liquid chromatography (Sharpsil T-C18,5 μm,30 mm. Times.150 mm, eluting system: H) ₂ O (0.1% trifluoroacetic acid), acetonitrile was increased from 30% (v/v) to 95% (v/v) in 18 minutes, and the detection wavelength was 214&254nm)The title product 8d (1.0 mg, yield: 53.7%) was obtained.

MS m/z(ESI):384.0[M+1]。

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-methylpropan-2-sulfinamide 8e

Compound 8d (1.0 g,2.6 mmol), compound 1e (828.5 mg,3.9 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (1.5 g,3.9mmol, shaoshan technology Shanghai Co., ltd.) were dissolved in N, N-dimethylformamide (15 mL). Diisopropylethylamine (1.0 g,7.8mmol, shanghai taitan technologies 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 (30 mL) and extracted with ethyl acetate (50 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude title product 8e (3.6 g), which was used in the next step without purification.

MS m/z(ESI):578.0[M+1]。

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-methylpropan-2-sulfinamide 8f

The crude compound 8e (3.6 g,6.2 mmol) was dissolved in acetic acid (30 mL). Sodium cyanoborohydride (980.3 mg,15.6mmol, shaoshan technology Shanghai Co., ltd.) was added under ice bath. The reaction was stirred at room temperature for 1 hour. Ice water (50 mL) 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×2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude title product 8f (2.8 g), which was used in the next step without purification.

MS m/z(ESI):564.0[M+1]。

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 (560.0 mg,1.0 mmol) was dissolved in ethanol (5 mL). Thionyl chloride (141.7 mg,1.2mmol, shanghai chemical Co., ltd.) was added at 0deg.C. Stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give 8g of the title product (480.0 mg), 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 for 8H

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

MS m/z(ESI):441.9[M+1]。

Eighth step

Compound 8h (170.0 mg,0.38 mmol), compound 1j (66.1 g,0.8mmol, shaoshan, inc.), tricyclohexylphosphine (64.6 mg,0.23mmol, shaoshan, inc.) and potassium phosphate (163.0 mg,0.8mmol, beijing carboline technologies Co., ltd.) were dissolved in toluene (15 mL) and water (3 mL). Palladium acetate (25.9 mg,0.12mmol, beijing enoki technologies Co., ltd.) was added. The nitrogen was replaced three times. The reaction was stirred at 100℃for 16 hours under nitrogen protection. Concentrating under reduced pressure, purifying with high performance liquid chromatography (Welch Ultimate XB-C18,5 μm,30 mm. Times.150 mm, eluting with H) ₂ O (0.1% trifluoroacetic acid), acetonitrile was increased from 30% (v/v) to 95% (v/v) in 12.1 minutes, and the detection wavelength was 214&254 nm) to give the title product 8 (7.0 mg, yield: 4.5%).

MS m/z(ESI):403.9[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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

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

3-bromo-4-fluorophenol 9a (1.0 g,5.24mmol, shaoshao technology (Shanghai) Co., ltd.) and tetrahydro-2H-pyran-4-ylmethane sulfonate 9b (1.2 g,6.66mmol, prepared by the method known from document "U.S. Pat. No. 3,182A 1, pages 7-8, example 8") were dissolved in N, N-dimethylformamide (10 mL), and potassium carbonate (1.1 g,7.97 mmol) was added and reacted at 90℃for 16 hours. Water (50 mL) was added, extracted 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 (850 mg, yield: 59.0%).

¹ H 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

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

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

Third step

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

Compound 9d (480 mg,3.08 mmol) and compound 2d (380 mg,3.13mmol, shanghai Bi-pharmaceutical technologies Co., ltd.) were dissolved in dichloromethane (10 mL), cesium carbonate (1.2 g,3.68 mmol) was added, and stirred at room temperature for 16 hours. The residue obtained was purified by silica gel column chromatography with eluent system A, filtered, concentrated under reduced pressure, to give the title product 9e (640 mg, yield: 63.5%).

MS m/z(ESI):328.1[M+1]。

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 (300 mg,0.916 mmol), compound 1b (150 mg,1.41mmol, shanghai Tectam technologies Co., ltd.) and N, N, N ', N' -tetramethyl ethylenediamine (0.3 mL, shanghai Ala Biochemical technologies Co., ltd.) were dissolved in anhydrous tetrahydrofuran (5.0 mL). Cooled to-78 ℃, 1M lithium bis (trimethylsilyl) amide in tetrahydrofuran (1.4 ml,1.4mmol, shanghai tai technology co., ltd.) was added dropwise. Stirring for 3 hours at-78 ℃ under the protection of nitrogen. The reaction was quenched by addition of 1N hydrochloric acid at-20 ℃. Saturated ammonium chloride solution (20 mL) was added and the organic phase separated. The aqueous phase was extracted with ethyl acetate (20 mL. Times.2), the organic phases were combined, washed with saturated sodium chloride solution (70 mL), 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 (320 mg, yield: 80.5%).

MS m/z(ESI):434.1[M+1]。

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 (320 mg, 0.328 mmol) was dissolved in tetrahydrofuran (4.0 mL) and 1N aqueous sodium hydroxide solution (1.5 mL,1.5 mmol) was added at 0deg.C. Stirring at room temperature for 1 hour. The pH was adjusted to 5 with saturated aqueous citric acid. Reduction ofConcentrating under pressure, purifying with high performance liquid chromatography (Sharpsil T-C18,5 μm,30 mm. Times.150 mm, eluting system: H) ₂ O (0.1% trifluoroacetic acid), acetonitrile was increased from 10% (v/v) to 90% (v/v) in 20 minutes, detection wavelength 214&254 nm) to give 9g (140 mg, yield: 46.8%).

MS m/z(ESI):405.9[M+1]。

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-methylpropan-2-sulfinamide 9H

9g (140 mg,0.345 mmol) of compound 1e (110 mg,0.518 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (200 mg,0.526 mmol) were dissolved in N, N-dimethylformamide (3.0 mL) at 0deg.C, diisopropylethylamine (140 mg,1.08 mmol) was added, stirred at room temperature for 16 hours, quenched with saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude title product 9h (210 mg, 101.4%) which was used directly 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-methylpropan-2-sulfinamide 9i

Compound 9h (210 mg,0.350 mmol) was dissolved in acetic acid (2.0 mL). Sodium cyanoborohydride (55.0 mg,0.873 mmol) was added under ice-bath. The reaction was stirred at room temperature for 1 hour. Ice water (20 mL) was added thereto, and extraction was performed with ethyl acetate (10 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (10 ml×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude title product 9i (210 mg, 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 (210 mg, 0.188 mmol) was dissolved in ethanol (2.0 mL) and thionyl chloride (50.0 mg,0.420 mmol) was added at 0deg.C. Stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give crude title product 9j (180 mg, 96.9%), which was used in the next step without purification.

MS m/z(ESI):482.1[M+1]。

Ninth step

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

MS m/z(ESI):464.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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 explained in further detail below in conjunction with test examples, which are not meant to limit the scope of the present disclosure.

The compounds of example 1, the present disclosure, were tested for their inhibitory effect 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 are briefly described below:

1. experimental material and instrument

1. Actin (cardioac action) (Cytoskeleton, AD 99)

2. Myosin S1 (Myosin Motor Protein S1 Fragment) (Cytoskeleton, CS-MYS 03)

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, 68475-100 ML-F)

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

8.EGTA(Sigma，E3889-100G)

9.96 well plate (Corning, 3697)

U-shaped bottom 96 well plate (Corning 3795)

11. Enzyme label instrument (BMG, PHERAstar)

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

2. Experimental procedure

Actin 1.61. Mu.M, myosin S1.07. Mu.M were mixed with small molecule compounds at different concentrations (initial 100. Mu.M, 3-fold gradient 9) and incubated at 37℃for 1 hour, and ATP 120. Mu.M was added and incubated at 37℃for 2 hours. Finally, the detection solution (70. Mu.L/well) in CytoPhosTM Phosphate Assay Biochem Kit was added to each well and incubated at room temperature for 10min. Reading OD value of 650nM wavelength with enzyme label instrument, calculating Pi value according to standard curve, processing data with GraphPad software, drawing inhibition curve according to compound concentration and corresponding inhibition rate, and calculating compound concentration (IC) when inhibition rate reaches 50% ₅₀ Values. The experimental results are detailed in table 1.

TABLE 1 inhibitory Activity of the compounds of the present disclosure against myosin ATPase enzyme

Examples numbering	IC ₅₀ (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

Conclusion: the compounds of the present disclosure have an inhibitory effect on myosin ATPase enzyme.

Claims

1. A compound of the general formula (IM) or a pharmaceutically acceptable salt thereof:

wherein:

R ^x is C _1-6 Alkyl or

R ^y Is a hydrogen atom or a halogen;

ring a is phenyl or pyridinyl;

l is a bond or an oxygen atom;

ring C is selected from cyclopropyl, pyridinyl, tetrahydrofuranyl and tetrahydropyranyl;

each R is ¹ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 A haloalkyl group;

each R is ² Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Haloalkoxy groups;

ring B is tetrahydropyranyl;

each R is ³ Is a hydrogen atom;

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

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

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

2. The compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (IN):

wherein:

ring a, ring C, L, R ¹ To R ² 、R ^x S and m are as defined in claim 1.

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

wherein:

ring a, ring C, L, R ¹ 、R ² 、R ^x S and m are as defined in claim 1.

4. The compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (I):

wherein:

ring a, ring B, ring C, L, R ¹ To R ³ S, m and n are as defined in claim 1.

5. The compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (I-1):

Wherein:

ring a, ring B, ring C, L, R ¹ To R ³ S, m and n are as defined in claim 1.

6. The compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (II):

wherein:

W ¹ to W ⁵ Is a carbon atom or W ¹ 、W ² 、W ⁴ And W is ⁵ Is a carbon atom and W ³ Is a nitrogen atom;

ring B, ring C, L, R ¹ To R ³ S, m and n are as defined in claim 1.

7. The compound represented by the general formula (IM) according to claim 1, which is a compound represented by the general formula (II-1):

wherein:

ring B, ring C, L, R ¹ To R ³ S, m and n are as defined in claim 1.

8. A compound of formula (IM) according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the following compounds:

9. a compound of the general formula (IMA):

wherein:

x is a bromine atom;

ring A, R ² 、R ^x 、R ^y And m is as defined in claim 1.

10. A compound of formula (IMA) according to claim 9, or a pharmaceutically acceptable salt thereof, selected from the following compounds:

11. a compound of the general formula (IMB) or a pharmaceutically acceptable salt thereof:

Wherein:

ring a, ring C, L, R ¹ 、R ² 、R ^x 、R ^y S and m are as defined in claim 1.

12. A compound of formula (IMB) according to claim 11, or a pharmaceutically acceptable salt thereof, selected from the following compounds:

13. a process for preparing a compound of the general formula (IM) or a pharmaceutically acceptable salt thereof, which comprises:

carrying out Suzuki coupling reaction on a compound shown in a general formula (IMA) or pharmaceutically acceptable salt thereof and a compound shown in a general formula (V) to obtain a compound shown in a general formula (IM) or pharmaceutically acceptable salt thereof;

wherein:

l is a bond;

x is selected from chlorine atom, bromine atom and iodine atom;

y is

R is a hydrogen atom or C _1-6 An alkyl group;

ring a, ring C, R ¹ 、R ² 、R ^x 、R ^y S and m are as defined in claim 1.

14. The process according to claim 13, wherein X is a bromine atom.

15. A process for preparing a compound of the general formula (IM) or a pharmaceutically acceptable salt thereof, which comprises:

generating a ring reaction of a compound of the general formula (IMB) or a pharmaceutically acceptable salt thereof to obtain a compound of the general formula (IM) or a pharmaceutically acceptable salt thereof;

wherein:

16. The method of claim 15, wherein the pharmaceutically acceptable salt of formula (IMB) is the hydrochloride salt.

17. A pharmaceutical composition comprising a compound of general formula (IM) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.

18. Use of a compound of general formula (IM) according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 17 for the preparation of a medicament for myosin inhibitors.

19. Use of a compound of general formula (IM) according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 17 in the manufacture of a medicament for the treatment of a disease or condition selected from the group consisting of ejection fraction preserved diastolic heart failure, ischemic heart disease, angina, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic cardiomyopathy, normal ejection fraction heart failure, ejection fraction median heart failure, valve disease, inflammatory cardiomyopathy, invasive cardiomyopathy, hemochromatosis, fabry's disease, glycogen storage disease, congenital heart disease, left ventricular hypertrophy and chagas disease.

20. The use of claim 19, wherein the disease or condition is selected from the group consisting of ischemic heart disease, restrictive cardiomyopathy, hypertrophic cardiomyopathy, inflammatory cardiomyopathy, invasive cardiomyopathy, congenital heart disease, aortic stenosis, refractory angina pectoris, and left ventricular hypertrophy.

21. The use according to claim 19, wherein the disease or condition is hypertrophic cardiomyopathy.

22. The use according to claim 19 or 20, wherein the hypertrophic cardiomyopathy is a non-obstructive hypertrophic cardiomyopathy or an obstructive hypertrophic cardiomyopathy; the inflammatory cardiomyopathy is luxer endocarditis or myocardial endocardial fibrosis; the congenital heart disease is Fallotetraia.