CN114456163A

CN114456163A - Tetrahydropyridopyrimidine diketone derivative, preparation method and medical application thereof

Info

Publication number: CN114456163A
Application number: CN202111311715.5A
Authority: CN
Inventors: 张晓敏; 胡伟民; 马殿强; 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: 2020-11-09
Filing date: 2021-11-08
Publication date: 2022-05-10
Anticipated expiration: 2041-11-08
Also published as: CN114456163B

Abstract

The present disclosure relates to tetrahydropyridopyrimidinedione derivatives, their preparation methods and their pharmaceutical uses. In particular, the disclosure relates to tetrahydropyridopyrimidinedione derivatives represented by general formula (I), a preparation method thereof, pharmaceutical compositions containing the derivatives, and uses of the derivatives as therapeutic agents, especially uses as Myosin (Myosin) inhibitors and uses in preparation of drugs for treating Hypertrophic Cardiomyopathy (HCM) or heart diseases with pathophysiological characteristics related to HCM.

Description

Tetrahydropyridopyrimidine diketone derivative, preparation method and medical application thereof

Technical Field

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

Background

Hypertrophic Cardiomyopathy (HCM) is a dominant hereditary myocardial disease associated with genetic mutations. The global incidence is about 0.2%, which is the most important cause of sudden death in young people under 35 years old (C. Vaughan Tuohy, et al, European Journal of Heart Failure,22,2020, 228-. Clinically, it is characterized by the asymmetrical hypertrophy of left ventricular wall, frequent invasion and ventricular septum, small ventricular cavity, obstruction of left ventricular blood filling, and decreased ventricular diastolic compliance. The disease is classified into obstructive and non-obstructive hypertrophic cardiomyopathy according to the presence or absence of obstruction in the left ventricular outflow tract. At present, beta-blockers and calcium channel blockers are mostly adopted for clinically treating hypertrophic cardiomyopathy to reduce cardiac contraction and relieve symptoms. However, these treatments are all palliative and not root-cause. HCM progression to late stages is only amenable to heart transplantation (R adhakrishnan Ramaraj, Cardiology in Review,16(4),2008, 172-. Therefore, it is very urgent to find a treatment method aiming at the pathogenesis source of HCM.

The present study found that 70% of HCM patients are caused by mutations in the sarcomere gene. Multiple site mutations are found in 5-7% of patients. More than about 70 pathogenic mutations have been identified, but most of these mutations are family-specific, with only a few hot spots identified, such as the MYH 7R 403Q and R453C mutations (Norbert Frey, et al, Nature Reviews biology, 9,2011, 91-100; m.sabater-Molina, et al, Clinical Genetics,93,2018, 3-14). Research aiming at the pathogenic probability of gene mutation finds that MYH7 gene mutation patients account for about 30%. MYH7 causes early onset of disease and more severe myocardial hypertrophy compared to other sarcomere genes. Myosin is a constituent unit of the thick myofilaments of myofibrils and plays an important role in muscle movement. The molecular shape is like bean sprout, and is composed of two heavy chains and a plurality of light chains. The myosin head combines with actin to form a transverse bridge, so that the ATPase activity of myosin is greatly improved, ATP hydrolysis reaction is catalyzed, energy is generated to promote the transverse bridge to slide, and muscle contraction is carried out. The results of the studies indicate that mutation in the MYH7 gene results in increased myosin ATPase activity, decreased myosin super-delayed State (SRX) ratio, and increased cross-bridging between myosin and actin, leading to abnormal systolic function (Eric M.Green, et al, Science,351(6273),2016, 617-. Myosin is therefore an important target for the treatment of hypertrophic cardiomyopathy.

Patent applications for myosin inhibitors have been disclosed including, inter alia, WO2014205223A1, WO2014205234A1, WO2019028360A1, WO2020092208A1 and CN 110698415A.

Disclosure of Invention

The purpose of the present disclosure is to provide a compound represented by the general 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;

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

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

R⁰Is alkyl or

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

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

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

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

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

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

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

m is 0, 1,2 or 3;

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

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

t is 0, 1 or 2.

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

wherein:

ring A, R⁰、R¹、R²S and m are as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (I-1), or a tautomer, racemate, enantiomer, or diastereomer thereof, 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 a 3-to 6-membered cycloalkyl group or a 3-to 6-membered heterocyclyl group; more preferably, ring a is tetrahydrofuranyl or cyclobutyl.

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

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, is a compound of formula (II), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

is a single bond or a double bond;

x and Z are the same or different and are each independently selected from a bond, a carbon atom, a nitrogen atom, an oxygen atom and a sulfur atom;

y is selected from (CR)⁹R¹⁰)_r-C ═ C-, nitrogen atom, oxygen atom, and sulfur atom;

R⁹and R¹⁰The same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy and hydroxyalkyl;

r is 1 or 2;

R⁰、R¹、R²s and m are as defined in formula (I).

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

wherein:

is a single bond or a double bond;

r is 1 or 2;

R⁰、R¹、R²s and m are as defined in formula (I).

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

wherein:

R⁰、R¹、R²x, Y, Z, s and m are as defined in formula (II).

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

wherein:

R⁰、R¹、R²x, Y, Z, s and m are as defined in formula (II).

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II-1), formula (III-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is R⁰Is C_1-6Alkyl or

Ring B is selected from 3-to 8-membered cycloalkyl, 3-to 12-membered heterocyclyl, 6-to 10-membered aryl and 5-to 10-membered heteroaryl, R³And n is as defined in formula (I); preferably, R⁰Is C_1-6Alkyl or

Ring B is a 3-to 12-membered heterocyclic group, R³And n is as defined in formula (I); more preferably, R⁰Is composed of

Ring B is a 3-to 6-membered heterocyclic group, R³And n is as defined in formula (I); most preferably, R⁰Is tetrahydropyranyl.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II-1), formula (III-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is R¹Selected from hydrogen atoms, halogens and C_1-6An alkyl group; preferably, R¹Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II-1), formula (III-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is R²Selected from hydrogen atoms, halogens, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkyl and C_1-6A haloalkoxy group; preferably, R²Is a hydrogen atom or a halogen; more preferably, R²Is a hydrogen atom or a fluorine atom.

In some preferred embodiments of the present disclosure, the compounds of formula (I), formula (I-1), formula (II-1), formula (III-1) A compound of formula (i) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is²Selected from hydrogen atoms, halogens, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkyl and C_1-6A haloalkoxy group; preferably, R²Is a fluorine atom.

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

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

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

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

Is a single bond; x and Z are the same or different and are each independently selected from a bond, a carbon atom and an oxygen atom; y is (CR)⁹R¹⁰)_r；R⁹And R¹⁰Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, cyano, amino, nitro, hydroxy and C_1-6A hydroxyalkyl group; r is 1 or 2.

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

Is a single bond; x is a bond or an oxygen atom, and Z is a carbon atom; y is (CR)⁹R¹⁰)_r；R⁹And R¹⁰Same, is a hydrogen atom; r is 1.

In some preferred embodiments of the present disclosure, the compound of formula (III), formula (III-1), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein X and Z are the same or different and are each independently selected from the group consisting of a bond, a carbon atom, and an oxygen atom; y is (CR)⁹R¹⁰)_r；R⁹And R¹⁰Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, cyano, amino, nitro, hydroxy and C_1-6A hydroxyalkyl group; r is 1 or 2.

In some preferred embodiments of the present disclosure, the compounds of formula (III) and formula (I)II-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein X is a bond or an oxygen atom, and Z is a carbon atom; y is (CR)⁹R¹⁰)_r；R⁹And R¹⁰Same, is a hydrogen atom; r is 1.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (I-1), or a tautomer, racemate, enantiomer, or diastereomer thereof, 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; r⁰Is C_1-6Alkyl or

Ring B is selected from 3-to 8-membered cycloalkyl, 3-to 12-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 10-membered heteroaryl; r¹Selected from hydrogen atoms, halogens and C_1-6An alkyl group; r²Selected from hydrogen atoms, halogens, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkyl and C_1-6A haloalkoxy group; r³Is a hydrogen atom; m is 0, 1 or 2; n is 0, 1 or 2; s is 0, 1 or 2.

Ring B is selected from 3-to 8-membered cycloalkyl, 3-to 12-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 10-membered heteroaryl; r¹Selected from hydrogen atoms, halogens and C_1-6An alkyl group; r²Selected from hydrogen atoms, halogens, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkyl and C_1-6A haloalkoxy group; m is 0, 1 or 2; n is 0; s is 0, 1 or 2.

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 3-to 6-membered cycloalkyl or 3-to 6-membered heterocyclyl; r⁰Is C_1-6Alkyl or

Ring B is a 3-to 12-membered heterocyclyl; r¹Selected from hydrogen atoms, halogens and C_1-6An alkyl group; r²Selected from hydrogen atoms, halogens, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkyl and C_1-6A haloalkoxy group; r³Is a hydrogen atom; m is 0, 1 or 2; n is 0, 1 or 2; s is 0, 1 or 2.

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 3-to 6-membered cycloalkyl or 3-to 6-membered heterocyclyl; r⁰Is composed of

Ring B is a 3-to 6-membered heterocyclyl; r²Is a hydrogen atom or a halogen; m is 0 or 1; n is 0; s 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 tetrahydrofuranyl or cyclobutyl; r⁰Is C_1-6Alkyl or tetrahydropyranyl; r¹Selected from hydrogen atoms, halogens and C_1-6An alkyl group; r²Selected from hydrogen atoms, halogens, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkyl and C_1-6A haloalkoxy group; m is 0, 1 or 2; s is 0, 1 or 2.

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 tetrahydrofuranyl or cyclobutyl; r⁰Is tetrahydropyranyl; r²Is a hydrogen atom or a halogen; m is 0 or 1; s is 0.

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

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

wherein:

ring A, R⁰、R¹、R²S and m 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, R⁰、R¹、R²S and m are as defined in the general formula (I-1).

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

wherein:

R⁰、R¹、R²x, Y, Z, s and m are as defined in formula (II).

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

wherein:

R⁰、R¹、R²x, Y, Z, s and m are as defined in formula (II-1).

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

wherein:

R⁰、R¹、R²x, Y, Z, s and m are as defined in formula (III).

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

wherein:

R⁰、R¹、R²x, Y, Z, s and m are as defined in formula (III-1).

The compound shown in the general formula (IA), the general formula (IA-1), the general formula (IIA-1), the general formula (IIIA) and the general formula (IIIA-1) in the disclosure, or a tautomer, a racemate, an enantiomer, a diastereoisomer, a mixture thereof or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt thereof is preferably hydrochloride.

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

another aspect of the present disclosure relates to a method of preparing a compound of formula (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 mixture thereof, or a pharmaceutically acceptable salt thereof (preferably hydrochloride) thereof, is subjected to a ring formation reaction to obtain a compound of the general formula (I) or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or pharmaceutically acceptable salt thereof;

wherein:

ring A, R⁰、R¹、R²S and m are as defined in formula (I).

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

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

wherein:

ring A, R⁰、R¹、R²S and m are as defined in the general formula (I-1).

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

a compound of the general formula (IIA) or a tautomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof (preferably hydrochloride) is subjected to a ring formation 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:

R⁰、R¹、R²x, Y, Z, s and m are as defined in formula (II).

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

a compound of the general formula (IIA-1) or a tautomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof (preferably hydrochloride) is subjected to a ring formation reaction to obtain a compound of 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:

R⁰、R¹、R²x, Y, Z, s and m are as defined in formula (II-1).

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

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

wherein:

R⁰、R¹、R²x, Y, Z, s and m are as defined in formula (III).

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

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

wherein:

R⁰、R¹、R²x, Y, Z, s and m are as defined in formula (III-1).

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

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

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

The present disclosure further relates to a method of inhibiting Myosin (Myosin) comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (I-1), formula (II-1), formula (III-1), and table a, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, 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 pectoris, restrictive cardiomyopathy, diastolic dysfunction, Hypertrophic Cardiomyopathy (HCM), nonallergic hypertrophic cardiomyopathy (nHCM), obstructive cardiomyopathy (oHCM), normal ejection fraction heart failure (HFpEF), ejection fraction ref median heart failure (hfmrf), or a pharmaceutical composition comprising the same, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (I-1), formula (II-1), formula (III-1), and table a, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, Valve disease, aortic stenosis, inflammatory cardiomyopathy, love endocarditis, myocardial endocardial fibrosis, invasive cardiomyopathy, hemochromatosis, fabry's disease, glycogen storage disease, congenital heart disease, french tetragon, left ventricular hypertrophy, refractory angina, and chagas disease; preferably selected from ischemic heart disease, restrictive cardiomyopathy, Hypertrophic Cardiomyopathy (HCM), non-obstructive hypertrophic cardiomyopathy (nHCM), obstructive hypertrophic cardiomyopathy (oHCM), inflammatory cardiomyopathy, invasive cardiomyopathy, congenital heart disease, and left ventricular hypertrophy; more preferably Hypertrophic Cardiomyopathy (HCM).

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

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

The present disclosure further relates to a compound of formula (I), formula (I-1), formula (II-1), formula (III-1) and table a or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in treating a disease or disorder selected from the group consisting of preserved ejection fraction diastolic heart failure, 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 (pehff), intermediate ejection fraction heart failure (HFmREF), valve disease, aortic stenosis, inflammatory cardiomyopathy, Love endocarditis, myocardial endocardial fibrosis, invasive cardiomyopathy, hemochromatosis, fabry's disease, glycogen storage disease, congenital heart disease, Fallo tetrad, left ventricular hypertrophy, refractory angina and Chagas disease; preferably selected from ischemic heart disease, restrictive cardiomyopathy, Hypertrophic Cardiomyopathy (HCM), non-obstructive hypertrophic cardiomyopathy (nHCM), obstructive hypertrophic cardiomyopathy (oHCM), inflammatory cardiomyopathy, invasive cardiomyopathy, congenital heart disease, and left ventricular hypertrophy; more preferably Hypertrophic Cardiomyopathy (HCM).

The compounds of the present disclosure of formula (I), formula (I-1), formula (II-1), formula (III-1), and Table A, or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, can alter the natural history of HCM and other diseases, rather than merely alleviate symptoms. The mechanisms that confer clinical benefit to HCM patients may be extended to patients with other forms of heart disease that share similar pathophysiology with or without significant genetic influence. For example, effective treatment of HCM by improving ventricular relaxation during diastole may also be effective for a wider range of populations characterized by diastolic dysfunction.

The compounds of the general formula (I), general formula (I-1), general formula (II-1), general formula (III-1) and Table A of the present disclosure or their tautomers, racemates, enantiomers, diastereomers or their mixtures, or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising them, can specifically target the root cause of a disorder or act on other downstream pathways. Accordingly, the compounds of the present disclosure of formula (I), formula (I-1), formula (II-1), formula (III-1), and Table A, or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, can confer a benefit to patients suffering from diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina, or restrictive cardiomyopathy.

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

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

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

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

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

As a general guide, the active compound is preferably administered in a unit dose or in a manner such that the patient can self-administer it in a single dose. The unit dose of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottle, powder, granule, lozenge, suppository, reconstituted powder, or liquid. A suitable unit dose may be 0.1 to 1000 mg.

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

Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents and lubricating agents. These tablets may be uncoated or they may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

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

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickener. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.

The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.

The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, and the injection or microemulsion may be injected into the bloodstream of a patient by local mass injection. Alternatively, it may be desirable to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump model Deltec CADD-PLUS. TM.5400.

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

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

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

As is well known to those skilled in the art, the dosage of a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular compound 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, the severity of the disease, and the like; in addition, the optimal treatment regimen, such as mode of treatment, daily amount of compound or type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Description of the terms

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

The term "alkyl" refers to a saturated straight or branched chain aliphatic hydrocarbon group having 1 to 20 (e.g., 1,2, 3, 4, 5,6,7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C)_1-20Alkyl groups). The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C)_1-12Alkyl), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C)_1-6Alkyl groups). Non-limiting examples of alkyl groups 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, N-nonyl, N-hexyl, N-pentyl, N-hexyl, N-2-ethylhexyl, N-methyl-3-ethylhexyl, N-hexyl, N-pentyl, N-hexyl, N-pentyl, N-hexyl, N-2-pentyl, N-hexyl, N-2, N-hexyl, N-2-methyl-2-ethyl, N-2-hexyl, N, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. Most preferred is a lower alkyl group having 1 to 6 carbon atoms, and 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-methylbutylButyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, the substituent preferably being selected from one or more of H atom, 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 divalent alkyl group, wherein alkyl is as defined above, having 1 to 20 (e.g., 1,2, 3, 4, 5,6,7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C)_1-20Alkylene). The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms, more preferably an alkylene group having 1 to 6 carbon atoms (i.e., C)_1-6Alkylene). Non-limiting examples of alkylene groups include, but are not limited to: methylene (-CH)₂-), 1-ethylene (-CH (CH)₃) -), 1, 2-ethylene (-CH)₂CH₂) -, 1-propylene (-CH (CH)₂CH₃) -), 1, 2-propylene (-CH)₂CH(CH₃) -), 1, 3-propylene (-CH)₂CH₂CH₂-) 1, 4-butylene (-CH₂CH₂CH₂CH₂-) and the like. The alkylene groups may be substituted or unsubstituted, and when substituted, the substituents 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 group containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above, preferably having 2Alkenyl of up to 12 (e.g. 2,3, 4, 5,6,7,8, 9, 10, 11 or 12) carbon atoms (i.e. C)_2-12Alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C)_2-6Alkenyl). Non-limiting examples include: ethenyl, propenyl, isopropenyl, butenyl, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group.

The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is defined above and has an alkynyl (i.e., C) group of 2 to 12 (e.g., 2,3, 4, 5,6,7,8, 9, 10, 11, or 12) carbon atoms_2-12Alkynyl). The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C)_2-6Alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring having 3 to 20 (e.g., 3, 4, 5,6,7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., 3 to 20 membered cycloalkyl groups), preferably 3 to 12 carbon atoms (i.e., 3 to 12 membered cycloalkyl groups), preferably 3 to 8 carbon atoms (i.e., 3 to 8 membered cycloalkyl groups), more preferably 3 to 6 carbon atoms (i.e., 3 to 6 membered cycloalkyl groups). Non-limiting examples of monocyclic cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocycloalkyl, fused ring alkyl, and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). Spirocycloalkyl groups are classified as mono-or polyspirocycloalkyl (e.g., a bispyridyl cycloalkyl group), preferably mono-and bispyridyl, depending on the number of spiro atoms shared between rings. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/4-membered or 6-membered/5-membered spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

the term "fused cyclic alkyl" refers to an all-carbon polycyclic group of 5 to 20 members sharing an adjacent pair of carbon atoms between the rings, wherein one or more of the rings may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into polycyclic fused cycloalkyl groups such as bicyclic, tricyclic, tetracyclic, etc., preferably bicyclic or tricyclic fused cycloalkyl groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 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 cycloalkyl groups, depending on the number of constituent rings. Non-limiting examples of fused ring alkyl groups include:

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

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

Etc.; preference is given to

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

The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic substituent comprising from 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form a sulfoxide or sulfone), but does not include the ring portion of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferably 3 to 12 (e.g., 3, 4, 5,6,7,8, 9, 10, 11, or 12) ring atoms, of which 1-4 (e.g., 1,2, 3, and 4) are heteroatoms (i.e., 3-to 12-membered heterocyclyl); more preferably 3 to 8 ring atoms (e.g., 3, 4, 5,6,7, and 8), wherein 1-3 are heteroatoms (e.g., 1,2, and 3) (i.e., 3-to 8-membered heterocyclyl); more preferably 3 to 6 ring atoms, of which 1-3 are heteroatoms (i.e., 3-to 6-membered heterocyclyl); most preferably having 5 or 6 ring atoms of which 1-3 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 heterocyclic groups include spiro heterocyclic groups, fused ring heterocyclic groups, and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which one atom (referred to as the spiro atom) is shared between monocyclic rings, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), with the remaining ring atoms being carbon. It may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). Spiro heterocyclic groups are classified into a mono-spiro heterocyclic group or a multi-spiro heterocyclic group (e.g., a bis-spiro heterocyclic group), preferably a mono-spiro heterocyclic group and a bis-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered or 6-membered/6-membered mono spiroheterocyclyl. Non-limiting examples of spiro heterocyclic groups include:

the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which the rings share an adjacent pair of atoms between them, and one or more of the rings may contain one or more double bonds, wherein one or more of the ring atoms is selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic, etc. polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic fused heterocyclic groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

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

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

and the like.

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

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

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

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

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

The above cycloalkyl, heterocyclyl, aryl and heteroaryl groups have 1 residue derived from the parent ring atom by removal of one hydrogen atom, or2 residues derived from the parent ring atom by removal of two hydrogen atoms from the same ring atom or two different ring atoms, i.e., "cycloalkylene", "heterocyclylene", "arylene", "heteroarylene".

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

The term "hydroxyl protecting group" refers to a group introduced on a hydroxyl group that is easily removed, typically to block or protect the hydroxyl group while reacting on other functional groups of the compound. Non-limiting examples include: trimethylsilyl (TMS), Triethylsilyl (TES), Triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-Tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl and the like.

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

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

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

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

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

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

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

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

The term "hydroxy" refers to-OH.

The term "mercapto" refers to-SH.

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

The term "cyano" refers to — CN.

The term "nitro" means-NO₂。

The term "oxo" refers to "═ O".

The term "carbonyl" refers to C ═ O.

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

The term "carboxylate" refers to-C (O) O (alkyl), -C (O) O (cycloalkyl), (alkyl) C (O) O-or (cycloalkyl) C (O) O-, wherein alkyl and cycloalkyl are as defined above.

The disclosed compounds may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which fall within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present disclosure. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents.

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

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

Can be that

Or

Or at the same time contain

And

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

The configuration is not specified, i.e., either the Z configuration or the E configuration, or both configurations are contemplated. For all carbon-carbon double bonds, both Z-and E-forms are included, even if only one configuration is named.

The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as proton transfer tautomers) include interconversion via proton migration, such as keto-enol and imine-enamine, lactam-lactam isomerizations. An example of a lactam-lactam equilibrium is between A and B as shown below.

All compounds in this disclosure can be drawn as form a or form B. All tautomeric forms are within the scope of the disclosure. The naming of the compounds does not exclude any tautomers.

The compounds of the present disclosure may also comprise isotopic derivatives thereof. The term "isotopic derivative" means that the structures differ only by the presence of one or moreA variety of isotopically enriched atom compounds. For example, having the structure of the present disclosure except that "deuterium" or "tritium" is substituted for hydrogen, or¹⁸F-fluorine labeling: (¹⁸Isotope of F) instead of fluorine, or with¹¹C-、¹³C-or¹⁴C-enriched carbon (C¹¹C-、¹³C-or¹⁴C-carbon labeling;¹¹C-、¹³c-or¹⁴C-isotopes) instead of carbon atoms are within the scope of the present disclosure. Such compounds are useful as analytical tools or probes in, for example, biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. The disclosure also includes various deuterated forms of the compounds. Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom.

The person skilled in the art is able to synthesize the deuterated forms of the compounds with reference to the relevant literature. Commercially available deuterated starting materials can be used in preparing the deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated boranes, trideuteroborane in tetrahydrofuran, deuterated lithium aluminum hydrides, deuterated iodoethanes, and deuterated iodomethanes, among others. Deuterations can generally retain activity comparable to non-deuterated compounds and can achieve better metabolic stability when deuterated at certain specific sites, thereby achieving certain therapeutic advantages.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.

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

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

"pharmaceutically acceptable salts" refers to salts of the disclosed compounds which are safe and effective for use in a mammalian body and which possess the requisite biological activity. Salts may be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate group with an appropriate base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

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

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

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

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

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

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

Synthesis of the Compounds of the disclosure

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

scheme one

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

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

wherein:

ring A, R⁰、R¹、R²S and m are as defined in formula (I).

Scheme two

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

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

wherein:

ring A, R⁰、R¹、R²S and m are as defined in the general formula (I-1).

Scheme three

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

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

wherein:

R⁰、R¹、R²x, Y, Z, s and m are as defined in formula (II).

Scheme four

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

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

wherein:

R⁰、R¹、R²x, Y, Z, s and m are as defined in formula (II-1).

Scheme five

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

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

wherein:

R⁰、R¹、R²x, Y, Z, s and m are as defined in formula (III).

Scheme six

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

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

wherein:

R⁰、R¹、R²x, Y, Z, s and m are as defined in formula (III-1).

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

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

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

Detailed Description

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

Examples

The structure of the compound isDetermined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. delta.) of 10^-6The units in (ppm) are given. NMR was measured using a Bruker AVANCE-400 nuclear magnetic instrument or Bruker AVANCE NEO 500M in deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated chloroform (CDCl)₃) Deuterated methanol (CD)₃OD), internal standard Tetramethylsilane (TMS).

MS was determined using an Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC MS (manufacturer: Agilent, MS model: 6110/6120Quadrupole MS).

waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector)

THERMO Ultimate 3000-Q active (manufacturer: THERMO, MS model: THERMO Q active)

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

Chiral HPLC assay using Agilent 1260 DAD HPLC.

High performance liquid phase preparation Waters 2545-2767, Waters 2767-SQ Detector 2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs were used.

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

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

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

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

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

Known starting materials of the present disclosure may be synthesized using or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & co.kg, Acros Organics, Aldrich Chemical Company, nephelo Chemical science and technology (Accela ChemBio Inc), dare chemicals, and the like.

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

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

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

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

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

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

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

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

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing solvent used for the reaction, a system of eluents for column chromatography used for purifying compounds and a developing solvent system for thin layer chromatography including: a: dichloromethane/methanol system, B: the volume ratio of the n-hexane/ethyl acetate system is adjusted according to the different polarities of the compounds, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.

Example 1

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

First step of

1, 4-dibromo-2- (2-chloroethoxy) -5-fluorobenzene 1c

2, 5-dibromo-4-fluorophenol 1a (8.0g, 29.6mmol, prepared by the method disclosed in "Synlett, 2009, No.4, pp 0633-0637") and 2-chloroethyl methanesulfonate 1b (4.7g, 29.7mmol, Bigde pharmaceutical science Co., Ltd.) were dissolved in N, N-dimethylformamide (80mL), and potassium carbonate (8.2g, 59.3mmol) was added. The reaction was carried out at 60 ℃ for 3 hours. Ice water was added, extraction was performed with ethyl acetate (80 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 B to give the title product 1c (5.3g, yield: 53.4%).

MS m/z(ESI):331.0[M+1]。

Second step of

5-fluoro-2, 3-dihydrobenzofuran-6-carbaldehyde 1d

A2.5M n-hexane solution of n-butyllithium (12.0mL, 28.5mmol, Shanghai Tantake Technique, Co., Ltd.) was dissolved in anhydrous tetrahydrofuran (40mL) at-40 ℃, and a solution of compound 1c (4.3g, 12.9mmol) in anhydrous tetrahydrofuran (10mL) was added dropwise. The reaction was stirred for 30 minutes at-40 ℃ under nitrogen. Anhydrous N, N-dimethylformamide (2.9g,38.9mmol) was added at-40 ℃. The reaction was stirred for 30 minutes at-40 ℃ under nitrogen. Saturated aqueous ammonium chloride (50mL) was added, extraction was performed with ethyl acetate (50 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 B to give the title product 1d (430.0mg, yield: 20.0%).

MS m/z(ESI):167.0[M+1]。

The third step

(R,) -N- ((5-fluoro-2, 3-dihydrobenzofuran-6-yl) methylidene) -2-methylpropane-2-sulfinamide 1f

Compound 1d (430.0mg, 2.6mmol) and (R) -2-methylpropane-2-sulfinamide 1e (329.4mg, 2.7mmol, Shanghai Tantake Techno Co., Ltd.) were dissolved in dichloromethane (14 mL). Cesium carbonate (1.0g, 3.1mmol) was added and the reaction stirred for 16 h. The reaction was filtered and the filtrate was concentrated under reduced pressure to give the crude title product 1f (697.0mg) which was used in the next step without purification.

MS m/z(ESI):270.0[M+1]。

The fourth step

(2R,3S) -3- ((R) -1, 1-Dimethylethylsulfinamide) -2-fluoro-3- (5-fluoro-2, 3-dihydrobenzofuran-6-yl) propionic acid ethyl ester 1h

Compound 1f (1.0g, 3.7mmol), ethyl 2-fluoroacetate 1g (590.9mg, 5.6mmol, Shanghai Tantake Technique, Ltd.), and N, N, N ', N' -tetramethylethylenediamine (862.9mg, 7.4mmol, Shanghai Aladdin Biotech, Ltd.) were dissolved in anhydrous tetrahydrofuran (12 mL). The reaction was cooled to-70 ℃ and a 1M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (6.0mL, 6.0mmol, Shanghai Tantake Technology Co., Ltd.) was added dropwise. The reaction was stirred at-70 ℃ for 3 hours under nitrogen. The reaction was quenched by addition of 1N hydrochloric acid at-20 ℃. Saturated aqueous ammonium chloride (20mL) was added and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (50 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 1h (650.0mg, yield: 46.6%).

MS m/z(ESI):376.1[M+1]。

The fifth step

(2R,3S) -3- ((R) -1, 1-Dimethylethylsulfinamide) -2-fluoro-3- (5-fluoro-2, 3-dihydrobenzofuran-6-yl) propionic acid 1i

Compound 1h (650.0mg, 1.7mmol) was dissolved in tetrahydrofuran (8mL) and 1N sodium hydroxide solution (3.5mL, 3.5mmol) was added. The reaction was stirred for 2 hours. The reaction mixture was diluted with water (20mL) and extracted with ethyl acetate (10 mL. times.2). Adjusting pH of the water phase to 5 with saturated citric acid aqueous solution, concentrating under reduced pressure, and purifying by high performance liquid chromatography (SharpSil T-C18,5 μm,30mm x 150mm, elution: H)₂O (0.1% trifluoroacetic acid), acetonitrile from 20% (v/v) to 95% (v/v) in 16 minutes, detection wavelength 214&254nm) to yield the title product 1i (210.0mg, yield: 34.9%).

MS m/z(ESI):348.0[M+1]。

The sixth step

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

Compound 1i (210.0mg, 0.6mmol), 1- (tetrahydro-2H-pyran-4-yl) pyrimidine-2, 4,6(1H,3H,5H) -trione 1j (192.5mg, 0.9mmol, prepared using the method disclosed in document "WO 2020092208a1, page 49" of the specification) and 2- (7-azabenzotriazole) -N, N' -tetramethylurea hexafluorophosphate (344.6mg, 0.9mmol, shanghai, shao science) were dissolved in N, N-dimethylformamide (4 mL). Diisopropylethylamine (234.4mg, 1.8mmol) was added at 0 ℃ and stirred at room temperature for 16 hours. The reaction was quenched by the addition of saturated sodium bicarbonate solution (10mL), extracted with ethyl acetate (20 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave the title product, 1k crude (600mg), which was used in the next step without purification.

MS m/z(ESI):542.1[M+1]。

Seventh step

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

Crude compound 1k (600.0mg, 1.1mmol) was dissolved in acetic acid (6 mL). Sodium cyanoborohydride (174.5mg, 2.8mmol) was added under ice bath. The reaction was stirred at room temperature for 1 hour. The reaction was quenched by addition of ice water (20mL), extracted with ethyl acetate (20 mL. times.3), and the organic phases were combined and washed with saturated sodium chloride solution (10 mL. times.2). Dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title product as 1l crude (584.0mg) which was used in the next step without purification.

MS m/z(ESI):528.1[M+1]。

Eighth step

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

Compound 1l crude (584.0mg, 1.1mmol) was dissolved in ethanol (7 mL). Thionyl chloride (158.1mg, 1.3mmol, Shanghai Kagaku Kogyo Co., Ltd.) was added at 0 ℃. The reaction was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure to give the title product 1m crude (468.0mg), which was used in the next step without purification. MS M/z (ESI) 424.1[ M +1 ].

The ninth step

The crude compound 1m (468.0mg, 1.0mmol) was suspended in acetonitrile (11 mL). The reaction was carried out at 120 ℃ for 1 hour by microwave. Concentrating under reduced pressure, and purifying by high performance liquid chromatography (SharpSil T-C18,5 μm,30mm x 150mm, elution system: H)₂O (0.1% trifluoroacetic acid), acetonitrile rising from 25% (v/v) to 95% (v/v) within 22 minutes, detection wavelength 214&254nm) to give the title product 1(90.0mg, yield: 21.8%).

MS m/z(ESI):406.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ9.81(s,1H),7.12(d,1H),6.87(d,1H),6.44(s,1H),5.07(d,1H),4.89-4.82(m,1H),4.73-4.53(m,3H),3.90(dd,2H),3.34-3.17(m,4H),2.67-2.55(m,4H),1.38(dd,2H)。

Example 2

(6S,7S) -6-fluoro-7- (4-fluorobicyclo [4.2.0] octan-1 (6),2, 4-trien-3-yl) -3- (tetrahydro-2H-pyran-4-yl) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidine-2, 4(1H,3H) -dione 2

First step of

3-bromo-4-fluorobicyclo [4.2.0] octa-1 (6),2, 4-triene 2b

To a solution of 4-bromobicyclo [4.2.0] octan-1 (6),2, 4-trien-3-amine 2a (2.8g, 14.2mmol, prepared by the method disclosed in WO2018057973A1, page 183-184, compound 4 of example 1 ", in patent application 7mL) at 0 ℃ were added dropwise an aqueous solution of 48% tetrafluoroboric acid (11.2mL, Afahesar (China) chemical Co., Ltd.) and an aqueous solution of sodium nitrite (981.0mg, 14.2mmol, Shanghai Kogyo chemical Co., Ltd.) (7 mL). The reaction was carried out at 0 ℃ for 1 hour. And filtering the reaction solution, collecting a filter cake, and drying in vacuum. The resulting compound (4.0g) was stirred at 130 ℃ under nitrogen for 2 hours. The resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 2B (700.0mg, yield: 24.6%).

¹H NMR(500MHz,CDCl₃)δ7.20(d,1H),6.85(d,1H),3.15-3.09(m,4H)。

Second step of

4-Fluorobicyclo [4.2.0] octa-1 (6),2, 4-triene-3-carbaldehyde 2c

To a solution of compound 2b (700.0mg, 3.5mmol) in anhydrous tetrahydrofuran (10mL) at-78 deg.C was added dropwise a 2.5M n-hexane solution of n-butyllithium (1.7mL, 4.2mmol, Shanghai Tantake Techno Co., Ltd.). The reaction was stirred at-78 ℃ for 30 minutes under nitrogen. Anhydrous N, N-dimethylformamide (333.0mg, 4.6mmol) was added and the reaction was stirred at 78 ℃ for 30 minutes. The reaction was slowly warmed to room temperature and stirred for 1 hour. Saturated aqueous ammonium chloride (20mL) was added, extracted with ethyl acetate (30 mL. times.2), and the organic phases were combined and concentrated under reduced pressure to give the title product, crude 2c (500.0mg), which was used in the next step without purification.

MS m/z(ESI):151.1[M+1]。

The third step

(R,) -N- ((4-fluorobicyclo [4.2.0] octa-1 (6),2, 4-trien-3-yl) methylidene) -2-methylpropane-2-sulfinamide 2d Compound 2c (500.0mg, 3.34mmol) and Compound 1e (434.0mg, 3.5mmol) were dissolved in dichloromethane (10 mL). Cesium carbonate (1.3g, 4.0mmol) was added and the reaction stirred for 16 h. The reaction was filtered and the filtrate was concentrated under reduced pressure to give the title product, 2d crude (1.0g), which was used in the next step without purification. MS M/z (ESI) 254.1[ M +1 ].

The fourth step

(2R,3S) -3- ((R) -1, 1-Dimethylethylsulfinamide) -2-fluoro-3- (4-fluorobicyclo [4.2.0] octan-1 (6),2, 4-trien-3-yl) propionic acid ethyl ester 2e

Compound 2d (1.0g, 4.0mmol), compound 1g (630.0mg, 5.9mmol) and N, N, N ', N' -tetramethylethylenediamine (917.0mg, 7.9mmol, Shanghai Aladdin Biotech Co., Ltd.) were dissolved in anhydrous tetrahydrofuran (12 mL). A1M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (6.0mL, 6.0mmol, Shanghai Tantake Techno Co., Ltd.) was added dropwise at-78 ℃. Reacting for 3 hours at-78 ℃ under the protection of nitrogen. The reaction was quenched by dropwise addition of 1N hydrochloric acid at-20 ℃. Saturated aqueous ammonium chloride (20mL) was added and extracted with ethyl acetate (30 mL. times.2). The organic phases were combined, washed with saturated aqueous sodium chloride (30mL) and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, and purification of the resulting residue by silica gel column chromatography with eluent system B gave the title product 2e (690.0mg, yield: 48.6%).

MS m/z(ESI):360.1[M+1]。

The fifth step

(2R,3S) -3- ((R) -1, 1-Dimethylethylsulfinamide) -2-fluoro-3- (4-fluorobicyclo [4.2.0] octa-1 (6),2, 4-trien-3-yl) propanoic acid 2f

Compound 2e (690.0mg, 1.9mmol) was dissolved in tetrahydrofuran (8mL), and a 1N aqueous solution of sodium hydroxide (3.9mL, 3.9mmol) was added dropwise. The reaction was carried out at room temperature for 2 hours. Adjusting pH to 5 with saturated citric acid solution, concentrating under reduced pressure, and purifying by high performance liquid chromatography (SharpSil T-C18,5 μm,30 mm. about.150 mm, elution system: H)₂O(10Mm NH₄HCO₃) Acetonitrile, acetonitrile from 20% (v/v) to 95% (v/v) within 20.2 min, detection wavelength 214&254nm) to give the title product 2f (290.0mg, yield: 45.6%).

MS m/z(ESI):332.0[M+1]。

The sixth step

(R) -N- ((1S,2R) -2-fluoro-1- (4-fluorobicyclo [4.2.0] octan-1 (6),2, 4-trien-3-yl) -3-oxo-3- (2,4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) propyl) -2-methylpropane-2-sulfinamide 2g

Compound 2f (280.0mg, 0.9mmol), compound 1j (269.0mg, 1.3mmol) and 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (482.0mg, 1.3mmol) were dissolved in N, N-dimethylformamide (5 mL). Diisopropylethylamine (328.0mg, 2.5mmol) was added at 0 ℃ and stirred at room temperature for 16 hours. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate (10mL), extracted with ethyl acetate (20 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave the title product as 2g of crude product (1.3g) which was used in the next step without further purification.

MS m/z(ESI):526.1[M+1]。

Seventh step

(R) -N- ((1S,2S) -2-fluoro-1- (4-fluorobicyclo [4.2.0] octan-1 (6),2, 4-trien-3-yl) -3- (2,4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) propyl) -2-methylpropane-2-sulfinamide 2H

2g of crude compound (1.3g, 2.5mmol) was dissolved in acetic acid (13 mL). Sodium cyanoborohydride (389.6mg, 6.2mmol) was added under ice bath. The reaction was stirred at room temperature for 1 hour. The reaction was quenched by addition of ice water (30mL), extracted with ethyl acetate (20 mL. times.3), and the organic phases were combined and washed with saturated sodium chloride solution (10 mL. times.2). Dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title product as a 2h crude product (1.3g) which was used in the next step without further purification.

MS m/z(ESI):512.1[M+1]。

Eighth step

5- ((2S,3S) -3-amino-2-fluoro-3- (4-fluorobicyclo [4.2.0] octan-1 (6),2, 4-trien-3-yl) propyl) -1- (tetrahydro-2H-pyran-4-yl) pyrimidine-2, 4,6(1H,3H,5H) -trione hydrochloride 2i

Dissolve compound 2h crude (1.3g, 2.5mmol) in ethanol (13 mL). Thionyl chloride (362.9mg, 3.1mmol) was added at 0 ℃. The reaction was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure to give the title product, crude 2i (1.0mg), which was used in the next step without purification.

MS m/z(ESI):408.1[M+1]。

The ninth step

The crude compound 2i (1.0g, 2.3mmol) was suspended in acetonitrile (12 mL). The reaction was carried out at 120 ℃ for 1.5 hours by microwave. Concentrating under reduced pressure, and purifying by high performance liquid chromatography (SharpSil T-C18,5 μm,30mm x 150mm, elution system: H)₂O(10Mm NH₄HCO₃) Acetonitrile, acetonitrile from 30% (v/v) to 95% (v/v) within 20.2 minutes, detection wavelength 214&254nm) to give the title product 2(177.0mg, yield: 20.2%). MS M/z (ESI) 390.1[ M +1]]。

¹H NMR(500MHz,DMSO-d₆)δ10.21(s,1H),7.10(d,1H),7.02(d,1H),6.41(s,1H),5.07(m,1H),4.97(m,1H),4.87(m,1H),3.91(dd,2H),3.35(s,1H),3.30(s,1H),3.15-3.09(m,4H),2.73-2.55(m,4H),1.42-1.36(m,2H)。

Example 3

(6S,7S) -7- (bicyclo [4.2.0] octan-1 (6),2, 4-trien-3-yl) -6-fluoro-3- (tetrahydro-2H-pyran-4-yl) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidine-2, 4(1H,3H) -dione 3

First step of

(R,) -N- (bicyclo [4.2.0] octan-1 (6),2, 4-trien-3-ylmethylidene) -2-methylpropane-2-sulfinamide 3b

Bicyclo [4.2.0] octa-1 (6),2, 4-triene-3-carbaldehyde 3a (1.4g, 10.8mmol, prepared by the method disclosed in step 1 "on page 512-513 of the specification of patent application WO2019023147A 1) and compound 1e (1.4g, 11.4mmol) were dissolved in dichloromethane (20 mL). Cesium carbonate (4.3g, 13.0mmol) was added and the reaction stirred for 16 h. The reaction was filtered and the filtrate was concentrated under reduced pressure to give the crude title product 3b (2.6g) which was used in the next step without further purification.

MS m/z(ESI):236.1[M+1]。

Second step of

(2R,3S) -3- (bicyclo [4.2.0] octan-1 (6),2, 4-trien-3-yl) -3- ((R) -1, 1-dimethylethylsulfenamide) -2-fluoro-3-propionic acid ethyl ester 3c

Compound 3b (2.6g, 11.1mmol), compound 1g (1.7g, 16.6mmol) and N, N, N ', N' -tetramethylethylenediamine (2.6g, 22.1mmol) were dissolved in anhydrous tetrahydrofuran (30 mL). A1M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (16.6mL, 16.6mmol) was added dropwise at-78 ℃. Reacting for 3 hours at-78 ℃ under the protection of nitrogen. The reaction was quenched by dropwise addition of 1N hydrochloric acid at-20 ℃. Saturated aqueous ammonium chloride (30mL) was added and extracted with ethyl acetate (50 mL. times.2). The organic phases were combined, washed with saturated aqueous sodium chloride (30mL) and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, and purification of the resulting residue by silica gel column chromatography with eluent system B gave the title product 3c (3.5g, yield: 92.5%).

MS m/z(ESI):342.1[M+1]。

The third step

(2R,3S) -3- (bicyclo [4.2.0] octan-1 (6),2, 4-trien-3-yl) -3- ((R) -1, 1-dimethylethylsulfenamide) -2-fluoropropionic acid 3d

Compound 3c (1.0g, 2.9mmol) was dissolved in tetrahydrofuran (10mL) and 1N aqueous sodium hydroxide (6mL, 6mmol) was added dropwise. The reaction was carried out at room temperature for 2 hours. Adjusting pH to 5 with saturated citric acid aqueous solution, concentrating under reduced pressure, and purifying by high performance liquid chromatography (SharpSil T-C18,5 μm,30 mm. times.150 mm, elution system: H₂O (0.1% TFA), acetonitrile, from 25% (v/v) to 95% (v/v) in 16 minutes, detection wavelength 214&254nm) to yield the title product 3d (350.0mg, yield: 38.1%).

MS m/z(ESI):314.0[M+1]。

The fourth step

(R) -N- ((1S,2R) -1- (bicyclo [4.2.0] octan-1 (6),2, 4-trien-3-yl) -2-fluoro-3-oxo-3- (2,4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) propyl) -2-methylpropane-2-sulfinamide 3e

Compound 3d (300.0mg, 1.0mmol), compound 1j (304.7mg, 1.4mmol) and 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (545.7mg, 1.4mmol) were dissolved in N, N-dimethylformamide (7 mL). Diisopropylethylamine (371.2mg, 2.9mmol) was added at 0 ℃ and stirred at room temperature for 16 hours. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate (20mL), extracted with ethyl acetate (30 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave the crude title product 3e (1.1g) which was used in the next step without purification.

MS m/z(ESI):508.1[M+1]。

The fifth step

(R) -N- ((1S,2S) -1- (bicyclo [4.2.0] octan-1 (6),2, 4-trien-3-yl) -2-fluoro-3- (2,4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) propyl) -2-methylpropan-2-sulfinamide 3f

The crude compound 3e (1.1g, 2.2mmol) was dissolved in acetic acid (11 mL). Sodium cyanoborohydride (341.7mg, 5.4mmol) was added under an ice bath. The reaction was stirred at room temperature for 1 hour. The reaction was quenched by addition of ice water (30mL), extracted with ethyl acetate (20 mL. times.3), and the organic phases were combined and washed with saturated sodium chloride solution (10 mL. times.2). Dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title product, crude 3f (1.1g), which was used in the next step without purification.

MS m/z(ESI):494.1[M+1]。

The sixth step

5- ((2S,3S) -3-amino-3- (bicyclo [4.2.0] octa-1 (6),2, 4-trien-3-yl) -2-fluoropropyl) -1- (tetrahydro-2H-pyran-4-yl) pyrimidine-2, 4,6(1H,3H,5H) -trione hydrochloride 3g

The crude compound 3f (1.1g, 2.2mmol) was dissolved in ethanol (11 mL). Thionyl chloride (318.6mg, 2.7mmol) was added at 0 ℃. The reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give the title product 3g of crude product (850.0mg), which was used in the next step without purification.

MS m/z(ESI):390.1[M+1]。

The seventh step (6S,7S) -7- (bicyclo [4.2.0] octan-1 (6),2, 4-trien-3-yl) -6-fluoro-3- (tetrahydro-2H-pyran-4-yl) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidine-2, 4(1H,3H) -dione 3

3g of crude compound (850.0g, 2.0mmol) was suspended in acetonitrile (9 mL). The reaction was carried out at 120 ℃ for 1.5 hours by microwave. Concentrating under reduced pressure, and purifying by high performance liquid chromatography (SharpSil T-C18,5 μm,30mm x 150mm, elution system: H)₂O(10mM NH₄HCO₃) Acetonitrile, acetonitrile from 25% (v/v) to 95% (v/v) in 20 minutes, detection wavelength 214&254nm) to give the title product 3(76.0mg, yield: 21.3%).

MS m/z(ESI):372.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ9.03(s,1H),7.19(d,1H),7.08(dd,2H),6.54(s,1H),4.97(dd,1H),4.86(m,1H),4.60(d,1H),3.90(dd,2H),3.31(dd,2H),3.13(s,4H),2.65-2.54(m,4H),1.39-1.35(m,2H)。

Biological evaluation

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

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

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

first, experimental material and instrument

1.Cardiac Actin(Cytoskeleton，AD99)

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

3.ATP(Sigma，A7699-1G)

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

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

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

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

8.EGTA(Sigma，E3889-100G)

9.96 well plate (Corning 3697)

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

11. Enzyme mark instrument (BMG, PHERAStar)

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

Second, the experimental procedure

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

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

Example numbering	IC₅₀(μM)
		1	2.7
2	1.45
		3	10.9

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

Claims

1. 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;

each R is¹The same or different, and each is independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitroHydroxyl and hydroxyalkyl groups;

R⁰Is alkyl or

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

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

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

m is 0, 1,2 or 3;

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

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

t is 0, 1 or 2.

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

wherein:

ring A, R⁰、R¹、R²S and m are as defined in claim 1.

3. A compound of formula (I) according to claim 1 or2, 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 a 3-to 6-membered cycloalkyl group or a 3-to 6-membered heterocyclyl group; more preferably, ring a is tetrahydrofuranyl or cyclobutyl.

4. A compound of formula (I) according to any one of claims 1 to 3, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of formula (II) or formula (II-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

is a single bond or a double bond;

r is 1 or 2;

R⁰、R¹、R²s and m are as defined in claim 1.

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

wherein:

R⁰、R¹、R²x, Y, Z, s and m are as defined in claim 4.

6. A compound of general formula (I) according to any one of claims 1 to 5, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is⁰Is C_1-6Alkyl or

Ring B is selected from 3-to 8-membered cycloalkyl, 3-to 12-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 10-membered heteroaryl; r is³And n is as defined in claim 1; preferably, R⁰Is tetrahydropyranyl.

7. The compound of general formula (I) according to any one of claims 1 to 6, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R¹Selected from hydrogen atoms, halogens and C_1-6An alkyl group; preferably, R¹Is a hydrogen atom.

8. The compound of general formula (I) according to any one of claims 1 to 7, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R²Selected from hydrogen atoms, halogens, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkyl and C_1-6A haloalkoxy group; preferably, R²Is a hydrogen atom or a halogen; more preferably, R²Is a hydrogen atom or a fluorine atom.

9. The compound of general formula (I) according to any one of claims 1 to 8, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R³Is a hydrogen atom.

10. A compound of general formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 9, selected from the group consisting of:

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

wherein:

the pharmaceutically acceptable salt thereof is preferably hydrochloride;

ring A, R⁰、R¹、R²S and m are as defined in claim 1.

12. The compound of formula (IA) according to claim 11, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

13. a process for the preparation of a compound of formula (I) according to claim 1, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

wherein:

ring A, R⁰、R¹、R²S and m are as defined in claim 1.

14. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 10, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

15. Use of a compound of general formula (I) according to any one of claims 1 to 10 or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, for the preparation of a medicament for the manufacture of a Myosin (Myosin) inhibitor.

16. Use of a compound of general formula (I) according to any one of claims 1 to 10 or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, for the preparation of a medicament for the treatment of a disease or disorder selected from the group consisting of diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, Hypertrophic Cardiomyopathy (HCM), nonallergic hypertrophic cardiomyopathy (nHCM), obstructive hypertrophic cardiomyopathy (oHCM), normal ejection fraction heart failure (HFpEF), intermediate ejection fraction heart failure (HFmREF), valve disease, aortic stenosis, inflammatory cardiomyopathy, love endocarditis, myocardial endocarditis fibrosis, invasive cardiomyopathy, Hemochromatosis, fabry's disease, glycogen storage disease, congenital heart disease, falo tetrad, left ventricular hypertrophy, refractory angina and chagas disease; preferably selected from ischemic heart disease, restrictive cardiomyopathy, Hypertrophic Cardiomyopathy (HCM), non-obstructive hypertrophic cardiomyopathy (nHCM), obstructive hypertrophic cardiomyopathy (oHCM), inflammatory cardiomyopathy, invasive cardiomyopathy, congenital heart disease, and left ventricular hypertrophy; more preferably Hypertrophic Cardiomyopathy (HCM).