CN114539257B - Pyrimidine diketone spiro derivative, preparation method and medical application thereof - Google Patents

Abstract

The present disclosure relates to pyrimidinedione spiro derivatives, methods of making and using them in medicine. In particular, the present disclosure relates to pyrimidinedione spiro derivatives of general formula (I), methods for their preparation and pharmaceutical compositions containing them, and their use as therapeutic agents, in particular in the preparation of Myosin (Myosin) inhibitors and in the preparation of medicaments for the treatment of Hypertrophic Cardiomyopathy (HCM) or heart diseases with pathophysiological characteristics associated with HCM. Wherein the definition of each group in the compound of the general formula (I) is defined as the specification.

Description

Pyrimidine diketone spiro derivative, preparation method and medical application thereof

Technical Field

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

Background

Hypertrophic Cardiomyopathy (HCM) is a dominant inherited cardiomyopathy associated with gene mutations. Global morbidity is about 0.2% and is the most important cause of sudden death in young people under 35 years of age (c.vaughan Tuohy et al European Journal of Heart Failure,22,2020,228-240). Clinically, the characteristics are that the left ventricle wall is asymmetrically hypertrophic, is frequently invaded and is frequently separated, the inner cavity of the ventricle is reduced, the left ventricle blood filling is blocked, and the compliance of the ventricular diastole is reduced. The left ventricular outflow tract is classified into obstructive and non-obstructive hypertrophic cardiomyopathy according to the presence or absence of obstruction. Currently, beta-blockers and calcium channel blockers are mostly used clinically for treating hypertrophic cardiomyopathy to reduce heart contraction and relieve symptoms. However, these treatments are both palliative and not palliative. HCM progresses to advanced stages where only heart transplants can be performed (R adhakrishnan Ramaraj, cardiology in Review,16 (4), 2008, 172-180). Thus, it is urgent to find a therapeutic method for the root cause of HCM.

The existing study found that 70% of HCM patients are caused by the mutation of sarcomere protein gene. Wherein a plurality of site mutations are found in 5-7% of patients. More than about 70 pathogenic mutations have been identified, but most of these have family specificity, with only a few hot spots being identified, such as MYH 7R 403Q and R453C mutations (Norbert Frey, et al, nature Reviews Cardiology,9,2011,91-100; M.Sabater-Molina, et al, clinical Genetics,93,2018,3-14). Studies on the probability of causing gene mutation have found that about 30% of patients with MYH7 gene mutation are involved. MYH7 causes early onset of disease and more severe myocardial hypertrophy compared to other sarcomere genes. Myosin is a constituent unit of myofibrillar crude muscle filaments and plays an important role in muscle movement. The molecular shape of the light chain is like bean sprout, and the light chain consists of two heavy chains and a plurality of light chains. The head of myosin is combined with actin to form transverse bridge, so that the ATPase activity of myosin is greatly raised, and the ATP hydrolysis reaction is catalyzed to produce energy to promote the transverse bridge to slide and to contract muscle. The results of the study indicate that mutations in the MYH7 gene lead to an increase in myosin ATPase activity, a decrease in the proportion of myosin super-relaxed State (SRX), and an increase in the cross-bridge between myosin and actin, leading to a systolic dysfunction (Eric M.Green et al, science,351 (6273), 2016,617-621;Ruth F.Sommese,et al, proceedings of the National Academy Sciences,110 (31), 2013,12607-12612). Thus, myosin is an important target for the treatment of hypertrophic cardiomyopathy.

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

Disclosure of Invention

The purpose of the present disclosure is to provide a compound represented by general formula (I):

wherein:

y is selected from CR⁵ R⁶ 、NR⁷ O atom, S atom, CR⁵ R⁶ CR⁵ R⁶ 、CR⁵ R⁶ NR⁷ 、CR⁵ R⁶ -O、CR⁵ R⁶ -S、N-R⁷ CR⁵ R⁶ 、O-CR⁵ R⁶ And S-CR⁵ R⁶ ；

U¹ 、U² 、U³ And U⁴ The same or different and are each independently a carbon atom or a nitrogen atom;

R⁰ selected from the group consisting of hydrogen atoms, alkyl groups, andwherein the alkyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, alkenyl, alkynyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

L₁ is a bond or (CH)₂ )_r ；

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

each R is⁸ The same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R^1a 、R^1b 、R^1c and R is^1d The same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, and hydroxyalkyl; or R is^1a And R is^1b 、R^1c And R is^1d Together forming an oxo group;

R² 、R³ 、R⁵ and R is⁶ The same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, and hydroxyalkyl; or R is² And R is³ 、R⁵ And R is⁶ Together forming an oxo group;

each R is⁴ The same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, COR⁹ 、C(O)OR¹⁰ 、S(O)_t R¹¹ 、S(O)_t NR¹² R¹³ 、C(O)NR¹² R¹³ 、NR¹² R¹³ Cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R⁷ selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups;

R⁹ selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R¹⁰ Selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups;

R¹¹ selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups,Haloalkyl, hydroxyalkyl, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R¹² and R is¹³ Identical or different and are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, - (CH)₂ )_r -cycloalkyl, heterocyclyl, - (CH)₂ )_r -heterocyclyl, aryl, - (CH)₂ )_r -aryl, heteroaryl and- (CH)₂ )_r -heteroaryl; or R is¹² And R is¹³ Together with the nitrogen atom to which they are attached, form a heterocyclic group, which is optionally substituted with one or more substituents selected from halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

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

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

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

t is 0, 1 or 2.

In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Iaa):

Wherein:

U¹ 、U² 、U³ 、U⁴ 、Y、R⁰ 、R^1a 、R^1b 、R^1c 、R^1d 、R² ～R⁴ and m is as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ibb):

wherein:

U¹ 、U² 、U³ 、U⁴ 、Y、R⁰ 、R^1a 、R^1b 、R^1c 、R^1d 、R² ～R⁴ and m is as defined in formula (I).

In some preferred embodiments of the present disclosure, the compounds of formula (I), formula (Iaa) and formula (Ibb) or pharmaceutically acceptable salts thereof, wherein U¹ 、U² 、U³ And U⁴ All are carbon atoms; or U¹ 、U² 、U³ And U⁴ One of which is a nitrogen atom and the remaining three are carbon atoms.

In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (II):

wherein:

Y、R⁰ 、R^1a 、R^1b 、R^1c 、R^1d 、R² ～R⁴ and m is as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (Iaa) or formula (II), or a pharmaceutically acceptable salt thereof, is a compound of formula (IIaa):

wherein:

Y、R⁰ 、R^1a 、R^1b 、R^1c 、R^1d 、R² ～R⁴ and m is as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (Ibb) or formula (II), or a pharmaceutically acceptable salt thereof, is a compound of formula (IIbb), or a pharmaceutically acceptable salt thereof:

Wherein:

Y、R⁰ 、R^1a 、R^1b 、R^1c 、R^1d 、R² ～R⁴ and m is as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (Iaa), formula (Ibb), formula (II), formula (IIaa) or formula (IIbb) or a pharmaceutically acceptable salt thereof, wherein Y is selected from CR⁵ R⁶ 、CR⁵ R⁶ CR⁵ R⁶ And CR (CR)⁵ R⁶ -O, wherein R⁵ And R is⁶ As defined in formula (I).

In some preferred embodiments of the present disclosure, the compounds of formula (II), formula (IIaa) and formula (IIbb) or pharmaceutically acceptable salts thereof, wherein Y is selected from CR⁵ R⁶ 、CR⁵ R⁶ CR⁵ R⁶ And CR (CR)⁵ R⁶ -O, wherein CR⁵ R⁶ The O end of the-O is connected with a benzene ring; r is R⁵ And R is⁶ As defined in formula (II).

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (Iaa), formula (Ibb), formula (II), formula (IIaa) and formula (IIbb) or a pharmaceutically acceptable salt thereof, wherein Y is CR⁵ R⁶ ，R⁵ And R is⁶ As defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (Iaa), formula (Ibb), formula (II), formula (IIaa) and formula (IIbb) or a pharmaceutically acceptable salt thereof, wherein R⁰ Selected from C_1-6 Alkyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterolepticA cyclic group, a 6 to 10 membered aryl group and a 5 to 10 membered heteroaryl group, wherein said C_1-6 Alkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are optionally selected from halogen, C_1-6 Alkyl, C_2-6 Alkenyl, C_2-6 Alkynyl, C_1-6 Alkoxy, C_1-6 Haloalkyl, C_1-6 Haloalkoxy, cyano, amino, nitro, hydroxy, C_1-6 Hydroxyalkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl, and 5 to 10 membered heteroaryl; preferably, R⁰ Is a 3 to 8 membered heterocyclyl; more preferably, R⁰ Is tetrahydropyranyl.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (Iaa), formula (Ibb), formula (II), formula (IIaa) and formula (IIbb) or a pharmaceutically acceptable salt thereof, wherein R^1a 、R^1b 、R^1c And R is^1d Identical or different and are each independently selected from the group consisting of hydrogen, halogen and C_1-6 An alkyl group; preferably, R^1a 、R^1b 、R^1c And R is^1d Are all hydrogen atoms.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (Iaa), formula (Ibb), formula (II), formula (IIaa) and formula (IIbb) or a pharmaceutically acceptable salt thereof, wherein R² 、R³ 、R⁵ And R is⁶ Identical or different and are each independently a hydrogen atom or C_1-6 An alkyl group; preferably, R² 、R³ 、R⁵ And R is⁶ The same or different, and are each independently a hydrogen atom.

In some preferred embodiments of the present disclosure, the compounds of formula (I), formula (Iaa), formula (Ibb), formula (II), formula (IIaa) and formula (IIbb) or pharmaceutically acceptable salts thereof, wherein each R⁴ Identical or different and are each independently selected from hydrogen atoms, halogen, C_1-6 Alkyl, C_2-6 Alkenyl, C_2-6 Alkynyl, C_1-6 Alkoxy, C_1-6 Haloalkyl, C_1-6 Haloalkoxy, cyano, amino, nitroHydroxy and C_1-6 A hydroxyalkyl group; preferably, each R⁴ Identical or different and are each independently selected from the group consisting of hydrogen, halogen and C_1-6 An alkyl group; more preferably, R⁴ Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compounds of formula (I), formula (Iaa), formula (Ibb), formula (II), formula (IIaa) and formula (IIbb) or pharmaceutically acceptable salts thereof, wherein each R⁴ The same or different, and are each independently a hydrogen atom or a halogen.

In some preferred embodiments of the present disclosure, the compounds of formula (II), formula (IIaa) and formula (IIbb) or pharmaceutically acceptable salts thereof, wherein m is 0, 1 or 2; preferably, m is 0 or 1.

In some preferred embodiments of the present disclosure, the compounds of formula (I), formula (Iaa) and formula (Ibb) or pharmaceutically acceptable salts thereof, wherein m is 1, 2, 3 or 4; preferably, m is 2, 3 or 4; more preferably, m is 3 or 4; most preferably, m is 4.

In some preferred embodiments of the present disclosure, the compounds of formula (II), formula (IIaa) and formula (IIbb) or pharmaceutically acceptable salts thereof, wherein m is 0; or each R⁴ Identical or different and are each independently halogen, and m is 1 or 2.

In some preferred embodiments of the present disclosure, the compounds of formula (II), formula (IIaa) and formula (IIbb) or pharmaceutically acceptable salts thereof, wherein: y is selected from CR⁵ R⁶ 、CR⁵ R⁶ CR⁵ R⁶ And CR (CR)⁵ R⁶ -O, wherein CR⁵ R⁶ The O end of the-O is connected with a benzene ring; r is R⁰ Is a 3 to 8 membered heterocyclyl; r is R^1a 、R^1b 、R^1c And R is^1d All are hydrogen atoms; r is R² 、R³ 、R⁵ And R is⁶ Identical or different and are each independently a hydrogen atom or C_1-6 An alkyl group; each R is⁴ Identical or different and are each independently selected from the group consisting of hydrogen, halogen and C_1-6 An alkyl group; and m is 0, 1 or 2.

In some preferred embodiments of the present disclosure, the compounds of formula (II), formula (IIaa) and formula (IIbb) or pharmaceutically acceptable salts thereof, wherein: y is selected from CR⁵ R⁶ 、CR⁵ R⁶ CR⁵ R⁶ And CR (CR)⁵ R⁶ -O, wherein CR⁵ R⁶ The O end of the-O is connected with a benzene ring; r is R⁰ Is a 3 to 8 membered heterocyclyl; r is R^1a 、R^1b 、R^1c And R is^1d All are hydrogen atoms; r is R² 、R³ 、R⁵ And R is⁶ Identical or different and are each independently a hydrogen atom or C_1-6 An alkyl group; m is 0; or each R⁴ Identical or different and are each independently halogen, and m is 1 or 2.

In some preferred embodiments of the present disclosure, the compounds of formula (II), formula (IIaa) and formula (IIbb) or pharmaceutically acceptable salts thereof, wherein: y is selected from CR⁵ R⁶ 、CR⁵ R⁶ CR⁵ R⁶ And CR (CR)⁵ R⁶ -O, wherein CR⁵ R⁶ The O end of the-O is connected with a benzene ring; r is R⁰ Is tetrahydropyranyl; r is R^1a 、R^1b 、R^1c And R is^1d All are hydrogen atoms; r is R² 、R³ 、R⁵ And R is⁶ Identical or different and are each independently a hydrogen atom or C_1-6 An alkyl group; each R is⁴ The same or different, and are each independently a hydrogen atom or a halogen; and m is 0 or 1.

In some preferred embodiments of the present disclosure, the compounds of formula (II), formula (IIaa) and formula (IIbb) or pharmaceutically acceptable salts thereof, wherein: y is selected from CR⁵ R⁶ 、CR⁵ R⁶ CR⁵ R⁶ And CR (CR)⁵ R⁶ -O, wherein CR⁵ R⁶ The O end of the-O is connected with a benzene ring; r is R⁰ Is tetrahydropyranyl; r is R^1a 、R^1b 、R^1c And R is^1d All are hydrogen atoms; r is R² 、R³ 、R⁵ And R is⁶ Identical or different and are each independently a hydrogen atom or C_1-6 An alkyl group; m is 0; or each R⁴ Identical or different and are each independently halogen, and m is 0 or 1.

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

another aspect of the present disclosure relates to a compound represented by the general formula (IA):

wherein: u (U)¹ 、U² 、U³ 、U⁴ 、Y、R⁰ 、R^1a 、R^1b 、R^1c 、R^1d 、R² ～R⁴ And m is as defined in formula (I).

Another aspect of the present disclosure relates to a compound represented by the general formula (IAaa):

Wherein: u (U)¹ 、U² 、U³ 、U⁴ 、Y、R⁰ 、R^1a 、R^1b 、R^1c 、R^1d 、R² ～R⁴ And m is as defined in formula (Iaa).

Another aspect of the present disclosure relates to a compound represented by the general formula (IAbb):

wherein: u (U)¹ 、U² 、U³ 、U⁴ 、Y、R⁰ 、R^1a 、R^1b 、R^1c 、R^1d 、R² ～R⁴ And m is as defined in formula (Ibb).

Another aspect of the present disclosure relates to a compound represented by the general formula (IIA):

wherein: y, R⁰ 、R^1a 、R^1b 、R^1c 、R^1d 、R² ～R⁴ And m is as defined in formula (II).

Another aspect of the present disclosure relates to a compound represented by the general formula (IIAaa):

wherein: y, R⁰ 、R^1a 、R^1b 、R^1c 、R^1d 、R² ～R⁴ And m is as defined in formula (IIaa).

Another aspect of the present disclosure relates to a compound represented by the general formula (IIAbb):

wherein: y, R⁰ 、R^1a 、R^1b 、R^1c 、R^1d 、R² ～R⁴ And m is as defined in formula (IIbb).

Another aspect of the present disclosure relates to a compound represented by general formulas (IA), (IAaa), (IAbb), (IIA), (IIAaa) and (IIAbb), or a salt thereof, wherein the salt is a hydrochloride salt.

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

another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

intramolecular reaction of the compound of formula (IA) or a salt thereof (preferably the hydrochloride salt) to give the compound of formula (I) or a pharmaceutically acceptable salt thereof;

wherein:

U¹ 、U² 、U³ 、U⁴ 、Y、R⁰ 、R^1a 、R^1b 、R^1c 、R^1d 、R² ～R⁴ And m is as defined in formula (I).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (Iaa) or a pharmaceutically acceptable salt thereof, comprising:

intramolecular reaction of a compound of formula (IAaa) or a salt thereof, preferably the hydrochloride salt, to obtain a compound of formula (IAaa) or a pharmaceutically acceptable salt thereof;

wherein:

U¹ 、U² 、U³ 、U⁴ 、Y、R⁰ 、R^1a 、R^1b 、R^1c 、R^1d 、R² ～R⁴ and m is as defined in formula (Iaa).

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (Ibb) or a pharmaceutically acceptable salt thereof, the method comprising:

intramolecular reaction of the compound of formula (IAbb) or a salt thereof, preferably the hydrochloride salt, to give the compound of formula (Ibb) or a pharmaceutically acceptable salt thereof;

wherein:

U¹ 、U² 、U³ 、U⁴ 、Y、R⁰ 、R^1a 、R^1b 、R^1c 、R^1d 、R² ～R⁴ and m is as defined in formula (Ibb).

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

intramolecular reaction of the compound of formula (IIA) or a salt thereof (preferably the hydrochloride salt) to give the compound of formula (II) or a pharmaceutically acceptable salt thereof;

wherein:

Y、R⁰ 、R^1a 、R^1b 、R^1c 、R^1d 、R² ～R⁴ and m is as defined in formula (II).

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (IIaa) or a pharmaceutically acceptable salt thereof, comprising:

Intramolecular reaction of a compound of formula (IIAaa) or a salt thereof, preferably the hydrochloride salt, to obtain a compound of formula (IIaa) or a pharmaceutically acceptable salt thereof;

wherein:

Y、R⁰ 、R^1a 、R^1b 、R^1c 、R^1d 、R² ～R⁴ and m is as defined in formula (IIaa).

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (IIbb) or a pharmaceutically acceptable salt thereof, comprising:

intramolecular reaction of the compound of formula (IIAbb) or a salt thereof (preferably hydrochloride) to give the compound of formula (IIbb) or a pharmaceutically acceptable salt thereof;

wherein:

Y、R⁰ 、R^1a 、R^1b 、R^1c 、R^1d 、R² ～R⁴ and m is as defined in formula (IIbb).

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound shown in general formula (I), general formula (Iaa), general formula (Ibb), general formula (II), general formula (IIaa), general formula (IIbb) and table a of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

The present disclosure further relates to the use of a compound shown in general formula (I), general formula (Iaa), general formula (Ibb), general formula (II), general formula (IIaa), general formula (IIbb) and table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of an Myosin (Myosin) inhibitor.

The present disclosure further relates to the use of a compound shown in general formula (I), general formula (Iaa), general formula (Ibb), general formula (II), general formula (IIaa), general formula (IIbb) and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for treating a disease or disorder selected from the group consisting of ejection fraction preserved diastolic heart failure, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic Cardiomyopathy (HCM), normal ejection fraction heart failure (HFpEF), ejection fraction median heart failure (HFmREF), valve disease, aortic valve stenosis, inflammatory cardiomyopathy, lux endocarditis, myocardial endocardial fibrosis, invasive cardiomyopathy, hemochromatosis, fabry's disease, glycogen storage disease, congenital heart disease, fabry quadruple disease, left ventricular hypertrophy, refractory angina and gauss disease; preferably selected from ischemic heart disease, limited cardiomyopathy, hypertrophic Cardiomyopathy (HCM), inflammatory cardiomyopathy, invasive cardiomyopathy, congenital heart disease and left ventricular hypertrophy; more preferably Hypertrophic Cardiomyopathy (HCM); most preferred are non-obstructive hypertrophic cardiomyopathy (nHCM) or obstructive hypertrophic cardiomyopathy (oHCM).

The present disclosure further relates to the use of a compound shown in general formula (I), general formula (Iaa), general formula (Ibb), general formula (II), general formula (IIaa), general formula (IIbb) and table a, 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 mediated by Myosin selected from the group consisting of ejection fraction preserved diastolic heart failure, ischemic heart disease, angina, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic Cardiomyopathy (HCM), normal ejection fraction heart failure (HFpEF), ejection fraction intermediate heart failure (HFmREF), valve disease, aortic valve stenosis, inflammatory cardiomyopathy, lux endocarditis, myocardial endocardial fibrosis, invasive cardiomyopathy, hemochromatosis, fabry's disease, glycogen storage disease, congenital heart disease, fabry quadruple disease, left hypertrophy, refractory angina and chagas disease; preferably selected from ischemic heart disease, limited cardiomyopathy, hypertrophic Cardiomyopathy (HCM), inflammatory cardiomyopathy, invasive cardiomyopathy, congenital heart disease and left ventricular hypertrophy; more preferably Hypertrophic Cardiomyopathy (HCM); most preferred are non-obstructive hypertrophic cardiomyopathy (nHCM) or obstructive hypertrophic cardiomyopathy (oHCM).

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 shown in formula (I), formula (Iaa), formula (Ibb), formula (II), formula (IIaa), formula (IIbb) and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a method of treating a disease or disorder selected from the group consisting of ejection fraction preserved diastolic heart failure, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic Cardiomyopathy (HCM), normal ejection fraction heart failure (HFpEF), ejection fraction intermediate heart failure (HFmREF), valve disease, aortic stenosis, inflammatory cardiomyopathy, lux endocarditis, myocardial endocardial fibrosis, invasive cardiomyopathy, hemochromatosis, fabry's disease, glycogen storage disease, congenital heart disease, fabry-perot-end disease, left ventricular hypertrophy, refractory angina, and chagas disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound shown in formula (I), formula (Iaa), formula (Ibb), formula (II), formula (IIaa), formula (IIbb), and table a, or a pharmaceutical composition comprising the same; preferably selected from ischemic heart disease, limited cardiomyopathy, hypertrophic Cardiomyopathy (HCM), inflammatory cardiomyopathy, invasive cardiomyopathy, congenital heart disease and left ventricular hypertrophy; more preferably Hypertrophic Cardiomyopathy (HCM); most preferred are non-obstructive hypertrophic cardiomyopathy (nHCM) or obstructive hypertrophic cardiomyopathy (oHCM).

The present disclosure further relates to a method of treating a disease or disorder mediated by Myosin, comprising administering to a patient in need thereof a therapeutically effective amount of a compound shown in formula (I), formula (Iaa), formula (Ibb), formula (II), formula (IIaa), formula (IIbb) and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, selected from the group consisting of ejection fraction preserved diastolic heart failure, ischemic heart disease, angina, limited cardiomyopathy, diastolic dysfunction, hypertrophic Cardiomyopathy (HCM), normal ejection fraction heart failure (HFpEF), ejection fraction median heart failure (HFmREF), valve disease, aortic valve stenosis, inflammatory cardiomyopathy, lux endocarditis, myocardial endocardial fibrosis, invasive cardiomyopathy, hemochromatosis, fabry's disease, glycogen storage disease, congenital heart disease, fabry four-way disease, left ventricular hypertrophy, refractory angina, and pick disease; preferably selected from ischemic heart disease, limited cardiomyopathy, hypertrophic Cardiomyopathy (HCM), inflammatory cardiomyopathy, invasive cardiomyopathy, congenital heart disease and left ventricular hypertrophy; more preferably Hypertrophic Cardiomyopathy (HCM); most preferred are non-obstructive hypertrophic cardiomyopathy (nHCM) or obstructive hypertrophic cardiomyopathy (oHCM).

The present disclosure further relates to a compound shown in general formula (I), general formula (Iaa), general formula (Ibb), general formula (II), general formula (IIaa), general formula (IIbb) and table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

The present disclosure further relates to a compound shown in general formula (I), general formula (Iaa), general formula (Ibb), general formula (II), general formula (IIaa), general formula (IIbb) and table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as an Myosin (Myosin) inhibitor.

The present disclosure further relates to a compound shown in general formula (I), general formula (Iaa), general formula (Ibb), general formula (II), general formula (IIaa), general formula (IIbb) and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament in the treatment of a disease or disorder selected from the group consisting of ejection fraction preserved diastolic heart failure, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic Cardiomyopathy (HCM), normal ejection fraction heart failure (HFpEF), ejection fraction intermediate heart failure (HFmREF), valve disease, aortic valve stenosis, inflammatory cardiomyopathy, lux endocarditis, myocardial endocardial fibrosis, invasive cardiomyopathy, hemochromatosis, fabry's disease, glycogen storage disease, congenital heart disease, fabry quadruple disease, left ventricular thickness, refractory angina and chagas disease; preferably selected from ischemic heart disease, limited cardiomyopathy, hypertrophic Cardiomyopathy (HCM), inflammatory cardiomyopathy, invasive cardiomyopathy, congenital heart disease and left ventricular hypertrophy; more preferably Hypertrophic Cardiomyopathy (HCM); most preferred are non-obstructive hypertrophic cardiomyopathy (nHCM) or obstructive hypertrophic cardiomyopathy (oHCM).

The present disclosure further relates to a compound shown in general formula (I), general formula (Iaa), general formula (Ibb), general formula (II), general formula (IIaa), general formula (IIbb) and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament in the treatment of a disease or disorder mediated by Myosin selected from the group consisting of ejection fraction preserved diastolic heart failure, ischemic heart disease, angina, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic Cardiomyopathy (HCM), normal ejection fraction heart failure (HFpEF), ejection fraction intermediate heart failure (HFmREF), valve disease, aortic valve stenosis, inflammatory cardiomyopathy, lux endocarditis, myocardial endocardial fibrosis, invasive cardiomyopathy, hemochromatosis, fabry's disease, glycogen storage disease, congenital heart disease, fabry quadruple disease, left ventricular hypertrophy, refractory angina and chagas disease; preferably selected from ischemic heart disease, limited cardiomyopathy, hypertrophic Cardiomyopathy (HCM), inflammatory cardiomyopathy, invasive cardiomyopathy, congenital heart disease and left ventricular hypertrophy; more preferably Hypertrophic Cardiomyopathy (HCM); most preferred are non-obstructive hypertrophic cardiomyopathy (nHCM) or obstructive hypertrophic cardiomyopathy (oHCM).

The compounds shown in general formula (I), general formula (Iaa), general formula (Ibb), general formula (II), general formula (IIaa), general formula (IIbb) and table a, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, of the present disclosure may alter the natural history of HCM and other diseases, rather than merely alleviate symptoms. The mechanism by which clinical benefit is imparted to HCM patients can be extended to patients with other forms of heart disease that together have similar pathophysiology, with or without the influence of significant genetic factors. For example, effective treatment of HCM by improving ventricular diastole during diastole may also be effective for a broader population characterized by diastolic dysfunction.

The compounds shown in general formula (I), general formula (Iaa), general formula (Ibb), general formula (II), general formula (IIaa), general formula (IIbb) and table a, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, of the present disclosure may specifically target the root cause of the disorder or act on other downstream pathways. Thus, the compounds shown in general formula (I), general formula (Iaa), general formula (Ibb), general formula (II), general formula (IIaa), general formula (IIbb) and table a, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, of the present disclosure may confer a benefit to patients suffering from diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina or restrictive cardiomyopathy.

The compounds shown in general formula (I), general formula (Iaa), general formula (Ibb), general formula (II), general formula (IIaa), general formula (IIbb) and table a, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, of the present disclosure may also promote beneficial ventricular remodeling of left ventricular hypertrophy due to volume or pressure overload; such as chronic mitral regurgitation, chronic aortic stenosis, or chronic systemic hypertension; the compounds or pharmaceutically acceptable salts thereof are combined with therapies aimed at correcting or alleviating the main cause of volume or pressure overload (valve repair/replacement, effective antihypertensive therapies). By lowering left ventricular filling pressure, the compounds may reduce the risk of pulmonary edema and respiratory failure. Reducing or eliminating functional mitral regurgitation and/or reducing left atrial pressure may reduce the risk of sudden or permanent atrial fibrillation, and it reduces the concomitant risk of arterial thromboembolic complications including, but not limited to, cerebral arterial embolic stroke. Reducing or eliminating dynamic and/or static left ventricular outflow tract obstruction may reduce the likelihood of requiring intermittent ablative treatment (surgical or percutaneous) and the attendant risks of short-term and long-term complications thereof.

The compounds shown in general formula (I), general formula (Iaa), general formula (Ibb), general formula (II), general formula (IIaa), general formula (IIbb) and table a, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, of the present disclosure may reduce the severity of chronic ischemic conditions associated with HCM and thereby reduce the risk of Sudden Cardiac Death (SCD) or equivalent diseases thereof in patients with implantable cardioverter-defibrillators (frequent and/or repeated ICD discharges) and/or reduce the need for potentially toxic antiarrhythmic drugs.

The compounds shown in general formula (I), general formula (Iaa), general formula (Ibb), general formula (II), general formula (IIaa), general formula (IIbb) and table a, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, of the present disclosure may be valuable in reducing or eliminating the need for concurrent drugs with their concomitant potential toxicity, drug-drug interactions and/or side effects.

The compounds of formula (I), formula (Iaa), formula (Ibb), formula (II), formula (IIaa), formula (IIbb) and table a, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, of the present disclosure may reduce interstitial myocardial fibrosis and/or slow the progression of left ventricular hypertrophy, prevent or reverse left ventricular hypertrophy.

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

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

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

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

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

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

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

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

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

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

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

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

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

Description of the terms

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

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group (i.e., C) containing from 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_1-20 Alkyl groups), preferably alkyl groups containing 1 to 12 carbon atoms (i.e. C_1-12 Alkyl), more preferably alkyl having 1 to 6 carbon atoms (i.e., C_1-6 Alkyl). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentaneA radical, 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, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. Most preferred lower alkyl groups having 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkylene" refers to a divalent alkyl group, where alkyl is as defined above, having a linear or branched group (i.e., C) of 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_1-20 Alkylene groups), preferably containing 1 to 12 carbon atoms (i.e. C_1-12 Alkylene groups), more preferably alkylene groups having 1 to 6 carbon atoms (i.e., C_1-6 An alkylene group). Non-limiting examples of alkylene groups include, but are not limited toMethylene (-CH)₂ (-), 1-ethylene (-CH (CH)₃ ) (-), 1, 2-ethylene (-CH)₂ CH₂ ) -, 1-propylene (-CH (CH)₂ CH₃ ) (-), 1, 2-propylene (-CH)₂ CH(CH₃ ) (-), 1, 3-propylene (-CH)₂ CH₂ CH₂ (-), 1, 4-butylene (-CH)₂ CH₂ CH₂ CH₂ (-), etc. The alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents preferably being selected from one or more of 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 having at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above, preferably alkenyl (i.e., C) having 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms_2-12 Alkenyl), more preferably alkenyl having 2 to 6 carbon atoms (i.e., C_2-6 Alkenyl). Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, where alkyl is as defined above, which has an alkynyl group (i.e., C) of 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms_2-12 Alkynyl). The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C_2-6 Alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkynyl groups may be substituted or unsubstituted and when substituted the substituents are preferably selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkylOne or more of cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

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

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

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

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

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

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

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

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which sulfur may optionally be oxo (i.e., form sulfoxides or sulfones), but excluding the ring portions of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferably from 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, of which 1 to 4 (e.g., 1,2,3, and 4) are heteroatoms (i.e., 3 to 12 membered heterocyclyl); more preferably 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), of which 1-3 (e.g., 1,2, and 3) are heteroatoms (i.e., 3 to 8 membered heterocyclyl); more preferably 3 to 6 ring atoms, 1-3 of which are heteroatoms (i.e., 3 to 6 membered heterocyclyl); most preferably contain 5 or 6 ring atoms, 1-3 of which are heteroatoms (i.e., 5 or 6 membered heterocyclyl). Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3, 6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups.

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

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

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

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

etc.

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

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

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

The term "heteroaryl" refers to heteroaromatic systems containing 1 to 4 heteroatoms (e.g., 1, 2, 3, and 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. 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 heteroaryl condensed onto an aryl, heterocyclyl, or cycloalkyl ring as described above, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

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

The cycloalkyl, heterocyclyl, aryl and heteroaryl groups described above include residues derived from the removal of one hydrogen atom from the parent ring atom, or residues derived from the removal of two hydrogen atoms from the same or two different ring atoms of the parent, i.e. "divalent cycloalkyl", "divalent heterocyclyl", "arylene" and "heteroarylene".

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

The term "hydroxy protecting group" is a suitable group known in the art for hydroxy protection, see the hydroxy protecting group in literature ("Protective Groups in Organic Synthesis",5Th Ed.T.W.Greene&P.G.M.Wuts) for blocking or protecting a hydroxy group for reaction on other functional groups of a compound. Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl, methyl, t-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-Tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, and the like.

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

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

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

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

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

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

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

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

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

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

The term "hydroxy" refers to-OH.

The term "mercapto" refers to-SH.

The term "amino" refers to-NH₂ 。

The term "cyano" refers to-CN.

The term "nitro" refers to-NO₂ 。

The term "oxo" or "oxo" refers to "=o".

The term "carbonyl" refers to c=o.

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

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

The compounds of the present disclosure include isotopic derivatives thereof. The term "isotopically-enriched derivative" refers to a compound that differs in structure only in the presence of one or more isotopically-enriched atoms. For example, with the structures of the present disclosure, replacement of hydrogen with "deuterium" or "tritium", or with¹⁸ F-fluorine labeling [ ]¹⁸ F isotope) instead of fluorine, or with¹¹ C-，¹³ C-, or¹⁴ C-enriched carbon¹¹ C-，¹³ C-, or¹⁴ C-carbon labeling;¹¹ C-，¹³ c-, or¹⁴ C-isotopes) are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays, or as diagnostic imaging tracers in vivo for diseases, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies.

The various deuterated forms of the compounds of the present disclosure mean that each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom. Those skilled in the art are able to refer to the relevant literature for the synthesis of deuterated forms of the compounds. Commercially available deuterated starting materials may be used in preparing the deuterated form of the compound or they may be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, tridentate borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like. Deuterated compounds generally retain activity comparable to non-deuterated compounds and may achieve better metabolic stability when deuterated at certain specific sites, thus achieving certain therapeutic advantages.

The compounds of the present disclosure may exist in particular 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, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present disclosure. The asymmetric carbon atom containing compounds of the present disclosure may be isolated in optically active pure or racemic forms. Optically pure forms can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.

In the chemical structure of the compounds of the present disclosure, the bondIndicating the unspecified configuration, i.e.the bond +.>Can be +.>Or at the same time contain->Two configurations.

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 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 known as proton transfer tautomers) include tautomers via proton transfer, such as keto-enol and imine-enamine, lactam-lactam isomerization. Examples of lactam-lactam balances are between a and B as shown below.

All compounds in the present disclosure may 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.

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

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

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

"pharmaceutically acceptable salts" refers to salts of the compounds of the present disclosure, which may be selected from inorganic salts or organic salts. Such salts are safe and effective when used in mammals and have desirable biological activity. Salts may be prepared separately during the final isolation and purification of the compounds, or by reacting the appropriate groups with an appropriate base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic and organic acids.

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

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

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

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

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

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

Methods of synthesizing compounds of the present disclosure

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

scheme one

The preparation method of the compound shown in the general formula (I) or the pharmaceutically acceptable salt thereof comprises the following steps:

intramolecular reaction of the compound of formula (IA) or a salt thereof (preferably the hydrochloride salt) under microwave conditions to give the compound of formula (I) or a pharmaceutically acceptable salt thereof;

wherein:

U¹ 、U² 、U³ 、U⁴ 、Y、R⁰ 、R^1a 、R^1b 、R^1c 、R^1d 、R² ～R⁴ and m is as defined in formula (I).

Scheme II

A process for the preparation of a compound of formula (Iaa) of the present disclosure, or a pharmaceutically acceptable salt thereof, which comprises:

intramolecular reaction of the compound of formula (IAaa) or a salt thereof (preferably the hydrochloride salt) under microwave conditions to give the compound of formula (IAaa) or a pharmaceutically acceptable salt thereof;

Wherein:

U¹ 、U² 、U³ 、U⁴ 、Y、R⁰ 、R^1a 、R^1b 、R^1c 、R^1d 、R² ～R⁴ and m is as defined in formula (Iaa).

Scheme III

A process for preparing a compound of formula (Ibb) of the present disclosure, or a pharmaceutically acceptable salt thereof, the process comprising:

intramolecular reaction of the compound of formula (IAbb) or a salt thereof (preferably a hydrochloride salt) under microwave conditions to obtain a compound of formula (Ibb) or a pharmaceutically acceptable salt thereof;

wherein:

U¹ 、U² 、U³ 、U⁴ 、Y、R⁰ 、R^1a 、R^1b 、R^1c 、R^1d 、R² ～R⁴ and m is as defined in formula (Ibb).

Scheme IV

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

intramolecular reaction of the compound of formula (IIA) or a salt thereof (preferably a hydrochloride) under microwave conditions to give a compound of formula (II) or a pharmaceutically acceptable salt thereof;

wherein:

Y、R⁰ 、R^1a 、R^1b 、R^1c 、R^1d 、R² ～R⁴ and m is as defined in formula (II).

Scheme five

A process for the preparation of a compound of formula (IIaa) of the present disclosure, or a pharmaceutically acceptable salt thereof, which comprises:

intramolecular reaction of the compound of formula (IIaaa) or a salt thereof (preferably hydrochloride) under microwave conditions to give the compound of formula (IIaa) or a pharmaceutically acceptable salt thereof;

wherein:

Y、R⁰ 、R^1a 、R^1b 、R^1c 、R^1d 、R² ～R⁴ and m is as defined in formula (IIaa).

Scheme six

A process for the preparation of a compound of formula (IIbb) of the present disclosure, or a pharmaceutically acceptable salt thereof, comprising:

Intramolecular reaction of the compound of formula (IIAbb) or a salt thereof (preferably hydrochloride) under microwave conditions to obtain a compound of formula (IIbb) or a pharmaceutically acceptable salt thereof;

wherein:

Y、R⁰ 、R^1a 、R^1b 、R^1c 、R^1d 、R² ～R⁴ and m is as defined in formula (IIbb).

The above microwave reaction is preferably carried out at 120 to 130 ℃, more preferably 120 ℃.

The preferable reaction time of the microwave reaction is 1-2 hours; more preferably 1 hour or 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, methylene chloride, 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 in conjunction with the examples, which are not intended to limit the scope of the present disclosure.

Examples

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) of 10^-6 Units of (ppm) are given. NMR was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus or Bruker AVANCE NEO M with deuterated dimethyl sulfoxide (DMSO-d)₆ ) Deuterated chloroform (CDCl)₃ ) Deuterated methanol (CD)₃ OD), internal standard is Tetramethylsilane (TMS).

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

High Performance Liquid Chromatography (HPLC) analysis used Agilent HPLC1200 DAD, agilent HPLC1200VWD, and Waters HPLC e2695-2489 high performance liquid chromatography.

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

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

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

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

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

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

Average inhibition rate of kinase and IC₅₀ The values were measured using a NovoStar microplate reader (BMG, germany).

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

The reaction can be carried out under argon atmosphere or nitrogen atmosphere without any particular explanation in examples.

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

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

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

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

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

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

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

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), the developing reagent used for the reaction, the system of eluent for column chromatography employed for purifying the compound and the developing reagent system of thin layer chromatography included: a: n-hexane/ethyl acetate system, B: the volume ratio of the methylene dichloride to the methanol is adjusted according to the polarity of the compound, and small amounts of alkaline or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.

Example 1

(S) -3' - (tetrahydro-2H-pyran-4-yl) -2,3,5',8' -tetrahydro-1 ' H-spiro [ indene-1, 7' -pyridine [2,3-d ] pyrimidine ] -2',4' (3 ' H,6' H) -dione 1

First step

(R) -N- (2, 3-dihydro-1H-inden-1-ylidene) -2-methylpropane-2-sulfinamide 1b

2, 3-dihydro-1H-inden-1-one 1a (5.00 g,37.83mmol, shanghai Shaoshan chemical Co., ltd.) was dissolved in toluene (70 mL), isopropyl titanate (16.20 g,57.04 mmol) was added, stirred at room temperature for 5 minutes, and (R) -2-methylpropan-2-sulfinamide (5.50 g,45.38mmol, techniais (Shanghai) chemical industry Co., ltd.) was added and reacted overnight at 110 ℃. Saturated potassium sodium tartrate solution was added, extracted with ethyl acetate (80 ml×3), and the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system a to give the title product 1b (2.46 g, yield: 27.6%).

MS m/z(ESI):235.9[M+1]。

Second step

2- ((S) -1- (((R) -tert-butylsulfinyl) amino) -2, 3-dihydro-1H-inden-1-yl) acetic acid methyl ester 1c

Lithium diisopropylamide (11.9 mL, 2.0M) was dissolved in THF (20 mL), replaced with nitrogen three times, methyl acetate (1.77 g,23.9 mmol) was added dropwise, the reaction stirred at that temperature for 30 minutes, titanium triisopropyloxide (25.3 mL, 1.0M) was added, and the reaction stirred at that temperature for 30 minutes. A solution of Compound 1b (1.70 g,7.22 mmol) in tetrahydrofuran (5 mL) was added dropwise at-78deg.C and the reaction stirred for an additional 3 hours. Saturated ammonium chloride solution (10 mL) was added at 0deg.C, extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 1c (1.70 g, yield: 76.1%).

MS m/z(ESI):310.0[M+1]。

Third step

2- ((S) -1- (((R) -tert-butylsulfinyl) amino) -2, 3-dihydro-1H-inden-1-yl) acetic acid 1d

Compound 1c (0.90 g,2.9 mmol) was dissolved in tetrahydrofuran (10 mL) and aqueous sodium hydroxide (233 mg,5.8 mmol) was added (4 mL). The reaction was stirred for 2 hours. The pH was adjusted to 5 with saturated citric acid solution. The residue was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system B to give the title product 1d (790 mg, yield: 91.9%).

MS m/z(ESI):296.0[M+1]。

Fourth step

(R) -2-methyl-N- ((1S) -1- (2-oxo-2- (2, 4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) ethyl) -2, 3-dihydro-1H-inden-1-yl) propane-2-sulfinamide 1f

Compound 1d (480 mg,1.62 mmol), 1- (tetrahydro-2H-pyran-4-yl) pyrimidine-2, 4,6 (1H, 3H, 5H) -trione 1e (345 mg,1.62mmol, prepared by the method disclosed in example 2-3 on page 50 of the specification of patent application "WO2020092208A 1") and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (573 mg,2.44mmol, shanghai Shao far chemical technology Co., ltd.) were dissolved in N, N-dimethylformamide (10 mL). Diisopropylethylamine (630 mg,4.87 mmol) was added thereto at 0℃and stirred at room temperature for 16 hours. The reaction was quenched by the addition of saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (50 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude title product 1f (1.18 g, yield: 72.9%), which was used in the next step without purification.

MS m/z(ESI):488.1[M-1]。

Fifth step

(R) -2-methyl-N- ((1R) -1- (2, 4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) ethyl) -2, 3-dihydro-1H-inden-1H-yl) propane-2-sulfinamide 1g

The crude compound 1f (580 mg,1.18 mmol) was dissolved in acetic acid (20 mL). Sodium cyanoborohydride (177 mg,2.96mmol, shanghai Shaoshao chemical technologies Co., ltd.) was added under ice bath. The reaction was stirred at room temperature for 1 hour. Ice water (20 mL) was added thereto, and extraction was performed with ethyl acetate (20 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1g of the title product as a crude product (560 mg, yield: 99.4%) which was used in the next step without purification.

MS m/z(ESI):474.1[M-1]。

Sixth step

5- (2- ((R) -1-amino-2, 3-dihydro-1H-inden-1-yl) ethyl) -1- (tetrahydro-2H-pyran-4-yl) pyrimidine-2, 4,6 (1H, 3H, 5H) -trione hydrochloride 1H

1g of the crude compound (560 mg,1.2 mmol) was dissolved in ethanol (10 mL) and thionyl chloride (280 mg,2.35 mmol) was added at 0deg.C. Stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give the title product as a crude product (480 mg, yield: 99.9%) for the next step without purification.

MS m/z(ESI):370.1[M-1]。

Seventh step

(S) -3' - (tetrahydro-2H-pyran-4-yl) -2,3,5',8' -tetrahydro-1 ' H-spiro [ indene-1, 7' -pyrido [2,3-d ] pyrimidine ] -2',4' (3 ' H,6' H) -dione 1

The crude compound 1h (480 mg,1.2 mmol) was suspended in acetonitrile (8 mL). The reaction was carried out for 1.5 hours at 120℃with microwaves. Concentrated under reduced pressure and purified by high performance liquid chromatography (Boston Phlex C18. Times.30 mm,5 μm, elution system: water (10 mmol/L ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, 15 min gradient elution, flow rate: 30 mL/min) to give the title product 1 (50 mg, yield: 12.0%).

MS m/z(ESI):354.1[M+1]。

¹ H NMR(500MHz,DMSO-d₆ )δ9.79(s,1H),7.27-7.19(m,4H),6.33(s,1H),4.87(m,1H),3.92-3.90(m,2H),3.34-3.30(m,2H),2.92-2.87(m,2H),2.62-2.58(m,2H),2.36-2.31(m,2H),2.14-2.02(m,2H),1.75-1.73(m,2H),1.40-1.36(m,2H)。

Example 2

(R) -3' - (tetrahydro-2H-pyran-4-yl) -2,3,5',8' -tetrahydro-1 ' H-spiro [ indene-1, 7' -pyrido [2,3-d ] pyrimidine ] -2',4' (3 ' H,6' H) -dione 2

First step

(S) -N- (2, 3-dihydro-1H-inden-1-ylidene) -2-methylpropane-2-sulfinamide 2a

Compound 1a (5.00 g,37.83 mmol) was dissolved in tetrahydrofuran (70 mL), tetraethyltitanate (10.36 g,45.42 mmol) was added, stirred at room temperature for 5 minutes, and (S) -2-methylpropane-2-sulfinamide (6.65 g,54.86mmol, pichia medical science, inc.) was added and reacted at 65℃overnight. Saturated sodium bicarbonate solution was added, extraction was performed with ethyl acetate (80 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 2a (1.90 g, yield: 21.3%).

MS m/z(ESI):236.0[M+1]。

Second step

2- ((R) -1- (((S) -tert-butylsulfinyl) amino) -2, 3-dihydro-1H-inden-1-yl) acetic acid methyl ester 2b

Lithium diisopropylamide (8.4 mL, 2.0M) was dissolved in THF (20 mL), replaced with nitrogen three times, methyl acetate (1.25 g,16.83 mmol) was added dropwise, the reaction stirred at that temperature for 30 minutes, titanium triisopropyloxide (17.8 mL, 1.0M) was added, and the reaction stirred at that temperature for 30 minutes. A solution of Compound 2a (1.25 g,16.83 mmol) in tetrahydrofuran (5 mL) was added dropwise at-78deg.C and the reaction stirred for an additional 3 hours. Saturated ammonium chloride solution (10 mL) was added at 0deg.C, extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 2b (1.49 g, yield: 94.4%).

MS m/z(ESI):310.0[M+1]。

Third step

2- ((R) -1- (((S) -tert-butylsulfinyl) amino) -2, 3-dihydro-1H-inden-1-yl) acetic acid 2c

Compound 2b (1.49 g,4.82 mmol) was dissolved in tetrahydrofuran (10 mL) and aqueous sodium hydroxide (385 mg,9.63 mmol) was added (4 mL). The reaction was stirred for 2 hours. The pH was adjusted to 5 with saturated citric acid solution. The residue obtained was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system B to give the title product 2c (1.20 g, yield: 84.4%).

MS m/z(ESI):296.0[M+1]。

Fourth step

(S) -2-methyl-N- ((1R) -1- (2-oxo-2- (2, 4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) ethyl) -2, 3-dihydro-1H-inden-1-yl) propane-2-sulfinamide 2d

Compound 2c (1.20 g,4.06 mmol), compound 1e (862mg, 4.06 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (1.43 g,6.09 mmol) were dissolved in N, N-dimethylformamide (20 mL). Diisopropylethylamine (1.58 g,12.19 mmol) was added at 0deg.C and stirred at room temperature for 16 hours. The reaction was quenched by the addition of saturated sodium bicarbonate solution (40 mL) and extracted with ethyl acetate (50 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude title product 2d (2.20 g), which was used in the next step without purification.

MS m/z(ESI):488.1[M-1]。

Fifth step

(S) -2-methyl-N- ((1S) -1- (2, 4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) ethyl) -2, 3-dihydro-1H-inden-1H-yl) propane-2-sulfinamide 2e

The crude compound 2d (700 mg,1.43 mmol) was dissolved in acetic acid (10 mL). Sodium cyanoborohydride (214 mg,3.57mmol, shanghai Shaoshan chemical technology Co., ltd.) was added under ice bath. The reaction was stirred at room temperature for 1 hour. Ice water (20 mL) was added thereto, and extraction was performed with ethyl acetate (20 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude title product 2e (450 mg, yield: 66.2%) which was used in the next step without purification.

MS m/z(ESI):474.1[M-1]。

Sixth step

5- (2- ((S) -1-amino-2, 3-dihydro-1H-inden-1-yl) ethyl) -1- (tetrahydro-2H-pyran-4-yl) pyrimidine-2, 4,6 (1H, 3H, 5H) -trione hydrochloride 2f

The crude compound 2e (390 mg,0.82 mmol) was dissolved in ethanol (10 mL) and thionyl chloride (195 mg,1.64 mmol) was added at 0deg.C. Stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give the crude product of the title product 2f (334 mg, yield: 99.9%), which was used in the next step without purification.

MS m/z(ESI):355.0[M-16]。

Seventh step

(R) -3' - (tetrahydro-2H-pyran-4-yl) -2,3,5',8' -tetrahydro-1 ' H-spiro [ indene-1, 7' -pyrido [2,3-d ] pyrimidine ] -2',4' (3 ' H,6' H) -dione 2

The crude compound 2f (334 mg,0.82 mmol) was suspended in acetonitrile (10 mL). The reaction was carried out for 1.0 hour at 120℃with microwaves. Concentrated under reduced pressure and purified by high performance liquid chromatography (Boston Phlex C18. Times.30 mm,5 μm, elution system: water (10 mmol/L ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, 15 min gradient elution, flow rate: 30 mL/min) to give the title product 2 (55 mg, yield: 19.0%).

MS m/z(ESI):354.0[M+1]。

¹ H NMR(500MHz,DMSO-d₆ )δ9.82(s,1H),7.28-7.19(m,4H),6.35(s,1H),4.88(m,1H),3.92-3.89(m,2H),3.35-3.29(m,2H),2.92-2.89(m,2H),2.62-2.58(m,2H),2.34-2.32(m,2H),2.14-2.02(m,2H),1.75-1.73(m,2H),1.40-1.37(m,2H)。

Example 3

(S) -7-fluoro-3 ' - (tetrahydro-2H-pyran-4-yl) -2,3,5',8' -tetrahydro-1 ' H-spiro [ indene-1, 7' -pyrido [2,3-d ] pyrimidine ] -2',4' (3 ' H,6' H) -dione 3

First step

(R) -N- (7-fluoro-2, 3-dihydro-1H-inden-1-ylidene) -2-methylpropane-2-sulfinamide 3b

7-fluoro-2, 3-dihydro-1H-inden-1-one 3a (5.00 g,33.30mmol, pickle medical science Co., ltd.) was dissolved in tetrahydrofuran (100 mL), isopropyl titanate (9.12 g,39.98 mmol) was added, stirred at room temperature for 5 minutes, and (R) -2-methylpropan-2-sulfinamide (5.85 g,48.27mmol, pickle medical science Co., ltd.) was added and reacted at 65℃overnight. Saturated sodium bicarbonate solution was added, extraction was performed with ethyl acetate (80 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 3b (2.10 g, yield: 24.9%). MS m/z (ESI) 254.0[ M+1].

Second step

2- ((S) -1- (((R) -tert-butylsulfinyl) amino) -7-fluoro-2, 3-dihydro-1H-inden-1-yl) acetic acid methyl ester 3c

Lithium diisopropylamide (3.9 mL, 2.0M) was dissolved in THF (20 mL), replaced with nitrogen three times, methyl acetate (579 mg,7.82 mmol) was added dropwise, the reaction stirred at that temperature for 30 minutes, titanium triisopropyloxide (8.3 mL, 1.0M) was added, and the reaction stirred at that temperature for 30 minutes. A solution of compound 3b (600 mg,2.37 mmol) in tetrahydrofuran (5 mL) was added dropwise at-78deg.C and the reaction stirred for an additional 3 hours. Saturated ammonium chloride solution (10 mL) was added at 0deg.C, extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 3c (750 g, yield: 96.7%).

MS m/z(ESI):328.0[M+1]。

Third step

2- ((S) -1- (((R) -tert-butylsulfinyl) amino) -7-fluoro-2, 3-dihydro-1H-inden-1-yl) acetic acid 3d

Compound 3c (0.75 g,2.29 mmol) was dissolved in tetrahydrofuran (10 mL) and aqueous sodium hydroxide (183 mg,4.58 mmol) was added (4 mL). The reaction was stirred for 2 hours. The pH was adjusted to 5 with saturated citric acid solution. The residue was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system B to give the title product 3d (370 mg, yield: 51.5%).

MS m/z(ESI):314.0[M+1]。

Fourth step

(R) -N- ((1S) -7-fluoro-1- (2-oxo-2- (2, 4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) ethyl) -2, 3-dihydro-1H-inden-1-yl) -2-methylpropan-2-sulfinamide 3e

Compound 3d (370 mg,1.18 mmol), compound 1e (251 mg,1.18 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (417 mg,1.77 mmol) were dissolved in N, N-dimethylformamide (10 mL). Diisopropylethylamine (458 mg,3.54 mmol) was added thereto at 0℃and stirred at room temperature for 16 hours. The reaction was quenched by the addition of saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (50 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude title product 3e (599 mg, yield: 99.9%) which was used in the next step without purification.

MS m/z(ESI):506.1[M-1]。

Fifth step

(R) -N- ((1R) -7-fluoro-1- (2, 4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) ethyl) -2, 3-dihydro-1H-inden-1-yl) -2-methylpropan-2-sulfinamide 3f

The crude compound 3e (599 mg,1.18 mmol) was dissolved in acetic acid (20 mL). Sodium cyanoborohydride (176 mg,2.94 mmol) was added under ice bath. The reaction was stirred at room temperature for 1 hour. Ice water (20 mL) was added thereto, and extraction was performed with ethyl acetate (20 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude title product 3f (582 mg, yield: 99.9%) which was used in the next step without purification.

MS m/z(ESI):492.1[M-1]。

Sixth step

5- (2- ((R) -1-amino-7-fluoro-2, 3-dihydro-1H-inden-1-yl) ethyl) -1- (tetrahydro-2H-pyran-4-yl) pyrimidine-2, 4,6 (1H, 3H, 5H) -trione hydrochloride 3g

The crude compound 3f (552 mg,1.18 mmol) was dissolved in ethanol (10 mL) and thionyl chloride (281mg, 2.36 mmol) was added at 0deg.C. Stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give 3g of the title product as a crude product (502 mg, yield: 99.9%) which was used in the next step without purification.

MS m/z(ESI):388.1[M-1]。

Seventh step

(S) -7-fluoro-3 ' - (tetrahydro-2H-pyran-4-yl) -2,3,5',8' -tetrahydro-1 ' H-spiro [ indene-1, 7' -pyrido [2,3-d ] pyrimidine ] -2',4' (3 ' H,6' H) -dione 3

3g of crude compound (502 mg,1.29 mmol) was suspended in acetonitrile (10 mL). The reaction was carried out for 1.0 hour at 120℃with microwaves. Concentrated under reduced pressure and purified by high performance liquid chromatography (Boston Phlex C18. Times.30 mm,5 μm, elution system: water (10 mmol/L ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, 15 min gradient elution, flow rate: 30 mL/min) to give the title product 3 (50 mg, yield: 10.4%).

MS m/z(ESI):372.0[M+1]。

¹ H NMR(500MHz,DMSO-d₆ )δ9.78(s,1H),7.32(m,1H),7.12(m,1H),7.02(m,1H),6.57(s,1H),4.86(m,1H),3.92-3.89(m,2H),3.34-3.29(m,2H),2.99-2.89(m,2H),2.61-2.57(m,2H),2.47(m,1H),2.27(m,1H),2.22-2.09(m,2H),1.98(m,1H),1.81(m,1H),1.39-1.35(m,2H)。

Example 4

(R) -7-fluoro-3 ' - (tetrahydro-2H-pyran-4-yl) -2,3,5',8' -tetrahydro-1 ' H-spiro [ indene-1, 7' -pyrido [2,3-d ] pyrimidine ] -2',4' (3 ' H,6' H) -dione 4

First step

(S) -N- (7-fluoro-2, 3-dihydro-1H-inden-1-ylidene) -2-methylpropane-2-sulfinamide 4a

Compound 3a (5.00 g,33.30mmol, pichia pharmaceutical technologies Co., ltd.) was dissolved in tetrahydrofuran (100 mL), isopropyl titanate (9.12 g,39.98 mmol) was added, stirred at room temperature for 5 minutes, and (S) -2-methylpropane-2-sulfinamide (5.85 g,48.27 mmol) was added and reacted at 65℃overnight. Saturated sodium bicarbonate solution was added, extraction was performed with ethyl acetate (80 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 4a (2.10 g, yield: 24.9%).

MS m/z(ESI):253.9[M+1]。

Second step

2- ((R) -1- (((S) -tert-butylsulfinyl) amino) -7-fluoro-2, 3-dihydro-1H-inden-1-yl) acetic acid methyl ester 4b

Lithium diisopropylamide (13.7 mL, 2.0M) was dissolved in THF (20 mL), replaced with nitrogen three times, methyl acetate (2.03 g,27.40 mmol) was added dropwise, the reaction stirred at that temperature for 30 minutes, titanium triisopropyloxide (29.0 mL, 1.0M) was added, and the reaction stirred at that temperature for 30 minutes. A solution of Compound 4a (2.20 g,8.29 mmol) in tetrahydrofuran (5 mL) was added dropwise at-78deg.C and the reaction stirred for an additional 3 hours. Saturated ammonium chloride solution (10 mL) was added at 0deg.C, extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 4b (2.30 g, yield: 84.7%).

MS m/z(ESI):328.0[M+1]。

Third step

2- ((R) -1- (((S) -tert-butylsulfinyl) amino) -7-fluoro-2, 3-dihydro-1H-inden-1-yl) acetic acid 4c

Compound 4b (1.00 g,3.05 mmol) was dissolved in tetrahydrofuran (10 mL) and aqueous sodium hydroxide (244 mg,6.10 mmol) was added (4 mL). The reaction was stirred for 2 hours. The pH was adjusted to 5 with saturated citric acid solution. The residue obtained was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system B to give the title product 4c (750 mg, yield: 78.4%).

MS m/z(ESI):314.0[M+1]。

Fourth step

(S) -N- ((1R) -7-fluoro-1- (2-oxo-2- (2, 4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) ethyl) -2, 3-dihydro-1H-inden-1-yl) -2-methylpropan-2-sulfinamide 4d

Compound 4c (400 mg,1.28 mmol), compound 1e (325 mg,1.53 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (328 mg,1.91 mmol) were dissolved in N, N-dimethylformamide (10 mL). Diisopropylethylamine (495mg, 3.83 mmol) was added thereto at 0℃and stirred at room temperature for 16 hours. The reaction was quenched by the addition of saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (50 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product 4d (647 mg, yield: 99.9%) as the title product, which was used in the next step without purification.

MS m/z(ESI):506.0[M-1]。

Fifth step

(S) -N- ((1S) -7-fluoro-1- (2, 4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) ethyl) -2, 3-dihydro-1H-inden-1-yl) -2-methylpropan-2-sulfinamide 4e

The crude compound 4d (647 mg,1.27 mmol) was dissolved in acetic acid (20 mL). Sodium cyanoborohydride (191 mg,3.19 mmol) was added under ice. The reaction was stirred at room temperature for 1 hour. Ice water (20 mL) was added thereto, and extraction was performed with ethyl acetate (20 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude title product 4e (629 mg, yield: 99.9%) which was used in the next step without purification.

MS m/z(ESI):492.1[M-1]。

Sixth step

5- (2- ((S) -1-amino-7-fluoro-2, 3-dihydro-1H-inden-1-yl) ethyl) -1- (tetrahydro-2H-pyran-4-yl) pyrimidine-2, 4,6 (1H, 3H, 5H) -trione hydrochloride 4f

The crude compound 4e (629 mg,1.27 mmol) was dissolved in ethanol (10 mL) and thionyl chloride (303 mg,2.55 mmol) was added at 0deg.C. Stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give the crude title product 4f (542 mg, yield: 99.9%), which was used in the next step without purification.

MS m/z(ESI):388.1[M-1]。

Seventh step

(R) -7-fluoro-3 ' - (tetrahydro-2H-pyran-4-yl) -2,3,5',8' -tetrahydro-1 ' H-spiro [ indene-1, 7' -pyrido [2,3-d ] pyrimidine ] -2',4' (3 ' H,6' H) -dione 4

The crude compound 4f (552 mg,1.39 mmol) was suspended in acetonitrile (10 mL). The reaction was carried out for 1.0 hour at 120℃with microwaves. Concentrated under reduced pressure and purified by high performance liquid chromatography (Boston Phlex C18. Times.30 mm,5 μm, elution system: water (10 mmol/L ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, 15 min gradient elution, flow rate: 30 mL/min) to give the title product 4 (85 mg, yield: 16.4%).

MS m/z(ESI):372.0[M+1]。

¹ H NMR(500MHz,DMSO-d₆ )δ9.78(s,1H),7.32(m,1H),7.12(m,1H),7.01(m,1H),6.54(s,1H),4.87(m,1H),3.92-3.89(m,2H),3.34-3.30(m,2H),2.98-2.92(m,2H),2.63-2.58(m,2H),2.38(m,1H),2.28(m,1H),2.16-2.07(m,2H),1.98(m,1H),1.83(m,1H),1.39-1.37(m,2H)。

Example 5

(S) -3' - (tetrahydro-2H-pyran-4-yl) -5',8' -dihydro-1 ' H-spiro [ chromane-4, 7' -pyrido [2,3-d ] pyrimidine ] -2',4' (3 ' H,6' H) -dione 5

First step

(S) -N- (chroman-4-ylidene) -2-methylpropane-2-sulfinamide 5b

Chroman-4-one 5a (10.00 g,67.50mmol, taitan technology) was dissolved in tetrahydrofuran (100 mL), tetraethyltitanate (18.48 g,81.01 mmol) was added, stirred at room temperature for 5 minutes, and (S) -2-methylpropan-2-sulfinamide (11.86 g,97.85mmol, pitakayak technologies) was added and reacted overnight at 65 ℃. Saturated sodium bicarbonate solution was added, extraction was performed with ethyl acetate (150 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (150 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 5b (13.60 g, yield: 80.17%).

MS m/z(ESI):252.0[M+1]。

Second step

2- ((R) -4- (((S) -tert-butylsulfinyl) amino) chroman-4-yl) acetic acid methyl ester 5c

Lithium diisopropylamide (13.1 mL, 2.0M) was dissolved in THF (20 mL), replaced with nitrogen three times, methyl acetate (1.95 g,26.32 mmol) was added dropwise, the reaction stirred at that temperature for 30 minutes, titanium triisopropyloxide (27.9 mL, 1.0M) was added, and the reaction stirred at that temperature for 30 minutes. A solution of Compound 5b (2.00 g,7.96 mmol) in tetrahydrofuran (5 mL) was added dropwise at-78deg.C and the reaction stirred for an additional 3 hours. Saturated ammonium chloride solution (10 mL) was added at 0deg.C, extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 5c (2.45 g, yield: 94.6%).

MS m/z(ESI):326.0[M+1]。

Third step

2- ((R) -4- (((S) -tert-butyl) sulfinyl) amino) chroman-4-yl) acetic acid 5d

Compound 5c (1.20 g,3.69 mmol) was dissolved in tetrahydrofuran (15 mL) and aqueous sodium hydroxide (295 mg,7.38 mmol) was added (3 mL). The reaction was stirred for 2 hours. The pH was adjusted to 5 with saturated citric acid solution. The residue was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system B to give the title product 5d (1.05 g, yield: 91.4%).

MS m/z(ESI):311.9[M+1]。

Fourth step

(S) -2-methyl-N- ((4R) -4- (2-oxo-2- (2, 4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) ethyl) chroman-4-yl) propane-2-sulfinamide 5e

Compound 5d (500 g,1.61 mmol), 1- (tetrahydro-2H-pyran-4-yl) pyrimidine-2, 4,6 (1H, 3H, 5H) -trione 1e (348 mg,1.64mmol, prepared using the procedure disclosed in examples 2-3 on page 50 of the specification of patent application "WO 2020092208A 1") and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (916 g,2.41mmol, shanghai Shao Yu chemical Co., ltd.) were dissolved in N, N-dimethylformamide (20 mL). Diisopropylethylamine (623 mg,4.82 mmol) was added thereto at 0℃and stirred at room temperature for 16 hours. The reaction was quenched by the addition of saturated sodium bicarbonate solution (40 mL) and extracted with ethyl acetate (50 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude title product 5e (750 mg, yield: 92.4%), which was used in the next step without purification.

MS m/z(ESI):504.0[M-1]。

Fifth step

(S) -2-methyl-N- ((4S) -4- (2, 4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) ethyl) chroman-4-yl) propane-2-sulfinamide 5f

The crude compound 5e (750 mg,1.48 mmol) was dissolved in acetic acid (10 mL). Sodium cyanoborohydride (222 mg,3.71 mmol) was added under ice bath. The reaction was stirred at room temperature for 1 hour. Ice water (20 mL) was added thereto, and extraction was performed with ethyl acetate (20 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude title product 5f (350 mg, yield: 48.0%) which was used in the next step without purification.

MS m/z(ESI):490.0[M-1]。

Sixth step

5- (2- ((S) -4-Aminochroman-4-yl) ethyl) -1- (tetrahydro-2H-pyran-4-yl) pyrimidine-2, 4,6 (1H, 3H, 5H) -trione hydrochloride 5g

The crude compound 5f (350 mg,0.71 mmol) was dissolved in ethanol (10 mL) and thionyl chloride (169 mg,1.42 mmol) was added at 0deg.C. Stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give 5g of the title product as a crude product (301 mg, yield: 99.7%) which was used in the next step without purification.

MS m/z(ESI):386.0[M-1]。

Seventh step

(S) -3' - (tetrahydro-2H-pyran-4-yl) -5',8' -dihydro-1 ' H-spiro [ chromane-4, 7' -pyrido [2,3-d ] pyrimidine ] -2',4' (3 ' H,6' H) -dione 5

5g of crude compound (301 mg,0.78 mmol) was suspended in acetonitrile (10 mL). The reaction was carried out for 1.0 hour at 120℃with microwaves. Concentrated under reduced pressure and purified by high performance liquid chromatography (Boston Phlex C18. Times.30 mm,5 μm, elution system: water (10 mmol/L ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, 15 min gradient elution, flow rate: 30 mL/min) to give the title product 5 (30 mg, yield: 10.5%).

MS m/z(ESI):370.0[M+1]。

¹ H NMR(500MHz,DMSO-d₆ )δ9.68(s,1H),7.32(m,1H),7.19(m,1H),6.93(m,1H),6.81(m,1H),6.45(s,1H),4.87(m,1H),4.27-4.13(m,2H),3.92-3.89(m,2H),3.35-3.29(m,2H),2.64-2.55(m,2H),2.39-2.28(m,2H),2.04-1.85(m,4H),1.40-1.30(m,2H)。

Example 6

(R) -3' - (tetrahydro-2H-pyran-4-yl) -3,4,5',8' -tetrahydro-1 ' H, 2H-spiro [ naphthalene-1, 7' -pyrido [2,3-d ] pyrimidine ] -2',4' (3 ' H,6' H) -dione 6

First step

(S) -N- (3, 4-dihydronaphthalene-1 (2H) -ylidene) -2-methylpropane-2-sulfinamide 6b

3, 4-Dihydronaphthalen-1 (2H) -one 6a (20.00 g,136.81mmol, shanghai Shaoshan chemical Co., ltd.) was dissolved in tetrahydrofuran (200 mL), tetraethyltitanate (37.45 g,164.18 mmol) was added, stirred at room temperature for 5 minutes, and (S) -2-methylpropan-2-sulfinamide (24.04 g,198.38 mmol) was added and reacted overnight at 65 ℃. Saturated sodium bicarbonate solution was added, extraction was performed with ethyl acetate (150 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (150 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 6b (11.00 g, yield: 32.2%).

MS m/z(ESI):249.9[M+1]。

Second step

2- ((R) -1- (((S) -tert-butylsulfinyl) amino) -1,2,3, 4-tetrahydronaphthalen-1-yl) acetic acid methyl ester 6c

Lithium diisopropylamide (13.2 mL, 2.0M) was dissolved in THF (20 mL) at-78deg.C, replaced with nitrogen three times, methyl acetate (7.31 g,28.07 mmol) was added dropwise, the reaction stirred at this temperature for 30 minutes, titanium triisopropyloxide (28.1 mL, 1.0M) was added, and the reaction stirred at this temperature for 30 minutes. A solution of Compound 6b (2.00 g,8.02 mmol) in tetrahydrofuran (5 mL) was added dropwise at-78deg.C and the reaction stirred for an additional 3 hours. Saturated ammonium chloride solution (10 mL) was added at 0deg.C, extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 6c (2.00 g, yield: 77.1%).

MS m/z(ESI):324.0[M+1]。

Third step

2- ((R) -1- (((S) -tert-butylsulfinyl) amino) -1,2,3, 4-tetrahydronaphthalen-1-yl) acetic acid 6d

Compound 6c (1.00 g,3.09 mmol) was dissolved in tetrahydrofuran (15 mL) and aqueous sodium hydroxide (247 mg,6.18 mmol) was added (3 mL). The reaction was stirred for 2 hours. The pH was adjusted to 5 with saturated citric acid solution. The residue obtained was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system B to give the title product 6d (900 mg, yield: 94.1%).

MS m/z(ESI):310.0[M+1]。

Fourth step (S) -2-methyl-N- ((1R) -1- (2-oxo-2- (2, 4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) ethyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) propane-2-sulfinamide 6e

Compound 6d (500 g,1.62 mmol), compound 1e (350 mg,1.65 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (92 g,2.42 mmol) were dissolved in N, N-dimethylformamide (20 mL). Diisopropylethylamine (6277 mg,4.85 mmol) was added thereto at 0℃and stirred at room temperature for 16 hours. The reaction was quenched by the addition of saturated sodium bicarbonate solution (40 mL) and extracted with ethyl acetate (50 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude title product 6e (740 mg, yield: 90.9%), which was used in the next step without purification.

MS m/z(ESI):502.1[M-1]。

Fifth step

(S) -2-methyl-N- ((1R) -1- (2, 4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) ethyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) propane-2-sulfinamide 6f

The crude compound 6e (740 mg,1.47 mmol) was dissolved in acetic acid (10 mL). Sodium cyanoborohydride (220 mg,3.67 mmol) was added under ice. The reaction was stirred at room temperature for 1 hour. Ice water (20 mL) was added thereto, and extraction was performed with ethyl acetate (20 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude title product 6f (400 mg, yield: 55.6%) which was used in the next step without purification.

MS m/z(ESI):488.1[M-1]。

Sixth step

5- (2- ((R) -1-amino-1, 2,3, 4-tetrahydronaphthalen-1-yl) ethyl) -1- (tetrahydro-2H-pyran-4-yl) pyrimidine-2, 4,6 (1H, 3H, 5H) -trione hydrochloride 6g

The crude compound 6f (400 mg,0.82 mmol) was dissolved in ethanol (10 mL) and thionyl chloride (194 mg,1.63 mmol) was added at 0deg.C. Stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give 6g of the title product (334 mg, yield: 99.9%) which was used in the next step without purification.

MS m/z(ESI):369.0[M-16]。

Seventh step

(R) -3' - (tetrahydro-2H-pyran-4-yl) -3,4,5',8' -tetrahydro-1 ' H, 2H-spiro [ naphthalene-1, 7' -pyrido [2,3-d ] pyrimidine ] -2',4' (3 ' H,6' H) -dione 6

6g of crude compound (344 mg,0.89 mmol) was suspended in acetonitrile (10 mL). The reaction was carried out for 1.0 hour at 120℃with microwaves. Concentrated under reduced pressure and purified by high performance liquid chromatography (Boston Phlex C18. Times.30 mm,5 μm, elution system: water (10 mmol/L ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, 15 min gradient elution, flow rate: 30 mL/min) to give the title product 6 (50 mg, yield: 15.2%).

MS m/z(ESI):368.0[M+1]。

¹ H NMR(500MHz,DMSO-d₆ )δ9.69(s,1H),7.33(m,1H),7.20-7.11(m,3H),6.29(s,1H),4.86(m,1H),3.92-3.89(m,2H),3.35-3.29(m,2H),2.82-2.73(m,2H),2.63-2.55(m,2H),2.34-2.22(m,2H),2.00-1.74(m,6H),1.39-1.37(m,2H)。

Example 7

(R) -6-fluoro-3 ' - (tetrahydro-2H-pyran-4-yl) -2,3,5',8' -tetrahydro-1 ' H-spiro [ indene-1, 7' -pyrido [2,3-d ] pyrimidine ] -2',4' (3 ' H,6' H) -dione 7

First step

(S) -N- (6-fluoro-2, 3-dihydro-1H-inden-1-ylidene) -2-methylpropane-2-sulfinamide 7b

6-fluoro-2, 3-dihydro-1H-inden-1-one 7a (5.00 g,33.30mmol, pichia pharmaceutical technology Co., ltd.) was dissolved in tetrahydrofuran (100 mL), isopropyl titanate (9.12 g,39.98 mmol) was added, and the mixture was stirred at room temperature for 5 minutes, and (S) -2-methylpropan-2-sulfinamide (4.04 g,33.33 mmol) was added and reacted at 65℃overnight. Saturated sodium bicarbonate solution was added, extraction was performed with ethyl acetate (80 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 7b (2.20 g, yield: 26.1%).

MS m/z(ESI):253.9[M+1]。

Second step

2- ((R) -1- (((S) -tert-butylsulfinyl) amino) -6-fluoro-2, 3-dihydro-1H-inden-1-yl) acetic acid methyl ester 7c

Lithium diisopropylamide (14.3 mL, 2.0M) was dissolved in THF (20 mL), nitrogen was replaced three times, methyl acetate (2.12 g,28.62 mmol) was added dropwise, the reaction was stirred at-78deg.C for 30 min, titanium triisopropyloxide (30.4 mL, 1.0M) was added, and stirring was continued at this temperature for 30 min. A solution of Compound 7b (2.20 g,8.68 mmol) in tetrahydrofuran (5 mL) was added dropwise at-78deg.C and the reaction stirred for an additional 3 hours. Saturated ammonium chloride solution (10 mL) was added at 0deg.C, extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 7c (2.40 g, yield: 84.4%). MS m/z (ESI) 328.0[ M+1].

Third step

2- ((R) -1- (((S) -tert-butylsulfinyl) amino) -6-fluoro-2, 3-dihydro-1H-inden-1-yl) acetic acid 7d

Compound 7c (1.00 g,3.05 mmol) was dissolved in tetrahydrofuran (10 mL) and aqueous sodium hydroxide (244 mg,6.10 mmol) was added (4 mL). The reaction was stirred for 2 hours. The pH of the reaction solution was adjusted to 5 with saturated citric acid solution. The residue was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system B to give the title product 7d (950 mg, yield: 99.3%).

MS m/z(ESI):314.0[M+1]。

Fourth step

(S) -N- ((1R) -6-fluoro-1- (2-oxo-2- (2, 4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) ethyl) -2, 3-dihydro-1H-inden-1-yl) -2-methylpropan-2-sulfinamide 7e

Compound 7d (400 mg,1.28 mmol), compound 1e (325 mg,1.53 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (328 mg,1.91 mmol) were dissolved in N, N-dimethylformamide (10 mL). Diisopropylethylamine (495mg, 3.83 mmol) was added thereto at 0℃and stirred at room temperature for 16 hours. The reaction was quenched by the addition of saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (50 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude title product 7e (647 mg, yield: 99.9%) which was used in the next step without purification.

MS m/z(ESI):506.0[M-1]。

Fifth step

(S) -N- ((1S) -6-fluoro-1- (2, 4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) ethyl) -2, 3-dihydro-1H-inden-1-yl) -2-methylpropan-2-sulfinamide 7f

The crude compound 7e (647 mg,1.27 mmol) was dissolved in acetic acid (20 mL). Sodium cyanoborohydride (191 mg,3.19 mmol) was added under ice. The reaction was stirred at room temperature for 1 hour. Ice water (20 mL) was added thereto, and extraction was performed with ethyl acetate (20 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude title product 7f (520 mg, yield: 82.6%) which was used in the next step without purification.

MS m/z(ESI):492.0[M-1]。

Sixth step

5- (2- ((S) -1-amino-6-fluoro-2, 3-dihydro-1H-inden-1-yl) ethyl) -1- (tetrahydro-2H-pyran-4-yl) pyrimidine-2, 4,6 (1H, 3H, 5H) -trione hydrochloride 7g

The crude compound 7f (520 mg,1.05 mmol) was dissolved in ethanol (10 mL) and thionyl chloride (313 mg,2.63 mmol) was added at 0deg.C. Stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give 7g of the title product (448 mg, yield: 99.9%) which was used in the next step without purification.

MS m/z(ESI):388.0[M-1]。

Seventh step

(R) -6-fluoro-3 ' - (tetrahydro-2H-pyran-4-yl) -2,3,5',8' -tetrahydro-1 ' H-spiro [ indene-1, 7' -pyrido [2,3-d ] pyrimidine ] -2',4' (3 ' H,6' H) -dione 7

7g of crude compound (4478 mg,1.15 mmol) was suspended in acetonitrile (12 mL). The reaction was carried out for 1.0 hour at 120℃with microwaves. Concentrated under reduced pressure and purified by high performance liquid chromatography (Boston Phlex C18. Times.30 mm,5 μm, elution system: water (10 mmol/L ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, 15 min gradient elution, flow rate: 30 mL/min) to give the title product 7 (150 mg, yield: 35.1%).

MS m/z(ESI):372.0[M+1]。

¹ H NMR(500MHz,DMSO-d₆ )δ9.83(s,1H),7.31-7.28(m,1H),7.11-7.07(m,1H),7.03-7.01(m,1H),6.39(s,1H),4.90-4.83(m,1H),3.92-3.89(m,2H),3.35-3.29(m,2H),2.91-2.83(m,2H),2.64-2.56(m,2H),2.38-2.29(m,2H),2.20-2.15(m,1H),2.10-2.06(m,1H),1.76-1.74(m,2H),1.41-1.37(m,2H)。

Example 8

(R) -5-fluoro-3 ' - (tetrahydro-2H-pyran-4-yl) -2,3,5',8' -tetrahydro-1 ' H-spiro [ indene-1, 7' -pyrido [2,3-d ] pyrimidine ] -2',4' (3 ' H,6' H) -dione 8

First step

(S) -N- (5-fluoro-2, 3-dihydro-1H-inden-1-ylidene) -2-methylpropane-2-sulfinamide 8b

5-fluoro-2, 3-dihydro-1H-inden-1-one 8a (5.00 g,33.30mmol, pichia pharmaceutical technology Co., ltd.) was dissolved in tetrahydrofuran (100 mL), isopropyl titanate (9.12 g,39.98 mmol) was added, stirred at room temperature for 5 minutes, and (S) -2-methylpropan-2-sulfinamide (5.85 g,48.27 mmol) was added and reacted at 65℃overnight. Saturated sodium bicarbonate solution was added, extraction was performed with ethyl acetate (80 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 8b (2.10 g, yield: 24.9%).

MS m/z(ESI):253.9[M+1]。

Second step

2- ((R) -1- (((S) -tert-butylsulfinyl) amino) -5-fluoro-2, 3-dihydro-1H-inden-1-yl) acetic acid methyl ester 8c

Lithium diisopropylamide (13.7 mL, 2.0M) was dissolved in tetrahydrofuran (20 mL), replaced with nitrogen three times, methyl acetate (2.03 g,27.40 mmol) was added dropwise, the reaction was stirred at that temperature for 30 minutes, titanium triisopropyloxide (29.0 mL, 1.0M) was added, and stirring was continued at that temperature for 30 minutes. A solution of compound 8b (2.10 g,8.29 mmol) in tetrahydrofuran (5 mL) was added dropwise at-78deg.C and the reaction stirred for an additional 3 hours. Saturated ammonium chloride solution (10 mL) was added at 0deg.C, extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 8c (2.20 g, yield: 81.1%). MS m/z (ESI) 328.0[ M+1].

Third step

2- ((R) -1- (((S) -tert-butylsulfinyl) amino) -5-fluoro-2, 3-dihydro-1H-inden-1-yl) acetic acid 8d

Compound 8c (1.00 g,3.05 mmol) was dissolved in tetrahydrofuran (10 mL) and aqueous sodium hydroxide (244 mg,6.10 mmol) was added (4 mL). The reaction was stirred for 2 hours. The pH of the reaction solution was adjusted to 5 with saturated citric acid solution. The residue was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system B to give the title product 8d (950 mg, yield: 99.3%).

MS m/z(ESI):314.0[M+1]。

Fourth step

(S) -N- ((1R) -5-fluoro-1- (2-oxo-2- (2, 4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) ethyl) -2, 3-dihydro-1H-inden-1-yl) -2-methylpropan-2-sulfinamide 8e

Compound 8d (400 mg,1.28 mmol), compound 1e (325 mg,1.53 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (328 mg,1.91 mmol) were dissolved in N, N-dimethylformamide (10 mL). Diisopropylethylamine (495mg, 3.83 mmol) was added thereto at 0℃and stirred at room temperature for 16 hours. The reaction was quenched by the addition of saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (50 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude title product 8e (647 mg, yield: 99.9%) which was used in the next step without purification.

MS m/z(ESI):506.0[M-1]。

Fifth step

(S) -N- ((1S) -5-fluoro-1- (2, 4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) ethyl) -2, 3-dihydro-1H-inden-1-yl) -2-methylpropan-2-sulfinamide 8f

The crude compound 8e (647 mg,1.27 mmol) was dissolved in acetic acid (20 mL). Sodium cyanoborohydride (191 mg,3.19 mmol) was added under ice. The reaction was stirred at room temperature for 1 hour. Ice water (20 mL) was added thereto, and extraction was performed with ethyl acetate (20 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product 8f (620 mg, yield: 98.5%) of the title product, which was used in the next step without purification.

MS m/z(ESI):492.1[M-1]。

Sixth step

8g of 5- (2- ((S) -1-amino-5-fluoro-2, 3-dihydro-1H-inden-1-yl) ethyl) -1- (tetrahydro-2H-pyran-4-yl) pyrimidine-2, 4,6 (1H, 3H, 5H) -trione hydrochloride

The crude compound 8f (620 mg,1.26 mmol) was dissolved in ethanol (10 mL) and thionyl chloride (264 mg,3.14 mmol) was added at 0deg.C. Stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give 8g of the title product (534 mg, yield: 99.8%) which was used in the next step without purification.

MS m/z(ESI):388.0[M-1]。

Seventh step

(R) -5-fluoro-3 ' - (tetrahydro-2H-pyran-4-yl) -2,3,5',8' -tetrahydro-1 ' H-spiro [ indene-1, 7' -pyrido [2,3-d ] pyrimidine ] -2',4' (3 ' H,6' H) -dione 8

8g of crude compound (534 mg,1.37 mmol) was suspended in acetonitrile (12 mL). The reaction was carried out for 1.0 hour at 120℃with microwaves. Concentrated under reduced pressure and purified by high performance liquid chromatography (Boston Phlex C18. Times.30 mm,5 μm, elution system: water (10 mmol/L ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, 15 min gradient elution, flow rate: 30 mL/min) to give the title product 8 (45 mg, yield: 8.8%).

MS m/z(ESI):372.0[M+1]。

¹ H NMR(500MHz,DMSO-d₆ )δ9.82(s,1H),7.23-7.20(m,1H),7.12-7.10(m,1H),7.06-7.02(m,1H),6.34(s,1H),4.90-4.83(m,1H),3.92-3.89(m,2H),3.35-3.30(m,2H),2.93-2.88(m,2H),2.64-2.54(m,2H),2.37-2.31(m,2H),2.19-2.14(m,1H),2.10-2.06(m,1H),1.75-1.73(m,2H),1.40-1.37(m,2H)。

Example 9

(R) -4-fluoro-3 ' - (tetrahydro-2H-pyran-4-yl) -2,3,5',8' -tetrahydro-1 ' H-spiro [ indene-1, 7' -pyrido [2,3-d ] pyrimidine ] -2',4' (3 ' H,6' H) -dione 9

First step

(S) -N- (4-fluoro-2, 3-dihydro-1H-inden-1-ylidene) -2-methylpropane-2-sulfinamide 9b

4-fluoro-2, 3-dihydro-1H-inden-1-one 9a (5.00 g,33.30mmol, pichia pharmaceutical technology Co., ltd.) was dissolved in tetrahydrofuran (100 mL), isopropyl titanate (9.12 g,39.98 mmol) was added, stirred at room temperature for 5 minutes, and (S) -2-methylpropan-2-sulfinamide (5.85 g,48.27 mmol) was added and reacted at 65℃overnight. Saturated sodium bicarbonate solution was added, extraction was performed with ethyl acetate (80 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 9b (2.10 g, yield: 24.9%).

MS m/z(ESI):254.0[M+1]。

Second step

2- ((R) -1- (((S) -tert-butylsulfinyl) amino) -4-fluoro-2, 3-dihydro-1H-inden-1-yl) acetic acid methyl ester 9c

Lithium diisopropylamide (13.7 mL, 2.0M) was dissolved in tetrahydrofuran (20 mL), replaced with nitrogen three times, methyl acetate (2.03 g,27.40 mmol) was added dropwise, the reaction was stirred at that temperature for 30 minutes, titanium triisopropyloxide (29.0 mL, 1.0M) was added, and stirring was continued at that temperature for 30 minutes. A solution of compound 9b (2.10 g,8.29 mmol) in tetrahydrofuran (5 mL) was added dropwise at-78deg.C and the reaction stirred for an additional 3 hours. Saturated ammonium chloride solution (10 mL) was added at 0deg.C, extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 9c (2.20 g, yield: 81.1%). MS m/z (ESI) 328.0[ M+1].

Third step

2- ((R) -1- (((S) -tert-butylsulfinyl) amino) -4-fluoro-2, 3-dihydro-1H-inden-1-yl) acetic acid 9d

Compound 9c (1.00 g,3.05 mmol) was dissolved in tetrahydrofuran (10 mL) and aqueous sodium hydroxide (244 mg,6.10 mmol) was added (4 mL). The reaction was stirred for 2 hours. The pH of the reaction solution was adjusted to 5 with saturated citric acid solution. The residue obtained was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system B to give the title product 9d (870 mg, yield: 90.9%).

MS m/z(ESI):314.0[M+1]。

Fourth step

(S) -N- ((1R) -4-fluoro-1- (2-oxo-2- (2, 4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) ethyl) -2, 3-dihydro-1H-inden-1-yl) -2-methylpropan-2-sulfinamide 9e

Compound 9d (400 mg,1.28 mmol), compound 1e (325 mg,1.53 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (328 mg,1.91 mmol) were dissolved in N, N-dimethylformamide (10 mL). Diisopropylethylamine (495mg, 3.83 mmol) was added thereto at 0℃and stirred at room temperature for 16 hours. The reaction was quenched by the addition of saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (50 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude title product 9e (647 mg, yield: 99.9%) which was used in the next step without purification.

MS m/z(ESI):506.0[M-1]。

Fifth step

(S) -N- ((1S) -4-fluoro-1- (2, 4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) ethyl) -2, 3-dihydro-1H-inden-1-yl) -2-methylpropan-2-sulfinamide 9f

The crude compound 9e (647 mg,1.27 mmol) was dissolved in acetic acid (20 mL). Sodium cyanoborohydride (191 mg,3.19 mmol) was added under ice. The reaction was stirred at room temperature for 1 hour. Ice water (20 mL) was added thereto, and extraction was performed with ethyl acetate (20 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude title product 9f (629 mg, yield: 99.9%) which was used in the next step without purification.

MS m/z(ESI):492.0[M-1]。

Sixth step

5- (2- ((S) -1-amino-4-fluoro-2, 3-dihydro-1H-inden-1-yl) ethyl) -1- (tetrahydro-2H-pyran-4-yl) pyrimidine-2, 4,6 (1H, 3H, 5H) -trione hydrochloride 9g

The crude compound 9f (629 mg,1.27 mmol) was dissolved in ethanol (10 mL) and thionyl chloride (379 mg,3.19 mmol) was added at 0deg.C. Stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give 9g of the title product (542 mg, yield: 99.9%) which was used in the next step without purification.

MS m/z(ESI):388.1[M-1]。

Seventh step

(R) -4-fluoro-3 ' - (tetrahydro-2H-pyran-4-yl) -2,3,5',8' -tetrahydro-1 ' H-spiro [ indene-1, 7' -pyrido [2,3-d ] pyrimidine ] -2',4' (3 ' H,6' H) -dione 9

9g of crude compound (552 mg,1.27 mmol) was suspended in acetonitrile (12 mL). The reaction was carried out for 1.0 hour at 120℃with microwaves. Concentrated under reduced pressure and purified by high performance liquid chromatography (Boston Phlex C18. Times.30 mm,5 μm, elution system: water (10 mmol/L ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, 15 min gradient elution, flow rate: 30 mL/min) to give the title product 9 (130 mg, yield: 27.5%).

MS m/z(ESI):372.0[M+1]。

¹ H NMR(500MHz,DMSO-d₆ )δ9.91(s,1H),7.35-7.02(m,3H),6.47-6.42(m,1H),4.95-4.81(m,1H),3.96-3.89(m,2H),3.44-3.28(m,2H),2.99-2.88(m,2H),2.64-2.54(m,2H),2.42-2.09(m,4H),1.82-1.73(m,2H),1.43-1.30(m,2H)。

Example 10

(S) -6-fluoro-3 ' - (tetrahydro-2H-pyran-4-yl) -2,3,5',8' -tetrahydro-1 ' H-spiro [ indene-1, 7' -pyrido [2,3-d ] pyrimidine ] -2',4' (3 ' H,6' H) -dione 10

First step

(R) -N- (6-fluoro-2, 3-dihydro-1H-inden-1-ylidene) -2-methylpropane-2-sulfinamide 10a

Compound 7a (10.00 g,66.60 mmol) was dissolved in toluene (200 mL), isopropyl titanate (21.27 g,93.25 mmol) was added, stirred at room temperature for 5 min, and (S) -2-methylpropane-2-sulfinamide (11.70 g,96.53 mmol) was added and reacted overnight at 110 ℃. Saturated sodium bicarbonate solution was added, extraction was performed with ethyl acetate (160 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 10a (8.80 g, yield: 52.2%).

MS m/z(ESI):253.9[M+1]。

Second step

2- ((S) -1- (((R) -tert-butylsulfinyl) amino) -6-fluoro-2, 3-dihydro-1H-inden-1-yl) acetic acid methyl ester 10b

Lithium diisopropylamide (57.3 mL, 2.0M) was dissolved in tetrahydrofuran (50 mL), replaced with nitrogen three times, methyl acetate (8.49 g,114.61 mmol) was added dropwise, the reaction was stirred at that temperature for 30 minutes, titanium triisopropyloxide (121.6 mL, 1.0M) was added, and stirring was continued at that temperature for 30 minutes. A solution of compound 10a (8.80 g,34.74 mmol) in tetrahydrofuran (30 mL) was added dropwise at-78deg.C and the reaction stirred for an additional 3 hours. Saturated ammonium chloride solution (30 mL) was added at 0deg.C, extracted with ethyl acetate (60 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 10b (4.50 g, yield: 39.6%).

MS m/z(ESI):328.0[M+1]。

Third step

2- ((S) -1- (((R) -tert-butylsulfinyl) amino) -6-fluoro-2, 3-dihydro-1H-inden-1-yl) acetic acid 10c

Compound 10b (4.50 g,13.74 mmol) was dissolved in tetrahydrofuran (50 mL) and aqueous sodium hydroxide (1.10 g,27.50 mmol) was added (10 mL). The reaction was stirred for 2 hours. The pH of the reaction solution was adjusted to 5 with saturated citric acid solution. The residue obtained was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system B to give the title product 10c (3.70 g, yield: 85.9%).

MS m/z(ESI):314.0[M+1]。

Fourth step

(R) -N- ((1S) -6-fluoro-1- (2-oxo-2- (2, 4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) ethyl) -2, 3-dihydro-1H-inden-1-yl) -2-methylpropan-2-sulfinamide 10d

Compound 10c (1.20 g,3.83 mmol), compound 1e (813 mg,3.83 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (2.18 g,5.73 mmol) were dissolved in N, N-dimethylformamide (20 mL). Diisopropylethylamine (1.48 mg,11.45 mmol) was added thereto at 0℃and stirred at room temperature for 16 hours. The reaction was quenched by the addition of saturated sodium bicarbonate solution (40 mL) and extracted with ethyl acetate (50 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product of the title product 10d (1.94 g, yield: 99.8%), which was used in the next step without purification.

MS m/z(ESI):506.1[M-1]。

Fifth step

(R) -N- ((1R) -6-fluoro-1- (2, 4, 6-trioxo-1- (tetrahydro-2H-pyran-4-yl) hexahydropyrimidin-5-yl) ethyl) -2, 3-dihydro-1H-inden-1-yl) -2-methylpropan-2-sulfinamide 10e

The crude compound 10d (1.94 g,3.82 mmol) was dissolved in acetic acid (40 mL). Sodium cyanoborohydride (457 mg,7.64 mmol) was added under ice bath. The reaction was stirred at room temperature for 1 hour. Ice water (60 mL) was added and extraction was performed with ethyl acetate (50 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL. Times.2), 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 10e (1.10 g, yield: 58.3%).

MS m/z(ESI):492.0[M-1]。

Sixth step

5- (2- ((R) -1-amino-6-fluoro-2, 3-dihydro-1H-inden-1-yl) ethyl) -1- (tetrahydro-2H-pyran-4-yl) pyrimidine-2, 4,6 (1H, 3H, 5H) -trione hydrochloride 10f

Compound 10e (1.10 g,2.23 mmol) was dissolved in ethanol (15 mL) and thionyl chloride (530 mg,4.45 mmol) was added at 0deg.C. Stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give a crude product (949 mg, yield: 100%) of the title product 10f, which was used in the next step without purification.

MS m/z(ESI):388.1[M-1]。

Seventh step

(S) -6-fluoro-3 ' - (tetrahydro-2H-pyran-4-yl) -2,3,5',8' -tetrahydro-1 ' H-spiro [ indene-1, 7' -pyrido [2,3-d ] pyrimidine ] -2',4' (3 ' H,6' H) -dione 10

Crude compound 10f (949 mg,2.44 mmol) was suspended in acetonitrile (15 mL). The reaction was carried out for 1.0 hour at 120℃with microwaves. Concentrated under reduced pressure and purified by high performance liquid chromatography (Boston Phlex C18. Times.30 mm,5 μm, elution system: water (10 mmol/L ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, 15 min gradient elution, flow rate: 30 mL/min) to give the title product 10 (210 mg, yield: 23.2%).

MS m/z(ESI):372.0[M+1]。

¹ H NMR(500MHz,DMSO-d₆ )δ9.82(s,1H),7.30(m,1H),7.09(m,1H),7.02(m,1H),6.39(s,1H),4.87(m,1H),3.92-3.89(m,2H),3.35-3.29(m,2H),2.88-2.86(m,2H),2.62-2.58(m,2H),2.35-2.32(m,2H),2.18(m,1H),2.08(m,1H),1.76-1.74(m,2H),1.41-1.37(m,2H)。

Biological evaluation

The present disclosure is explained in further detail below in conjunction with test examples, which are not meant to limit the scope of the present disclosure.

Test example 1, the inhibitory effect of the compounds of the present disclosure on myosin atpase activity.

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

1. experimental material and instrument

1. Myocardial actin (Cytoskeleton, AD 99)

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

3.ATP(Sigma，A7699-1G)

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

5.CytoPhos^TM Phosphate detection biological reagent box (Cytoskeleton, BK 054)

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

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

8.EGTA(Sigma，E3889-100G)

9.96 well plate (Corning, 3697)

U-shaped bottom 96 well plate (Corning 3795)

11. Enzyme label instrument (BMG, PHERAstar)

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

2. Experimental procedure

Myocardial actin 1.61. Mu.M, myosin motor protein S1 fragment 0.07. Mu.M was mixed with small molecule compounds of different concentrations (initial 100. Mu.M, 3-fold gradient 9) and incubated at 37℃for 1 hour, and ATP 120. Mu.M was added and incubated at 37℃for 2 hours. Finally, adding CytoPhos into each hole^TM The detection solution (70. Mu.L/well) in the phosphate detection biological kit was incubated at room temperature for 10min. Reading OD value of 650nM wavelength with enzyme labeling instrument, calculating Pi generation amount according to standard curve, and data Using GraphPad software to draw inhibition curves according to each concentration of the compound and corresponding inhibition rate, and calculating the concentration of the compound, namely IC when the inhibition rate reaches 50 percent₅₀ Values. The experimental results are detailed in table 1.

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

Conclusion: the compound disclosed by the disclosure has a good inhibition effect on myosin ATPase.

Claims (22)

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

wherein:

y is selected from CR⁵ R⁶ O atom, CR⁵ R⁶ CR⁵ R⁶ 、CR⁵ R⁶ -O and O-CR⁵ R⁶ ；

U¹ 、U² 、U³ And U⁴ All are carbon atoms;

R⁰ is that

L₁ Is a bond;

ring a is a 3 to 12 membered cycloalkyl or 3 to 12 membered heterocyclyl;

each R is⁸ Identical or different and are each independently selected from hydrogen atoms, halogen, C_1-6 Alkyl, C_1-6 Alkoxy, C_1-6 Haloalkyl, C_1-6 Haloalkoxy and cyano;

R^1a 、R^1b 、R^1c and R is^1d Identical or different and are each independently selected from hydrogen atoms, halogen, C_1-6 Alkyl, C_1-6 Alkoxy, C_1-6 Haloalkyl, C_1-6 Haloalkoxy and cyano;

R² 、R³ 、R⁵ and R is⁶ Identical or different and are each independently selected from hydrogen atoms, halogen, C_1-6 Alkyl, C_1-6 Alkoxy, C_1-6 Haloalkyl, C_1-6 Haloalkoxy and cyano;

each R is⁴ Identical or different and are each independently selected from hydrogen atoms, halogen, C_1-6 Alkyl, C_1-6 Alkoxy, C_1-6 Haloalkyl, C_1-6 Haloalkoxy, cyano, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocyclyl;

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

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

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

wherein:

Y、R⁰ 、R^1a 、R^1b 、R^1c 、R^1d 、R² ～R⁴ and m is as defined in claim 1.

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

wherein:

Y、R⁰ 、R^1a 、R^1b 、R^1c 、R^1d 、R² ～R⁴ and m is as defined in claim 1.

4. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 wherein Y is selected from CR⁵ R⁶ 、CR⁵ R⁶ CR⁵ R⁶ And CR (CR)⁵ R⁶ -O, wherein CR⁵ R⁶ The O end of the-O is connected with a benzene ring; r is R⁵ And R is⁶ As defined in claim 1.

5. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R⁰ Is a 3-to 8-membered cycloalkyl group or a 3-to 8-membered heterocyclic group.

6. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R⁰ Is a 3-to 8-membered heterocyclic group.

7. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R⁰ Is tetrahydropyranyl.

8. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R^1a 、R^1b 、R^1c And R is^1d Identical or different and are each independently selected from the group consisting of hydrogen, halogen and C_1-6 An alkyl group.

9. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R² 、R³ 、R⁵ And R is⁶ Identical or different and are each independently a hydrogen atomOr C_1-6 An alkyl group.

10. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein each R⁴ The same or different, and are each independently a hydrogen atom or a halogen.

11. A compound of general formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is the following compound:

12. a compound of the general formula (IA):

wherein: u (U)¹ 、U² 、U³ 、U⁴ 、Y、R⁰ 、R^1a 、R^1b 、R^1c 、R^1d 、R² ～R⁴ And m is as defined in claim 1.

13. The compound of formula (IA) or a salt thereof according to claim 12, wherein the salt is a hydrochloride salt.

14. A compound of formula (IA) according to claim 12, or a salt thereof, selected from the following compounds:

15. a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which comprises:

Intramolecular reaction of the compound of formula (IA) or a salt thereof to obtain a compound of formula (I) or a pharmaceutically acceptable salt thereof;

wherein:

U¹ 、U² 、U³ 、U⁴ 、Y、R⁰ 、R^1a 、R^1b 、R^1c 、R^1d 、R² ～R⁴ and m is as defined in claim 1.

16. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

17. Use of a compound of general formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 16 for the preparation of a myosin inhibitor.

18. Use of a compound of general formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 16 in the manufacture of a medicament for the treatment of a disease or condition selected from the group consisting of ejection fraction preserved diastolic heart failure, ischemic heart disease, angina, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic cardiomyopathy, normal ejection fraction heart failure, ejection fraction median heart failure, valve disease, lux endocarditis, myocardial endocardial fibrosis, invasive cardiomyopathy, hemochromatosis, fabry's disease, glycogen storage disease, fabry's quadruple, left ventricular hypertrophy and chagas disease.

19. The use of claim 18, wherein the disease or disorder is selected from ischemic heart disease, restrictive cardiomyopathy, hypertrophic cardiomyopathy, inflammatory cardiomyopathy, invasive cardiomyopathy, congenital heart disease, and left ventricular hypertrophy.

20. The use of claim 18, wherein the disease or disorder is hypertrophic cardiomyopathy.

21. The use of claim 18, wherein the disease or disorder is a non-obstructive hypertrophic cardiomyopathy or an obstructive hypertrophic cardiomyopathy.

22. The use of claim 18, wherein the disease or condition is selected from aortic valve stenosis, congenital heart disease, and refractory angina.