CN115636814A

CN115636814A - Pyrimidine derivative and application thereof

Info

Publication number: CN115636814A
Application number: CN202211296899.7A
Authority: CN
Inventors: 王中利; 匡亮; 郝欣; 罗志阳; 柳梦林
Original assignee: Ruishi Biomedical Co ltd
Current assignee: Ruishi Biomedical Co ltd
Priority date: 2022-02-28
Filing date: 2022-10-21
Publication date: 2023-01-24

Abstract

The present disclosure relates to a pyrimidine derivative and uses thereof. In particular to a compound shown as a formula I or a pharmaceutically acceptable salt thereof, wherein R is ¹ ～R ⁵ Y, m and ring a are as defined herein.

Description

Pyrimidine derivative and application thereof

Technical Field

The disclosure belongs to the field of medicine, and relates to a pyrimidine derivative and application thereof.

Background

Mitogen-activated protein kinase 2 (MAPKAP K2 or MK 2) mediates multiple p38 MAPK-dependent cellular responses. MK2 is an important intracellular regulator of the production of cytokines such as tumor necrosis factor α (TNF- α), interleukin 6 (IL-6) and interferon γ (IFN γ), which are involved in many acute and chronic inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease.

WO2005018557 reports a number of potential inhibitors of p38 kinase, including pyridone backbone structures,

US2007/0167621 reports compounds useful in the treatment of disorders resulting from a deregulated p38MAP kinase and/or TNF activity, including compounds comprising a pyrimidinone backbone structure,

other p38MAP kinases with pyridone or pyrimidinone backbone structures have also been reported, such as WO2003047577, WO2003068230, WO2004087677, WO2007081901, WO2009149188, WO2012078684, WO2014055548, WO2015153683, WO2014197846, WO2017177974, WO2021022186, US7893061.

However, no MK2 inhibitor is currently on the market, while the compounds of the present disclosure are not disclosed in any literature, and such compounds exhibit specific MK2 inhibitory effects, and exhibit selectivity for other kinases (e.g., CDK 2).

Disclosure of Invention

The disclosure provides compounds of formula I or pharmaceutically acceptable salts or isotopic substitutions thereof

Wherein R is ¹ Selected from halogen, C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy being optionally substituted by one or more R ^1A Substituted, R ^1A Each independently selected from halogen, hydroxy, oxo, nitro, cyano or amino;

R ² selected from hydrogen, -OR ^2a or-SR ^2b Wherein R is ^2a Or R ^2b Selected from hydrogen, C _1-6 Alkyl, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, said alkyl, cycloalkyl or heterocycloalkyl optionally substituted with one or more R ^2A Substituted;

R ^2A each independently selected from deuterium, halogen, hydroxy, oxo, amino, C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, 6-to 10-aryl or 5-to 10-heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl being optionally substituted by one or more groups selected from halogen, hydroxy, amino, cyano, C _1-6 Alkyl, halo C _1-6 Alkyl or C _1-6 Alkoxy substituted;

R ³ selected from hydrogen, halogen, hydroxy, cyano, amino, C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl being optionally substituted with one or more R ^3A Substituted, R ^3A Each independently selected from halogen, hydroxy, oxo, nitro, cyano or amino;

R ⁴ selected from hydrogen, halogen, hydroxy, cyano, amino, C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl optionally substituted with one or more R ^4A Substituted, R ^4A Each independently selected from halogen, hydroxy, oxo,Nitro, cyano or amino;

R ⁵ each independently selected from halogen, hydroxy, cyano, amino, C _1-6 Alkyl radical, C _1-6 Alkoxy, said alkyl or alkoxy being optionally substituted by one or more R ^5A Substituted;

R ^5A each independently selected from halogen, hydroxy, amino, C _1-6 Alkyl or C _1-6 An alkoxy group;

R ⁶ 、R ⁷ each independently selected from hydrogen, halogen, hydroxyl, amino, C _1-6 Alkyl or C _1-6 An alkoxy group;

x and Y are each selected from N or-CR ⁸ And X and Y are not both N;

R ⁸ selected from hydrogen, halogen, C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy being optionally substituted with one or more halogen, hydroxy or amino;

R ⁹ 、R ¹⁰ each independently selected from hydrogen, halogen, hydroxy, cyano, amino, C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy being optionally substituted with one or more halogen, hydroxy or amino;

z is selected from N or-CR ¹¹ -，R ¹¹ Selected from hydrogen, halogen, C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy being optionally substituted with one or more halogen, hydroxy or amino groups;

ring A is selected from a 3-6 membered carbocyclic ring or a 3-6 membered heterocyclic ring;

m is an integer from 0 to 4.

In some embodiments, R in the compound of formula I ¹ Selected from halogen, preferably fluorine or chlorine; or R ¹ Is selected from C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy being optionally substituted by one or more R ^1A Substituted, R ^1A As defined above.

In some embodiments, R in the compound of formula I ² Is selected from-OR ^2a Wherein R is ^2a Selected from hydrogen or C _1-6 An alkyl group optionally substituted with one or more R ^2A Substituted, R ^2A As defined above;

in some embodiments, R in the compound of formula I ² Selected from 3 to 6 membered cycloalkyl or 3 to 6 membered heterocycloalkyl, said cycloalkyl or heteroalkyl optionally substituted with one or more R ^2A Substituted, R ^2A As defined above.

In some embodiments, R in the compound of formula I ³ Selected from hydrogen, halogen, hydroxy, cyano or amino, preferably hydrogen.

In some embodiments, R in the compound of formula I ³ Is selected from C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 6-membered cycloalkyl or 3-to 6-membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl being optionally substituted with one or more R ^3A Substituted, R ^3A As defined above.

In some embodiments, R in the compound of formula I ⁴ Selected from hydrogen, halogen, hydroxy, cyano or amino. In some embodiments, R in the compound of formula I ⁴ Is selected from C _1-6 Alkyl or C _1-6 Alkoxy, preferably C _1-6 Alkyl radicals, such as the methyl, ethyl and propyl radicals, and furthermore, the radicals R ⁴ Optionally substituted by one or more R ^4A Substituted, R ^4A As defined above;

in some embodiments, R in the compound of formula I ⁴ Selected from 3 to 6 membered cycloalkyl or 3 to 6 membered heterocycloalkyl, said cycloalkyl or heterocycloalkyl optionally substituted with one or more R ^4A Substituted, R ^4A As defined above.

In some embodiments, Y in the compounds of formula I is selected from CR ⁸ -，R ⁸ Selected from hydrogen.

In some embodiments, X is selected from N in the compounds of formula I.

In some embodiments, Y in the compounds of formula I is selected from CR ⁸ -，R ⁸ Selected from hydrogen and X is selected from N.

In some embodiments, R in the compound of formula I ² Is selected from-OR ^2a Wherein R is ^2a Selected from hydrogen or C _1-6 An alkyl group optionally substituted with one or more R ^2A Substituted, R ^2A As defined above.

In some embodiments, R in the compound of formula I ² Is selected from-SR ^2b Wherein R is ^2b Selected from hydrogen or C _1-6 An alkyl group optionally substituted with one or more R ^2A Substituted, R ^2A As defined above.

In some embodiments, R in the compound of formula I ² Is selected from-OR ^2a Wherein R is ^2a Selected from 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, said cycloalkyl or heteroalkyl optionally substituted with one or more R ^2A Substituted, R ^2A As defined above.

In some embodiments, R in the compound of formula I ² Is selected from-SR ^2b Wherein R is ^2b Selected from 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, said cycloalkyl or heteroalkyl optionally substituted with one or more R ^2A Substituted, R ^2A As defined above.

In some embodiments, R in the compound of formula I ^2A Selected from deuterium, 3-to 6-membered cycloalkyl or 3-to 6-membered heterocycloalkyl, said cycloalkyl or heteroalkyl being optionally substituted with one or more substituents selected from halogen, hydroxy, amino, cyano, C _1-6 Alkyl, halo C _1-6 Alkyl or C _1-6 Alkoxy groups.

In some embodiments, R in the compound of formula I ^2A Each independently selected from deuterium, halogen, hydroxy, oxo, amino.

In some embodiments, R in the compound of formula I ^2A Each independently selected from deuterium, C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl being optionally substituted by one or more groups selected from halogen, hydroxy, amino, C _1-6 Alkyl or C _1-6 Alkoxy groups.

In some embodiments, R in the compound of formula I ^2A Each independently selected from deuterium, 6 to 10 aryl or 5 to 10 heteroaryl, said aryl or heteroarylOptionally substituted by one or more groups selected from halogen, hydroxy, amino, cyano, C _1-6 Alkyl, halo C _1-6 Alkyl or C _1-6 Alkoxy groups are substituted.

In some embodiments, R in the compound of formula I ^2A Selected from the group consisting of:

further, the heteroaryl group is optionally substituted by one or more groups selected from halogen, hydroxy, amino, cyano, C _1-6 Alkyl, halo C _1-6 Alkyl or C _1-6 Alkoxy groups.

In another aspect, some embodiments provide that the compound of formula I is

Wherein R is ¹² 、R ¹³ Each independently selected from deuterium, hydrogen, halogen, hydroxy, amino, C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy being optionally substituted by one or more halogens, hydroxy, amino, C _1-6 Alkyl or C _1-6 Alkoxy substituted;

or, R ¹² 、R ¹³ Form a 3-to 6-membered cycloalkyl or 3-to 6-membered heterocycloalkyl group with the adjacent carbon atom, said cycloalkyl or heterocycloalkyl group being optionally substituted by one or more halogens, hydroxy, amino, C _1-6 Alkyl or C _1-6 Alkoxy substituted;

or, p =1,R ¹² 、R ¹³ Oxo (= O) to an adjacent carbon atom;

R ¹⁴ each independently selected from halogen, hydroxy, amino, cyano, C _1-6 Alkyl, halo C _1-6 Alkyl or C _1-6 An alkoxy group;

n is an integer of 0 to 3;

p is an integer between 1 and 3;

R ¹ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁹ 、R ¹⁰ z and m are as defined above.

In some embodiments, R in the compound of formula I or formula IIa or formula IIb ⁷ Selected from hydrogen.

In some embodiments, R in the compound of formula I or formula IIa or formula IIb ⁷ Selected from halogen (such as chlorine, bromine or fluorine), hydroxyl and amino.

In some embodiments, R in the compound of formula I or formula IIa or formula IIb ⁷ Is selected from C _1-6 Alkyl or C _1-6 Alkoxy groups, such as methyl, ethyl, methoxy or ethoxy.

In some embodiments, R in the compound of formula I or formula IIa or formula IIb ⁶ Selected from hydrogen.

In some embodiments, R in the compound of formula I or formula IIa or formula IIb ⁶ Selected from halogen (such as chlorine, bromine or fluorine), hydroxyl and amino.

In some embodiments, R in the compound of formula I or formula IIa or formula IIb ⁶ Is selected from C _1-6 Alkyl or C _1-6 Alkoxy groups, such as methyl, ethyl, methoxy or ethoxy.

In another aspect, some embodiments provide a compound of formula IIa or IIb wherein R is ⁹ 、R ¹⁰ Each independently selected from hydrogen.

Some embodiments provide a compound of formula IIa or IIb wherein R is ⁹ 、R ¹⁰ Each independently selected from halogen, hydroxy, amino.

Some embodiments provide a compound of formula IIa or IIb wherein R ⁹ 、R ¹⁰ Each independently selected from C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy being optionally substituted with one or more halogen, hydroxy or amino groups.

In some embodiments, Z in the compound of formula I or formula IIa or formula IIb is selected from N. In some embodiments, Z in the compound of formula I or formula IIa or formula IIb is selected from-CR ¹¹ -，R ¹¹ Selected from hydrogen.

In some embodiments, formula I or formula IIa or formula IIb in the compound Z is selected from-CR ¹¹ -，R ¹¹ Selected from halogen, C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy being optionally substituted with one or more halogen, hydroxy or amino groups.

In some embodiments, R in a compound of formula IIa or IIb ¹⁴ Each independently selected from halogen, C _1-6 Alkyl or C _1-6 Alkoxy, for example fluorine, chlorine, methyl, ethyl, methoxy or ethoxy.

In some embodiments, R in the compound of formula IIa or IIb ¹⁴ Each independently selected from cyano, C _1-6 Alkyl, halo C _1-6 Alkyl, such as cyano, chloro, fluoro, difluoromethyl or trifluoromethyl.

In some embodiments, p =1,r in the compound of formula IIa or formula IIb ¹² 、R ¹³ Form a 3-to 6-membered cycloalkyl group with the adjacent carbon atom, said cycloalkyl group being optionally substituted by 1-3 halogens, C _1-6 Alkyl or C _1-6 Alkoxy radicals, such as cyclopropyl, cyclobutyl.

In some embodiments, R in the compound of formula I or formula IIa or formula IIb ⁵ Each independently selected from halogen, hydroxy, amino.

In some embodiments, R in the compound of formula I or formula IIa or formula IIb ⁵ Each independently selected from C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy being optionally substituted by one or more R ^5A Substituted, R ^5A As defined above.

In some embodiments, R in the compound of formula I or formula IIa or formula IIb ⁵ Each independently selected from hydroxy, amino, methyl or ethyl.

In some embodiments, ring A in the compounds of formula I or formula IIa or formula IIb is selected from a 3-4 membered carbocyclic ring or a 3-4 membered heterocyclic ring; or ring A is selected from a 5-6 membered carbocyclic ring or a 5-6 membered heterocyclic ring.

Typical compounds of formula I include, but are not limited to:

in some embodiments, the compound of formula I is selected from:

in some embodiments, the compound of formula I is selected from:

in some embodiments, the compound of formula I is selected from:

in some embodiments, the compound of formula I is selected from:

in some embodiments, the compound of formula I is selected from:

in some embodiments, the compound of formula I is selected from:

in some embodiments, the compound of formula I is selected from:

in some embodiments, the compound of formula I is selected from:

in some embodiments, the compound of formula I is selected from:

in some embodiments, the compound of formula I is selected from:

in some embodiments, the compound of formula I is selected from:

the present disclosure also provides isotopic substitutions of the foregoing compounds or pharmaceutically acceptable salts thereof. In some embodiments, the isotopic substituent is a deuteron.

The compound disclosed by the invention has a good inhibition effect on p38a-MK2 kinase. In some embodiments, the disclosed compounds have IC for p38a-MK2 kinase inhibition ₅₀ Values were between 0.01 and 500nM. In some embodiments, the disclosed compounds have IC for p38a-MK2 kinase inhibition ₅₀ Values were between 0.01 and 100nM. In some embodiments, the disclosed compounds have IC for p38a-MK2 kinase inhibition ₅₀ Values were between 0.01 and 20nM. In some embodiments, the disclosed compounds have IC for p38a-MK2 kinase inhibition ₅₀ Values were between 0.1 and 20nM. In some embodiments, the disclosed compounds have IC for p38a-MK2 kinase inhibition ₅₀ Values were between 0.1 and 30nM. In some embodiments, the disclosed compounds have IC for p38a-MK2 kinase inhibition ₅₀ Value of<50nM。

The present disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one compound represented by formula I, IIa or IIb, or a pharmaceutically acceptable salt thereof, or an isotopic substitute thereof, and a pharmaceutically acceptable excipient.

In some embodiments, the unit dose of the pharmaceutical composition is 0.001mg to 1000mg.

In certain embodiments, the pharmaceutical composition comprises from 0.01% to 99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof or isotopically substituted version thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof or isotopic substitution thereof. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof or isotopic substitution thereof. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of the aforementioned compound or a pharmaceutically acceptable salt thereof or isotopic substitution thereof. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of the aforementioned compound or a pharmaceutically acceptable salt or isotopic substitution thereof.

In certain embodiments, the pharmaceutical composition contains 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2% to 98% of a pharmaceutically acceptable excipient.

The present disclosure also provides a method for preventing and/or treating a patient having an MK2 mediated disease or condition by administering to the patient a therapeutically effective amount of a compound of formula I or IIa or IIb, or a pharmaceutically acceptable salt or isotopic substitution thereof, or a pharmaceutical composition of the foregoing.

In some embodiments, the MK 2-mediated disease or disorder is selected from an autoimmune disorder, an inflammatory disorder, a cancer, a fibrotic disorder, or a metabolic disorder.

The present disclosure also provides a method of preventing and/or treating a patient suffering from a systemic immune disorder, an inflammatory disorder, cancer, a fibrotic disorder or a metabolic disorder comprising administering to the patient a therapeutically effective amount of a compound of formula I or IIa or IIb as described above or a pharmaceutically acceptable salt or isotopic substitution thereof, or a pharmaceutical composition of the foregoing.

The present disclosure also provides the use of a compound represented by formula I or IIa or IIb or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as described above in the preparation of a medicament for the prevention and/or treatment of an MK2 mediated disease or condition. In some embodiments, the MK2 mediated disease or disorder is preferably a systemic immune disorder, an inflammatory disorder, cancer, a fibrotic disorder or a metabolic disorder.

The present disclosure also provides the use of a compound of formula I or IIa or IIb as described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the foregoing, in the manufacture of a medicament for the prevention and/or treatment of a autoimmune disorder, an inflammatory disorder, cancer, a fibrotic disorder or a metabolic disorder.

The pharmaceutically acceptable salts of the compounds described in this disclosure may be selected from inorganic or organic salts.

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

Optically active (R) -and (S) -isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one of the enantiomers of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and the pure enantiomers are recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amines).

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

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

Can be that

Or at the same time comprise

Two configurations.

On the other hand, some compounds of the present disclosure may have chirality, although they do not have chiral centers, resulting from the presence of chiral axes or faces in these compounds. For example, when two benzene rings are in the same plane in a biphenyl type compound, the molecule is symmetrical. When two hydrogen atoms at the ortho position of each benzene ring are substituted by two different larger groups, if the two benzene rings are continuously positioned on the same plane, the steric hindrance of the substituent groups is very large, and the steric hindrance can be eliminated only if the two benzene rings are positioned at the mutually vertical positions, so that a stable molecular conformation is formed. The stable conformation makes the molecule lose the symmetry factor, thereby generating a pair of enantiomers which are not overlapped with each other,

in the chemical structure of the compounds described in this disclosure, a bond

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

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

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

The present disclosure also includes certain isotopically-labeled compounds of the present disclosure which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as respectively ² H、 ³ H、 ¹¹ C、 ¹³ C、 ¹⁴ C、 ¹³ N、 ¹⁵ N、 ¹⁵ O、 ¹⁷ O、 ¹⁸ O、 ³¹ P、 ³² P、 ³⁵ S、 ¹⁸ F、 ¹²³ I、 ¹²⁵ I and ³⁶ cl, and the like.

Unless otherwise indicated, when a position is specifically designated as deuterium (D), that position is understood to be deuterium having an abundance that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). The compound of examples can have a natural abundance of deuterium greater than at least 1000 times the abundance of deuterium, at least 2000 times the abundance of deuterium, at least 3000 times the abundance of deuterium, at least 4000 times the abundance of deuterium, at least 5000 times the abundance of deuterium, at least 6000 times the abundance of deuterium, or more abundant deuterium. The disclosure also includes various deuterated forms of the compounds of formula (I). Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. The person skilled in the art is able to synthesize the deuterated forms of the compounds of the formula (I) with reference to the relevant literature. Commercially available deuterated starting materials can be used in preparing the deuterated forms of the compounds of formula (I), or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated methanol, deuterated sodium borohydride, deuterated borane, tri-deuterated borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.

"optionally" or "optionally" means that the description that follows is intended to beThe event or circumstance of (a) may, but need not, occur, and the description includes instances where the event or circumstance occurs or does not occur. For example "C optionally substituted by halogen or cyano _1-6 Alkyl "means that halogen or cyano may, but need not, be present, and the description includes the case where alkyl is substituted with halogen or cyano and the case where alkyl is not substituted with halogen and cyano.

Interpretation of terms:

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

"pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifier that has been approved by the U.S. food and drug administration for use in humans or livestock animals.

The "effective amount" or "therapeutically effective amount" described in this disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on the following factors: such as the condition to be treated, the general health of the patient, the method and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.

"alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, various branched isomers thereof, and the like. The alkyl group may be substituted or unsubstitutedSubstituted, when substituted, the substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from deuterium, halogen, hydroxy, oxo, amino, C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, 6-to 10-aryl or 5-to 10-heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl being optionally substituted by one or more groups selected from halogen, hydroxy, amino, cyano, C _1-6 Alkyl, halo C _1-6 Alkyl or C _1-6 Alkoxy groups.

"halo C _1-6 Alkyl "refers to alkyl substituted by halogen, wherein alkyl is as defined above. Non-limiting examples include dichloromethyl, difluoromethyl, or trifluoromethyl.

The term "cycloalkyl" or "carbocyclic ring" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. Cycloalkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from deuterium, halogen, hydroxy, oxo, amino, C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, 6-to 10-aryl or 5-to 10-heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl being optionally substituted by one or more groups selected from halogen, hydroxy, amino, cyano, C _1-6 Alkyl, halo C _1-6 Alkyl or C _1-6 Alkoxy groups are substituted.

The term "heterocycloalkyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 6 ring atoms, non-limiting examples of "heterocycloalkyl" include:

and so on.

The heterocycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from deuterium, halogen, hydroxy, oxo, amino, C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, 6-to 10-aryl or 5-to 10-heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl being optionally substituted by one or more groups selected from halogen, hydroxy, amino, cyano, C _1-6 Alkyl, halo C _1-6 Alkyl or C _1-6 Alkoxy groups are substituted.

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 3 heteroatoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 or 6 membered. For example. Non-limiting examples thereof include:

heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from deuterium, halogen, hydroxy, oxo, amino, C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, 6-to 10-aryl or 5-to 10-heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl being optionally substituted by one or more groups selected from halogen, hydroxy, amino, cyano, C _1-6 Alkyl, halo C _1-6 Alkyl or C _1-6 Alkoxy groups are substituted.

The term "alkoxy" refers to-O- (alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one orA plurality of groups independently selected from deuterium, halogen, hydroxy, oxo, amino, C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, 6-to 10-aryl or 5-to 10-heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl being optionally substituted by one or more groups selected from halogen, hydroxy, amino, cyano, C _1-6 Alkyl, halo C _1-6 Alkyl or C _1-6 Alkoxy groups are substituted.

The term "hydroxy" refers to an-OH group.

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

The term "cyano" refers to — CN.

The term "amino" refers to the group-NH ₂ 。

The term "nitro" means-NO ₂ 。

The term "oxo" refers to an = O substituent.

"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in a group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort.

Detailed Description

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

Experimental procedures, in which specific conditions are not noted in the examples of the present disclosure, are generally performed under conventional conditions, or under conditions recommended by manufacturers of raw materials or commercial products. Reagents of specific sources are not indicated, and conventional reagents are purchased in the market.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) of 10 ^-6 The units in (ppm) are given. NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated Methanol (Methanol-d) ₄ ) Internal standard isTetramethylsilane (TMS).

The HPLC assay used an Agilent1100 high pressure liquid chromatograph, GAS15B DAD uv detector, water Vbridge C18 x 4.6mm 5um column.

MS was measured using an Agilent6120 triple quadrupole mass spectrometer, G1315D DAD detector, waters Xbridge C18.6 x 50mm,5um chromatography column, scanning in positive/negative ion mode with a mass scan range of 80-1200.

Preparative HPLC conditions: waters; column: sunfire (Prep C18 OBD 19X 250mm 10 μm);

chiral column resolution conditions: column:

OD 10 μm 25 by 250mm; mobile phase: supercritical CO ₂ MeOH (+ 0.1%7.0mol/l ammonia solution) =50, wavelength 214 nm).

The silica gel plate for thin layer chromatography is HSGF254 silica gel plate of cigarette platform yellow sea, and the silica gel plate for Thin Layer Chromatography (TLC) is 0.2mm + -0.03 mm, and the specification of the product for thin layer chromatography separation and purification is 0.4mm-0.5mm.

The flash column purification system used either Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage).

The forward column chromatography generally uses 200-300 mesh or 300-400 mesh silica gel of Taiwan yellow sea as carrier, or uses the ultra-pure forward phase silica gel column (40-63 μm,60g,24g,40g,120g or other specifications) pre-filled by Santai in Changzhou.

Known starting materials in this disclosure can be synthesized using or according to methods known in the art, or can be purchased from companies such as Shanghai Tantan technology, ABCR GmbH & Co. KG, acros Organics, aldrich Chemical Company, shao Yuan Chemical technology (Accela ChemBio Inc), biddy medicine, and the like.

In the examples, the reactions were all carried out under a nitrogen atmosphere without specific indication.

The nitrogen atmosphere means that the reaction flask is connected with a nitrogen balloon with a volume of about 1L.

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

The hydrogen was produced by QPH-1L model hydrogen generator, shanghai Quanpu scientific instruments.

The nitrogen atmosphere or the hydrogen atmosphere is usually evacuated, and nitrogen or hydrogen is charged, and the operation is repeated 3 times.

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

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

The monitoring of the reaction progress in the examples employs Thin Layer Chromatography (TLC), a developing agent used for the reaction, an eluent system for column chromatography used for purifying a compound, and a developing agent system for thin layer chromatography, and the volume ratio of a solvent is adjusted according to the polarity of the compound, and may also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.

Example 1

Step 1) Compound 1a (25.00g, 157.14mmol) was dissolved in absolute ethanol (300 mL), thionyl chloride (25.00mL, 344.63mmol) was added dropwise at 0 ℃ and stirred at 70 ℃ for 12 hours. Concentrated under reduced pressure, dichloromethane (100mL X2) dissolved, and concentrated under reduced pressure to give crude compound 1b.

LCMS:m/z＝188.2(M+H) ⁺ 。

Step 2) Compound 1b (60.00g, 256.48mmol) was dissolved in ethanol (200 mL), sodium borohydride (15.00g, 396.51mmol) was added at 0 deg.C, and the mixture was allowed to warm to room temperature and stirred for 12 hours. The temperature is reduced to 0 ℃, saturated ammonium chloride solution (100 ml) is quenched, and ethyl acetate (200mL X3) is extracted. The organic phase was washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 1c.

LCMS:m/z＝146.2(M+H) ⁺ 。

Step 3) Compound 1c (5.00g, 34.48mmol) was dissolved in dichloromethane (50 mL), thionyl chloride (5.00ml, 68.92mmol) was added dropwise in an ice bath, replaced with nitrogen three times, and stirred at room temperature for 1 hour. Concentrated under reduced pressure, dichloromethane (50mL X2) dissolved, concentrated under reduced pressure to give compound 1d.

LCMS:m/z＝164.1(M+H) ⁺ 。

Step 4) Compound 1e (50.00g, 351.74mmol) was added to tetrahydrofuran (1L) with nitrogen substitution three times, lithium bistrimethylsilyl amine (351.74mL, 351.74mmol, 1.0M) was added dropwise at-78 deg.C and stirred for 1 hour. Acetyl chloride (15.00mL, 211.05mmol) was slowly added dropwise and stirred at 78 deg.C for 1 hour. Quenched by slowly adding 1N hydrochloric acid (500 mL) and extracted with ethyl acetate (500mL X3). Washing the organic phase with brine (100mL X3), drying over anhydrous sodium sulfate, concentrating under reduced pressure, and subjecting the residue to column chromatography (SiO) ₂ Petroleum ether/ethyl acetate) to give compound 1f.

LCMS:m/z＝185.1(M+H) ⁺ 。

Step 5) Compound 1f (46.50g, 252.47mmol) was dissolved in dioxane (200 mL), and 2-chloro-5-methyl-4-aminopyridine (24.00g, 168.32mmol) was added and the mixture was replaced with nitrogen three times and reacted at 100 ℃ for 3 hours. Concentrated sulfuric acid (26.92mL, 504.94mmol) was added dropwise thereto, and the reaction was carried out at 90 ℃ for 0.5 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was slurried with water for 0.5 hour, filtered and dried to give 1g of the compound.

LC-MS:m/z＝251.2(M+H) ⁺ 。

Step 6) Compound 1g (15.00g, 59.84mmol) was dissolved in N, N-dimethylformamide (200 mL), and to the reaction solution were added compound 1d (11.74g, 71.80mmol), 18-crown-6 (0.32g, 1.20mmol) and potassium carbonate (24.81g, 179.51mmol), and the mixture was replaced with nitrogen three times, and stirred at 60 ℃ overnight. The reaction was cooled to room temperature, water (200 mL) was added, and extraction was performed with ethyl acetate (200mL X2). Washing the organic phase with water (200mL X2), drying, concentrating under reduced pressure, and subjecting the residue to column chromatography (SiO) ₂ Petroleum ether/ethyl acetate) to give compound 1h.

LC-MS:m/z＝378.1(M+H) ⁺ 。

Step 7) Compound 1h (15.00g, 39.71mmol), tributyl (1-ethoxyvinyl) tin (43.02g, 119.12mmol) and bis (triphenylphosphine) palladium dichloride (27.87g, 39.71mmol) were added to dioxane (200 mL) and replaced with nitrogen three times, stirred at 110 ℃ overnight. Quenched by adding saturated aqueous potassium fluoride (200 mL) and extracted with ethyl acetate (200mL X3). The organic phase was dried and concentrated under reduced pressure to give compound 1i.

LC-MS:m/z＝414.3(M+H) ⁺ 。

Step 8) Compound 1i (14.70g, 35.56mmol) was dissolved in tetrahydrofuran (100 mL), 20% hydrochloric acid (17.71mL, 106.67mmol) was added dropwise, and stirred at room temperature for two hours. Adjusting the pH value of the saturated sodium carbonate solution to 8-9, and extracting with ethyl acetate (200mL X3). Drying the organic phase, concentrating under reduced pressure, and subjecting the residue to column chromatography (SiO) ₂ Petroleum ether/ethyl acetate) to give compound 1j.

LC-MS:m/z＝386.2(M+H) ⁺ 。

Step 9) Compound 1j (13.00g, 33.73mmol) was dissolved in isopropanol (200 mL), N-chlorosuccinimide (4.95g, 37.11mmol) and dichloroacetic acid (0.09g, 0.68mmol) were added, nitrogen was substituted three times, and reaction was carried out at 60 ℃ for 1.5 hours. Cooling the reaction solution to room temperature, concentrating under reduced pressure, and subjecting the residue to column chromatography (SiO) ₂ Petroleum ether/ethyl acetate) to give compound 1k.

LC-MS:m/z＝420.1(M+H) ⁺ 。

Step 10) Compound 1k (150mg, 0.36mmol) and N, N-dimethylformamide dimethyl acetal (128mg, 1.07mmol) were dissolved in N, N-dimethylformamide (8 mL), replaced with nitrogen three times, and stirred at 60 ℃ for 3 hours. After that, excess N, N-dimethylformamide dimethyl acetal was removed by vacuum, potassium carbonate (148mg, 1.07mmol) and cyclopropylformamidine hydrochloride (86mg, 0.72mmol) were added to the reaction solution, and the mixture was stirred at 80 ℃ for 5 hours. The reaction mixture was cooled to room temperature, water (30 mL) was added, and extraction was performed with ethyl acetate (20mL X3). The organic phase was dried and concentrated under reduced pressure, and the residue was subjected to prep-HPLC (C18, acetonitrile/water (ammonium bicarbonate)) to give a mixture of enantiomers, which was subjected to chiral resolution to give compound 1-1 and compound 1-2.

Compound 1-1:

LC-MS:m/z＝496.0(M+H) ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ8.72(s,1H),8.70(d,J＝5.2Hz,1H),8.41(d,J＝2.4Hz,1H),8.22(s,1H),8.09(d,J＝5.2Hz,1H),7.37–7.29(m,1H),6.41(s,1H),5.42(d,J＝1.6Hz,2H),2.33–2.25(m,1H),2.17(s,3H),1.99(s,3H),1.21–1.15(m,2H),1.12–1.05(m,2H).

compounds 1-2:

LC-MS:m/z＝496.0(M+H) ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ8.72(s,1H),8.70(d,J＝5.2Hz,1H),8.41(d,J＝2.4Hz,1H),8.22(s,1H),8.09(d,J＝5.2Hz,1H),7.37–7.29(m,1H),6.41(s,1H),5.43(d,J＝1.6Hz,2H),2.32–2.25(m,1H),2.18(s,3H),1.99(s,3H),1.21–1.15(m,2H),1.11–1.05(m,2H).

example 2

Compounds 2-1 and 2-2 were synthesized according to the procedure of example 1, starting from cyclobutylformamidine hydrochloride.

Compound 2-1:

LC-MS:m/z＝510.0(M+H) ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ8.82(d,J＝5.2Hz,1H),8.74(s,1H),8.41(d,J＝2.4Hz,1H),8.32(s,1H),8.16(d,J＝5.2Hz,1H),7.38–7.29(m,1H),6.43(s,1H),5.43(d,J＝1.6Hz,2H),3.89–2.79(m,1H),2.47–2.41(m,2H),2.40–2.34(m,2H),2.18(s,3H),2.17–2.01(m,1H),1.99(s,3H),1.98–1.92(m,1H).

compound 2-2:

LC-MS:m/z＝510.0(M+H) ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ8.82(d,J＝5.2Hz,1H),8.74(s,1H),8.41(d,J＝2.4Hz,1H),8.32(s,1H),8.16(d,J＝5.2Hz,1H),7.38–7.29(m,1H),6.43(s,1H),5.43(d,J＝1.6Hz,2H),3.89–2.79(m,1H),2.51–2.43(m,2H),2.42–2.34(m,2H),2.18(s,3H),2.17–2.01(m,1H),1.99(s,3H),1.98–1.92(m,1H).

example 3

Compound 3 was synthesized according to the procedure of example 1, using tetrahydrofuran-2-formamidine hydrochloride as a starting material.

LC-MS:m/z＝526.1(M+H) ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ8.86(dd,J＝14.4,5.2Hz,1H),8.72(s,1H),8.40(d,J＝2.0Hz,1H),8.28(d,J＝6.0Hz,1H),8.24(dd,J＝5.2,2.6Hz,1H),7.33(td,J＝9.2,2.3Hz,1H),6.40(s,1H),5.42(d,J＝1.6Hz,2H),5.18–5.10(m,1H),4.26–4.17(m,1H),4.07–3.98(m,1H),2.47–2.36(m,1H),2.22–2.18(m,1H),2.18(s,3H),2.15–2.00(m,2H),1.99(s,3H).

Example 4

Step 1) methanol (14 mL) and methyl tert-butyl ether (40 mL) were mixed, nitrogen was replaced, the temperature was reduced to 0 ℃ and acetyl chloride (16.00mL, 225.02mmol) was slowly added dropwise. After returning to room temperature, a hydrogen chloride-methanol solution (7.30mL, 21.90mmol, 3.0M) was added, and a solution of compound 4a (4.70g, 21.74mmol) in methyl t-butyl ether (10 mL) and methanol (2 mL) was slowly added, and the mixture was stirred at room temperature overnight. Filtration and washing with methyl tert-butyl ether (50 mL) collected the filter cake and dried in vacuo to give compound 4b.

LCMS:m/z＝249.2(M+H) ⁺ 。

Step 2) Compound 4b (4.00g, 16.11mmol) was dissolved in methanol (20 mL) with nitrogen being replaced, and the solution was stirred at room temperature overnight with ammonia-methanol (4.00mL, 28.00mmol, 7.0M). The solvent was evaporated under reduced pressure, tetrahydrofuran (15 mL) was added, and after concentration under reduced pressure to about half the volume, the mixture was cooled to room temperature and allowed to stand for 2 hours, whereupon a white solid precipitated. Filtration and washing of the filter cake with tetrahydrofuran (15 mL) collected the solid to give compound 4c.

LC-MS:m/z＝234.2(M+H) ⁺ 。

Step 3) Compound 4c (7.00g, 30.01mmol) was dissolved in methanol (70 mL) and hydrogen chloride-methanol solution (0.60mL, 1.80mmol, 3.0M) and 10% palladium on carbon (0.70g, 6.58mmol) were added. After replacement of hydrogen, the mixture was stirred at room temperature overnight. Filtration over celite, washing with methanol (25 mL), collection of the filtrate, and concentration under reduced pressure afforded compound 4d.

LC-MS:m/z＝100.1(M+H) ⁺ 。

Step 4) Synthesis of Compounds 4-1 and 4-2 Using Compound 4d as the starting Material, according to the method of example 1.

Compound 4-1:

LC-MS:m/z＝511.3(M+H) ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ8.88(d,J＝5.2Hz,1H),8.85(s,1H),8.61(d,J＝2.2Hz,1H),8.55(s,1H),8.18–8.14(m,1H),8.10(dd,J＝14.0,4.7Hz,1H),6.83(s,1H),5.49(s,2H),2.10(s,3H),1.97(s,3H),1.47–1.41(m,1H),1.39–1.33(m,1H),1.15–1.09(m,2H).

compound 4-2:

LC-MS:m/z＝511.3(M+H) ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ8.88(d,J＝5.2Hz,1H),8.85(s,1H),8.61(d,J＝2.2Hz,1H),8.55(s,1H),8.15–8.05(m,2H),6.83(s,1H),5.49(s,2H),2.10(s,3H),1.97(s,3H),1.47–1.41(m,1H),1.37–1.31(m,1H),1.14–1.08(m,2H).

example 5

Step 1) Compound 5a (9.00g, 56.57mmol) was dissolved in methanol (50 mL) under ice bath, thionyl chloride (6.16mL, 84.86mmol) was added, nitrogen was replaced, and reaction was carried out at 60 ℃ for 3 hours. Concentrated under reduced pressure, the residue quenched with saturated aqueous sodium bicarbonate (50 mL), extracted with ethyl acetate (30mL X2), the organic phase dried, filtered, and concentrated under reduced pressure to give crude compound 5b.

LCMS:m/z＝174.0(M+H) ⁺ 。

Step 2) Compound 5b (4.50g, 25.99mmol) and calcium chloride (11.52g, 103.96mmol) were added to a mixture of deuterated methanol (50 mL) and tetrahydrofuran (50 mL) at room temperature, cooled to 0 deg.C, and sodium borodeuteride (3.24g, 77.97mmol) was added to displace nitrogen and reacted at 55 deg.C for 2 hours. Cool to room temperature, add ethyl acetate (100 mL), filter off insoluble material on celite, and concentrate the filtrate under reduced pressure. The residue was quenched with heavy water (10 mL), extracted with ethyl acetate (30mL X2), the organic phase was dried, filtered, and concentrated under reduced pressureConcentrating, and subjecting the residue to column chromatography (SiO) ₂ Petroleum ether/ethyl acetate) to yield compound 5c.

LC-MS:m/z＝148.1(M+H) ⁺ 。

Step 3) Compound 5c (730mg, 4.96mmol) and N, N-dimethylformamide (0.01mL, 0.13mmol) were dissolved in dichloromethane (20 mL) under ice bath, thionyl chloride (0.72mL, 9.92mmol) was added dropwise, and the mixture was replaced with nitrogen three times, and then the mixture was naturally warmed to room temperature and stirred for 5 hours. Concentration under reduced pressure, dichloromethane dissolution, concentration under reduced pressure (30mL X2) afforded crude compound 5d.

LC-MS:m/z＝166.1(M+H) ⁺ 。

Step 4) Compound 1k (2.00g, 4.76mmol) was dissolved in concentrated hydrochloric acid (40mL, 478.99mmol) at room temperature and stirred under nitrogen at 120 ℃ for 48 hours. Concentration under reduced pressure, adjusting the pH of the residue to 8 with a saturated sodium bicarbonate solution, concentration under reduced pressure, washing the residue with dichloromethane/methanol (4) ₂ Dichloromethane/methanol) to yield compound 5e.

LC-MS:m/z＝293.2(M+H) ⁺ 。

Step 5) Compound 5e (930mg, 3.18mmol) and Compound 5d (789.05mg, 4.77mmol) were dissolved in N, N-dimethylformamide (20 mL) at room temperature, and potassium carbonate (2.20g, 15.89mmol) was added thereto, and the mixture was purged with nitrogen three times and stirred at 60 ℃ for 18 hours. Water (100 mL) was added, extracted with ethyl acetate (30mL X2), the organic phase was dried, filtered and concentrated under reduced pressure. The residue is subjected to column chromatography (SiO) ₂ Dichloromethane/methanol) to yield compound 5f.

LC-MS:m/z＝422.4(M+H) ⁺ 。

Step 6) Synthesis of Compound 5 with Compound 5f as the starting material, according to the method of example 1.

LC-MS:m/z＝513.2(M+H) ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ8.88–8.84(m,2H),8.61(d,J＝2.4Hz,1H),8.55(s,1H),8.19(s,1H),8.13(d,J＝5.2Hz,1H),8.12–8.06(m,1H),6.83(s,1H),2.10(s,3H),1.97(s,3H),1.40(dt,J＝9.2,6.1Hz,2H),1.13(d,J＝3.6Hz,2H).

Example 6

Step 1) sodium hydride (0.31g, 12.92mmol, 60%) was slowly added to N-N-dimethylformamide (15 mL) under ice bath, followed by addition of compound 6a (1.00g, 8.61mmol), stirring at 0 ℃ for 10 minutes, addition of benzyl bromide (2.21g, 12.92mmol), and stirring at room temperature overnight. The reaction mixture was added to ice water (50 mL), ethyl acetate (50mL X2) was added for extraction, the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (SiO) ₂ Petroleum ether/ethyl acetate) to yield compound 6b.

LCMS:m/z＝207.1(M+H) ⁺ 。

Step 2) ammonium chloride (584mg, 10.90mmol) was added to toluene (5 mL) at room temperature, argon was replaced, the temperature was lowered to 0 ℃ and trimethylaluminum in toluene (6.80mL, 1.6M, 10.9mmol) was added dropwise, after the dropwise addition was completed, the mixture was stirred at room temperature until no gas was released from the system, and then compound 6b (450mg, 2.18mmol) was added and stirred at 80 ℃ overnight. Cooled to room temperature, methanol (5 mL) was added, cooled to 0 ℃ and stirred for 1 hour. Filtration and cake rinsing with a small amount of methanol, collection of the filtrate, concentration and purification by prep-HPLC (C18, acetonitrile/water (formic acid)) gave compound 6C.

LC-MS:m/z＝191.1(M+H) ⁺ 。

Step 3) Compound 1g (6.00g, 23.90mmol), potassium carbonate (9.92g, 71.80mmol), 4-methoxybenzyl chloride (4.50g, 28.70mmol), and 18-crown-6 (0.06g, 0.24mmol) was added to N, N-dimethylformamide (80 mL) at room temperature. Stirred at room temperature overnight under nitrogen. Quenched with water (50 mL) and extracted with ethyl acetate (20mL X3). Concentrating, and subjecting the residue to column chromatography (SiO) ₂ Petroleum ether/ethyl acetate) to yield compound 6d.

LC-MS:m/z＝371.2(M+H) ⁺ 。

Step 4) at room temperature, compound 6d (2.00g, 5.39mmol), dioxane (8 mL), palladium (40mg, 0.054mmol) and tributyl (1-ethoxyethylene) tin (6 mL, 17.76mmol) were added in this order and placedThe mixture was stirred overnight at 110 ℃ with nitrogen exchange. To the reaction mixture was added a saturated potassium fluoride solution, and the mixture was stirred for 30 minutes (solid was formed), and the solid was removed by filtration, and the filtrate was concentrated under reduced pressure, and tetrahydrofuran (10 ml) and 1N hydrochloric acid (10 ml) were added. After two hours of reaction, the reaction mixture was adjusted to pH 7, water (10 ml) was added, and extraction was performed with ethyl acetate (5ml. Times.3). Concentrating under reduced pressure, and performing column chromatography (SiO) on the residue ₂ Petroleum ether/ethyl acetate) to yield compound 6e.

LC-MS:m/z＝379.2(M+H) ⁺ 。

Step 5) Compound 6e (1.50g, 3.96mmol) was dissolved in N-N-dimethylformamide (10 mL) at room temperature, and N-N-dimethylformamide dimethyl acetal (1.42mg, 11.89mmol) was replaced with nitrogen three times and reacted at 80 ℃ for 2 hours. The mixture was concentrated under reduced pressure, and the mixture was added to N-N-dimethylformamide (10 mL), compound 6c (3.77g, 19.82mmol), potassium carbonate (2.19g, 15.86mmol), and the mixture was reacted for 16 hours at 80 ℃ with nitrogen substitution three times. Filtering, adding water (40 mL) into the filtrate, extracting with ethyl acetate (40mL X3), drying the organic phase, filtering, concentrating under reduced pressure, and subjecting the residue to column chromatography (SiO) ₂ Dichloromethane/methanol) to yield compound 6f.

LC-MS:m/z＝561.3(M+H) ⁺ 。

Step 6) Compound 6f (690mg, 1.23mmol) was dissolved in trifluoroacetic acid (5 mL) at room temperature and reacted at 50 ℃ for 24 hours. Concentrating under reduced pressure, and performing column chromatography (SiO) on the residue ₂ Dichloromethane/methanol) to yield 6g of compound.

LC-MS:m/z＝351.0(M+H) ⁺ 。

Step 7) Compound 6g (130mg, 0.37mmol) was dissolved in N, N-dimethylformamide (3 mL) at room temperature, and cesium carbonate (1.21g, 3.71mmol) was added and stirred at room temperature for 10 minutes. Subsequently, a solution of compound 5d (185mg, 1.11mmol) in N, N-dimethylformamide was added dropwise thereto, and the mixture was stirred at room temperature for 1 hour. Filtering, adding water (50 mL) into the filtrate, extracting with ethyl acetate (50mL X3), drying the organic phase, filtering, concentrating under reduced pressure, and performing column chromatography (SiO) on the residue ₂ Dichloromethane/methanol) to obtain the compound for 6h.

LC-MS:m/z＝480.1(M+H) ⁺ 。

Step 8) Compound 6h (40mg, 0.083mmol) was dissolved in isopropanol (3 mL) at room temperature, N-chlorosuccinimide (10.03mg, 0.075mmol) was added, nitrogen was replaced, and stirring was carried out at 60 ℃ for 10 minutes. Dichloroacetic acid (1.08mg, 0.008mmol) was added thereto, and the reaction was carried out at 60 ℃ for 1 hour. Filtration and concentration under reduced pressure and purification of the residue by prep-HPLC (C18, acetonitrile/water (formic acid)) gave compound 6.

LC-MS:m/z＝514.2(M+H) ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ8.90–8.83(m,2H),8.62–8.54(m,2H),8.16–8.06(m,2H),6.84(s,1H),6.04(s,1H),2.11(s,3H),1.98(s,3H),1.42–1.32(m,2H),1.24–1.16(m,2H).

Example 7

Using tetrahydropyran-4-carboxamidine hydrochloride as a starting material, compounds 7-1 and 7-2 were synthesized in the same manner as in example 1.

Compound 7-1:

LC-MS:m/z＝540.2(M+H) ⁺ 。

¹ H NMR(400MHz,DMSO-d6)δ8.94(d,J＝5.2Hz,1H),8.86(s,1H),8.61(s,1H),8.36(s,1H),8.21(d,J＝5.2Hz,1H),8.13–8.04(m,1H),6.82(s,1H),5.49(s,2H),3.97-3.94(m,2H),3.47(brs,2H),3.15(dd,J＝9.6,5.6Hz,1H),2.10(s,3H),1.97(s,3H),1.88(ddd,J＝25.2,14.8,8.0Hz,4H).

compound 7-2:

LC-MS:m/z＝540.1(M+H) ⁺ 。

¹ H NMR(400MHz,DMSO-d6)δ8.94(d,J＝4.8Hz,1H),8.86(s,1H),8.61(s,1H),8.37(s,1H),8.21(d,J＝4.8Hz,1H),8.14–8.03(m,1H),6.82(s,1H),5.49(s,2H),3.99–3.93(m,2H),3.47(bs,2H),3.17–3.08(m,1H),2.10(s,3H),1.97(s,3H),1.95–1.85(m,4H).

example 8

Step 1) Compound 8a (200mg, 1.03mmol) and N, N-dimethylformamide (0.002mL, 0.027mmol) were dissolved in dichloromethane (2 mL) under ice bath, thionyl chloride (0.2mL, 2.757mmol) was added, nitrogen was replaced, and stirring was carried out at 0 ℃ for 30 minutes. Concentration under reduced pressure, dichloromethane dissolution, concentration under reduced pressure (30mL X2) afforded crude compound 8b.

LCMS:m/z＝213.0(M+H) ⁺ 。

Step 2) Compound 6g (350mg, 1.00mmol) was dissolved in N, N-dimethylformamide (4 mL) at room temperature, and cesium carbonate (1.05g, 3.22mmol) was added and stirred at 60 ℃ for 10 minutes. Compound 8b (319mg, 1.50mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours. Filtering, adding water (50 mL) into the filtrate, extracting with ethyl acetate (50mL X3), drying the organic phase, filtering, concentrating under reduced pressure, and performing column chromatography (SiO) on the residue ₂ Dichloromethane/methanol) to give compound 8c.

LC-MS:m/z＝527.3(M+H) ⁺ 。

Step 3) Compound 8c (100mg, 0.19mmol) was dissolved in isopropanol (2 mL) at room temperature, N-bromosuccinimide (41mg, 0.23mmol) was added, nitrogen was replaced, and the mixture was heated to 60 ℃ and stirred for 1 hour. Concentration under reduced pressure and purification of the residue by prep-HPLC (C18, acetonitrile/water (formic acid)) gave compound 8.

LC-MS:m/z＝605.2(M+H) ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ8.92–8.82(m,2H),8.56(s,1H),8.15(d,J＝5.12Hz,1H),8.11(d,J＝4.72Hz,1H),7.91(s,1H),7.59(t,J＝9.12Hz,1H),6.86(s,1H),5.50(s,2H),2.10(s,3H),1.99(s,3H),1.44–1.30(m,2H),1.19(t,J＝7.12Hz,2H).

Example 9

Step 1) Compound 8c (100mg, 0.19mmol) was dissolved in isopropanol (2 mL) at room temperature, N-chlorosuccinimide (30mg, 0.225mmol) and dichloroacetic acid (1mg, 0.008mmol) were added, nitrogen was replaced, and the mixture was heated to 60 ℃ and stirred for 1 hour. Concentrated under reduced pressure and the residue purified by prep-HPLC (C18, acetonitrile/water (formic acid)) to give compound 9.

LC-MS:m/z＝561.2(M+H) ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ8.92–8.81(m,2H),8.57(s,1H),8.15(d,J＝5.12Hz,1H),8.09(d,J＝4.4Hz,1H),7.92(s,1H),7.59(t,J＝9.2Hz,1H),6.89(s,1H),6.05(s,1H),5.50(s,2H),2.11(s,3H),2.00(s,3H),1.45–1.30(m,2H),1.19(t,J＝6.72Hz,2H).

Example 10

Step 1) Compound 10a (163mg, 1.12mmol) was dissolved in dichloromethane (2 mL) at room temperature, thionyl chloride (270mg, 2.27mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour while replacing nitrogen. Concentration under reduced pressure, dichloromethane dissolution, concentration under reduced pressure (30mL X2) afforded crude compound 10b.

LCMS:m/z＝164.0(M+H) ⁺ 。

Step 2) Compound 6g (100mg, 0.28mmol) was dissolved in N, N-dimethylformamide (3 mL) at room temperature, and cesium carbonate (930mg, 2.84mmol) was added and stirred at room temperature for 10 minutes. Compound 10b (140mg, 0.85mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. Filtering, adding water (50 mL) into the filtrate, extracting with ethyl acetate (50mL X3), drying the organic phase, filtering, concentrating under reduced pressure, and performing column chromatography (SiO) on the residue ₂ Dichloromethane/methanol) to give compound 10c.

LC-MS:m/z＝478.2(M+H) ⁺ 。

Step 3) Compound 10c (60mg, 0.13mmol) was dissolved in isopropanol (4 mL) at room temperature, N-chlorosuccinimide (15.10mg, 0.11mmol) was added thereto, nitrogen gas was replaced, and the mixture was stirred at 60 ℃ for 10 minutes. Dichloroacetic acid (1mg, 0.008mmol) was added thereto, and the mixture was stirred at 60 ℃ for 1 hour. Concentrated under reduced pressure and the residue purified by prep-HPLC (C18, acetonitrile/water (formic acid)) to give compound 10.

LC-MS:m/z＝512.2(M+H) ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ8.91–8.81(m,2H),8.63–8.54(m,2H),8.18–8.05(m,2H),6.84(s,1H),6.04(s,1H),5.50(s,2H),2.11(s,3H),1.98(s,3H),1.42–1.15(m,4H).

Example 11

Step 1) Compound 10c (40mg, 0.084mmol) was dissolved in isopropanol (3 mL) at room temperature, N-bromosuccinimide (13.42mg, 0.075mmol) was added, nitrogen was replaced, and the mixture was stirred at 60 ℃ for 10 minutes. Dichloroacetic acid (1.08mg, 0.008mmol) was added and stirred at 60 ℃ for 1 hour. Concentration under reduced pressure and purification of the residue by prep-HPLC (C18, acetonitrile/water (formic acid)) affords compound 11.

LC-MS:m/z＝556.0(M+H) ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ8.91–8.82(m,2H),8.63–8.52(m,2H),8.17–8.04(m,2H),6.80(s,1H),6.05(s,1H),5.49(s,2H),2.11(s,3H),1.97(s,3H),1.43–

1.30(m,2H),1.24–1.12(m,2H).

Biological evaluation

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

Structure of reference Compound A

Compound A is prepared by the process disclosed in patent application CN105263326B, example 49 on page 33

Test example 1: in vitro p38a-MK2 cascade reaction enzyme activity detection experiment

1. Experimental Material

2. Experimental procedure

In vitro p38a-MK2 kinase activity was tested by the method of Mobility Shift Assay. In the experiment, the test starting concentration of the test compound for inhibition of p38a-MK2 activity was 10000nM, 3-fold diluted, 10 concentrations in total, and the test was repeated in wells. Compound a was used as a standard control.

1-fold kinase buffer (50mM HEPES, pH 7.5,0.0015% Brij-35) and stop buffer (100mM HEPES, pH 7.5,0.015% Brij-35,0.2% Coating Reagent #3,50mM EDTA) were prepared. Adding a proper amount of kinase (active p38a and inactive MK 2) into a 1-time kinase buffer solution to prepare a 2.5-time enzyme solution; preparing 5-fold dilutions of the compounds (1-fold kinase buffer, 10% dmso) corresponding to the test concentrations of the compounds; adding a proper amount of FAM-labeled polypeptide and ATP into 1-time kinase buffer solution to prepare 2.5-time substrate solution. Adding 5 mul of 5 times compound diluent and 10 mul of 2.5 times enzyme solution into reaction holes of a 384-hole reaction plate, uniformly mixing, and incubating for 10 minutes at room temperature; then 10. Mu.l of 2.5 fold substrate solution was added to the 384-well plate and centrifuged at 1000rpm for 1 minute; the reaction plate was incubated at 28 ℃ for 60 min; adding 25. Mu.l of stop solution to a 384-well reaction plate to terminate the reaction, and centrifuging at 1000rpm for 1 minute; and finally reading the conversion rate data on a Caliper EZ Reader II.

IC50 values for compounds were fitted with XLFit excel add-in version 5.4.0.8. Fitting formula:

Y＝Bottom+(Top-Bottom)/(1+(IC50/X)^HillSlope)。

biochemical inhibition Activity of P38a-MK2 kinase for Compounds of the disclosure the IC determined by the above assay ₅₀ The values are shown in Table 1. IC for p38a-MK2 kinase inhibition by the compounds of the disclosure ₅₀ The value is obtained.

TABLE 1

Compound number	P38/MK2 IC ₅₀ (nM)	Compound numbering	P38/MK2 IC ₅₀ (nM)
				Compound A	25	1-1	4339
1-2	8.3	2-1	7455
				2-2	8.7	3	34
4-1	12	4-2	1982
				5	240	6	11
7-1	11	7-2	9720
				8	9.21	9	11.31
10	6.2	11	5

Note: N/A not detected

And (4) conclusion: the disclosed compound p38a-MK2 kinase has good inhibitory activity.

Test example 2: in vitro detection of cytokines by PBMC cells

1. Experimental Material

Name(s)	Brand	Goods number/model
			Frozen PBMCs	HemaCare	PB009C-2
RPMI Medium 1640	Gibco	11875093
			FBS	Biological Industries	04-002-1A
Penicillin-Streptomycin(P/S)	Gibco	15140122
			PBS	Biosera	LM-S2041/500
LPS	Sigma	L2880
			CellTiter Glo	Promega	G7573
96-well Flat Bottom Microplate	Corning	3903
			Human TNF-αDuoset ELISA	R&D	DY210

2. Experimental procedure

In vitro PBMC cell assay cytokine assays were tested by LPS-induced cell production of the cytokine TNF-. Alpha.. In the experiment, the test starting concentration of the test compound was 10000nM, 3-fold diluted, 9 concentrations in total, and the test was repeated in wells.

PBMC cells were collected and cell counts and viability calculations were performed. 0.2million PBMC/0.1mL/well were seeded into 96-well plates. Compound and LPS dilution were prepared. Mu.l of compound diluent and 50. Mu.l of LPS diluent (final concentration 0.1 ng/ml) were added to each well at 37 ℃ with 5% CO ₂ Incubate for 24 hours. The normal control group replaced compound diluent with DMSO, and the experimental control group replaced LPS diluent with culture medium.

Collect 120. Mu.l of supernatant. The concentration of TNF-. Alpha.in the samples was tested using ELISA kits.

Add 80. Mu.L to each well

Reagent, detecting cell activity.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt or isotopic substitute thereof

R ³ selected from hydrogen, halogen, hydroxy, cyano, amino, C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkylSaid alkyl, alkoxy, cycloalkyl or heterocycloalkyl group being optionally substituted by one or more R ^3A Substituted, R ^3A Each independently selected from halogen, hydroxy, oxo, nitro, cyano or amino;

R ⁴ selected from hydrogen, halogen, hydroxy, cyano, amino, C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl optionally substituted with one or more R ^4A Substituted, R ^4A Each independently selected from halogen, hydroxy, oxo, nitro, cyano or amino;

R ⁶ 、R ⁷ each independently selected from hydrogen, halogen, hydroxy, amino, C _1-6 Alkyl or C _1-6 An alkoxy group;

x and Y are each selected from N or-CR ⁸ And X and Y are not both N;

R ⁸ selected from hydrogen, halogen, C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy being optionally substituted with one or more halogen, hydroxy or amino groups;

R ⁹ 、R ¹⁰ each independently selected from hydrogen, halogen, hydroxy, cyano, amino, C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy being optionally substituted with one or more halogen, hydroxy or amino groups;

z is selected from N or-CR ¹¹ -，R ¹¹ Selected from hydrogen, halogen, C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy being optionally substituted with one or more halogen, hydroxy or amino;

m is an integer of 0 to 4.

2. The compound of claim 1, or a pharmaceutically acceptable salt or isotopic substituent thereof, wherein R ¹ Selected from halogen, preferably fluorine or chlorine; or R ¹ Is selected from C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy being optionally substituted by one or more R ^1A And (4) substitution. R ² Is selected from-OR ^2a Wherein R is ^2a Selected from hydrogen or C _1-6 An alkyl group optionally substituted with one or more R ^2A Substituted, R ^2A As defined in claim 1; or R ^2a Selected from 3 to 6 membered cycloalkyl or 3 to 6 membered heterocycloalkyl, said cycloalkyl or heteroalkyl optionally substituted with one or more R ^2A And (4) substitution. R ³ Selected from hydrogen, halogen, hydroxy, cyano or amino, preferably hydrogen; or R ³ Is selected from C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 6-membered cycloalkyl or 3-to 6-membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl optionally substituted with one or more R ^3A And (4) substituting. R ⁴ Selected from hydrogen, halogen, hydroxy, cyano or amino; or R ⁴ Is selected from C _1-6 Alkyl or C _1-6 Alkoxy, preferably C _1-6 Alkyl radicals, such as the methyl, ethyl and propyl radicals, and furthermore, the radicals R ⁴ Optionally substituted by one or more R ^4A Substituted, R ^4A As defined in claim 1; or R ⁴ Selected from 3 to 6 membered cycloalkyl or 3 to 6 membered heterocycloalkyl, said cycloalkyl or heterocycloalkyl optionally substituted with one or more R ^4A And (4) substitution. R is ^1A 、R ^2A 、R ^3A 、R ^4A As defined in claim 1.

3. The compound according to any one of claims 1-2, or a pharmaceutically acceptable salt or isotopic substituent thereof, wherein X is selected from N and Y is selected from CR ⁸ -，R ⁸ Selected from hydrogen, Z is selected from N; or Z is selected from-CR ¹¹ -，R ¹¹ Selected from hydrogen.

4. A compound according to claims 1-3 or a pharmaceutically acceptable salt or salt thereofIsotopically substituted versions thereof, wherein R ² Is selected from-SR ^2a Wherein R is ^2a Selected from hydrogen or C _1-6 An alkyl group optionally substituted with one or more R ^2A Substituted, R ^2A As defined in claim 1; r ² Selected from 3 to 6 membered cycloalkyl or 3 to 6 membered heterocycloalkyl, said cycloalkyl or heteroalkyl optionally substituted with one or more R ^2A Substituted, R ^2A As defined in claim 1.

5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt or isotopic substituent thereof, wherein the compound of formula I is

Wherein R is ¹² 、R ¹³ Each independently selected from hydrogen, deuterium, halogen, hydroxy, amino, C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy being optionally substituted by one or more halogen, hydroxy, amino, C _1-6 Alkyl or C _1-6 Alkoxy substituted;

or, R ¹² 、R ¹³ Oxo (= O) with an adjacent carbon atom;

n is an integer of 0 to 3;

p is an integer between 1 and 3;

R ¹ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁹ 、R ¹⁰ z and m are defined as in claim 1.

6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt or isotopic substituent thereof, wherein R ⁶ Selected from hydrogen; or R ⁶ Selected from halogen, hydroxyl, amino; or R ⁶ Is selected from C _1-6 Alkyl or C _1-6 An alkoxy group; such as methyl, ethyl, methoxy or ethoxy. Wherein R is ⁷ Selected from hydrogen; or R ⁷ Selected from halogen, hydroxyl, amino; or R ⁷ Is selected from C _1-6 Alkyl or C _1-6 Alkoxy groups, such as methyl, ethyl, methoxy or ethoxy. Wherein R is ⁹ 、R ¹⁰ Each independently selected from hydrogen; or R ⁹ 、R ¹⁰ Each independently selected from halogen, hydroxy, amino; or R ⁹ 、R ¹⁰ Each independently selected from C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy being optionally substituted with one or more halogen, hydroxy or amino groups. Wherein R is ¹⁴ Each independently selected from halogen, C _1-6 Alkyl or C _1-6 Alkoxy, preferably fluorine, chlorine, methyl, ethyl, methoxy or ethoxy.

7. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt or isotopic substituent thereof, wherein p =1,R ¹² 、R ¹³ Form a 3-to 6-membered cycloalkyl group with the adjacent carbon atom, said cycloalkyl group being optionally substituted by 1-3 halogens, C _1-6 Alkyl or C _1-6 Alkoxy is preferred, cyclopropyl and cyclobutyl are preferred. Wherein R is ¹² 、R ¹³ Each independently selected from hydrogen, halogen or C _1-6 Alkyl optionally substituted with 1-3 halogens, hydroxy or amino groups, preferably hydrogen, fluoro, chloro, methyl, ethyl or hydroxyethyl, more preferably hydrogen or fluoro. Wherein R is ⁵ Each independently selected from halogen, hydroxy, amino; or R ⁵ Each independently selected from C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy being optionally substituted by one or more R ^5A Substituted, R ^5A As defined in claim 1.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt or isotopic substituent thereof, wherein ring a is selected from a 3-4 membered carbocyclic ring or a 3-4 membered heterocyclic ring; or ring A is selected from a 5-6 membered carbocyclic ring or a 5-6 membered heterocyclic ring.

9. The compound of claim 1, or a pharmaceutically acceptable salt or isotopic substitution thereof, wherein the compound of formula I is:

10. use of a compound according to any one of claims 1-9, or a pharmaceutically acceptable salt or isotopic substitution thereof, or a pharmaceutical composition of claim 21, in the manufacture of a medicament for the prevention and/or treatment of a condition mediated by MK 2.