CN113583026A

CN113583026A - Compound containing fused tricyclic structure

Info

Publication number: CN113583026A
Application number: CN202010368199.9A
Authority: CN
Inventors: 张汉承; 叶向阳; 程鑫
Original assignee: Hangzhou Innogate Pharma Co Ltd
Current assignee: Hangzhou Innogate Pharma Co Ltd
Priority date: 2020-04-30
Filing date: 2020-04-30
Publication date: 2021-11-02
Also published as: WO2021219100A1

Abstract

The invention provides a compound containing a fused tricyclic structure. Specifically, the invention provides a compound with a structure shown as the following formula (I) (each group is defined as the specification), a pharmaceutical composition containing the compound of the formula (I), the compound, and isotopic derivatives, chiral isomers, variants, different salts, prodrugs, preparations and the like of the compound. The compound of the formula (I) can effectively inhibit protein kinases such as SYK and/or JAK, and the like, thereby playing a role in treating various autoimmune diseases and tumors.

Description

Compound containing fused tricyclic structure

Technical Field

The present invention relates to the field of pharmaceutical chemistry; in particular to a novel fused tricyclic-containing derivative, a synthetic method thereof and application thereof as one or more protein kinase inhibitors in preparing medicaments for treating related diseases such as tumors and the like.

Background

Cancer, also known as malignant tumor, is one of the diseases with the highest morbidity and mortality in the world and is characterized by abnormal proliferation and metastasis of cells, spreading and metastasizing within a short time or relatively short time after the onset of disease. Conventional treatment regimens include resection (if resection conditions are met), radiation therapy, and chemotherapy. The target therapy developed in recent years has the advantages of reducing toxicity and side effects on patients, improving survival rate and the like. However, the target drug will develop drug resistance for a period of time, and then the growth spread of cancer cells will be abnormally rapid. Common cancers are: blood cancer, lung cancer, liver cancer, bladder cancer, rectal cancer, stomach cancer, and the like.

Autoimmune diseases refer to diseases caused by the body's immune reaction to autoantigens, which results in damage to the tissues. Many diseases are listed as autoimmune diseases one after another, and it is worth mentioning that the existence of autoantibodies is not two equivalent concepts to autoimmune diseases, and autoantibodies may exist in normal persons without autoimmune diseases, particularly in the elderly, such as anti-thyroglobulin antibodies, thyroid epithelial cell antibodies, parietal cell antibodies, nuclear DNA antibodies, and the like. Sometimes, damaged or antigenically altered tissue can trigger autoantibody production, e.g., in myocardial ischemia, necrotic myocardium can lead to the formation of anti-myocardial autoantibodies, but such antibodies have no pathogenic effect and are secondary immune responses. The clinical table has the following components: (1) organ-specific autoimmune diseases, such as chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, goodpasture's syndrome, pemphigus vulgaris, pemphigoid, primary biliary cirrhosis, multiple sclerosis, acute idiopathic polyneuritis, etc. (2) Systemic autoimmune diseases, such as lupus erythematosus, rheumatoid arthritis, scleroderma, systemic vasculitis, pemphigus, dermatomyositis, ulcerative colitis, etc.

The spleen tyrosine kinase (SYK) gene was first cloned from pig spleen cDNA in 1991 and encodes an unresponsive protein tyrosine kinase. Human SYK gene is located in chromosome 9 q22 region, SYK protein contains 635 amino acids, and plays an important role in autoimmune diseases and hematological malignancies, for example, SYK gene can inhibit proliferation and metastasis of malignant tumor cells such as breast cancer, melanoma and liver cancer. Currently, SYK inhibitors have been used in phase II/III clinical trials in rheumatoid arthritis, chronic lymphocytic leukemia, and the like. Recent studies have shown that the use of SYK inhibitors or interfering with the expression of the SYK gene can effectively slow down the progression of liver fibrosis/cirrhosis, with a good therapeutic effect (see CN 105664178A).

Janus kinases (JAKs) are cytoplasmic tyrosine kinases that transduce cytokine signals from membrane receptors to STAT transcription factors, also known as Janus kinase-signaling and transcriptional activators (Janus-activated kinase-involved transducers and activators of transcription). This is a newly discovered intracellular signal transduction pathway closely related to cytokines in recent years, and is involved in many important biological processes such as proliferation, differentiation, apoptosis, immunoregulation, and the like of cells. Janus kinase is a non-receptor tyrosine protein kinase. There are 4 family members, JAK1, JAK2, TYK2 and JAK3, respectively. The first 3 are widely present in various tissues and cells, while JAK3 is present only in the bone marrow and lymphatic system. These JAK family members all possess 7 homology domains (JAK homologydomains, JH) in order from C-terminus to N-terminus: JH1 is a kinase domain that functions to encode a kinase protein; JH2 is a kinase-like or "pseudo" kinase domain that modulates the activity of JH 1; JH 3-JH 7 form a four-in-one domain to regulate the binding of JAK and a receptor. Scientific research shows that JAK inhibition can become a promising target of anticancer drugs.

SYK and JAK belong to different signal pathways. The targeting of the two targets by one small molecule has superiority. Cerdulatinib, developed by Portola Pharmaceuticals, is a research, oral, inhibitor of both spleen tyrosine kinase (Syk) and Janus kinase (JAK) for the treatment of Peripheral T Cell Lymphoma (PTCL). New data for this study were reported in 2018 on the american clinical oncology society (ASCO) annual meeting and the European Hematology Association (EHA) 23 rd congress. Cerdulatinib showed broad clinical activity with an objective response rate of 47% in all patients and was well tolerated. ASN002 is a SYK-JAK dual-channel inhibitor developed by Asana BioSciences, entitled by the FDA to the rapid channel for the treatment of moderate to severe atopic dermatitis by the end of 2018.

The SYK-JAK dual-channel inhibitor is expected to be applied to the field of diseases such as lymphoma, solid tumor, atopic dermatitis, arthritis, alopecia, lupus erythematosus and the like.

In conclusion, the development of novel SYK-JAK dual-channel inhibitors is of great significance.

Disclosure of Invention

The invention aims to provide a novel protein kinase inhibitor.

In a first aspect of the present invention, there is provided a compound having a structure represented by the following formula (I), or an optical isomer (including racemate, single enantiomer, and possible diastereoisomer), a pharmaceutically acceptable salt, a prodrug, a deuterated form, a hydrate, or a solvate thereof:

wherein "+" represents a chiral center; in the case where R or S is not indicated, the compounds with "+" represent racemates, or optical isomers of R configuration or S configuration;

R¹selected from the group consisting of: 3-to 8-membered cycloalkyl, 3-to 12-membered heterocyclyl (including monocyclic, spiro and fused rings), aryl, heteroaryl, OR^bOr NR^bR^c(ii) a In said R¹Wherein each cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with 1-3 substituents each independently selected from the group consisting of: deuterium, halogen, CN, OR^h、NR^hR^h、C(O)R^e、C(O)OR^h、C(O)NR^hR^h、NR^hC(O)R^e、S(O)₂R^e、S(O)₂NR^hR^h、C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy-substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl, cyano-substituted C_1-4Alkyl, di (C)_1-4Alkyl) amino substituted C_1-4Alkyl, 3-to 6-membered heterocyclyl substituted C_1-4Alkyl, aryl substituted C_1-4Alkyl, heteroaryl substituted C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, aryl, or heteroaryl, provided that the chemical structure formed is stable and meaningful;

wherein R is^bAnd R^cEach independently is hydrogen, C_1-4Alkyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, aryl, heteroaryl;

each R is²Each independently of the other being deuterium, halogen, C_1-4Alkyl radical, C_1-4Haloalkyl, C_2-4Alkenyl radical, C_2-4Alkynyl, OR^h、SR^h、NR^hR^h、CN、C(O)R^e、C(O)OR^h，C(O)NR^hR^h、OC(O)R^e、NR^hC(O)R^eOr S (O)₂R^e；

Each R is³Each independently is deuterium, or C_1-4An alkyl group; or when two R are³When both R are attached to the same carbon atom³Together with the carbon atom to which they are attached form a carbonyl group (C ═ O); said R³At any position on the ring except the N atom and the G atom;

j and G are each independently NR^f、O、S、S(O)、S(O)₂Or CR^gR^g；

n is 0, 1,2, or 3;

q is 0, 1,2, or 3;

R^fis hydrogen, C_1-8Alkyl radical, C_1-8Haloalkyl, C_2-8Alkenyl radical, C_2-8Alkynyl, 3-to 8-membered cycloalkyl, 3-to 12-membered heterocyclyl, aryl, heteroaryl, C (O) R^e、C(O)OR^h、C(O)NR^hR^h、S(O)₂R^eOr S (O)₂NR^hR^h(ii) a Wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally and independently substituted with 1-3 substituents eachSubstituted with substituents independently selected from the group consisting of: halogen, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, aryl, heteroaryl, CN, NO₂、OR^h、SR^h、NR^hR^h、C(O)R^e、C(O)OR^h、C(O)NR^hR^h、NR^hC(O)R^e、S(O)₂R^eOr S (O)₂NR^hR^h；

Each R is^eEach independently is a group selected from: hydrogen, C_1-4Alkyl radical, C_1-4Haloalkyl, C_2-4Alkenyl radical, C_2-4Alkynyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, aryl, or heteroaryl;

each R is^gEach independently selected from the group consisting of: hydrogen, deuterium, halogen, or C_1-4An alkyl group; or two R^gTogether with the carbon atom to which they are attached form a carbonyl group (C ═ O); or two R^gTogether with the same carbon atom to which it is attached, form a 3-to 8-membered cyclic structure optionally containing 0, 1 or 2 heteroatoms selected from N, O, S;

each R is^hEach independently of the other being hydrogen, or C_1-4An alkyl group; or two R^hTogether with the nitrogen atom to which they are attached form a 3-to-8-membered heterocyclic group containing 1 or 2N atoms and 0 or 1 heteroatom selected from O, S;

wherein, unless otherwise specified, each of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally and independently substituted with 1 to 3 substituents each independently selected from the group consisting of: deuterium, halogen, C_1-4Alkyl radical, C_1-4Haloalkyl, C_2-4Alkenyl radical, C_2-4Alkynyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, aryl, heteroaryl, CN, NO₂、OR^h、SR^h、NR^hR^h、C(O)R^e、C(O)OR^h、C(O)NR^hR^h、NR^hC(O)R^eOr S (O)₂R^eProvided that the chemical structure formed isAre stable and meaningful; wherein R is^eAnd R^hIs as defined above;

the above-mentioned aryl group is an aromatic group having 6 to 12 carbon atoms unless otherwise specified; heteroaryl is a 5-to 15-membered heteroaromatic group; the cyclic structure is a saturated or unsaturated, heteroatom-containing or heteroatom-free cyclic group.

In another preferred embodiment, R is¹Selected from the group consisting of: a 3-to 12-membered heterocyclyl, aryl, or heteroaryl group; wherein each heterocyclyl, aryl and heteroaryl is optionally substituted with 1-2 substituents each independently selected from the group consisting of: deuterium, halogen, CN, OR^h、NR^hR^h、C(O)R^e、C(O)OR^h、C(O)NR^hR^h、NR^hC(O)R^e、S(O)₂R^e、S(O)₂NR^hR^h、C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy-substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl, cyano-substituted C_1-4Alkyl, di (C)_1-4Alkyl) amino substituted C_1-4Alkyl, 3-to 6-membered heterocyclyl substituted C_1-4Alkyl, aryl substituted C_1-4Alkyl, heteroaryl substituted C_1-4Alkyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, aryl, or heteroaryl, provided that the chemical structure formed is stable and meaningful;

each R is²Each independently of the others being hydrogen, deuterium, halogen, C_1-4Alkyl, NR^hR^hOr NR^hC(O)R^e；

Each R is³Each independently is hydrogen or C_1-4An alkyl group; or when two R are³When both R are attached to the same carbon atom³Together with the carbon atom to which they are attached form a carbonyl group (C ═ O);

n is 0, 1, or 2;

q is 0, 1, or 2;

wherein R is^eAnd R^hIs as defined in the first aspect of the invention.

In another preferred embodiment, formula (I) is:

wherein the definitions of the various groups are as described in the first aspect of the invention.

In another preferred embodiment, the structural fragment in the formula (IIa)

Selected from:

represents the linking site of the above-mentioned structural fragment with other structures in formula (IIa);

wherein each R is²Each independently of the others being hydrogen, deuterium, halogen, C_1-2Alkyl, NR^hR^hOr NR^hC(O)R^e；

Each R is³Each independently is hydrogen or C_1-4An alkyl group; when two R are³When bound to the same carbon atom, two R³And the carbon atoms connecting them may together form C ═ O;

n is 0, 1, or 2; q is 0 or 1;

R^fis hydrogen, C_1-4Alkyl radical, C_1-4Haloalkyl, C_2-4Alkenyl radical, C_2-4Alkynyl, 3-to 8-membered cycloalkyl, 3-to 9-membered heterocyclyl, aryl, heteroaryl, C (O) R^e、C(O)OR^h、C(O)NR^hR^h、S(O)₂R^eOr S (O)₂NR^hR^h(ii) a Wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally and each independently substituted with 1-3 substituents each independently selected from the group consisting of: deuterium, halogen, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, aryl, heteroaryl, CN, NO₂、OR^h、SR^h、NR^hR^h、C(O)R^e、C(O)OR^h、C(O)NR^hR^h、NR^hC(O)R^e、S(O)₂R^eOr S (O)₂NR^hR^h；

R^eAnd R^hIs as defined in the first aspect of the invention.

In another preferred embodiment, formula (I) is:

wherein R is²Is hydrogen, deuterium, halogen, C_1-2Alkyl, NR^hR^hOr NR^hC(O)R^e；

R¹Is as defined in the first aspect of the invention; r^eAnd R^hIs as defined in the first aspect of the invention.

In another preferred embodiment, formula (I) is:

In another preferred embodiment, R is²Is hydrogen, halogen, C_1-2An alkyl group;

R^fselected from the group consisting of: hydrogen, C_1-4Alkyl radical, C_1-4Haloalkyl, 3-to 8-membered cycloalkyl, 3-to 9-membered heterocyclyl, aryl, heteroaryl, C (O) R^eOr S (O)₂R^e(ii) a Wherein each of alkyl, cycloalkyl, heterocyclyl, aryl andheteroaryl is optionally and independently substituted with 1-3 substituents each independently selected from the group consisting of: deuterium, halogen, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, aryl, heteroaryl, CN, NO₂、OR^e、SR^e、NR^eR^e、C(O)R^e、C(O)OR^e、C(O)NR^eR^e、NR^eC(O)R^e、S(O)₂R^eOr S (O)₂NR^hR^h；

R^eAnd R^hIs as defined in the first aspect of the invention.

In another preferred embodiment, formula (I) is:

wherein R is²Is hydrogen, halogen, C_1-2An alkyl group;

s and t are each independently 1,2, or 3;

a is NR^kO, or CR^gR^g(ii) a Wherein R is^kIs hydrogen, C_1-4Alkyl radical, C_1-4Haloalkyl, hydroxy-substituted C_1-4Alkyl radical, C_1-4Alkoxy-substituted C_1-4Alkyl, di (C)_1-4Alkyl) amino substituted C_1-4Alkyl, 3-to 8-membered cycloalkyl, 3-to 9-membered heterocyclyl, aryl, heteroaryl, C (O) R^e、C(O)OR^h、C(O)NR^hR^h、S(O)₂R^eOr S (O)₂NR^hR^h；

R¹Is as defined in the first aspect of the invention; r^g、R^eAnd R^hIs as defined in the first aspect of the invention.

In another preferred embodiment, R¹Is a 3-to 12-membered heterocyclyl; wherein said heterocyclic group means a saturated or partially unsaturated monocyclic or polycyclic heterocyclic group; polycyclic heterocyclic radicals are intended to mean heterocycles comprising spiro, fused and bridged ringsA group; the heterocyclyl is optionally substituted with 1-2 substituents each independently selected from the group consisting of: deuterium, halogen, CN, OR^h、NR^hR^h、C(O)R^e、C(O)OR^h、C(O)NR^hR^h、NR^hC(O)R^e、S(O)₂R^e、S(O)₂NR^hR^h、C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy-substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl, cyano-substituted C_1-4Alkyl, di (C)_1-4Alkyl) amino substituted C_1-4Alkyl, 3-to 6-membered heterocyclyl substituted C_1-4Alkyl, aryl substituted C_1-4Alkyl, heteroaryl substituted C_1-4Alkyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, aryl, or heteroaryl, provided that the chemical structure formed is stable and meaningful.

In another preferred embodiment, R¹Selected from the group consisting of:

represents the linking site of the above structural fragment with other structures in formula (I);

wherein each R is^sEach independently of the others being hydrogen, deuterium, halogen, C_1-4Alkyl, CN, OR^h、NR^hR^h(ii) a Or when two R are^sWhen both R are attached to the same carbon atom^sThe carbon atoms to which they are attached may optionally be taken together to form a carbonyl group (C ═ O);

or two R on different carbon atoms^sTogether forming a structure selected from the group consisting of: chemical bond, C_1-2An alkylene group of (a);

b is NR^tO, or CR^wR^w(ii) a Each R is^wEach independently selected from the group consisting of: hydrogen, deuterium, halogen, CN, OR^h、NR^hR^h、C(O)R^e、C(O)OR^h、C(O)NR^hR^h、NR^hC(O)R^e、S(O)₂R^e、S(O)₂NR^hR^h、C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy-substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl, cyano-substituted C_1-4Alkyl, di (C)_1-4Alkyl) amino substituted C_1-4An alkyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, aryl, or heteroaryl group; or two R^wTogether with the same carbon atom to which they are attached form a 3-to 8-membered cyclic structure optionally containing 0, 1 or 2 members selected from NR^tRing members of O, S;

each R is^tEach independently is hydrogen, C_1-4Alkyl radical, C_1-4Haloalkyl, hydroxy-substituted C_1-4Alkyl radical, C_1-4Alkoxy-substituted C_1-4Alkyl, cyano-substituted C_1-4Alkyl, di (C)_1-4Alkyl) amino substituted C_1-4Alkyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, aryl, heteroaryl, C (O) R^eOr S (O)₂R^e；

p is 0, 1, or 2;

u and v are each independently 0, 1, or 2;

each R is^eAnd R^hIs as defined in the first aspect of the invention.

In another preferred embodiment, R¹Selected from the group consisting of:

represents the linking site of the above structural fragment with other structures in formula (I).

In another preferred embodiment, the compound is selected from the group consisting of:

in a second aspect of the present invention, there is provided a use of a compound of formula (I) as described in the first aspect of the present invention, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate thereof, for:

(a) preparing a medicament for treating diseases related to the activity or expression amount of protein kinase;

(b) preparing a protein kinase targeted inhibitor; and/or

(c) Non-therapeutically inhibiting the activity of a protein kinase in vitro;

wherein the protein kinase is selected from the group consisting of: SYK, JAK1, JAK2, JAK3, TYK2, and the like, or combinations thereof.

In a third aspect of the present invention, there is provided a pharmaceutical composition comprising: (i) an effective amount of a compound of formula I as described in the first aspect of the invention, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate thereof; and (ii) a pharmaceutically acceptable carrier.

In a fourth aspect of the invention, there is provided a process for the preparation of a compound according to the first aspect of the invention, comprising the steps of:

(1) reacting the compound of formula C2 with DMF-DMA to obtain a compound of formula C3;

(2) with compounds of formula C3 and NaIO₄Reacting to obtain a compound of formula C4;

(3) reaction of a compound of formula C4 with NH2NH2 affords compounds of formula I.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Detailed Description

The inventor has long and intensive research and unexpectedly found a compound containing a fused tricyclic structure with a novel structure as an inhibitor of SYK and JAK kinase, and a preparation method and application thereof. The compounds of the present invention may be used in the treatment of various diseases associated with the activity of SYK, JAK1, JAK2, JAK3, TYK 2. Based on the above findings, the inventors have completed the present invention.

Term(s) for

Unless otherwise indicated, reference to "or" herein has the same meaning as "and/or" (meaning "or" and ").

Unless otherwise specified, each chiral carbon atom (chiral center) in all compounds of the invention may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.

As used herein, the term "alkyl", alone or as part of another substituent, refers to a straight-chain (i.e., unbranched) or branched-chain saturated hydrocarbon group containing only carbon atoms, or a combination of straight-chain and branched-chain groups. When the alkyl group is preceded by a carbon atom number limitation (e.g. C)_1-10) When used, it means that the alkyl group contains 1 to 10 carbon atoms. E.g. C_1-8Alkyl means containing 1 to 8 carbon atomsThe alkyl group of (1) includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.

As used herein, the term "alkenyl", alone or as part of another substituent, refers to a straight or branched chain carbon chain radical having at least one carbon-carbon double bond. Alkenyl groups may be substituted or unsubstituted. When the alkenyl radical is preceded by a carbon atom number limitation (e.g. C)_2-8) When used, it means that the alkenyl group has 2 to 8 carbon atoms. E.g. C_2-8Alkenyl means alkenyl having 2 to 8 carbon atoms and includes ethenyl, propenyl, 1, 2-butenyl, 2, 3-butenyl, butadienyl, or the like.

As used herein, the term "alkynyl", alone or as part of another substituent, refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond. The alkynyl group can be linear or branched, or a combination thereof. When alkynyl is preceded by a carbon atom number limitation (e.g. C)_2-8Alkynyl) means that the alkynyl group contains 2 to 8 carbon atoms. For example, the term "C_2-8Alkynyl "refers to straight or branched chain alkynyl groups having 2 to 8 carbon atoms and includes ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl, tert-butynyl, or the like.

As used herein, the term "cycloalkyl", alone or as part of another substituent, refers to a monocyclic, bicyclic, or polycyclic (fused, bridged, or spiro) ring system group having a saturated or partially saturated unit ring. When a cycloalkyl group is preceded by a carbon atom number limitation (e.g. C)_3-10) When used, means that the cycloalkyl group contains 3 to 10 carbon atoms. In some preferred embodiments, the term "3-to 8-membered cycloalkyl" refers to a saturated or partially saturated monocyclic or bicyclic alkyl group having 3 to 8 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or the like. "spirocycloalkyl" refers to a bicyclic or polycyclic group having a single ring with a common carbon atom (called the spiro atom) between them, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. "fused cycloalkyl" refers to an all-carbon bicyclic or polycyclic ring system wherein each ring shares an adjacent pair of carbon atoms with other rings in the systemGroups in which one or more rings may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. "bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings share two carbon atoms not directly connected, and these may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. The cycloalkyl groups contain all carbon atoms. Some examples of cycloalkyl groups are given below, and the present invention is not limited to only the cycloalkyl groups described below.

Unless stated to the contrary, the following terms used in the specification and claims have the following meanings. "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, such as phenyl and naphthyl. The aryl ring may be fused to other cyclic groups (including saturated and unsaturated rings) but must not contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent must be at a carbon atom on the ring which has a conjugated pi-electron system. The aryl group may be substituted or unsubstituted. Some examples of aryl groups are given below, and the present invention is not limited to only the aryl groups described below.

"heteroaryl" refers to a monocyclic or polycyclic group having aromaticity comprising one to more heteroatoms (optionally selected from nitrogen, oxygen, and sulfur), or a polycyclic group comprising a heterocyclic group (comprising one to more heteroatoms optionally selected from nitrogen, oxygen, and sulfur) fused to an aryl group with the attachment site being on the aryl group. Heteroaryl groups may be optionally substituted or unsubstituted. Some examples of heteroaryl groups are given below, to which the present invention is not limited.

"Heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more ring atoms are selected from nitrogen, oxygen, or sulfur and the remaining ring atoms are carbon. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl. Polycyclic heterocyclic groups refer to heterocyclic groups including spiro rings, fused rings, and bridged rings. "Spirocyclic heterocyclyl" refers to polycyclic heterocyclic groups in which each ring in the system shares one atom (referred to as a spiro atom) with other rings in the system, where one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. "fused ring heterocyclyl" refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more of the rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system, and in which one or more of the ring atoms is selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon. "bridged heterocyclyl" means a polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system, and in which one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. If both saturated and aromatic rings are present in the heterocyclyl (e.g., the saturated and aromatic rings are fused together), the point of attachment to the parent moiety must be at the saturated ring. Note: when the point of attachment to the parent is on the aromatic ring, it is referred to as heteroaryl and not as heterocyclyl. The following are some examples of heterocyclic groups, and the present invention is not limited to only the heterocyclic groups described below.

As used herein, the term "halogen", alone or as part of another substituent, refers to F, Cl, Br, and I.

As used herein, the term "substituted" (with or without "optionally" modifying) means that one or more hydrogen atoms on a particular group are replaced with a particular substituentAnd (4) substitution. Particular substituents are those described correspondingly in the foregoing, or as appearing in the examples. Unless otherwise specified, an optionally substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituents may be the same or different at each position. A cyclic substituent, such as a heterocyclic group, may be attached to another ring, such as a cycloalkyl group, to form a spiro bicyclic ring system, i.e., the two rings have a common carbon atom. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. Such substituents are for example (but not limited to): c_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, 3-to 8-membered cycloalkyl, 3-to 12-membered heterocyclyl, aryl, heteroaryl, halogen, hydroxy, carboxy (-COOH), C_1-8Aldehyde group, C_2-10Acyl radical, C_2-10Ester group and amino group.

For convenience and in accordance with conventional understanding, the terms "optionally substituted" or "optionally substituted" are only applicable to sites which can be substituted by substituents, and do not include those substitutions which are not chemically achievable.

As used herein, unless otherwise specified, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for contact with the tissues of a subject (e.g., a human) without undue side effects. In some embodiments, pharmaceutically acceptable salts of a certain compound of the invention include salts of a compound of the invention having an acidic group (e.g., potassium, sodium, magnesium, calcium) or a basic group (e.g., sulfate, hydrochloride, phosphate, nitrate, carbonate).

The application is as follows:

the invention provides the use of a class of compounds of formula (I), or deuterated derivatives thereof, salts thereof, isomers (enantiomers or diastereomers, if present), prodrugs, hydrates, solvates, pharmaceutically acceptable carriers or excipients, for inhibiting protein kinases. The protein kinases referred to herein include, but are not limited to, SYK, JAK1, JAK2, JAK3, TYK2, and the like.

The compounds of the invention are useful as inhibitors of one or more kinases, for example in some embodiments certain classes of compounds of the invention are useful as inhibitors of SYK, JAK1, JAK2, JAK3, TYK2 kinases.

In cancer patients, the expression or activity of the above-mentioned protein kinases is significantly increased. These overexpressed and/or abnormal levels of protein kinase activity are directly linked to the development of tumors. The compounds of the present invention are single and/or dual inhibitors of these protein kinases. Diseases are prevented, alleviated or cured by modulating the activity of these protein kinases. The diseases include liver cancer, rectal cancer, bladder cancer, throat cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous carcinoma, cervical cancer, esophageal cancer, renal cancer, pancreatic cancer, colon cancer, skin cancer, lymphoma, stomach cancer, multiple myeloma cancer, solid tumor and the like.

In some respects, dual protein kinase inhibitors interfere with two different kinases simultaneously, and the resulting antitumor effects tend to be additive, thus having the potential to more effectively treat a variety of cancers.

The compounds of the invention can be used with biological agents such as PD-1 inhibitors

And

can be used as a combined medicine for treating various cancers and related diseases.

The compounds of the present invention and deuterated derivatives thereof, as well as pharmaceutically acceptable salts or isomers thereof (if present) or hydrates thereof and/or compositions can be formulated together with pharmaceutically acceptable excipients or carriers and the resulting compositions can be administered to mammals, such as men, women and animals, in vivo for the treatment of conditions, symptoms and diseases. The composition may be: tablets, pills, suspensions, solutions, emulsions, capsules, aerosols, sterile injections. Sterile powders, and the like. In some embodiments, pharmaceutically acceptable excipients include microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, mannitol, hydroxypropyl- β -cyclodextrin, β -cyclodextrin (plus), glycine, disintegrants (such as starch, croscarmellose sodium, complex silicates, and polymeric polyethylene glycols), granulation binders (such as polyvinylpyrrolidone, sucrose, gelatin, and acacia), and lubricants (such as magnesium stearate, glycerol, and talc). In a preferred embodiment, the pharmaceutical composition is in a dosage form suitable for oral administration, including but not limited to tablets, solutions, suspensions, capsules, granules, powders. The amount of a compound or pharmaceutical composition of the present invention administered to a patient is not fixed and is generally administered in a pharmaceutically effective amount. Also, the amount of the compound actually administered can be determined by a physician, in the light of the actual circumstances, including the condition being treated, the chosen route of administration, the actual compound administered, the individual condition of the patient, and the like. The dosage of the compounds of the invention will depend on the particular use being treated, the mode of administration, the state of the patient, and the judgment of the physician. The proportion or concentration of the compounds of the invention in the pharmaceutical composition will depend on a variety of factors including dosage, physicochemical properties, route of administration and the like.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments.

General synthetic method of compound

The compound of formula (I) of the present invention can be prepared by the following method, and reagents and conditions for each step may be selected from those conventional in the art for such preparation methods, and reactants, solvents, bases, amounts of compounds used, reaction temperature, time required for the reaction, and the like are not limited to the following explanation. The compounds of the present invention may also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, and such combinations may be readily carried out by those skilled in the art to which the present invention pertains.

In the preparation method of the invention, each reaction is usually carried out in an inert solvent at a temperature of-20 to 150 ℃ (preferably 0 to 120 ℃), and the reaction time of each step is usually 0.5 to 48 hours, preferably 2 to 12 hours.

Equation 1 describes the general synthetic approach for intermediates 1-A-5-1 and 1-A5-2:

reaction formula 1:

equation 2 describes a general synthetic approach for intermediates 2-B3-1 and 2-B3-2:

reaction formula 2:

compound IIa is part of compound I. Equation 3 describes a general synthetic method for compound IIa:

reaction formula 3:

compound IIb is part of compound I. Equation 4 describes the general synthesis of compound IIb:

reaction formula 4:

equation 5 describes another general synthetic approach for compound IIa:

reaction formula 5:

r in the above reaction formula 1-5²、R^fAnd q are as defined above.

Pharmaceutical compositions and methods of administration

The compound has excellent inhibitory activity on a series of protein kinases, so that the compound, various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof and a pharmaceutical composition containing the compound as a main active ingredient can be used for treating, preventing and relieving diseases related to the activity or expression level of protein kinases such as EGFR, EGFR (C797S), ALK, HPK1 and the like.

The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof in a safe and effective amount range and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 5-200mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.

"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g. tween, etc.)

) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.

In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.

The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 5 to 500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.

The main advantages of the invention include:

1. a compound represented by the formula (I) is provided.

2. The inhibitor of protein kinases such as SYK, JAK1, JAK2, JAK3, TYK2 and the like with novel structures and preparation and application thereof are provided, and the inhibitor can inhibit the activity of the protein kinases at extremely low concentration.

3. Provides a pharmaceutical composition for treating diseases related to the activity of protein kinases such as SYK, JAK1, JAK2, JAK3, TYK2 and the like.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.

EXAMPLE 1 preparation of Compound 1R

Compound 1R-a was prepared according to the experimental procedure in patent WO 2018108084. Compound 1R-a (200mg,0.85mmol) and palladium on carbon catalyst (10%, 50mg) were added to methanol (10mL) at room temperature, and the reaction mixture was reacted overnight at room temperature under a hydrogen atmosphere of 1 atm. TLC monitored the reaction completion. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (DCM: MeOH ═ 60:1) to give 1R-b (150mg, yield 86%) as a brown solid.

Compound 1R-b (100mg,0.48mmol) was dissolved in acetonitrile (10mL), and then methyl 2, 4-dichloro-6-methylpyrimidine-5-carboxylate (1R-c,118mg,0.54mmol) and diisopropylethylamine (125mg,0.97mmol) were added in that order under ice bath. The reaction mixture was slowly warmed to room temperature for 3 hours. TLC monitored the reaction was complete. The reaction solution was concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (dichloromethane: ethyl acetate 50:1) to give 1R-d (145mg, yield 76%) as a pale yellow solid.

Compound 1R-d (145mg,0.37mmol) was dissolved in acetonitrile (10mL), followed by the addition of 2- (piperidin-4-yl) acetonitrile hydrochloride (1R-e,72mg,0.45mmol) and diisopropylethylamine (144mg,1.11mmol) in that order. The reaction mixture was stirred at 60 ℃ for 3 hours. TLC monitored the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (dichloromethane: ethyl acetate ═ 30:1) to give 1R-f (136mg, yield 77%) as a pale yellow solid.

Compound 1R-f (60mg,0.13mmol) was dissolved in DMF (5mL) and DMF-DMA (0.2mL) was added. The reaction mixture was stirred at 130 ℃ overnight. TLC monitored the reaction was complete. The reaction was poured into an appropriate amount of saturated sodium chloride solution and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were dried over anhydrous sodium sulfate. The drying agent is removed by filtration, and the obtained filtrate is concentrated under reduced pressure to obtain crude compound 1R-g (which is directly used for the next reaction without purification).

Crude compound 1R-g (67mg,0.13mmol) was dissolved in methanol (5mL) and sodium periodate (134mg,0.63mmol) was added portionwise under ice bath. The reaction mixture was warmed to room temperature and stirred for 3 hours. TLC monitored the reaction was complete. The reaction solution was filtered, and the obtained filtrate was concentrated under reduced pressure to give a crude compound 1R-h (used in the next reaction without purification).

The crude compound 1R-h (62mg, 0.13mmol) was dissolved in ethanol (5mL) and hydrazine hydrate (16mg, 0.26mmol) was added. The reaction mixture was stirred at 80 ℃ for 3 hours. TLC monitored the reaction was complete. The reaction mixture was filtered to obtain a filter cake, which was then separated and purified by preparative thin plate chromatography to give compound 1R as a yellow solid (2.2mg, yield 3.7%).¹H NMR(500MHz,DMSO-d₆)δ12.76(s,1H),11.15(s,1H),7.88(s,1H),7.28(d,J＝2.3Hz,1H),7.06(dd,J＝8.7,2.4Hz,1H),6.89(d,J＝8.9Hz,1H),4.85-4.62(br.,2H),4.24(dd,J＝10.6,2.6Hz,1H),3.97(dd,J＝11.0,3.2Hz,1H),3.90-3.84(m,2H),3.68-3.55(m,2H),3.18(t,J＝10.7Hz,1H),3.14-3.07(m,1H),3.03-2.98(m,2H),2.71-2.65(m,1H),2.55(d,J＝6.7Hz,2H),2.01-1.93(m,1H),1.82(d,J＝11.4Hz,2H),1.28-1.20(m,2H).

EXAMPLE 2 preparation of Compound 2R

Compound 2R-a was prepared according to the experimental procedure in patent WO 2018108084. Compound 2R-a (2.0g,5.96mmol) was dissolved in dichloromethane (15mL) and dioxane hydrochloride solution (4M,2mL) was added under ice bath. The reaction mixture was warmed to room temperature and stirred overnight. TLC monitored the reaction was complete. The reaction mixture was concentrated under reduced pressure to give compound 2R-b (1.32g, yield 81%) as a yellow solid.

Compound 2R-b (80mg,0.34mmol) was dissolved in dichloromethane (10mL) and methanesulfonyl chloride (2R-c,58mg,0.51mmol) and triethylamine (103mg,1.02mmol) were added sequentially under ice bath. The reaction mixture was warmed to room temperature and stirred for 2 hours. TLC monitored the reaction was complete. Water (30mL) was added to the reaction solution, followed by extraction with dichloromethane (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (dichloromethane: ethyl acetate ═ 10:1) to give 2R-d (75mg, yield 70%) as a yellow solid.

The compound 2R-i is synthesized from 2R-d according to the preparation steps of the compound 1R-h.

Compound 2R-i (60mg,0.11mmol) was dissolved in ethanol (5mL) and hydrazine hydrate (20mg,0.32mmol) was added. The reaction mixture was stirred at 80 ℃ for 3 hours. TLC monitored the reaction was complete. The reaction solution was filtered to obtain a filter cake, which was then separated and purified by preparative thin plate chromatography to give compound 2R as a yellow solid (3.0mg, yield 5.2%). MS M/z 552.4[ M + H ]]⁺。

EXAMPLE 3 preparation of Compound 3R

The compound 3R-b is synthesized from the compound 2R-b according to the preparation steps of the compound 2R-d.

Compound 3R-g was synthesized starting from 3R-b according to the procedure for the preparation of compound 1R-h.

Compound 3R-g (50mg,0.09mmol) was dissolved in ethanol (5mL), followed by addition of hydrazine hydrate (16mg, 0.26 mmol). The reaction mixture was stirred at 80 ℃ for 3 hours. TLC monitored the reaction was complete. The reaction mixture was filtered to obtain a filter cake, which was then separated and purified by preparative thin plate chromatography to give compound 3R as a yellow solid (5.0mg, yield 10%).MS m/z 566.7[M+H]⁺。

EXAMPLE 4 preparation of Compound 4R

The compound 4R-b is synthesized from 2R-b according to the preparation steps of the compound 2R-d.

Compound 4R-g was synthesized starting from 4R-b according to the procedure for the preparation of compound 1R-h.

Compound 4R-g (52mg,0.09mmol) was dissolved in ethanol (5mL), followed by addition of hydrazine hydrate (16mg, 0.26 mmol). The reaction mixture was stirred at 80 ℃ for 3 hours. TLC monitored the reaction was complete. The reaction mixture was filtered to obtain a filter cake, which was then separated and purified by preparative thin plate chromatography to give compound 4R as a yellow solid (5.1mg, yield 10%). MS M/z 578.7[ M + H ]]⁺。

EXAMPLE 5 preparation of Compound 5R

Compound 2R-b (100mg,0.43mmol) was dissolved in dichloromethane (10mL) and acetic anhydride (5R-a,87mg,0.85mmol) was added under ice-bath. The reaction mixture was warmed to room temperature and stirred overnight. TLC monitored the reaction was complete. To the reaction mixture was added an appropriate amount of saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (dichloromethane: ethyl acetate ═ 20:1) to give 5R-b (73mg, yield 73%) as a yellow solid.

Compound 5R-g was synthesized starting from 5R-b according to the procedure for the preparation of compound 1R-h.

Compound 5R-g (50mg,0.09mmol) was dissolved in ethanol (5mL), followed by addition of hydrazine hydrate (18mg, 0.28 mmol). The reaction mixture was stirred at 80 ℃ for 3 hours. TLC monitored the reaction was complete. Filtering the reaction solution to obtain a filter cake, and separating and purifying the filter cake by using a preparative thin plate chromatographyCompound 5R was obtained as a yellow solid (2.1mg, yield 4.3%). MS M/z 516.4[ M + H ]]⁺。

EXAMPLE 6 preparation of Compound 6R

Compound 2R-b (100mg,0.37mmol) was dissolved in dichloroethane (10mL), 37% aqueous formaldehyde (1mL) was added, 2 drops of acetic acid were added, and stirring was carried out at room temperature for 30 minutes. Sodium cyanoborohydride (58mg,0.92mmol) was then added and stirred at room temperature for 3 hours. TLC monitored the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (dichloromethane: methanol ═ 60:1) to give 6R-a (82mg, yield 89%) as a yellow solid.

The compound 6R-f is synthesized starting from 6R-a according to the preparation steps of the compound 1R-h.

Compound 6h (50mg, 0.01mmol) was dissolved in ethanol (5mL) and hydrazine hydrate (19mg, 0.30mmol) was added. The reaction mixture was stirred at 80 ℃ for 3 hours. TLC monitored the reaction was complete. The reaction mixture was filtered to obtain a filter cake, which was slurried with acetonitrile and filtered to obtain compound 6R as a yellow solid (11.0mg, yield 23%).¹H NMR(500MHz,DMSO-d₆)δ12.75(s,1H),11.13(s,1H),7.87(s,1H),7.26(s,1H),7.04(dd,J＝8.6,1.9Hz,1H),6.88(d,J＝8.8Hz,1H),4.85-4.62(br.,2H),4.25(dd,J＝10.6,2.2Hz,1H),3.95-3.88(m,1H),3.69(d,J＝11.4Hz,1H),3.08-2.94(m,3H),2.86(d,J＝10.8Hz,1H),2.79(d,J＝10.2Hz,1H),2.68-2.58(m,1H),2.54(d,J＝6.7Hz,2H),2.22(s,3H),2.13-2.03(m,1H),2.02-1.94(m,1H),1.82(d,J＝11.8Hz,2H),1.69(t,J＝10.6Hz,1H),1.28-1.20(m,2H)。MS m/z 488.6[M+H]⁺。

Example 7 preparation of Compound 6S

Compound 6S-b was synthesized starting from 6S-a according to the procedure for the preparation of compound 2R-b.

Compound 6S-c was synthesized starting from 6S-b according to the procedure for the preparation of compound 6R-a.

The compound 6S-h is synthesized starting from 6S-c according to the preparation procedure of the compound 1R-h.

Compound 6S-h (55mg, 0.11mmol) was dissolved in ethanol (5mL), followed by addition of hydrazine hydrate (21mg, 0.33 mmol). The reaction mixture was stirred at 80 ℃ for 3 hours. TLC monitored the reaction was complete. The reaction solution was filtered to obtain a filter cake, which was slurried with acetonitrile and filtered to obtain compound 6S as a yellow solid (13.0mg, yield 24%).¹HNMR(500MHz,DMSO-d₆)δ12.75(br.s,1H),11.13(s,1H),7.87(s,1H),7.26(d,J＝2.3Hz,1H),7.04(dd,J＝8.7,2.4Hz,1H),6.88(d,J＝8.9Hz,1H),4.85-4.62(br.,2H),4.25(dd,J＝10.6,2.7Hz,1H),3.95-3.88(m,1H),3.69(d,J＝11.5Hz,1H),3.07-2.94(m,3H),2.86(d,J＝10.2Hz,1H),2.79(d,J＝10.2Hz,1H),2.68-2.58(m,1H),2.54(d,J＝6.7Hz,2H),2.22(s,3H),2.12-2.04(m,1H),2.03-1.94(m,1H),1.82(d,J＝10.7Hz,2H),1.69(t,J＝10.6Hz,1H),1.28-1.20(m,2H)。MS m/z 488.6[M+H]⁺。

Example 8 preparation of Compound 7R

To a solution of compound 2R-b (150mg,0.55mmol) in dichloroethane (10mL) was added 7R-a (111mg,1.10mmol) and 2 drops of acetic acid in that order. The reaction mixture was stirred at room temperature for 30 minutes. Sodium cyanoborohydride (87mg,1.38mmol) was then added. The reaction mixture was stirred at room temperature for 3 hours. TLC monitored the reaction was complete. The reaction solution was concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (dichloromethane: methanol ═ 60:1) to give 7R-b (130mg, yield 74%) as a yellow solid.¹H NMR(500MHz,CDCl₃)δ6.61(d,J＝8.5Hz,1H),6.28-6.18(m,2H),4.14(dd,J＝10.5,2.6Hz,1H),4.10-3.91(m,3H),3.60(d,J＝11.6Hz,1H),3.45-3.32(m,2H),3.11-3.00(m,2H),2.89(d,J＝10.5Hz,1H),2.79-2.70(m,1H),2.57-2.42(m,2H),2.04(t,J＝10.5Hz,1H),1.79(d,J＝12.3Hz,2H),1.66-1.54(m,2H)。

Compound 7R-g was synthesized starting from 7R-b according to the procedure for the preparation of compound 1R-h.

Compound 7R-g (126mg, 0.22mmol) was dissolved in ethanol (8mL), followed by addition of hydrazine hydrate (41mg, 0.66 mmol). The reaction mixture was stirred at 80 ℃ for 3 hours. TLC monitored the reaction was complete. The reaction mixture was filtered to obtain a filter cake, which was slurried with acetonitrile and filtered to obtain compound 7R as a yellow solid (57.5mg, yield 47%).¹H NMR(500MHz,DMSO-d₆)δ12.74(bs,1H),11.14(s,1H),7.87(s,1H),7.25(d,J＝1.9Hz,1H),7.04(dd,J＝8.7,2.1Hz,1H),6.87(d,J＝8.9Hz,1H),4.85-4.62(br.,2H),4.27(dd,J＝10.5,2.1Hz,1H),4.33-4.21(m,3H),3.72(d,J＝11.3Hz,1H),3.27(d,J＝11.5Hz,2H),3.05-2.90(m,5H),2.66-2.53(m,3H),2.43(t,J＝11.3Hz,1H),2.34-2.24(m,1H),2.02-1.94(m,1H),1.91-1.79(m,3H),1.73(d,J＝12.1Hz,2H),1.49-1.37(m,2H),1.28-1.20(m,2H)。MS m/z 558.8[M+H]⁺。

Example 9 preparation of Compound 8R

Compound 2R-b (150mg,0.55mmol) was dissolved in DMF (6mL) and then sodium iodide (17mg,0.11mmol), potassium carbonate (229mg, 1.66mmol) and 2-bromoethanol (8R-a,103mg,0.83mmol) were added in that order. The reaction mixture was stirred at 50 ℃ overnight. TLC monitored the reaction was complete. Water (30mL) was added to the reaction mixture and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (dichloromethane: ethyl acetate ═ 3:1) to give compound 8R-b (130mg, yield 84%) as a yellow solid.

Compound 8R-g was synthesized starting from 8R-b according to the procedure for the preparation of compound 1R-h.

Compound 8R-g (110mg, 0.21mmol) was dissolved in ethanol (8mL), followed by addition of hydrazine hydrate (39mg, 0.62 mmol). The reaction mixture was stirred at 80 ℃ for 3 hours. TLC monitored the reaction was complete. Filtering the reaction solution to obtain a filter cake, pulping the filter cake with acetonitrile, and filtering to obtain a yellow solid compound 8R (38.0mg, yieldRate 36%).¹H NMR(500MHz,DMSO-d₆)δ12.75(s,1H),11.14(s,1H),7.87(s,1H),7.26(s,1H),7.04(d,J＝8.0Hz,1H),6.88(d,J＝8.7Hz,1H),4.85-4.62(br.,2H),4.46(s,1H),4.25(d,J＝9.5Hz,1H),3.91(t,J＝9.7Hz,1H),3.68(d,J＝11.1Hz,1H),3.60-3.50(m,2H),3.06-2.95(m,4H),2.92(d,J＝10.3Hz,1H),2.66-2.58(m,1H),2.55(d,J＝6.4Hz,2H),2.48-2.40(m,2H),2.18(t,J＝10.6Hz,1H),2.02-1.94(m,1H),1.85-1.78(m,3H),1.28-1.20(m,2H)。MS m/z 518.7[M+H]⁺。

EXAMPLE 10 preparation of Compound 9R

Compound 9R-a (1.04g, 1.81mmol, synthesized using the preparative procedure for compound 5R) was dissolved in dichloromethane/methanol (v/v ═ 20/20mL) and a solution of HCl in 1, 4-dioxane (4.0M, 2mL) was added dropwise under ice bath. The reaction mixture was stirred at room temperature overnight. TLC monitored the reaction was complete. The reaction was stripped of solvent under reduced pressure, dichloromethane (20mL) and saturated aqueous sodium bicarbonate (20mL) were added, stirred at room temperature for 0.5h, and extracted with dichloromethane (3X20 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (dichloromethane: methanol ═ 10:1) to give compound 9R (825mg, yield 96%) as a yellow solid.¹H NMR(500MHz,DMSO-d₆)δ12.75(bs,1H),11.12(s,1H),7.86(s,1H),7.23(d,J＝2.5Hz,1H),7.03(dd,J＝8.7,2.5Hz,1H),6.84(d,J＝8.9Hz,1H),4.85-4.62(br.,2H),4.22(dd,J＝10.6,2.6Hz,1H),3.92-3.84(m,1H),3.63-3.57(m,1H),3.05-2.88(m,5H),2.77-2.70(m,1H),2.54(d,J＝6.6Hz,2H),2.53-2.51(m,1H),2.30(t,J＝11.7Hz,1H),2.03-1.92(m,1H),1.85-1.78(m,2H),1.25-1.19(m,2H)。MSm/z 474.7[M+H]⁺。

EXAMPLE 11 preparation of Compound 10R

To methanol (2mL) at room temperature was added compound 9R (60mg,0.13mmol), N-methyl-4-piperidone (10R-a,43mg, 0.38mmol) and palladium on carbon catalyst (10%, 10 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere of 1 atm overnight. TLC monitored the reaction completion. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to remove the solvent. The crude product was isolated and purified by preparative thin-plate chromatography (dichloromethane: methanol 10:1) to give compound 10R (14mg, yield 19%) as a yellow solid.¹H NMR(500MHz,DMSO-d₆)δ12.75(s,1H),11.14(s,1H),7.87(s,1H),7.25(d,J＝2.4Hz,1H),7.03(dd,J＝8.9,2.4Hz,1H),6.87(d,J＝9.0Hz,1H),4.85-4.62(br.,2H),4.26(dd,J＝10.5,2.6Hz,1H),3.95-3.88(m,1H),3.75-3.65(m,1H),3.07-2.79(m,7H),2.61-2.56(m,1H),2.54(d,J＝6.6Hz,2H),2.53-2.51(m,1H),2.32-2.26(m,1H),2.25-2.15(m,4H),2.02-1.94(m,2H),1.88(t,J＝10.4Hz,1H),1.85-1.79(m,2H),1.79-1.73(m,2H),1.52-1.40(m,2H),1.28-1.22(m,2H)。MS m/z 571.8[M+H]⁺。

EXAMPLE 12 preparation of Compound 11R

Compound 9R (60mg,0.13mmol) was dissolved in DMF (1mL), diisopropylethylamine (33mg, 0.25mmol) was added, and acryloyl chloride (11R-a,14mg, 0.16mmol) was added dropwise at 0 ℃. After the completion of the dropwise addition, the reaction mixture was stirred at 0 ℃ for 1 hour. TLC monitored the reaction was complete. Water (5mL) was added to the reaction solution and extracted with dichloromethane (3 × 10 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was isolated and purified by preparative thin-plate chromatography (dichloromethane: methanol ═ 10:1) to give compound 11R (33mg, yield 49%) as a yellow solid.¹H NMR(500MHz,DMSO-d₆)δ12.75(s,1H),11.14(s,1H),7.86(s,1H),7.28(d,J＝11.2Hz,1H),7.06(t,J＝9.2Hz,1H),6.93(d,J＝8.9Hz,1H),6.91-6.84(m,1H),6.16(dd,J＝16.7,2.3Hz,1H),5.73(dd,J＝10.4,2.3Hz,1H),4.85-4.62(br.,2H),4.55-4.45(m,1H),4.37(t,J＝13.1Hz,1H),4.25-4.14(m,1H),4.00-3.92(m,1H),3.88-3.79(m,1H),3.31-3.22(m,1H),3.06-2.93(m,3H),2.92-2.82(m,1H),2.65-2.57(m,1H),2.55(d,J＝6.6Hz,2H),2.01-1.92(m,1H),1.82(d,J＝12.7Hz,2H),1.27-1.20(m,2H)。MS m/z 528.5[M+H]⁺。

Example 13 preparation of Compound 12R

Compound 9R (60mg,0.13mmol), 2-butynoic acid (12R-a,11mg,0.13mmol), N-methylimidazole (36mg, 0.44mmol) were dissolved in acetonitrile (1mL), and tetramethylchlorourea hexafluorophosphate (43mg, 0.15mmol) was further added. The reaction mixture was stirred at room temperature for 3 hours. TLC monitored the reaction was complete. Water (5mL) was added to the reaction mixture and extracted with dichloromethane (3 × 10 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was isolated and purified by preparative thin-plate chromatography (dichloromethane: methanol ═ 10:1) to give compound 12R (28mg, yield 41%) as a yellow solid.¹H NMR(500MHz,DMSO-d₆)δ12.75(s,1H),11.14(s,1H),7.87(s,1H),7.29(dd,J＝10.0,2.5Hz,1H),7.10-7.03(m,1H),6.94(d,J＝8.5Hz,1H),4.85-4.62(br.,2H),4.43-4.26(m,3H),4.00-3.92(m,1H),3.92-3.83(m,1H),3.30-2.93(m,4H),2.91-2.59(m,1H),2.58-2.52(m,3H),2.06(d,J＝2.3Hz,3H),2.02-1.94(m,1H),1.85-1.79(m,2H),1.26-1.22(m,2H)。MS m/z 540.5[M+H]⁺。

Example 14 preparation of Compound 13R

Compound 9R (60mg,0.13mmol), iodoethane (13R-a,20mg,0.13mmol) were dissolved in DMF (2mL), and anhydrous potassium carbonate (36mg, 0.26mmol) was added. The reaction mixture was stirred at 90 ℃ overnight. TLC monitored the reaction was complete. Water (5mL) was added to the reaction mixture and extracted with dichloromethane (3 × 10 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product is subjected toPreparative thin-plate chromatography (dichloromethane: methanol ═ 10:1) isolated and purified to give compound 13R (25mg, yield 39%) as a yellow solid.¹H NMR(500MHz,DMSO-d₆)δ12.75(s,1H),11.14(s,1H),7.87(s,1H),7.26(d,J＝2.4Hz,1H),7.04(dd,J＝8.8,2.5Hz,1H),6.87(d,J＝9.0Hz,1H),4.85-4.60(br.,2H),4.27(dd,J＝10.7,2.7Hz,1H),3.95-3.86(m,1H),3.73-3.66(m,1H),3.05-2.94(m,4H),2.90(d,J＝10.1Hz,1H),2.64-2.59(m,1H),2.54(d,J＝6.6Hz,2H),2.42-2.33(m,2H),2.11-2.04(m,1H),2.02-1.92(m,1H),1.85-1.79(m,2H),1.67(t,J＝10.8Hz,1H),1.29-1.20(m,2H),1.03(t,J＝7.2Hz,3H)。MS m/z 502.5[M+H]⁺。

EXAMPLE 15 preparation of Compound 14R

Compound 9R (60mg,0.13mmol), bromoacetonitrile (14R-a,15mg,0.13mmol) were dissolved in DMF (1mL), and potassium carbonate (35mg, 0.25mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. TLC monitored the reaction was complete. Water (5mL) was added to the reaction mixture, which was extracted with dichloromethane (3 × 10 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was isolated and purified by preparative thin-plate chromatography (dichloromethane: methanol ═ 10:1) to give compound 14R (26mg, yield 39%) as a yellow solid.¹H NMR(500MHz,CDCl₃)δ10.81(s,1H),9.73(s,1H),7.82(s,1H),7.35(d,J＝2.5Hz,1H),7.09(dd,J＝8.8,2.5Hz,1H),6.77(d,J＝8.8Hz,1H),5.00-4.93(br.,2H),4.21(dd,J＝10.6,2.7Hz,1H),4.09-4.01(m,1H),3.76-3.71(m,1H),3.60(s,2H),3.26-3.19(m,1H),2.99-2.88(m,3H),2.88-2.81(m,1H),2.80-2.76(m,1H),2.70-2.65(m,1H),2.35(d,J＝6.7Hz,2H),2.27(t,J＝10.5Hz,1H),2.05-1.92(m,3H),1.37-1.32(m,2H)。MS m/z 513.5[M+H]⁺。

EXAMPLE 16 preparation of Compound 15R

Compound 9R (60mg,0.13mmol), 2-chloroethylmethyl ether (15R-a,15mg,0.13mmol) was dissolved in DMF (2mL), and diisopropylethylamine (50mg, 0.39mmol) was added. The reaction mixture was stirred at 90 ℃ overnight. TLC monitored the reaction was complete. Water (5mL) was added to the reaction mixture, which was extracted with dichloromethane (3 × 10 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative thin plate chromatography (dichloromethane: methanol ═ 10:1) to give compound 15R (13mg, yield 19%) as a yellow solid.¹H NMR(500MHz,DMSO-d₆)δ12.75(s,1H),11.14(s,1H),7.87(s,1H),7.26(d,J＝2.6Hz,1H),7.04(dd,J＝8.9,2.4Hz,1H),6.87(d,J＝9.2Hz,1H),4.85-4.60(br.,2H),4.25(dd,J＝10.5,2.7Hz,1H),3.96-3.88(m,1H),3.71-3.66(m,1H),3.47(t,J＝5.8Hz,2H),3.25(s,3H),3.05-2.95(m,4H),2.94-2.88(m,1H),2.65-2.58(m,1H),2.57-2.52(m,4H),2.23-2.17(m,1H),2.03-1.93(m,1H),1.86-1.77(m,3H),1.28-1.22(m,2H)。MS m/z 532.6[M+H]⁺。

EXAMPLE 17 preparation of Compound 16R

Compound 9R (100mg, 0.21mmol), 2,2, 2-trifluoroethyl trifluoromethanesulfonate (16R-a,49mg, 0.21mmol) was dissolved in DMF (3mL), and diisopropylethylamine (81mg,0.63mmol) was added. The reaction mixture was stirred at 60 ℃ for 2 hours. TLC monitored the reaction was complete. Water (5mL) was added to the reaction mixture, which was extracted with dichloromethane (3 × 10 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was isolated and purified by preparative thin plate chromatography (dichloromethane: methanol ═ 20:1) to give compound 16R (42mg, yield 36%) as a yellow solid.¹H NMR(500MHz,DMSO-d₆)δ12.75(s,1H),11.14(s,1H),7.87(s,1H),7.27(s,1H),7.04(d,J＝8.7Hz,1H),6.89(d,J＝8.8Hz,1H),4.85-4.60(br.,2H),4.30-4.23(m,1H),3.95-3.87(m,1H),3.75-3.68(m,1H),3.27(q,J＝10.3Hz,2H),3.10-2.93(m,5H),2.69-2.61(m,1H),2.61-2.56(m,1H),2.54(d,J＝6.7Hz,2H),2.18(t,J＝11.0Hz,1H),2.03-1.93(m,1H),1.86-1.78(m,2H),1.29-1.17(m,2H)。MS m/z 556.5[M+H]⁺。

EXAMPLE 18 preparation of Compound 17R

Compound 9R (60mg,0.13mmol), 3-bromopyridine (17R-a,23mg,0.14mmol), sodium tert-butoxide (24mg, 0.23mmol), Pd₂(dba)₃(12mg, 0.013mmol) and BINAP (16mg, 0.026mmol) were dissolved in toluene (2 mL). The reaction mixture was stirred overnight at 110 ℃ under nitrogen. TLC monitored the reaction was complete. After the reaction mixture was cooled to room temperature, water (5mL) was added and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was isolated and purified by preparative thin-plate chromatography (dichloromethane: methanol ═ 10:1) to give compound 17R (16mg, yield 23%) as a yellow solid.¹HNMR(500MHz,CDCl₃)δ10.85(s,1H),10.35(s,1H),8.38(s,1H),8.17(d,J＝3.5Hz,1H),7.83(s,1H),7.38(d,J＝2.5Hz,1H),7.29-7.25(m,1H),7.24-7.19(m,1H),7.12(dd,J＝8.7,2.5Hz,1H),6.83(d,J＝8.8Hz,1H),5.05-4.85(br.,2H),4.31(dd,J＝10.6,2.7Hz,1H),4.15-4.09(m,1H),3.88-3.80(m,1H),3.78-3.72(m,1H),3.63-3.56(m,1H),3.38-3.30(m,1H),3.09-2.88(m,4H),2.66(t,J＝11.1Hz,1H),2.35(d,J＝6.7Hz,2H),2.06-1.90(m,3H),1.41-1.30(m,2H)。MS m/z 551.6[M+H]⁺。

EXAMPLE 19 preparation of Compound 18R

Compound 18R-a (400mg,0.82mmol) was dissolved in acetonitrile (5mL), followed by the addition of hexamethyleneimine (18R-b,81mg,0.82mmol) and diisopropylethylamine (317mg,2.46mmol) in that order. The reaction mixture was stirred at 60 ℃ for 3 hours. TLC monitored the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (dichloromethane: methanol ═ 30:1) to give 18R-c (326mg, yield 72%) as a pale yellow solid.

Compound 18R-c (300mg,0.54mmol) was dissolved in DMF (10mL) and DMF-DMA (2mL) was added. The reaction mixture was stirred at 130 ℃ overnight. TLC monitored the reaction was complete. The reaction solution was concentrated under reduced pressure to give crude compound 18R-d (used in the next reaction without purification).

Crude compound 18R-d (329mg,0.54mmol) was dissolved in methanol (5mL) and sodium periodate (347mg,1.62mmol) was added portionwise under ice bath. The reaction mixture was warmed to room temperature and stirred for 3 hours. TLC monitored the reaction was complete. The reaction solution was filtered, and the obtained filtrate was concentrated under reduced pressure to give crude compound 18R-e (used in the next reaction without purification).

Crude compound 18R-e (306mg, 0.54mmol) was dissolved in ethanol (5mL) and hydrazine hydrate (68mg, 1.08mmol) was added. The reaction mixture was stirred at 80 ℃ for 3 hours. TLC monitored the reaction was complete. The reaction mixture was distilled under reduced pressure, and the crude product was isolated and purified by preparative thin plate chromatography to give compound 18R-f as a yellow solid (56mg, yield 19%).

Compound 18R-f (56mg,0.10mmol) was dissolved in methanol (5mL) and HCl in dioxane (4.0M,1mL) was added. The reaction mixture was stirred at 40 ℃ for 3 hours. TLC monitored the reaction was complete. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Dissolving the obtained mixture in a small amount of methanol, adjusting the pH value to 7-8 by using ammonia water, and then concentrating under reduced pressure. The crude product was isolated and purified by preparative thin-plate chromatography (dichloromethane: methanol ═ 20:1, 2% aqueous ammonia) to give compound 18R-g (44mg, yield 98%) as a pale yellow solid. MS M/z 449.2[ M + H ]]⁺。

Compound 18R-g (20mg,0.04mmol), paraformaldehyde (3mg,0.09mmol), and anhydrous zinc chloride (19mg,0.14mmol) were dissolved in methanol (3mL), followed by addition of sodium cyanoborohydride (9mg,0.14 mmol). The reaction mixture was heated to 60 ℃ and stirred for 1 hour. TLC monitored the reaction was complete. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was isolated and purified by preparative thin-plate chromatography (dichloromethane: methanol ═ 20:1, 2% aqueous ammonia) to give compound 18R (14mg, yield 68%) as a yellow solid.¹H NMR(500MHz,CDCl₃)δ10.81(s,1H),9.66(s,1H),7.81(s,1H),7.47(d,J＝1.8Hz,1H),7.14(dd,J＝8.7,2.0Hz,1H),6.75(d,J＝8.8Hz,1H),4.23-4.16(m,1H),4.05-3.99(m,1H),3.89-3.77(m,4H),3.69-3.63(m,1H),3.25-3.16(m,1H),2.99-2.92(m,1H),2.89-2.77(m,2H),2.36(s,3H),2.43-2.19(m,1H),1.89-1.79(m,5H),1.62-1.55(m,4H)。MS m/z 463.5[M+H]⁺。

EXAMPLE 20 preparation of Compound 19R

Compound 18R-g (23mg,0.05mmol) and 2-bromoethanol (8R-a,6mg,0.05mmol) were dissolved in DMF (2mL), and potassium carbonate (21mg,0.15mmol) was added. The reaction mixture was heated at 60 ℃ and stirred overnight. TLC monitored the reaction was complete. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting crude product was isolated and purified by preparative thin-plate chromatography (dichloromethane: methanol ═ 20:1, 2% aqueous ammonia) to give compound 19R (10mg, yield 40%) as a yellow solid.¹H NMR(500MHz,CDCl₃)δ11.04(s,1H),7.86(s,1H),7.47(d,J＝2.3Hz,1H),7.13(dd,J＝8.8,2.2Hz,1H),6.74(d,J＝8.8Hz,1H),4.34(t,2H),4.17(dd,J＝10.5,2.5Hz,1H),4.05-3.96(m,3H),3.88-3.76(m,4H),3.66-3.61(m,1H),3.19-3.13(m,1H),3.09-2.94(m,3H),2.71-2.64(m,1H),2.53(t,J＝11.1Hz,1H),1.90-1.77(m,4H),1.59-1.54(m,4H)。MS m/z 493.4[M+H]⁺。

EXAMPLE 21 preparation of Compound 20R

Compound 20R-a (200mg,1.13mmol) was dissolved in DMSO (5mL), and then compound (R) -1-Boc-3-hydroxymethylpiperazine (20R-b,244mg,1.13mmol) and potassium hydroxide (190mg,3.39mmol) were added in that order. The reaction mixture was stirred at room temperature for 1 hour, then heated to 60 ℃ and stirred for 2 hours. TLC monitored the reaction was complete. The reaction was poured into an appropriate amount of saturated sodium chloride solution and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (dichloromethane) to give compound 20R-c as a pale yellow solid (316mg, yield 79%).

Compound 20R-c (300mg,0.42mmol) and palladium on carbon catalyst (10%, 40mg) were added to methanol (10mL) at room temperature, and the reaction mixture was stirred at 40 ℃ under a hydrogen atmosphere of 1 atm for 0.5 hour. TLC monitored the reaction was complete. The reaction mixture was filtered through celite, and the resulting filtrate was concentrated under reduced pressure to give a crude product. The crude product was isolated and purified by silica gel column chromatography (dichloromethane: methanol ═ 30:1) to give compound 20R-d (180mg, yield 62%) as a pale yellow solid.

Compound 20R-d (180mg,0.56mmol) was dissolved in acetonitrile (5mL), followed by the addition of methyl 2, 4-dichloro-6-methylpyrimidine-5-carboxylate (1R-c,123mg,0.56mmol) and diisopropylethylamine (217mg,1.68mmol) in that order. The reaction mixture was stirred at 60 ℃ overnight. TLC monitored the reaction was complete. The reaction solution was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane: methanol ═ 50:1) to give compound 20R-e (164mg, yield 58%) as a pale yellow solid.

Compound 20R-e (164mg,0.32mmol) was dissolved in acetonitrile (5mL), followed by the addition of 2- (piperidin-4-yl) acetonitrile hydrochloride (1R-e,51mg,0.32mmol) and diisopropylethylamine (124mg,0.96mmol) in that order. The reaction mixture was stirred at 60 ℃ for 1 hour. TLC monitored the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane: methanol ═ 30:1) to give compound 20R-f (160mg, yield 83%) as a pale yellow solid.

Compound 20R-f (160mg,0.27mmol) was dissolved in DMF (3mL) and DMF-DMA (1mL) was added. The reaction mixture was stirred at 130 ℃ overnight. TLC monitored the reaction was complete. The reaction solution was concentrated under reduced pressure to give a crude compound 20R-g (used in the next reaction without purification).

Crude compound 20R-g (174mg,0.27mmol) was dissolved in methanol (5mL) and sodium periodate (172mg,0.82mmol) was added portionwise under ice bath. The reaction mixture was warmed to room temperature and stirred for 3 hours. TLC monitored the reaction was complete. The reaction solution was filtered, and the resulting filtrate was concentrated under reduced pressure to give a crude compound 20R-h (used in the next reaction without purification).

Crude compound 20R-h (163mg, 0.27mmol) was dissolved in ethanol (5mL) and hydrazine hydrate (33mg, 0.53mmol) was added. The reaction mixture was stirred at 80 ℃ for 5 hours. TLC monitored the reaction was complete. The reaction mixture was filtered to obtain a filter cake, which was then separated and purified by preparative thin plate chromatography to give compound 20R-i as a yellow solid (67mg, yield 42%).

Compound 20R-i (67mg,0.11mmol) was dissolved in methanol (5mL) and HCl in dioxane (4.0M,1mL) was added. The reaction mixture was stirred at 40 ℃ for 3 hours. TLC monitored the reaction was complete. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Dissolving the obtained mixture in a small amount of methanol, adjusting the pH value to 7-8 by using ammonia water, and then concentrating under reduced pressure. The crude product was isolated and purified by preparative thin-plate chromatography (dichloromethane: methanol ═ 20:1, 2% aqueous ammonia) to give compound 20R-j (47mg, yield 84%) as a pale yellow solid. MS M/z 449.2[ M + H ]]⁺。

Compound 20R-j (47mg,0.10mmol), paraformaldehyde (6mg,0.19mmol), and anhydrous zinc chloride (39mg,0.29mmol) were dissolved in methanol (3mL), followed by addition of sodium cyanoborohydride (18mg,0.29 mmol). The reaction mixture was heated to 60 ℃ and stirred for 1 hour. TLC monitored the reaction was complete. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was isolated and purified by preparative thin-plate chromatography (dichloromethane: methanol ═ 20:1, 2% aqueous ammonia) to give compound 20R (31mg, yield 64%) as a yellow solid.¹H NMR(500MHz,DMSO-d₆)δ12.79(s,1H),11.21(s,1H),7.89(s,1H),7.16(dd,J＝15.0,2.4Hz,1H),7.05(s,1H),4.99-4.48(br.,2H),4.20(dd,J＝10.8,2.6Hz,1H),4.10-4.04(m,1H),3.60-3.52(m,1H),3.18-3.11(m,1H),3.09-2.96(m,3H),2.70-2.61(m,2H),2.55(d,J＝6.6Hz,2H),2.40-2.33(m,1H),2.30-2.23(m,1H),2.20(s,3H),2.03-1.95(m,1H),1.83(d,J＝12.2Hz,2H),1.29-1.19(m,2H)。MS m/z 506.3[M+H]⁺。

EXAMPLE 22 preparation of Compound 21S

Compound 21S-a (300mg,0.86mmol) was dissolved in methanol (5mL) and HCl in dioxane (4.0M,5mL) was added. The reaction mixture was stirred at room temperature for 3 hours. TLC monitored the reaction was complete. The reaction was stripped of solvent under reduced pressure, dichloromethane (10mL) and saturated aqueous sodium bicarbonate (10mL) were added, stirred at room temperature for 0.5h, and extracted with dichloromethane (3X10 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting yellow solid compound 21S-b was used directly in the next reaction. MS M/z 250.2[ M + H ]]⁺。

Compound 21S-b (214mg,0.86mmol), paraformaldehyde (52mg,1.72mmol), and anhydrous zinc chloride (351mg,2.58mmol) were dissolved in methanol (10mL), followed by addition of sodium cyanoborohydride (162mg,2.58 mmol). The reaction mixture was heated to 60 ℃ and stirred for 1 hour. TLC monitored the reaction was complete. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was isolated and purified by preparative thin-plate chromatography (dichloromethane: methanol ═ 30:1, 2% aqueous ammonia) to give compound 21S-c (226mg, yield 100%) as a yellow solid. MS M/z 264.4[ M + H ]]⁺。

To methanol (5mL) at room temperature was added compound 21S-c (226mg,0.86mmol) and palladium on carbon catalyst (10%, 100 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. TLC monitored the reaction was complete. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was isolated and purified by silica gel column chromatography (dichloromethane: methanol ═ 20:1) to give compound 21S-d (130mg, 65% yield in three steps). MS M/z 234.3[ M + H ]]⁺。

Compound 21S-d (130mg,0.56mmol) and compound 1R-c (123mg,0.56mmol) were dissolved in acetonitrile (5mL) and diisopropylethylamine (0.28mL,1.68mmol) was added dropwise under an ice salt bath. After stirring for half an hour, the mixture was warmed to room temperature and stirred at room temperature for 3 hours. TLC monitored the reaction was complete. The reaction mixture was concentrated under reduced pressure (low temperature). The crude product was isolated and purified by preparative thin-plate chromatography (dichloromethane: methanol ═ 20:1) to give the yellow compound 21S-e (100mg, yield 43%). MS M/z 418.4[ M + H ]]⁺。

Compound 21S-e (100mg,0.24mmol) and compound 1R-e (59mg,0.48mmol) were dissolved in acetonitrile (5mL) and diisopropylethylamine (0.28mL,1.68mmol) was added dropwise. The reaction mixture was stirred at 60 ℃ for 3 hours. TLC monitored the reaction was complete.The reaction mixture was concentrated under reduced pressure. The crude product was isolated and purified by preparative thin-plate chromatography (dichloromethane: methanol ═ 30:1) to give the compound 21S-f (92mg, yield 76%) as a yellow solid. MS M/z 506.7[ M + H ]]⁺。

Compound 21S-f (92mg,0.18mmol) was dissolved in DMF (2mL) and DMF-DMA (393mg,3.30mmol) was added. The reaction mixture was stirred at 130 ℃ overnight. TLC monitored the reaction was complete. The reaction solution was concentrated under reduced pressure to give crude compound 21S-g (used in the next reaction without purification).

Crude compound 21S-g (102mg,0.18mmol) was dissolved in methanol (5mL) and sodium periodate (195mg,0.91mmol) was added portionwise under ice bath. The reaction mixture was warmed to room temperature and stirred for 3 hours. TLC monitored the reaction was complete. The reaction solution was filtered, and the resulting filtrate was concentrated under reduced pressure to give crude compound 21S-h (used in the next reaction without purification).

The crude compound 21S-h (94mg, 0.18mmol) was dissolved in ethanol (5mL) and hydrazine hydrate (113mg, 1.80mmol) was added. The reaction mixture was stirred at 80 ℃ for 3 hours. TLC monitored the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the crude product was isolated and purified by preparative thin-plate chromatography (dichloromethane: methanol ═ 15:1) to give the compound 21S as a pale yellow solid (6mg, yield 6%). MS M/z 502.4[ M + H ]]⁺。

Example 23 inhibition of kinase Activity

Syk kinase Activity inhibition assay

The method comprises the following steps: the Syk protein kinase activity was determined using Caliper mobility shift assay (Caliper mobility shift assay). Compounds were dissolved in DMSO and then treated with kinase buffer (20mM HEPES, 0.01% Triton X-100, 5mM MgCl)₂，1mM MnCl₂2mM DTT) and 5 μ L of compound (10% DMSO) at 5-fold final reaction concentration was added to the 384-well plate. mu.L of a 2.5-fold enzyme (with Syk) solution was added and incubated at room temperature for 10 minutes, followed by 10. mu.L of a 2.5-fold substrate (Peptide FAM-P22 and ATP) solution. After incubation at 28 ℃ for 30 minutes, 25. mu.L of stop solution (100 mM HEPES, pH 7.5, 0.015% Brij-35, 0.2% Coating Reagent #3, 50mM EDTA) was added to stop the reaction. Conversion data were read on a Caliper EZ Reader II (Caliper Life Sciences). Converting the conversion rateInhibition rate data (% inhibition rate ═ max-conversion rate)/(max-min) × 100). Wherein max refers to the conversion rate of a DMSO control, and min refers to the conversion rate of an enzyme-free control. The concentration and the inhibition rate of the compound are used as horizontal and vertical coordinates to draw a curve, XLFitexcel add-in version4.3.1 software is used for fitting the curve and calculating IC₅₀。

The method 2 comprises the following steps: the inhibitory effect of compounds on the kinase Syk was tested using the Caliper Mobility Shift Assay method with a final test concentration of compounds starting at 1000nM, 3-fold dilution, 7 or 8 concentrations. 250nL of 100-fold final concentration compound was transferred to 384-well reaction plates using a dispenser Echo 550, 10. mu.L of kinase solution at a final concentration of 1nM Syk was added, and pre-incubation was performed for 10 minutes at room temperature (negative control wells contained 10. mu.L of kinase buffer and 250nL of 100% DMSO; positive control wells contained 10. mu.L of kinase solution and 250nL of 100% DMSO). The reaction was initiated by adding 15. mu.L of a mixed solution of ATP at a final concentration of 4. mu.M and substrate No. 22 peptide at 3. mu.M to Syk, and the reaction was stopped at room temperature for 30 minutes by adding 30. mu.L of a termination detection solution containing EDTA. The conversion was read using a Caliper EZ Reader. And the conversion inhibition rate is (the positive control conversion rate mean value-the sample conversion rate%/(the positive control conversion rate mean value-the negative control conversion rate mean value%). wherein, the negative control hole represents the conversion rate reading of the hole without enzyme activity, the positive control hole represents the conversion rate reading of the hole without compound inhibition, the log value of the concentration is taken as an X axis, the percentage inhibition rate is taken as a Y axis, and an energy efficiency curve is fitted by adopting the log (inhibitor) of GraphPad Prism 5 of analysis software vs₅₀The value is obtained. Calculating the formula: y ═ Bottom + (Top-Bottom)/(1+10^ ((LogIC)₅₀-X)*HillSlope))。

The activity of some representative compounds is shown in table 1. IC (integrated circuit)₅₀The values are expressed by:

A:IC₅₀the value is less than or equal to 20 nM; b20 nM<IC₅₀The value is less than or equal to 50 nM; c50 nM<IC₅₀The value is less than or equal to 100 nM; d is IC₅₀Value of>100nM。

TABLE 1 Syk kinase Activity Inhibition (IC)₅₀，nM)

Jak2 kinase Activity inhibition assay

The method comprises the following steps: IC for inhibiting kinase Jak2 enzyme activity₅₀Evaluation experiment: the buffer solution is prepared from the following components: 50mM HEPES, pH 7.5, 0.00015% Brij-35. Compounds were formulated as a concentration gradient in 100% DMSO and diluted with buffer to 10% DMSO and added to 384 well plates. For example, the compound starting concentration is 250nM, then 100% DMSO is used to make 12.5. mu.M, and the gradient dilution is 5 or 6 concentrations, then buffer dilution 10 times, make 10% DMSO compound intermediate dilution, transfer 5L to 384 hole plate. The Jak2 enzyme was diluted to optimal concentration with the following buffer: 50mM HEPES, pH 7.5, 0.00015% Brij-35, 2mM DTT. Transfer 10. mu.L to 384 well plates and incubate with compound for 10-15 min. The substrate was diluted to optimal concentration with the following buffers: 50mM HEPES, pH 7.5, 0.00015% Brij-35, 10mM MgCl₂Adenosine triphosphate at Km. The reaction was initiated by adding 10. mu.L to 384-well plates and reacted at 28 ℃ for 1 hour. Then reading the conversion rate by using a Caliper Reader, and calculating the inhibition rate. The formula is as follows: percent inhibition is (max-conversion)/(max-min) × 100. Wherein max refers to the conversion rate of a DMSO control, and min refers to the conversion rate of an enzyme-free control. Fitting of IC with XLFit excel add-in version 5.4.0.8₅₀The value is obtained. Fitting formula Y ═ Bottom + (Top-Bottom)/(1+ (IC)₅₀/X)^HillSlope)。

The method 2 comprises the following steps: the inhibitory effect of compounds on kinase Jak2 was tested using the Caliper Mobility Shift Assay method with a final test concentration of compounds of 200nM starting, 3-fold dilution, 7 or 8 concentrations. 250nL of 100 fold final concentration compound was transferred to 384 well reaction plates using a dispenser Echo 550, 10. mu.L of kinase solution with a final concentration of 0.25nM Jak2 was added and pre-incubated for 10 minutes at room temperature (negative control wells containing 10. mu.L of kinase buffer and 250nL of 100% DMSO; positive control wells containing 10. mu.L of kinase solution and 250nL of 100% DMSO). The reaction was initiated by adding 15. mu.L of a mixed solution of ATP at a final concentration of 11.4. mu.M and substrate No. 22 peptide at 3. mu.M to Jak2, and the kinase reaction was stopped by adding 30. mu.L of a termination assay solution containing EDTA at room temperature for 15 minutes. Read conversion with Caliper EZ ReaderAnd (4) rate. And the conversion inhibition rate is (the positive control conversion rate mean value-the sample conversion rate%/(the positive control conversion rate mean value-the negative control conversion rate mean value%). wherein, the negative control hole represents the conversion rate reading of the hole without enzyme activity, the positive control hole represents the conversion rate reading of the hole without compound inhibition, the log value of the concentration is taken as an X axis, the percentage inhibition rate is taken as a Y axis, and an energy efficiency curve is fitted by adopting the log (inhibitor) of GraphPad Prism 5 of analysis software vs₅₀The value is obtained. Calculating the formula: y ═ Bottom + (Top-Bottom)/(1+10^ ((LogIC)₅₀-X)*HillSlope))。

The activity of some representative compounds is shown in table 2. IC (integrated circuit)₅₀The values are expressed by:

A:IC₅₀the value is less than or equal to 5 nM; b is 5nM<IC₅₀The value is less than or equal to 20 nM; c20 nM<IC₅₀The value is less than or equal to 100 nM; d is IC₅₀Value of>100nM。

TABLE 2 inhibition of Jak2 kinase Activity (IC)₅₀，nM)

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims

1. A compound having a structure represented by the following formula (I), or an optical isomer (including racemate, single enantiomer, and possible diastereoisomer), a pharmaceutically acceptable salt, a prodrug, a deuterated form, a hydrate, and a solvate thereof:

j and G are each independently NR^f、O、S、S(O)、S(O)₂Or CR^gR^g；

n is 0, 1,2, or 3;

q is 0, 1,2, or 3;

R^fis hydrogen, C_1-8Alkyl radical, C_1-8Haloalkyl, C_2-8Alkenyl radical, C_2-8Alkynyl, 3-to 8-membered cycloalkyl, 3-to 12-membered heterocyclyl, aryl, heteroaryl, C (O) R^e、C(O)OR^h、C(O)NR^hR^h、S(O)₂R^eOr S (O)₂NR^hR^h(ii) a Wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally and each independently substituted with 1-3 substituents each independently selected from the group consisting of: halogen, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, aryl, heteroaryl, CN, NO₂、OR^h、SR^h、NR^hR^h、C(O)R^e、C(O)OR^h、C(O)NR^hR^h、NR^hC(O)R^e、S(O)₂R^eOr S (O)₂NR^hR^h；

wherein, unless otherwise specified, each of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally and independently substituted with 1 to 3 substituents each independently selected from the group consisting of: deuterium, halogen, C_1-4Alkyl radical, C_1-4Haloalkyl, C_2-4Alkenyl radical, C_2-4Alkynyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, aryl, heteroaryl, CN, NO₂、OR^h、SR^h、NR^hR^h、C(O)R^e、C(O)OR^h、C(O)NR^hR^h、NR^hC(O)R^eOr S (O)₂R^eProvided that the chemical structure formed is stable and meaningful; wherein R is^eAnd R^hIs as defined above;

2. A compound of claim 2 wherein R is¹Selected from the group consisting of: a 3-to 12-membered heterocyclyl, aryl, or heteroaryl group; wherein each heterocyclyl, aryl and heteroaryl is optionally substituted with 1-2 substituents each independently selected from the group consisting of: deuterium, halogen, CN, OR^h、NR^hR^h、C(O)R^e、C(O)OR^h、C(O)NR^hR^h、NR^hC(O)R^e、S(O)₂R^e、S(O)₂NR^hR^h、C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy-substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl, cyano-substituted C_1-4Alkyl, di (C)_1-4Alkyl) amino substituted C_1-4Alkyl, 3-to 6-membered heterocyclyl substituted C_1-4Alkyl, aryl substituted C_1-4Alkyl, heteroaryl substituted C_1-4Alkyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, aryl, or heteroaryl, provided that the chemical structure formed is stable and meaningful;

n is 0, 1, or 2;

q is 0, 1, or 2;

wherein R is^eAnd R^hIs as defined in claim 1.

3. The compound of claim 2, wherein formula (I) is:

wherein the definitions of the respective radicals are as described in claim 2.

4. The compound of claim 3, wherein the structural fragment of formula (IIa)

Selected from:

n is 0, 1, or 2; q is 0 or 1;

R^eAnd R^hIs as defined in claim 1.

5. A compound according to any one of claims 3 to 4, wherein formula (I) is:

R¹As defined in claim 2; r^eAnd R^hIs as defined in claim 1.

6. A compound according to claim 3, wherein formula (I) is:

R¹As defined in claim 2; r^eAnd R^hIs as defined in claim 1.

7. A compound according to any one of claims 5 to 6 wherein R is²Is hydrogen, halogen, C_1-2An alkyl group;

R^fselected from the group consisting of: hydrogen, C_1-4Alkyl radical, C_1-4Haloalkyl, 3-to 8-membered cycloalkyl, 3-to 9-membered heterocyclyl, aryl, heteroaryl, C (O) R^eOr S (O)₂R^e(ii) a Wherein each of the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally and independently substituted with 1-3 substituents each independently selected from the group consisting of: deuterium, halogen, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, aryl, heteroaryl, CN, NO₂、OR^e、SR^e、NR^eR^e、C(O)R^e、C(O)OR^e、C(O)NR^eR^e、NR^eC(O)R^e、S(O)₂R^eOr S (O)₂NR^hR^h；

R^eAnd R^hIs as defined in claim 1.

8. The compound of claim 7, wherein formula (I) is:

wherein R is²Is hydrogen, halogen, C_1-2An alkyl group;

s and t are each independently 1,2, or 3;

R¹As defined in claim 2; r^g、R^eAnd R^hIs as defined in claim 1.

9. A compound according to any one of claims 1 to 8 wherein R is¹Is a 3-to 12-membered heterocyclyl; wherein said heterocyclic group means a saturated or partially unsaturated monocyclic or polycyclic heterocyclic group; polycyclic heterocyclic groups refer to heterocyclic groups including spiro rings, fused rings, and bridged rings; the heterocyclyl is optionally substituted with 1-2 substituents each independently selected from the group consisting of: deuterium, halogen, CN, OR^h、NR^hR^h、C(O)R^e、C(O)OR^h、C(O)NR^hR^h、NR^hC(O)R^e、S(O)₂R^e、S(O)₂NR^hR^h、C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy-substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl, cyano-substituted C_1-4Alkyl, di (C)_1-4Alkyl) amino substituted C_1-4Alkyl, 3-to 6-membered heterocyclyl substituted C_1-4Alkyl, aryl substituted C_1-4Alkyl, heteroaryl substituted C_1-4Alkyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, aryl, or heteroaryl, provided that the chemical structure formed is stable and meaningful.

10. The compound of claim 9, wherein R is¹Selected from the group consisting of:

each of the above R^tEach independently is hydrogen, C_1-4Alkyl radical, C_1-4Haloalkyl, hydroxy-substituted C_1-4Alkyl radical, C_1-4Alkoxy-substituted C_1-4Alkyl, cyano-substituted C_1-4Alkyl, di (C)_1-4Alkyl) amino substituted C_1-4Alkyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, aryl, heteroaryl, C (O) R^eOr S (O)₂R^e；

p is 0, 1, or 2;

u and v are each independently 0, 1, or 2;

each R is^eAnd R^hIs as defined in claim 1.

11. The compound of claim 10, wherein R is¹Selected from the group consisting of:

12. The compound of claim 1, wherein the compound is selected from the group consisting of:

13. use of a compound of formula (I), or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate thereof, as claimed in claim 1 for:

(b) preparing a protein kinase targeted inhibitor; and/or

(c) Non-therapeutically inhibiting the activity of a protein kinase in vitro;

14. A pharmaceutical composition, comprising: (i) an effective amount of a compound of formula I as described in claim 1, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof; and (ii) a pharmaceutically acceptable carrier.

15. A process for the preparation of a compound according to claim 1, comprising the steps of:

(3) with compounds of the formula C4 and NH₂NH₂Reacting to obtain the compound shown in the formula I.