WO2021219140A1

WO2021219140A1 - Jak2 inhibitor and application thereof

Info

Publication number: WO2021219140A1
Application number: PCT/CN2021/091658
Authority: WO
Inventors: 吕志俭; 李佳; 苏明波; 高安慧
Original assignee: 百极弘烨(南通)医药科技有限公司
Priority date: 2020-04-30
Filing date: 2021-04-30
Publication date: 2021-11-04
Also published as: CN113583020B; CN113583020A

Abstract

Provided are a JAK2 inhibitor and an application thereof. Specifically, the present invention relates to the compound shown in formula I, or a stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug or solvate thereof, and also relates to a pharmaceutical composition of the compound and a use thereof as a JAK inhibitor, and a medical use in preparing a drug which prevents and/or treats diseases related to JAK, in particular JAK2.

Description

A JAK2 inhibitor and its application

Technical field

The invention belongs to the field of medicinal chemistry, and specifically relates to a JAK2 inhibitor and its application.

Background technique

Protein kinases (PK) are a group of enzymes that regulate a variety of important biological processes, which constitute one of the largest enzyme families in humans. The biological processes especially include cellular kinases that catalyze protein, lipid, sugar, nucleoside and other cellular metabolism. The phosphorylation of substances plays a key role in all aspects of eukaryotic cell physiology. It has been shown that abnormal kinase activity is involved in many human diseases, including cancer, autoimmune diseases and inflammatory diseases.

Janus kinase (JAK) is a cytoplasmic tyrosine kinase that transduces cytokine signals from membrane receptors to STAT transcription factors. It plays an important role in the process of cytokine signal transmission. The JAK family includes four members, JAK1, JAK2, JAK3, and Tyrosine Kinase 2 (TYK2). JAK usually associates with cytokine receptors in pairs as homodimers or heterodimers. The cytokine binds to its receptor, causing the dimerization of the receptor molecule, and the JAKs coupled to the receptor approach each other and are activated by the phosphorylation of interacting tyrosine residues. The JAK family transmits cytokine-mediated signals to cells through the JAK-STAT (signal transducer and activator of transcription) pathway.

Signal Transducer and Activator of Transcription (STAT) is a group of cytoplasmic proteins that can bind to the DNA of the regulatory region of target genes. As the downstream substrate of JAKs, STATs can be activated by tyrosine phosphorylation under the stimulation of external signals, and then transferred to the nucleus to regulate gene transcription. When cytokines bind to their receptors, JAK family members autophosphorylate and/or transphosphorylate each other, and then STATs are phosphorylated and then migrate to the nucleus to regulate transcription.

Many abnormal immune responses, such as autoimmune diseases such as allergies, asthma, (allo) transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, myelodysplastic disorders, leukemia and lymphoma Such as hematological malignancies, their regulation is related to the JAK/STAT signaling pathway.

The study found that in more than 90% of patients with polycythemia vera and about 50% of patients with primary myelofibrosis and essential thrombocythemia, the JAK2 pseudokinase domain V617F point mutation was identified. The mutation was also found in Ph-negative chronic myeloid leukemia, chronic myeloid monocytic leukemia, megakaryocyte acute myeloid leukemia and juvenile myeloid monocytic leukemia (10-20%). Other mutations in the JAK2 pseudokinase domain (including the point mutation of Arg683) have been detected in approximately 20% of Down’s syndrome-related acute lymphoblastic leukemia and acute myeloid leukemia.

Currently, there are four JAK inhibitors on the market, but they are all pan-JAK inhibitors, showing varying degrees of selectivity to JAK1, JAK2, JAK3 and TYK2. Among JAK inhibitors, the lack of selectivity for JAK2 can cause some side effects, especially the increased risk of infection. Therefore, there is a need in the art to develop small molecule inhibitors that target JAK, especially JAK2 kinase.

Summary of the invention

The present invention provides a new type of inhibitor targeting JAK, which has a selective inhibitory effect on JAK, especially JAK2, and thus has clinical significance and application prospects.

The first aspect of the present invention provides a compound represented by formula I or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate,

Where

X ₁ , X ₂ , X ₃ and X ₄ are each independently selected from the following group: N, C or CR _d ; and among X ₁ , X ₂ , X ₃ and X ₄ , 0, 1, 2, and 3 are N ；

Or, when X ₁ is CR _d , R _d is fused with X ₂ to form a substituted or unsubstituted 5-6 membered cycloalkyl, heterocyclic, aryl or heteroaryl group;

Or, when X ₂ is CR _d , R _d is fused with X ₁ to form a substituted or unsubstituted 5-6 membered cycloalkyl, heterocyclic, aryl or heteroaryl group;

Or, when X ₃ is CR _d , R _d is fused with X ₄ to form a substituted or unsubstituted 5-6 membered cycloalkyl, heterocyclic, aryl or heteroaryl group;

Or, when X ₄ is CR _d , R _d is fused with X ₃ to form a substituted or unsubstituted 5-6 membered cycloalkyl, heterocyclic, aryl or heteroaryl group;

X is selected from the following group: bond, CR _b R _c , C(=O)O-, O, NR _b , S, SO, SO ₂ , C3-C10 cycloalkylene, 3-10 membered heterocyclylene, 5-12 membered heteroarylene, C6-C12 arylene;

R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R _b , R _c and _Rd are each independently selected from the following group: H, D, halogen, amino, nitro, hydroxyl, Cyano, carboxyl, sulfone, sulfoxide, amide, sulfonamide, ester, formyl, formamide, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2- C6 alkynyl, 3-10 membered heterocyclic group, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl;

Or R ₃ and R ₄ together with the C atom to which they are attached form a substituted or unsubstituted 5-6 membered cycloalkyl, heterocyclic, aryl or heteroaryl group;

Or R ₅ and R ₆ together with the C atom to which they are attached form a substituted or unsubstituted 5-6 membered cycloalkyl, heterocyclic, aryl or heteroaryl group;

Or R _b and R _c together with the C atom to which they are connected form =0, or a substituted or unsubstituted C3-C10 cycloalkylene, 3-10 membered heterocyclylene;

(CH ₂₎ H n atoms may be optionally substituted with one or more substituents R _a;

n is 1, 2, 3, 4, 5, 6, 7 or 8;

Unless otherwise specified, the substitution refers to substitution by one or more groups selected from the following group: D, halogen, amino, nitro, hydroxyl, cyano, carboxy, sulfone, sulfoxide, amide , Sulfonamide group, ester group, formyl group, formamide group, C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, C2-C6 alkynyl group, 3-10 membered heterocyclic group, C3- C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl;

Unless otherwise specified, the above-described alkyl group, alkoxy group, alkenyl group, alkynyl group, heterocyclic group, cycloalkyl, heteroaryl, aryl groups may be further optionally substituted with one or more of R _a, wherein each R _a is independently selected from the group consisting of: halogen, amino, nitro, hydroxyl, mercapto group, a cyano group, a carboxyl group, a sulfone group, a sulfoxide group, an amide group, a sulfonamide group, an ester group, a formyl, carboxamido , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl.

In another preferred example, n is 1, 2, 3, 4, or 5.

In another preferred example, X ₁ is N.

In another preferred example, X ₂ is N.

In another preferred example, X ₃ is N.

In another preferred example, X ₄ is N.

In another preferred embodiment, the compound or its stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates, wherein:

Part is a group selected from the following group:

in,

Y ₁ and Y ₂ are each independently selected from the following group: CR _b R _c , NR _b , O, S;

R _A , R _B , R _C and R _D are each independently selected from the following group: H, deuterium, halogen, amino, nitro, hydroxyl, sulfhydryl, cyano, carboxy, sulfone, sulfoxide, amide, sulfonate Amido, ester, formyl, carboxamido, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 Cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl;

p is 1, 2, 3, 4;

m is 1 or 2;

The definitions of R _a , R _b and R _c are as described above.

In another preferred embodiment, the compound or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate, wherein X is selected from the following group: bond, CR _b R _c , O, S; wherein _{the definitions of R b} and R _c are as described above.

In another preferred embodiment, the compound or its stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates, have the structure shown in Formula II:

Where

R ₁ and R ₂ are each independently selected from the following group: H, D, halogen, amino, nitro, hydroxyl, cyano, carboxy, sulfone, sulfoxide, amide, sulfonamide, ester, and formyl , Carboxamido, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocyclyl, C3-C10 cycloalkyl, 5-12 membered hetero Aryl, C6-C12 aryl;

Or R ₁ and R ₂ are fused together with the C atom to which they are attached to form a substituted or unsubstituted 5-6 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group;

The definitions of R _a , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , X and n are as described above;

In another preferred embodiment, the compound or its stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates, have the structure shown in formula A:

in,

_{_{_{R 1, R 2, R a}}} , R 3, R 4, R 5, R 6, X and n are as defined above.

In another preferred example, X is O or CH ₂ .

In another preferred example, R ₃ and R ₄ are each independently selected from: H, D, halogen, C1-C6 alkyl, C1-C6 alkoxy; wherein, the alkyl and alkoxy may be further One or more groups selected from the following group are substituted: halogen, amino, hydroxy, carboxy, C1-C6 alkyl, C1-C6 alkoxy.

In another preferred embodiment, R ₅ and R ₆ are each independently selected from: H, D, halogen, C1-C6 alkyl, C1-C6 alkoxy, 3-10 membered heterocyclic group, C3-C10 cycloalkane Group, 5-12 membered heteroaryl group, C6-C12 aryl group; wherein, the alkyl group, alkoxy group, heterocyclic group, cycloalkyl group, heteroaryl group, aryl group may be further selected from one or more Substitution of the following groups: halogen, amino, hydroxy, carboxy, C1-C6 alkyl, C1-C6 alkoxy.

In another preferred embodiment, X ₁ , X ₂ , X ₃ , X ₄ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , X and n are specific compounds in the embodiment The corresponding specific group.

In another preferred embodiment, the compound or its stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates are selected from the following group:

In another preferred embodiment, the compound is the compound shown in the embodiment.

The second aspect of the present invention provides a pharmaceutical composition containing the compound described in the first aspect or its stereoisomer or optical isomer, or a pharmaceutically acceptable salt, prodrug or Solvates, and pharmaceutically acceptable carriers or excipients.

In another preferred embodiment, the pharmaceutical composition further includes a drug selected from the following group:

PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemipilimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10 , BAT1306, AK105, LZM 009 or biological analogues of the above drugs, etc.), PD-L1 inhibitors (such as duvacizumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obin utuzumab, Ofatumumab, veltuzumab, tositumomab, 131I-tositumomab, ibitumomab, 90Y- ibitumomab, 90In- ibitumomab, ibrituzumab ( ibritumomab tiuxetan), etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01) , ALK inhibitors (such as ceritinib, alectinib, brigatinib, loratinib, okatinib), PI3K inhibitors (such as Aidelaris, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipalisib, Buparlisib, etc.), BTK inhibitors (such as ibrutinib, Tirabrutinib, acatinib, zambutinib, Vecabrutinib, etc.), EGFR inhibitors (such as afatinib, gefitinib, erlotinib, etc.) Ni, lapatinib, dacomitinib, icotinib, canetinib, saputinib, Naquotinib, pyrrotinib, rolotinib, osimertinib, etc.), VEGFR inhibitors (such as Sorafenib, pazopanib, regorafenib, stritinib, Ningetinib, cabotinib, sunitinib, donafenib, etc.), HDAC inhibitors (such as Givinostat, Tucidinostat, Vorib) Nottal, Fimepinostat, Droxinostat, Entenuot, Daxilast, Quisinostat, Tecdinaline, etc.), CDK inhibitors (e.g. Pabocinil, Ribocinil, Abemaciclib, Milciclib, Trilaciclib, Lerociclib, etc.) , MEK inhibitors (such as simetinib (AZD6244), trametinib (GSK1120212), PD0325901, U0126, Pim asertib (AS-703026), PD184352 (CI-1040), etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.), or combinations thereof.

In another preferred embodiment, a method for preparing a pharmaceutical composition is provided, which comprises the steps of: combining a pharmaceutically acceptable carrier with the compound according to the first aspect of the present invention or its stereoisomers or optical isomers. , Pharmaceutically acceptable salts, prodrugs or solvates are mixed to form a pharmaceutical composition.

In another preferred embodiment, the compound of the present invention can be prepared into powders, tablets, granules, capsules, solutions, emulsions, suspensions and the like.

The third aspect of the present invention provides the use of the compound described in the first aspect or its stereoisomer or optical isomer, or a pharmaceutically acceptable salt, prodrug or solvate thereof, for the preparation of prophylactic or therapeutic JAK2 Drugs for mediated diseases; and/or for the preparation of JAK2 inhibitors.

In another preferred example, the JAK2-mediated disease is myelodysplastic syndrome (MDS), eosinophilia, tumor, inflammatory disease, or infection caused by bacteria, viruses or fungi.

In another preferred embodiment, the tumor is selected from the group consisting of: myeloproliferative carcinoma (MPN), melanoma, lung cancer, kidney cancer, ovarian cancer, prostate cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, skin cancer , Head and neck cancer, uterine cancer, rectal cancer, anal cancer, stomach cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vagina cancer, vulvar cancer, Hodgkin’s disease, non-Hodgkin’s lymphoma, esophagus Cancer, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, acute myeloid leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, children Solid tumors, lymphocytic lymphoma, bladder cancer, renal or ureteral cancer, renal pelvis cancer, central nervous system (CNS) tumors, primary CNS lymphoma, tumor angiogenesis, spinal axonoma, brainstem glioma, Pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma.

In another preferred example, the inflammatory disease is selected from the group consisting of rheumatoid arthritis, ankylosing spondylitis, autoimmune hemolytic anemia, arthritis, myasthenia gravis, systemic lupus erythematosus, pernicious anemia, polymuscular inflammation.

In another preferred embodiment, the virus is selected from the following group: hepatitis virus (type A, B and C), sporangia virus, influenza virus, adenovirus, coronavirus, measles virus, dengue virus, polio Virus, rabies virus.

In another preferred embodiment, the bacteria are selected from the following group: Chlamydia, Rickettsia, Mycobacterium, Staphylococcus, Pneumococcus, Cholera, Tetanus.

In another preferred embodiment, the fungus is selected from the group consisting of Candida, Aspergillus, and Saccharomyces dermatitis.

The fourth aspect of the present invention provides a JAK2 inhibitor, which contains the compound described in the first aspect or its stereoisomers or optical isomers, or its pharmaceutically acceptable salts, prodrugs or solvates or second The pharmaceutical composition described in the aspect.

The fifth aspect of the present invention provides a method for preventing or treating a JAK2-mediated disease, the method comprising administering to a subject identified or diagnosed as having a JAK2-related disease a therapeutically effective amount of the compound of the first aspect or A pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition described in the second aspect.

The sixth aspect of the present invention provides a method for inhibiting JAK2 kinase activity in a cell or a subject, the method comprising contacting the cell or administering to the subject the compound of the first aspect or The steps of the pharmaceutical composition described in the second aspect.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as the embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, I will not repeat them one by one here.

Detailed ways

After extensive and in-depth research, the inventor unexpectedly discovered a series of macrocyclic compounds with novel structures. Such compounds can selectively inhibit JAK2 kinase, the selectivity represented by the ratio of JAK1/JAK2 or

The selectivity represented by the ratio of JAK3/JAK2 is increased by more than ten times or even dozens of times on average, which can become a small molecule lead compound for the study of JAK2 inhibitors, thereby providing a new material basis for the development of immune inflammation and anti-tumor drugs. . The present invention has been completed on this basis.

the term

In the present invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left. For example, -CH ₂ O- is equivalent to -OCH ₂ -.

As used herein, when used in reference to a specifically recited value, the term "about" means that the value can vary from the recited value by no more than 1%. For example, as used herein, the expression "about 100" includes all values between 99 and 101 (eg, 99.1, 99.2, 99.3, 99.4, etc.).

As used herein, the term "containing" or "including (including)" can be open, semi-closed, and closed. In other words, the term also includes "substantially consisting of" or "consisting of".

As used herein, the term "alkyl" includes straight or branched chain alkyl groups. For example, C ₁ -C ₆ alkyl means a straight or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl Wait.

As used herein, the term "alkenyl" includes linear or branched alkenyl. For example, C ₂ -C ₆ alkenyl refers to a straight or branched alkenyl group having 2-6 carbon atoms, including but not limited to vinyl, allyl, 1-propenyl, isopropenyl, 1-butene Group, 2-butenyl group, or similar group.

As used herein, the term "alkynyl" includes straight-chain or branched alkynyl groups. For example, C ₂ -C ₆ alkynyl refers to a linear or branched alkynyl group having 2-6 carbon atoms, including but not limited to ethynyl, propynyl, butynyl, or the like.

As used herein, the term "cycloalkyl" refers to a cyclic alkyl group containing a specific number of C atoms, such as "C3-C10 cycloalkyl" refers to having 3-10 (preferably 3, 4, 5, 6, 7 Or 8) cycloalkyl of carbon atoms. It may be a monocyclic ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or similar groups. It may also be in the form of a bicyclic ring, such as a bridged ring or a spiro ring. In the present invention, cycloalkyl is intended to include substituted cycloalkyl.

As used herein, the term "C1-C6 alkoxy" refers to a linear or branched alkoxy group having 1 to 6 carbon atoms; it has the formula C1-C6 alkyl-O- or -C1-C5 alkyl Group -O-C1-C5 alkyl (e.g., -CH ₂ -O-CH ₂ CH ₃ , -CH ₂ -O-(CH ₂ ) ₂ CH ₃ , -CH ₂ CH ₂ -O-CH ₂ CH ₃ ) Structure, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy and the like.

As used herein, "heterocyclic group" refers to a saturated or partially saturated cyclic group having heteroatoms selected from N, S, and O, and "3-10 membered heterocyclic group" refers to having 3-10 atoms A saturated or partially saturated cyclic group in which 1-3 atoms are heteroatoms selected from the group consisting of N, S and O. It can be a single ring or a double ring form, such as a bridged ring or a spiro ring. The 3-10 membered heterocyclic group is preferably a 3-8 membered heterocyclic group, and more preferably a 6-8 membered heterocyclic group. Specific examples can be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl and the like.

As used herein, "aryl" refers to an aromatic ring group without heteroatoms on the ring, and "C6-C12 aryl" refers to an aromatic ring group with 6 to 12 carbon atoms that does not contain heteroatoms on the ring The aryl group can be fused on a heteroaryl, heterocyclic or cycloalkyl ring, and the ring connected to the parent structure is an aryl ring. Such as phenyl (ie six-membered aromatic ring), naphthyl, etc., where six-membered aryl also means to include six-membered aryl and 5-6 membered cycloalkyl and six-membered aryl and 5-6 membered heterocycloalkyl . The C6-C12 aryl group is preferably a C6-C10 aryl group. Aryl groups can be optionally substituted or unsubstituted.

As used herein, "heteroaryl group" refers to a cyclic aromatic group having 1-3 atoms selected from the group consisting of N, S, and O, and "5-12 membered heteroaryl group" refers to having 5-12 Atomic cyclic aromatic group in which 1-3 atoms are heteroatoms selected from the group consisting of N, S and O. It may be a monocyclic ring or a condensed ring form. Specific examples can be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2, 4)-Triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring. Heteroaryl groups can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio , Alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, amide, sulfonamide, Formyl group, formamide group, carboxyl group and carboxylate group, etc.

When a substituent is a non-terminal substituent or a related group has one H atom removed, it is a subunit of the corresponding group, usually a divalent group, for example, an alkyl group has an alkylene group after removing one H atom (for example: Methylene, ethylene, propylene, isopropylidene (such as

), butylene (e.g.

), pentylene (e.g.

), hexyl (e.g.

), Heptyl (e.g.

), etc.), cycloalkyl corresponds to cycloalkylene (such as:

Etc.), the heterocyclic group corresponds to the heterocyclylene group (such as:

), cycloalkyl corresponds to heterocyclylene (such as:

Etc.), alkoxy corresponds to alkyleneoxy (-CH ₂ O-, -CH ₂ CH ₂ -O-CH ₂ -, -CH ₂ OCH ₂ CH ₂ CH ₂ -) and so on.

As used herein, "halogen" or "halogen atom" refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl and Br.

In the present invention, the term "amide group" refers to a group with the structure -CONRR', wherein R and R'can independently represent hydrogen, alkyl, cycloalkyl, aryl, heterocyclic group, as above Defined. R and R'may be the same or different in the dialkylamine segment.

In the present invention, the term "sulfonamide group" refers to a group with the structure -SO ₂ NRR', wherein R and R'can independently represent hydrogen, alkyl, cycloalkyl, aryl, heterocyclic group, As defined above. R and R'may be the same or different in the dialkylamine segment.

In the present invention, the term "formyl" refers to a group containing -CHO.

In the present invention, the term "carboxamido" means to contain

The carboxamido group is also meant to include substituted carboxamido groups, having the formula

Wherein, R each independently represents hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic group, as defined above. Each R may be the same or different.

In the present invention, "amino" means having the structure -N-RR', R and R'each independently represent hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic group, as defined above , R and R'can be the same or different.

In the present invention, "sulfoxide group" means having -S(O)-R, R independently represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic group, as defined above.

In the present invention, "sulfone group" means having -S(O) ₂ -R, R independently represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic group, as defined above.

In the present invention, "ester group" refers to a structure -C(O)-OR or RC(O)-O-, where R independently represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl , Heterocyclic group, as defined above.

In the present invention, the term "substituted" means that one or more hydrogen atoms on a specific group are replaced by a specific substituent. The specific substituents are the substituents correspondingly described in the foregoing, or the substituents appearing in each embodiment. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different in each position. Those skilled in the art should understand that the combinations of substituents contemplated by the present invention are those that are stable or chemically achievable.

Unless specifically stated to be "substituted or unsubstituted", the groups described in the present invention can be substituted by substituents selected from the following group: deuterium, halogen, cyano, nitro, hydroxyl , Amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl Group, C6-C12 aryl group.

In the present invention, the term "plurality" means 2, 3, 4, 5 independently.

As used herein, the term "tautomers" means that structural isomers with different energies can exceed the low energy barrier to convert into each other. For example, proton tautomers (ie, proton transfer) include interconversion through proton transfer, such as 1H-indazole and 2H-indazole. Valence tautomers include interconversion through the recombination of some bonding electrons.

As used herein, the term "solvate" refers to a complex in which the compound of the present invention coordinates with solvent molecules to form a specific ratio.

The term "substituted" as used herein refers to the replacement of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent may be the correspondingly described substituent in the foregoing, or may be a specific substituent appearing in each embodiment or a conventional substituent in the art. Therefore, in the present invention, the substituents in the general formula can also be each independently the corresponding group in the specific compound in the embodiment; that is, the present invention includes not only the combination of the substituents in the above general formula, but also the general formula Combinations of some of the substituents shown in the examples with other specific substituents appearing in the examples. It is not difficult for those skilled in the art to prepare a compound having such a combination of substituents and test that the resulting compound is active based on the usual technical means in the field.

Based on the teachings of the present invention and the common knowledge in the field, those skilled in the art will understand that each group in the compound of the present invention can be further substituted to obtain derivatives capable of having the same or similar activity as the compounds specifically disclosed in the present invention. Things. Each group in the compound of the present invention can be substituted by various substituents conventional in the art, as long as the substitution does not violate the rules of chemical synthesis or valence.

Active ingredient

As used herein, the terms "compounds of the present invention" or "active ingredients of the present invention" are used interchangeably and refer to formula (I) or its stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs Or solvate. The term also includes racemates, optical isomers,

In formula I, X ₁ , X ₂ , X ₃ , X ₄ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and n have the definitions as described above.

Preferably, the compound of the present invention has the structure shown in Formula II:

Wherein, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , X and n are as defined above.

Preferably, the compound of the present invention has the structure shown in formula A:

in,

The definitions of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , X and n are as described above.

Preferably, in the present invention, X ₁ , X ₂ , X ₃ and X ₄ are all CH.

Preferably, in the present invention, both R ₈ and R ₉ are H.

Preferably, in the present invention, X is O or CH ₂ ;

R ₁ and R ₂ are both H;

n is 3, 4 or 5;

R ₃ and R ₄ are each independently selected from: H, D, halogen, C1-C6 alkyl, C1-C6 alkoxy; wherein, the alkyl group and alkoxy group may be further selected from one or more of the following Group substitution: halogen, amino, hydroxy, carboxy, C1-C6 alkyl, C1-C6 alkoxy;

R ₅ and R ₆ are each independently selected from: H, D, halogen, C1-C6 alkyl, C1-C6 alkoxy, 3-10 membered heterocyclic group (preferably 5-6 membered, such as morpholinyl, piper Azinyl, piperidinyl), C3-C10 cycloalkyl (preferably C3-C6), 5-12 membered heteroaryl (preferably 5-6 membered), C6-C12 aryl (preferably phenyl); The alkyl group, alkoxy group, heterocyclic group, cycloalkyl group, heteroaryl group, and aryl group may be further substituted by one or more groups selected from the following group: halogen, amino, hydroxyl, carboxyl, C1-C6 alkane Group, C1-C6 alkoxy.

The salts that may be formed by the compounds of the present invention also belong to the scope of the present invention. Unless otherwise specified, the compounds in the present invention are understood to include their salts. The term "salt" as used herein refers to a salt formed into an acid or basic form with an inorganic or organic acid and a base. In addition, when the compound of the present invention contains a basic fragment, it includes but is not limited to pyridine or imidazole, and when it contains an acidic fragment, including but not limited to carboxylic acid, the zwitterion ("internal salt") that may be formed is contained in Within the scope of the term "salt". Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, for separation or purification steps in the preparation process. The compound of the present invention may form a salt. For example, the compound I can be obtained by reacting with a certain amount of acid or base, such as an equivalent amount of acid or base, and salting out in the medium, or freeze-dried in an aqueous solution.

The basic fragments contained in the compounds of the present invention, including but not limited to amines or pyridine or imidazole rings, may form salts with organic or inorganic acids. Typical acids that can form salts include acetate (such as acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, and benzoate. , Benzene sulfonate, hydrogen sulfate, borate, butyrate, citrate, camphor salt, camphor sulfonate, cyclopentane propionate, diglycolate, dodecyl sulfate, Ethane sulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodide, isethionate (E.g. 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g. 2-naphthalenesulfonate), nicotinate, nitrate, oxalic acid Salt, pectinate, persulfate, phenylpropionate (such as 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, Sulfate (such as formed with sulfuric acid), sulfonate, tartrate, thiocyanate, toluenesulfonate such as p-toluenesulfonate, dodecanoate, etc.

The acidic fragments that some compounds of the present invention may contain, including but not limited to carboxylic acids, may form salts with various organic or inorganic bases. Typical salts formed by bases include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts formed by organic bases (such as organic amines) such as benzathine and bicyclohexyl. Amine, Hypamine (a salt formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butyl Base amines, and salts with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecular alkyl halides (such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (Eg, dimethyl sulfate, diethyl, dibutyl and dipentyl sulfate), long-chain halides (such as chlorides and bromides of decyl, dodecyl, tetradecyl and tetradecyl And iodides), aralkyl halides (such as benzyl and phenyl bromides) and so on.

The prodrugs and solvates of the compounds of the present invention are also covered. The term "prodrug" herein refers to a compound that undergoes metabolic or chemical transformation to produce the compound, salt, or solvate of the present invention when treating related diseases. The compounds of the present invention include solvates, such as hydrates.

The compounds, salts or solvates of the present invention may exist in tautomeric forms (such as amides and imine ethers). All these tautomers are part of the invention.

All stereoisomers of compounds (for example, those asymmetric carbon atoms that may exist due to various substitutions), including their enantiomeric and diastereomeric forms, fall within the scope of the present invention. The independent stereoisomers of the compound in the present invention may not coexist with other isomers (for example, as a pure or substantially pure optical isomer with special activity), or may be a mixture, such as Racemates, or mixtures with all other stereoisomers or part of them. The chiral center of the present invention has two configurations, S or R, defined by the International Union of Theoretical and Applied Chemistry (IUPAC) in 1974. The racemic form can be resolved by physical methods, such as fractional crystallization, or separation of crystallization by derivatization into diastereomers, or separation by chiral column chromatography. Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to traditional methods, such as salt formation with an optically active acid and then recrystallization.

In the compound of the present invention, the weight content of the compound obtained by successive preparation, separation and purification is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compound), as described in the text Listed. Here, such "very pure" compounds of the invention are also part of the invention.

All configuration isomers of the compounds of the present invention are within the scope of coverage, whether in mixture, pure or very pure form. The definition of the compound of the present invention includes two olefin isomers, cis (Z) and trans (E), as well as cis and trans isomers of carbocyclic and heterocyclic rings.

Throughout the specification, groups and substituents can be selected to provide stable fragments and compounds.

Specific functional groups and chemical term definitions are described in detail below. For purposes of the present invention, the chemical elements with the Periodic Table of the Elements, CAS version , of Chemistry and Physics, 75 th Ed same as defined in Handbook.. The definition of specific functional groups is also described therein. In addition, the basic principles of organic chemistry and specific functional groups and reactivity are also explained in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and the entire contents are included in the list of references.

Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention covers all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, and exogenous Spin mixtures and other mixtures. In addition, the asymmetric carbon atom may represent a substituent, such as an alkyl group. All isomers and their mixtures are included in the present invention.

According to the present invention, the ratio of the mixture of isomers containing the isomers can be varied. For example, a mixture of only two isomers can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98: 2,99:1, or 100:0, all ratios of isomers are within the scope of the present invention. Similar ratios, which are easily understood by those skilled in the art, and ratios that are mixtures of more complex isomers are also within the scope of the present invention.

The present invention also includes isotopically labeled compounds, which are equivalent to the original compounds disclosed herein. In practice, however, it usually occurs when one or more atoms are replaced by atoms whose atomic weight or mass number is different. Examples of isotopes that can be classified as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, such as ² H, ³ H, ¹³ C, ¹¹ C, ¹⁴ C, ¹⁵ N, and ¹⁸ O, respectively. , ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl. The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotopic atoms of the above compounds are all within the scope of the present invention. Certain isotope-labeled compounds in the present invention, such as ^{radioisotopes of 3} H and ¹⁴ C, are also among them, which are useful in tissue distribution experiments of drugs and substrates. Tritium, namely ³ H and carbon-14, namely ¹⁴ C, their preparation and detection are relatively easy. It is the first choice among isotopes. In addition, heavier isotopic substitutions such as deuterium, ie ² H, have advantages in certain therapies due to its good metabolic stability, such as increasing the half-life or reducing the dosage in the body, so it can be given priority in some cases. Isotopically-labeled compounds can be prepared by general methods, by replacing readily available isotope-labeled reagents with non-isotopic reagents, using the protocol disclosed in the example.

If you want to design the synthesis of a specific enantiomer of the compound of the present invention, it can be prepared by asymmetric synthesis, or derivatized with a chiral adjuvant, separating the resulting diastereomeric mixture, and then removing the chiral adjuvant. Pure enantiomer. In addition, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, a suitable optically active acid or base can be used to form a diastereomeric salt with it, and then through separation crystallization or chromatography, etc. After separation by conventional means, the pure enantiomers are obtained.

The metabolites of the compounds and their pharmaceutically acceptable salts involved in the application, as well as the prodrugs that can be transformed into the structure of the compounds and their pharmaceutically acceptable salts involved in the application, are also included in the claims of the application. middle.

Preparation

The compounds of the present invention can be prepared according to conventional routes or methods, and can also be obtained according to the methods or routes described herein.

The preparation methods of the compounds of the present invention are described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.

Generally, in the preparation process, each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (such as 0°C to 150°C, preferably 10°C to 100°C). The reaction time is usually 0.1 hour to 60 hours, preferably 0.5 to 48 hours.

Optionally, the present invention provides a synthetic method of formula I, the synthetic route is as follows:

A-I can be obtained through conventional methods purchased or reported in the literature;

In the formula, X ₁ , X ₂ , X ₃ , X ₄ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , X and n are as defined above;

(i) In an inert solvent (such as DMF), Al and a halide undergo a substitution reaction under the action of a _{base (such as NaH, LiAlH 4, etc.) to obtain A-II;}

(ii) in an inert solvent (e.g., methanol, ethanol, etc.), a reducing agent (e.g. Pd / C, SnCl _2, etc.) in the presence of, A-II reduction reaction, to give A-III;

(iii) In an inert solvent, in a base (such as sodium carbonate, potassium carbonate, cesium carbonate, etc.) and a palladium catalyst (such as tris(dibenzylideneacetone)dipalladium, bistriphenylphosphonium dichloride, etc.) Under the action, A-III and

Coupling reaction occurs to obtain A-IV;

(iv) A-IV is hydrolyzed in an inert solvent (such as tetrahydrofuran and/or water) under alkaline (such as lithium hydroxide) conditions to obtain A-V;

(v) In an inert solvent (such as dioxane), under acidic (such as HCl) conditions, A-V removes the Boc protecting group to obtain amino acid A-VI;

(vi) Under common condensation conditions (e.g. in an inert solvent (e.g. methylene chloride), alkaline (e.g. N,N-diisopropylethylamine) conditions), A-VI will undergo condensation reaction to obtain the target Product A-VII (i.e. compound of formula I).

In the above synthesis steps, the starting materials and reagents used can be purchased commercially or synthesized by methods reported in the literature.

Pharmaceutical composition and method of administration

Because the compound of the present invention has excellent inhibitory activity of JAK kinase, especially JAK2 kinase, the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and containing the compound of the present invention The pharmaceutical composition as the main active ingredient can be used to prevent and/or treat (stabilize, reduce or cure) JAK kinase-related diseases (for example, myelodysplastic syndrome (MDS), eosinophilia, tumors, inflammatory diseases) Or infections caused by bacteria, viruses or fungi, etc.).

The pharmaceutical composition of the present invention contains a safe and effective amount of the compound of the present invention and a pharmaceutically acceptable excipient or carrier. The "safe and effective amount" refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per agent, and more preferably, contains 10-200 mg of the compound of the present invention per agent. Preferably, the "one 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 have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid). , Magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween)

), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

The administration method of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but are not limited to): oral, parenteral (intravenous, intramuscular, or subcutaneous).

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 mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, hard Calcium fatty acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microcapsules 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 compound, the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

In addition to these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.

In addition to the active compound, the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.

The composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (for example, anti-HBV agents).

When administered in combination, the pharmaceutical composition also includes one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds. One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compounds can be used for the prevention and/or treatment of JAK simultaneously, separately or sequentially with the compound of the present invention , Especially JAK2 related diseases.

When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment. The dosage is usually 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage should also consider factors such as the route of administration and the patient's health status, which are all within the skill range of a skilled physician.

The main advantages of the present invention are:

1. The compound of the present invention has novel structure and excellent JAK kinase, especially JAK2 kinase inhibitor;

2. The compound of the present invention has better selectivity inhibition for JAK2.

The present invention will be further explained below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods that do not indicate specific conditions in the following examples usually follow the conventional conditions or the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are weight percentages and parts by weight.

The experimental materials and reagents used in the following examples can be obtained from commercial channels unless otherwise specified.

General materials and test methods:

The synthetic methods of the compounds of the present invention are shown in the following schemes, methods and examples. The starting materials are commercially available or can be prepared according to known methods in the art or described herein. The compound of the present invention can be illustrated by the specific examples shown below. However, these specific embodiments should not be construed as the only kind of the present invention. These examples further illustrate the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of conditions and procedures can be used to prepare these compounds. All temperatures are in degrees Celsius, unless otherwise stated.

The preparation of thin layer chromatography (PTLC) is carried out on a 20×20 cm plate (500 μm thick silica gel). Biotage flash chromatography system was used for silica gel chromatography.

1H NMR uses Bruker AscendTM400 spectrometer, 400MHz, 298°K, and the chemical shift (ppm) of the residual proton in the deuterated reagent is given as a reference:

CHCl3δ=7.26ppm, CH3OH or CH3ODδ=3.30ppm, DMSO-d6δ=2.50ppm

LCMS chromatography adopts Agilent Technologies 1200 series or 6120 quadrupole spectrometer. For the LC mobile phase is acetonitrile (A) and water (B) and 0.01% formic acid, eluent gradient: 6.0 minutes 5-95% A, 5.0 minutes 60-95% A, 5.0 minutes 80-100% A and 10 minutes 85-100% A, using SBC1850 mm x 4.6 mm x 2.7 micron capillary column.

Mass spectrometry (MS) is measured by electrospray ionization mass spectrometry (ESI).

HPLC mass spectrometry analysis conditions:

LC1: Column: SB-C18 50mm×4.6mm×2.7μm

Temperature: 50℃

Eluent: 5:95 to 95:5 volume/volume acetonitrile/water+0.01% formic acid, 6 minutes.

Flow rate: 1.51.5mL/min, injection of 5μL

Detection: PDA, 200-600nm

MS: mass range 150-750amu; positive ion electrospray ionization

LC2: Column: SB-C18 50mm×4.6mm×2.7μm

Temperature: 50℃

Eluent: 5:95 to 95:5 volume/volume acetonitrile/water + 0.05% TFA gradient over 3.00 minutes.

Flow rate: 1.51.5mL/min, injection of 5μL

Detection: PDA, 200-600nm

MS: mass range 150-750amu; positive ion electrospray ionization

LC3 column: SB-C18 50mm×4.6mm×2.7μm

Temperature: 50℃

Eluent: 10:90 to 98:2 volume/volume acetonitrile/water + 0.05% TFA gradient over 3.75 minutes.

Flow rate: 1.0mL/min, injection of 10μL

Detection: PDA, 200-600nm

MS: mass range 150-750amu; positive ion electrospray ionization

Abbreviation list:

AcOH = acetic acid

Alk is alkyl

AR is aryl

Boc=tert-Butoxycarbonyl

bs = broad peak

CH ₂ Cl ₂ = dichloromethane

d = doublet

dd = double doublet

DBU=1,8-diazabicyclo[5.4.0]undec-7-ene

DCM=dichloromethane

DEAD = diethyl azodicarboxylate

DMF=N,N-Dimethylformamide

DMSO = dimethyl sulfoxide

EA = ethyl acetate

ESI = electrospray ionization

Et=ethyl

EtOAc = ethyl acetate

EtOH=ethanol

h = hour

HOAc = acetic acid

LiOH = lithium hydroxide

m = multiple

Me = methyl

MeCN = Acetonitrile

MeOH = methanol

MgSO4 = magnesium sulfate

min = minutes

MS = mass spectrum

NaCl = sodium chloride

NaOH = sodium hydroxide

Na2SO4 = sodium sulfate

NMR = nuclear magnetic resonance spectroscopy

PE = petroleum ether

PG = protecting group

Ph = phenyl

rt = room temperature

s=single peak

t = triplet

TFA = trifluoroacetic acid

THF = tetrahydrofuran

TS = p-toluenesulfonyl (toluenesulfonyl)

Example 1 Synthesis of Compound A1

Step 1: Methyl 5-(2-morpholine-5-nitrobenzyloxy)valerate (A1-2)

Under nitrogen protection, 2-morpholine-5-nitrobenzyl alcohol (A1-1, 500mg, 2.1mmol) was added to anhydrous N,N-dimethylformamide (5ml), cooled to 0℃ in an ice bath, and added Sodium hydride (60%, 168mg, 4.2mmol), stirring on ice bath for 30 minutes, and then slowly adding 5-bromovalerate methyl ester (614mg, 3.15mmol) in N,N-dimethylformamide (6ml) solution, Naturally rise to room temperature and continue to stir for 16h. After TLC confirmed that the reaction was almost complete, it was quenched by adding saturated ammonium chloride solution under ice bath, extracted with EA, washed with deionized water three times, dried over anhydrous sodium sulfate, concentrated EA solution, and the residue was purified by column chromatography to obtain 5-(2 -Methylmorpholine-5-nitrobenzyloxy)valerate (A1-2, 505 mg, yield 68%). ¹ H NMR(400MHz,CDCl3)δ8.36(d,J=2.6Hz,1H), 8.15(dd,J=8.9,2.7Hz,1H), 7.08(d,J=8.9Hz,1H), 4.54( s,2H),3.93-3.85(m,4H),3.69(s,3H),3.57(t,J=6.0Hz,2H),3.13-3.02(m,4H),2.37(t,J=7.1Hz , 2H), 1.31 (s, 2H), 1.28 (s, 2H).

Step 2: Methyl 5-(2-morpholine-5-aminobenzyloxy)valerate (A1-3)

5-(2-morpholine-5-nitrobenzyloxy)pentanoic acid methyl ester (A1-2, 505mg, 1.43mmol) was added to methanol (5ml), and then palladium/carbon (25mg, 10% on carbon( Wetted with ca. 55% Water), stirred at room temperature for 6 hours, TLC confirmed the completion of the reaction, suction filtration, concentrated the filtrate, the residue was purified by column chromatography to obtain a yellow oily 5-(2-morpholine-5-aminobenzyloxy) Methyl valerate (A1-3, 285mg, yield 61.7%). MS (ESI) m/z: theoretical value (calcd) 323.20 (M+H), found value (found) 323.42.

The third step: tert-butyl (4-(2-chloropyrimidine-4-)phenyl)carbamate (A1-4)

Under nitrogen protection, 2,4-dichloropyrimidine (1.50g, 10.1mmol) and 4-(N-Boc-amino)phenylboronic acid (2.37g, 10mmol) were added to the mixed solvent N,N-dimethylformamide:1 , 4-Dioxane: water = 12ml: 7.5ml: 3ml, then add sodium carbonate (2.12g, 20mmol), then add bistriphenylphosphorus palladium dichloride (73mg, 0.1mmol), and heat to 80 Stir at ℃ for 16h. After TLC confirms that the reaction is complete, concentrate 1,4-dioxane, extract with EA, wash the organic phase with deionized water three times, dry with anhydrous sodium sulfate, concentrate EA, and purify the residue by column chromatography to obtain a white solid A1-4 (2.50g, yield 82%). MS (ESI) m/z: theoretical value 306.10 (M+H), measured value 306.32; ¹ H NMR (400MHz, CDCl3): δ8.73 (d, J=5.2Hz, 1H), 8.24–8.16 (m, 4H), 7.73 (d, J=5.2 Hz, 1H), 3.99 (s, 3H).

The fourth step: 5-(5-((4-(4-(tert-butoxycarbonylamino)phenyl)pyrimidine-2-)amino)-2-morpholinebenzyloxy)pentanoic acid methyl ester (A1-5)

Nitrogen protection, 5-(2-morpholine-5-aminobenzyloxy)pentanoic acid methyl ester (A1-3, 142.5mg, 0.44mmol), (4-(2-chloropyrimidine-4-)phenyl)carbamic acid Tert-Butyl ester (A1-4, 162mg, 0.53mmol) and potassium carbonate (122mg, 0.88mmol) were added to 1,4-dioxane (10ml), stirred for 5min, and tris(dibenzylideneacetone) was added all at once Dipalladium (40.5mg, 0.04mmol) and 2-dicyclohexylphosphorus-2',4',6'-triisopropylbiphenyl (42mg, 0.09mmol) were heated to 100°C and stirred for 16h. After TLC confirmed that the reaction was complete, 1,4-dioxane was concentrated, EA and deionized water were added, and the liquids were extracted and separated. The organic layer was dried over anhydrous sodium sulfate, and the EA was concentrated. The residue was purified by column chromatography to obtain A1- 5 (175 mg, 67% yield).

The fifth step: 5-(5-((4-(4-(tert-butoxycarbonylamino)phenyl)pyrimidine-2-)amino)-2-morpholinebenzyloxy)valeric acid (A1-6)

5-(5-((4-(4-(tert-butoxycarbonylamino)phenyl)pyrimidine-2-)amino)-2-morpholinebenzyloxy)pentanoic acid methyl ester (A1-5, 175mg, 0.30mmol ) Add tetrahydrofuran (3ml) and water (1ml), then add lithium hydroxide monohydrate (62mg, 1.50mmol), and stir at room temperature for 16h. After TLC confirms that the reaction is complete, add 1mol/L HCl to adjust the pH=5~6, concentrate tetrahydrofuran, add EA and deionized water, extract the layers, dry with anhydrous sodium sulfate, concentrate EA, and purify the residue by column chromatography. Obtain 5-(5-((4-(4-(tert-butoxycarbonylamino)phenyl)pyrimidine-2-)amino)-2-morpholinebenzyloxy)pentanoic acid (A1-6, 110mg, yield 64.4 %).

The sixth step: 5-((5-((4-(4-aminophenyl)pyrimidine-2-)amino)-2-morpholinebenzyloxy)pentanoic acid (A1-7)

5-(5-((4-(4-(tert-butoxycarbonylamino)phenyl)pyrimidine-2-)amino)-2-morpholinebenzyloxy)pentanoic acid (A1-6, 110mg, 0.19mmol) was added Add 4mol/L Dioxane solution (2ml) of HCl to 1,4-dioxane (2ml) dropwise, and stir at room temperature for 16h. After LCMS confirmed that the reaction was complete, 1,4-dioxane was concentrated, saturated aqueous sodium bicarbonate solution was added to adjust the pH to neutral, EA was extracted, dried, and concentrated EA. The residue was purified by reverse phase column and lyophilized to obtain 5 -((5-((4-(4-Aminophenyl)pyrimidine-2-)amino)-2-morpholinebenzyloxy)pentanoic acid (A1-7, 30 mg, yield 33%).

The seventh step: 4 ⁴ -morpholine-6-oxa-3,12-diaza-2(4,2)-pyrimidine hetero-1(1,4),4(1,3)-diphenyl hetero Cyclododecanophen-11-one (A1)

2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (47.8mg, 0.13mmol) and N,N-diisopropylethylamine ( 16.3mg, 0.13mmol) was added to dichloromethane (2ml) and stirred for 5min. At room temperature, slowly add 5-((5-((4-(4-aminophenyl)pyrimidine-2-)amino)-2-morpholinebenzyloxy)pentanoic acid (A1-7, 30mg, 0.06mmol) The mixed solution of DCM (8ml) and DMF (1ml) was dripped and stirred at room temperature for 5h. After LCMS confirmed that the reaction was complete, deionized water was added to quench the reaction. The product was purified by a reverse phase column and lyophilized to obtain a white solid 4 ⁴ -morpholine-6-oxa-3,12-diaza-2(4,2)-pyrimidinhe-1(1,4), 4(1,3)-Diphenylcyclododecanophen-11-one (A1, 8.3mg, yield 28.7%). MS (ESI) m/z: theoretical value 460.23 (M+H), measured value 460.41 ; ¹ H NMR(400MHz,DMSO)δ9.55(d,J=6.7Hz,2H), 8.52(d,J=5.0Hz,1H), 8.48(s,1H), 7.88(d,J=8.3Hz , 2H), 7.36 (d, J = 8.2 Hz, 2H), 7.22 (d, J = 5.1 Hz, 1H), 7.10-7.06 (m, 1H), 7.03 (s, 1H), 4.47 (s, 2H) , 3.75–3.68(m,4H), 3.30–3.29(m,2H), 2.85–2.80(m,4H), 2.28–2.22(m,2H), 1.33–1.28(m,4H).

Example 2 Synthesis of Compound A2

The first step 2-morpholine-5-nitrobenzyl diethyl phosphate (A2-1)

4-(2-Bromomethyl-4-nitrophenyl)morpholine (800mg, 2.66mmol) and triethyl phosphite (0.55mL, 3.20mmol) were added to the sealed tube, stirred at 140°C for 3h, LCMS showed After the completion of the reaction, the reaction mixture was directly purified by silica gel column to obtain 2-morpholine-5-nitrobenzyl diethyl phosphate (A2-1, 950 mg, yield 99%). MS (ESI) m/z: theoretical value 359.13 (M+H), measured value 359.49.

The second step 6-oxohexanoate ethyl (A2-2)

Ethyl 6-hydroxyhexanoate (640 mg, 4.00 mmol) was dissolved in EA (30 mL), 2-iodoyl benzoic acid (1.68 g, 6.00 mmol) was added, and the mixture was stirred at 80°C for 3 hours. TLC showed that all the raw materials were converted into products A2- 2. The solid was filtered off, and the filtrate was concentrated to obtain ethyl 6-oxohexanoate (A2-2,630 mg, yield 99%) as a colorless oil.

The third step 7-(2-morpholine-5-nitro)phenyl-6-heptenoic acid ethyl ester (A2-3)

Under nitrogen protection, A2-1 (238mg, 0.66mmol) was dissolved in anhydrous THF (30mL), cooled to 0℃ in an ice bath, NaH (40mg, 0.99mmol, 60%) was slowly added, and stirring was continued for 30 min under ice bath. Slowly add A2-2 (125mg, 0.80mmol) in THF (3ml) solution, remove the ice bath, naturally warm to room temperature and continue stirring for 3h. After TLC confirms that the reaction is complete, it is quenched by adding saturated ammonium chloride solution in an ice bath, concentrated under reduced pressure to remove THF, extracted with EA, washed with deionized water three times, dried with anhydrous sodium sulfate, concentrated EA solution, and the residue is passed through the column Analyze and purify to obtain A2-3 (128mg, yield 53.5%). MS (ESI) m/z: theoretical value 363.18 (M+H), measured value 363.07.

The fourth step 7-(2-morpholine-5-amino)phenyl-heptanoic acid ethyl ester (A2-4)

A2-3 (128mg, 0.35mmol) was added to absolute ethanol (30ml), Raney nickel (20mg) was added, catalytic hydrogenation was carried out under 1atm of hydrogen pressure, and the mixture was stirred at room temperature for 5h. After LCMS confirmed the completion of the reaction, the catalyst was filtered off, and the filtrate was concentrated to obtain A2-4 (118 mg, yield 99%) as a colorless oil. MS (ESI) m/z: theoretical value 335.23 (M+H), measured value 335.30;

Step 5: Ethyl 7-(5-((4-(4-(tert-butoxycarbonylamino)phenyl)pyrimidine-2-)amino)-2-morpholinephenyl)heptanoate (A2-5)

Nitrogen protection, 7-(2-morpholine-5-amino)phenyl-heptanoic acid ethyl ester (A2-4, 118mg, 0.35mmol), (4-(2-chloropyrimidin-4-yl)phenyl)amino Tert-Butyl formate (A1-4, 128.4mg, 0.42mmol) and potassium carbonate (97mg, 0.70mmol) were added to 1,4-dioxane (20ml), stirred for 5min, and tris(dibenzylidene Acetone) two palladium (64mg, 0.07mmol) and 2-dicyclohexylphosphorus-2',4',6'-triisopropylbiphenyl (67mg, 0.14mmol), heated to 100°C, and stirred for 16h. After the completion of the reaction was confirmed by TLC, the 1,4-dioxane was concentrated, EA and deionized water were added to extract and separate the liquids, the organic layer was dried over anhydrous sodium sulfate, the EA was concentrated, and the residue was purified by column chromatography to obtain 7- Ethyl (5-((4-(4-(tert-butoxycarbonylamino)phenyl)pyrimidine-2-)amino)-2-morpholinephenyl)heptanoate (A2-5, 132mg, yield 63% ). MS (ESI) m/z: theoretical value 604.34 (M+H), measured value 604.48.

The sixth step 7-(5-((4-(4-(tert-butoxycarbonylamino)phenyl)pyrimidine-2-)amino)-2-morpholinephenyl)heptanoic acid (A2-6)

(4-(tert-butoxycarbonylamino)phenyl)pyrimidine-2-)amino)-2-morpholinephenyl) ethyl heptanoate (A2-5, 132mg, 0.22mmol) was added to THF (3ml) and water ( 1ml), then lithium hydroxide monohydrate (92mg, 2.20mmol) was added, and the mixture was stirred at 70°C for 5h. After confirming the completion of the reaction by TLC, 1mol/L HCl was added dropwise to adjust pH=5~6, the reaction solution was purified by reversed-phase column and lyophilized to obtain 7-(5-((4-(4-(tert-butoxycarbonylamino) )Phenyl)pyrimidine-2-)amino)-2-morpholinephenyl)heptanoic acid (A2-6, 120 mg, yield 94.5%). MS (ESI) m/z: theoretical value 576.31 (M+H), measured value 576.51.

The seventh step 7-((5-((4-(4-aminophenyl)pyrimidine-2-)amino)-2-morpholinephenyl)heptanoic acid (A2-7)

7-(5-((4-(4-(tert-butoxycarbonylamino)phenyl)pyrimidine-2-)amino)-2-morpholinephenyl)heptanoic acid (A2-6, 120mg, 0.21mmol) was added Add 3mol/L HCl EA solution (3ml) dropwise to EA (3ml), and stir at room temperature for 5h. After confirming the completion of the reaction by LCMS, the reaction solution was concentrated, the crude product was purified by reverse phase column, and lyophilized to obtain 7-((5-((4-(4-aminophenyl)pyrimidine-2-)amino)-2- Morpholine phenyl) heptanoic acid (A2-7, 83 mg, yield 84%). MS (ESI) m/z: theoretical value 476.26 (M+H), measured value 476.50.

The eighth step 4 ⁴ -morpholine-3,12-diaza-2(4,2)-pyrimidine hetero-1(1,4),4(1,3)-diphenyl heterocyclic dodecanophen-11 -Ketone (A2)

2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (132.3mg, 0.35mmol) and N,N-diisopropylethylamine ( 225mg, 1.74mmol) was added to dichloromethane (20ml) and stirred for 5min. Slowly add 7-((5-((4-(4-aminophenyl)pyrimidine-2-)amino)-2-morpholinephenyl)heptanoic acid (A2-7, 83mg, 0.17mmol) at room temperature. The mixed solution of DCM (8ml) and DMF (1ml) was dripped and stirred at room temperature for 24h. After LCMS confirmed that the reaction was complete, deionized water was added to quench the reaction, the extraction and separation, the organic layer was dried over anhydrous sodium sulfate, the DCM was concentrated, and the residue was Purified by reversed-phase column and freeze-dried to obtain a pale yellow solid A2 (20mg, yield 25.2%). MS (ESI) m/z: theoretical value 458.26 (M+H), measured value 458.58; ¹ H NMR (400MHz, DMSO) -d6)δ9.63(s,1H),9.52(s,1H),8.51(d,J=5.0Hz,1H),8.37(s,1H),7.93(d,J=8.0Hz,2H), 7.37(d,J=8.0Hz,2H),7.22(d,J=5.0Hz,1H),7.04-6.94(m,2H),3.73-3.70(m,4H),2.81-2.73(m,4H) , 2.80-2.51 (m, 2H), 2.38-2.35 (m, 2H), 1.37-1.33 (m, 4H), 1.27-1.25 (m, 4H).

Refer to the experimental procedures of Examples 1 and 2, using different starting materials to obtain Examples 3-5, as shown in Table 1 below.

Table 1

Example 6: Biological testing method

The JAK kinase activity measurement method uses homogeneous time-resolved fluorescence technology. The reaction of this method is in a 384 shallow well plate, and the total reaction volume is 10 μL. The mixture of kinase protein, compound, ATP and substrate is _{carried out in a reaction buffer of 50 mM Hepes (pH 7.0), NaN 3} 0.02%, BSA 0.01%, 0.1 mM Orthocanadate, 5 mM MgCl ₂ , and 1 mM DTT for 1 hour. Afterwards, an antibody capable of recognizing the phosphorylation of the substrate, the dye XL-615, and a detection buffer (Cisbio) containing EDTA were added to the system. The reaction signal of kinase is detected by PE company's multi-well plate detector. The parameter settings are excitation light 320nm, emission light 615nm and 665nm. The signal ratio of 665nm and 615nm indirectly reflects the activity of JAK. A background hole without enzyme and a full enzyme activity hole without compound are set up in the reaction.

IC ₅₀ values of compounds to inhibit protein by the equation: Y = 100 / (1 + 10 ^ ((LogIC50-X) * HillSlope)) is obtained. In the JAK1 reaction system, the concentration of ATP is 2μM and the concentration of JAK1 protein is 0.2ng/μL.

In the JAK2 reaction system, the concentration of ATP is 2μM and the concentration of JAK2 protein is 0.01ng/μL.

In the JAK3 reaction system, the concentration of ATP is 2μM and the concentration of JAK3 protein is 0.04ng/μL.

In the TYK2 reaction system, the concentration of ATP is 2μM, and the concentration of TYK2 protein is 0.2ng/μL.

The test data is divided into the following types: A: IC ₅₀ <10nM; B: IC ₅₀ 11-100nM; C: IC ₅₀ 101-1000nM; D: IC ₅₀ 1001-10000nM; E: IC ₅₀ >10000nM.

The test results are shown in Table 2.

Table 2 JAK inhibitory activity table

JAK1/JAK2 ratio, JAK3/JAK2 ratio and TYK2/JAK2 ratio are calculated based on C1/C2, where C1 is the IC50 value of a compound of the present invention against JAK1, JAK3, TYK2; C2 is the IC50 value of the same compound against JAK2;

In JAK1/JAK2 ratio, JAK1/JAK3 ratio, and TYK2/JAK2 ratio, + means 1-5; ++ means 6-20; +++ means 21-50; ++++ means >50.

discuss:

The above experimental results suggest:

(1) The compound of formula I of the present invention exhibits very excellent JAK inhibitory activity, especially against JAK2. The IC50 value of the compound of the present invention against JAK2 can be as low as 10 nM or lower, so for a subject weighing about 70 kg (such as a patient, especially a patient with rheumatoid arthritis or psoriasis), the daily dose is usually 10 mg- 30mg can inhibit JAK2 extremely effectively.

(2) The compound of formula I of the present invention shows very excellent JAK selectivity, that is, the IC50 ratio of JAK1/JAK2 and/or the IC50 ratio of JAK3/JAK2 and/or the IC50 ratio of TYK2/JAK2 is better than or compared with The existing compounds are comparable.

All documents mentioned in the present invention are cited as references in this application, as if each document was individually cited as a reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims

The compound represented by formula I or its stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates,

Where

X 1 , X 2 , X 3 and X 4 are each independently selected from the following group: N, C or CR d ; and among X 1 , X 2 , X 3 and X 4 , 0, 1, 2, and 3 are N ；

Or, when X 1 is CR d , R d is fused with X 2 to form a substituted or unsubstituted 5-6 membered cycloalkyl, heterocyclic, aryl or heteroaryl group;

Or, when X 2 is CR d , R d is fused with X 1 to form a substituted or unsubstituted 5-6 membered cycloalkyl, heterocyclic, aryl or heteroaryl group;

Or, when X 3 is CR d , R d is fused with X 4 to form a substituted or unsubstituted 5-6 membered cycloalkyl, heterocyclic, aryl or heteroaryl group;

Or, when X 4 is CR d , R d is fused with X 3 to form a substituted or unsubstituted 5-6 membered cycloalkyl, heterocyclic, aryl or heteroaryl group;

X is selected from the following group: bond, CR b R c , C(=O)O-, O, NR b , S, SO, SO 2 , C3-C10 cycloalkylene, 3-10 membered heterocyclylene, 5-12 membered heteroarylene, C6-C12 arylene;

R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R b , R c and Rd are each independently selected from the following group: H, D, halogen, amino, nitro, hydroxyl, Cyano, carboxyl, sulfone, sulfoxide, amide, sulfonamide, ester, formyl, formamide, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2- C6 alkynyl, 3-10 membered heterocyclic group, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl;

Or R 3 and R 4 together with the C atom to which they are attached form a substituted or unsubstituted 5-6 membered cycloalkyl, heterocyclic, aryl or heteroaryl group;

Or R 5 and R 6 together with the C atom to which they are attached form a substituted or unsubstituted 5-6 membered cycloalkyl, heterocyclic, aryl or heteroaryl group;

Or R b and R c together with the C atom to which they are connected form =0, or a substituted or unsubstituted C3-C10 cycloalkylene, 3-10 membered heterocyclylene;

(CH 2) H n atoms may be optionally substituted with one or more substituents R a;

n is 1, 2, 3, 4, 5, 6, 7 or 8;

Unless otherwise specified, the substitution refers to substitution by one or more groups selected from the following group: D, halogen, amino, nitro, hydroxyl, cyano, carboxy, sulfone, sulfoxide, amide , Sulfonamide group, ester group, formyl group, formamide group, C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, C2-C6 alkynyl group, 3-10 membered heterocyclic group, C3- C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl;

Unless otherwise specified, the above-described alkyl group, alkoxy group, alkenyl group, alkynyl group, heterocyclic group, cycloalkyl, heteroaryl, aryl groups may be further optionally substituted with one or more of R a, wherein each R a is independently selected from the group consisting of: halogen, amino, nitro, hydroxyl, mercapto group, a cyano group, a carboxyl group, a sulfone group, a sulfoxide group, an amide group, a sulfonamide group, an ester group, a formyl, carboxamido , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl.
The compound of claim 1 or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate, characterized in that:
Part is a group selected from the following group:

in,

Y 1 and Y 2 are each independently selected from the following group: CR b R c , NR b , O, S;

R A , R B , R C and R D are each independently selected from the following group: H, deuterium, halogen, amino, nitro, hydroxyl, sulfhydryl, cyano, carboxy, sulfone, sulfoxide, amide, sulfonate Amido, ester, formyl, carboxamido, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 Cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl;

p is 1, 2, 3, 4;

m is 1 or 2;

The definitions of R a , R b and R c are as described in claim 1.
The compound of claim 1 or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate, wherein X is selected from the following group: bond, CR b R c , O, S; wherein the definitions of R b and R c are as described in claim 1.
The compound according to claim 1 or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate, characterized in that it has the structure shown in formula II:

Where

R 1 and R 2 are each independently selected from the following group: H, D, halogen, amino, nitro, hydroxyl, cyano, carboxy, sulfone, sulfoxide, amide, sulfonamide, ester, and formyl , Carboxamido, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocyclyl, C3-C10 cycloalkyl, 5-12 membered hetero Aryl, C6-C12 aryl;

Or R 1 and R 2 are fused together with the C atom to which they are attached to form a substituted or unsubstituted 5-6 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group;

(CH 2) H n atoms may be optionally substituted with one or more substituents R a;

R a , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , X and n are as defined in claim 1;

Unless otherwise specified, the substitution refers to substitution by one or more groups selected from the following group: D, halogen, amino, nitro, hydroxyl, cyano, carboxy, sulfone, sulfoxide, amide , Sulfonamide group, ester group, formyl group, formamide group, C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, C2-C6 alkynyl group, 3-10 membered heterocyclic group, C3- C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl;

Unless otherwise specified, the above-described alkyl group, alkoxy group, alkenyl group, alkynyl group, heterocyclic group, cycloalkyl, heteroaryl, aryl groups may be further optionally substituted with one or more of R a, wherein each R a is independently selected from the group consisting of: halogen, amino, nitro, hydroxyl, mercapto group, a cyano group, a carboxyl group, a sulfone group, a sulfoxide group, an amide group, a sulfonamide group, an ester group, a formyl, carboxamido , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl.
The compound according to claim 1 or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate, characterized in that it has the structure represented by formula A:

in,

(CH 2) H n atoms may be optionally substituted with one or more substituents R a;

The definitions of R 1 and R 2 are as described in claim 4;

The definitions of R a , R 3 , R 4 , R 5 , R 6 , X and n are as described in claim 1.
The compound according to any one of claims 1 to 5 or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate, wherein X is O or CH 2 .
The compound according to any one of claims 1 to 6 or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate, wherein R 3 and R 4 are each independently Ground is selected from: H, D, halogen, C1-C6 alkyl, C1-C6 alkoxy; wherein the alkyl, alkoxy may be further substituted by one or more groups selected from the following group: halogen , Amino, hydroxy, carboxy, C1-C6 alkyl, C1-C6 alkoxy.
The compound according to any one of claims 1-7, or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate, wherein R 5 and R 6 are each independently It is selected from: H, D, halogen, C1-C6 alkyl, C1-C6 alkoxy, 3-10 membered heterocyclic group, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl Group; wherein, the alkyl, alkoxy, heterocyclyl, cycloalkyl, heteroaryl, aryl group may be further substituted by one or more groups selected from the following group: halogen, amino, hydroxyl, carboxyl , C1-C6 alkyl, C1-C6 alkoxy.
The compound according to claim 1 or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate, wherein the compound is selected from the following group:
A pharmaceutical composition, characterized in that the pharmaceutical composition contains the compound according to any one of claims 1-9 or its stereoisomer or optical isomer, or a pharmaceutically acceptable salt thereof, Prodrugs or solvates, and pharmaceutically acceptable carriers or excipients.
The use of the compound according to any one of claims 1-9 or its stereoisomers or optical isomers, or pharmaceutically acceptable salts, prodrugs or solvates thereof, characterized in that they are used for preparing prophylactic Or drugs for treating JAK2-mediated diseases; and/or for preparing JAK2 inhibitors.
The use according to claim 8, wherein the JAK2-mediated disease is myelodysplastic syndrome (MDS), eosinophilia, tumor, inflammatory disease or caused by bacteria, viruses or fungi Infect.
A JAK2 inhibitor, characterized in that it contains the compound according to any one of claims 1-9 or its stereoisomer or optical isomer, or a pharmaceutically acceptable salt, prodrug or solvate thereof Or the pharmaceutical composition of claim 10.