RU2812575C2 - Jak inhibitor and method of its obtaining - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a compound represented by general formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, which has an inhibitory effect on JAK kinase. In the formula, IA represents C; R₅ represents H; X represents R represents C_1-10 linear or branched alkyl; Y represents R₃ and R₄ represent H; m is any integer from 1 to 3, in particular 1, 2 or 3; Z represents C_3-12-cycloalkyl; R₁ and R₂ are each optionally H, C_1-10 linear or branched alkyl, where the H on the carbon atom may be replaced by groups such as -N(C_0-10-alkyl)(C_0-10-alkyl), -OC_0-10-alkyl, C_3-10-cycloalkyl, C_6-18-aryl, -N-heterocycloaryl, -O-heterocycloaryl or -S-heterocycloaryl; where H on C_6-18-aryl or heterocycloaryl can be replaced by a halogen group or C_1-4 linear alkyl; each R₇ and R₈ represents H. The invention also relates to a method of producing a compound represented by the general formula I, a pharmaceutical composition comprising the said compound, and its use in the preparation of a medicinal product intended for the treatment of a disease associated with the JAK-STAT signaling pathway, including for the prevention and/or treatment of inflammatory or oncological diseases.

EFFECT: obtaining of JAK inhibitor and a method of its obtaining.

12 cl, 2 tbl, 9 ex

Description

TECHNICAL APPLICATION AREA

The present invention relates to the field of medicine and, in particular, relates to a JAK inhibitor, as well as to a method for its preparation.

HISTORICAL REFERENCE

The JAK-STAT signaling pathway is a pathway that transmits cytokine signals to participate in cell proliferation, differentiation, apoptosis, immunoregulation, and a variety of other important biological processes. Unlike other signaling pathways, this signaling pathway has a relatively simple transduction process and mainly consists of three components, namely receptor tyrosine kinase-associated Janus kinase (or JAK) and the transcription factor STAT.

The JAK-STAT signaling pathway is mediated by receptor tyrosine kinase, a variety of cytokines, and growth factors, including interleukins 2-7 (IL-2-7), granulocyte/macrophage colony-stimulating factor (GM-CSF), and growth hormone. (GH), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), interferon (IFN), etc. These cytokines and growth factors have corresponding receptors in the cytoplasmic cell membrane. A common characteristic feature of such receptors is that each such receptor does not exhibit its own kinase activity, but has JAK tyrosine kinase binding centers in its intracellular domain. After binding to the ligand, the receptor, activated by the associated JAK, phosphorylates the tyrosine residues of various target proteins, thereby transmitting a signal from the extracellular space into the cell.

Janus kinase (JAK), many tyrosine kinases are cell membrane receptors, collectively referred to as receptor tyrosine kinase (RTK); JAK is a type of tyrosine kinase that does not have transmembrane properties. JAK is an acronym for Janus kinase; since Janus is the deity in charge of matters of beginning and end. The reason it is called Janus kinase (or Janus kinase) is that JAK can not only phosphorylate its associated cytokine receptors, but can also phosphorylate many signaling molecules containing specific SH2 domains. The JAK family includes 4 proteins: JAK1, JAK2, JAK3 and Tyk2; in their structure there are 7 JAK homology domains (JH), where the JH1 domain is a kinase domain, the JH2 domain is a “false” kinase domain; JH6 and JH7 are receptor binding domains.

In the concept of “transcription factor STAT”, the abbreviation “STAT” stands for “signal transducer and activator of transcription”, or “signal transducer and activator of transcription”. As its name suggests, STAT plays a critical role in signal transduction and activation of transcriptional activity. Currently, 6 proteins of the STAT family have been identified, namely STAT1-STAT6. Based on its structure, the STAT protein can be divided into several functional regions: the N-terminal conserved sequence, the DNA-binding domain, the SH3 domain, the SH2 domain, and the C-terminal transcription activation domain. The zone that is most conserved in sequence, but most important in function, is the SH2 domain, which has the core sequence “GTFLLRFSS”, which is identical to the core sequence of the SH2 domain of the Src tyrosine kinase.

The JAK-STAT signaling pathway has extensive functions and is involved in cell proliferation, differentiation, apoptosis, immunoregulation, and many other important biological processes. Today, the main focus of disease-related research and innovative drug treatment solutions is on inflammatory and neoplastic diseases. These inflammatory diseases include rheumatoid arthritis, canine dermatitis, psoriasis, ulcerative colitis or Crohn's disease; and these tumor diseases mainly include myelofibrosis, polycythemia vera and idiopathic thrombocythemia. Moreover, mutation of the JAK molecule itself can also lead to the development of acute myelocytic leukemia (AML), acute lymphocytic leukemia (ALL), ductal breast carcinoma, non-small cell lung cancer (NSCLC), etc.

A JAK inhibitor can selectively inhibit JAK kinase to block the JAK-STAT signaling pathway. Currently, JAK inhibitors that have been approved by the US Food and Drug Administration include tofacitinib, ruxolitinib, oclacitinib, and baricitinib. Oclacitinib is a novel JAK inhibitor, which in turn is able to suppress the functions of JAK1-dependent cytokines in several allergic, inflammatory and pruritic reactions. Studies show that when administered orally to laboratory animals (dogs) at twice daily doses of 0.4-0.6 mg/kg, oclacitinib has proven to be safe and effective in the treatment of pruritus symptoms associated with atopic dermatitis and has demonstrated superior more effective than oral corticosteroids such as prednisolone. During treatment, oclacitinib was able to relieve pruritus within 24 hours, and by day ⁷ , more than 50% of the symptoms of the pruritic reaction were reduced in more than 70% of laboratory animals. Oclacitinib was approved by the US Food and Drug Administration in 2013 and is still used to treat itch and atopic dermatitis caused by canine allergic dermatitis. However, oclacitinib is even more effective in treating allergic dermatitis in domestic dogs. Since oclacitinib has little effect on cytokines not involved in JAK1 activation, oclacitinib can only inhibit the release of the allergic milieu that provokes an anaphylactic reaction and cannot directly block the binding of such allergic milieu to cognate receptors and, accordingly, cannot block the development and progression of allergic reactions. dermatitis, which leads to a limitation of the scope of use of oclacitinib. Another JAK inhibitor, baricitinib, is a selective inhibitor of JAK1 and JAK2; with an IC ₅₀ of 5.9 and 5.7 nM, respectively, which is approximately 70 and 10 times greater than the degree of selectivity for JAK3 and Tyk2, while it does not have an inhibitory effect on c-Met and Chk2. Baricitinib is a type of rheumatoid arthritis drug developed by Eli Lily and Company and its partner Insight that has a relatively narrow indication. Other indications for baricitinib, particularly psoriasis and diabetic nephropathy, are in Phase II clinical development. To overcome the shortcomings of the prior art and expand the scope of application of this type of JAK inhibitors, the present invention provides a JAK inhibitor that can be used in both humans and animals; Moreover, this inhibitor has such advantages as high efficiency, wide range of action and low toxicity.

SUMMARY OF ESSENCE

An object of the present invention is to provide a JAK inhibitor, and another object of the present invention is to provide a method for producing a JAK inhibitor.

These objectives of the present invention are achieved by the following technical solutions:

The present invention provides a compound represented by general formula I:

where A represents a choice of C or N; when A is N, R ₅ is absent; when A is C, R ₅ is optionally: H, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl , substituted or unsubstituted amino, substituted or unsubstituted sulfo, or substituted or unsubstituted sulfonyl.

Preferably R ₅ is optionally: H, C _1-3 -alkyl, as well as -OC _0-2 -alkyl.

More preferably, R ₅ is optionally H and also -CH ₃ .

X represents your choice of: -O- or ; R is optionally: H, C _1-10 linear or branched alkyl, C _1-10 linear or branched alkenyl, C _1-10 linear or branched alkynyl, C _6-18 aryl, C _6-18 heterocycloaryl, C _{3 -10} cycloalkyl, -OC _0-10 -alkyl or -O-heterocycloalkyl; in this case, H on the carbon atom can be replaced by groups such as deutero, hydroxy, halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , C _1-10 linear or branched alkyl, -N(C _{0- 10} -alkyl) (C _0-10 -alkyl), -OC _0-10 -alkyl, C _3-10 -cycloalkyl, -O-heterocycloalkyl, -N-heterocycloalkyl, -S-heterocycloalkyl, C _6-18 -aryl, -N-heterocycloaryl, -O-heterocycloaryl or -S-heterocycloaryl; wherein the alkyl moiety of said groups may optionally be replaced by any one or more of -SO ₂ , -SO ₂ N(C _0-10 -alkyl) (C _0-10 -alkyl), -N(C _{0 -10} -alkyl)SO ₂ (C _0-10 -alkyl), -CON (C _0-10 -alkyl) (C _0-10 -alkyl), -N (C _0-10 -alkyl), CO(C _{0 -10} -alkyl), -N(C _0-10 -alkyl), COO(C _0-10 -alkyl), -OCON (C _0-10 -alkyl) (C _0-10 -alkyl), halogen, -CN , -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -N(C _0-10 -alkyl) (C _0-10 -alkyl), -OC _0-10 -alkyl, C _6-18 -aryl, -N -heterocycloaryl, -O-heterocycloaryl or -S-heterocycloaryl;

Preferably X is optionally: ; R is optionally: H, C _1-10 linear alkyl, as well as C _3-10 cycloalkyl; H on the carbon atom can be replaced by groups such as deutero, hydroxy, halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , C _1-3 linear alkyl, -N(C _0-3 -alkyl)( C _0-3 -alkyl), -OC _0-6 -alkyl or C _3-8 -cycloalkyl; wherein the alkyl moiety of said groups may optionally be replaced by any one or more of -SO ₂ , -SO ₂ N(C _0-10 -alkyl) (C _0-10 -alkyl), -N(C _{0 -10} -alkyl) SO ₂ (C _0-10 -alkyl), -CON (C _0-10 -alkyl) (C _0-10 -alkyl), -N(C _0-10 -alkyl), CO(C _{0 -10} -alkyl), -N(C _0-10 -alkyl), COO(C _0-10 -alkyl), -OCON(C _0-10 -alkyl) (C _0-10 -alkyl), halogen, -CN , -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -N(C _0-10 -alkyl) (C _0-10 -alkyl), -OC _0-10 -alkyl, C _6-18 -aryl, -N -heterocycloaryl, -O-heterocycloaryl or -S-heterocycloaryl.

More preferably, X was a choice of: ; R is optionally C _1-6 linear alkyl; H on the carbon atom can be replaced by groups such as deutero, hydroxy, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , C _1-3 linear alkyl or C _3-6 cycloalkyl;

In preferred embodiments of the present invention, X is .

Y represents your choice: R ₃ and R ₄ are each optionally: H, halogen, -CN, C _1-10 linear alkyl, C _3-10 -cycloalkyl, -CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, substituted or unsubstituted haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OC _0-10 -alkyl, -S(O) _m C _0-10 -alkyl, -SO ₂ N(C _0-10 - alkyl) (C _0-10 -alkyl), -N(C _0-10 -alkyl) (C _0-10 -alkyl), -N(C _0-10 -alkyl) C(=O)(C _0-10 -alkyl), -N(C _0-10 -alkyl)C(=O)O(C _0-10 -alkyl), -N(C _0-10 -alkyl)C(=O)N(C _0-10 -alkyl), -C(=O)C _0-10 -alkyl, -C(=O)OC _0-10 -alkyl, -C(=O)N(C _0-10 -alkyl) (C _0-10 -alkyl), -O-heterocycloalkyl, -N(C _0-10 -alkyl) heterocycloalkyl, -N(C _0-10 -alkyl) heterocycloaryl, -S-heterocycloaryl or -O-heterocycloaryl, where heterocycloalkyl can be replaced by any one or any several of such groups as oxygen, C _1-10 -alkyl, C _1-10 -alkenyl, C _1-10 -alkynyl, C _6-18 -aryl, C(=O)OC _0-10 -alkyl, C (=O)N(C _0-10 -alkyl) (C _0-10 -alkyl), -SO ₂ N(C _0-10 -alkyl) (C _0-10 -alkyl) or SO ₂ C _1-10 - alkyl, wherein the alkyl moiety may optionally be replaced by any one or more of hydroxy, -OC _1-10 -alkyl, -N(C _0-10 -alkyl) (C _0-10 -alkyl), - C(=O)N(C _0-10 -alkyl) (C _0-10 -alkyl), C(=O)OC _0-10 -alkyl, C _6-18 -aryl, heterocycloalkyl or heterocycloaryl, m represents any an integer from 0 to 6, such as 0, 1, 2, 3, 4, 5 or 6;

Preferably, R ₃ and R ₄ are each optionally: H, halogen, -CN, C _1-6 linear alkyl, and C _3-6 cycloalkyl; wherein the alkyl moiety may optionally be replaced by any one or more of groups such as hydroxy, -OC _1-10 -alkyl, -N(C _0-10 -alkyl) (C _0-10 -alkyl), C _{6 -18} -aryl, heterocycloalkyl or heterocycloaryl; m is equal to your choice of 0, 1, 2, 3 or 4;

More preferably, R ₃ and R ₄ are each optionally: H; m is equal to your choice of 0, 1 or 2;

Z represents optionally: C _1-10 linear or branched alkyl, C _1-10 linear or branched alkenyl, C _1-10 linear or branched alkynyl, substituted or unsubstituted hydroxyalkyl, C _3-12 cycloalkyl, C _1-20 - alkoxy, C _3-12 -cycloalkoxy, heterocycloalkyl, (-N, -O and -S), C _6-18 -aryl, -N-heterocycloaryl, -S-heterocycloaryl or -O-heterocycloaryl, aromatic dicyclo, aromatic heterodicyclo and tricyclo, wherein the alkyl moiety may be optionally replaced by any one or more of -N( _C0-10 -alkyl)( _C0-10- alkyl), -CON( _C0-10 -alkyl)( C _0-10 -alkyl), -N(C _0-10 -alkyl)CO(C _0-10 -alkyl), -N(C _0-10 -alkyl) COO(C _0-10 -alkyl), -OCON (C _0-10 -alkyl)(C _0-10 -alkyl), halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -OC _0-10 -alkyl, C _6-18 -alkyl, -N-heterocycloaryl, -O-heterocycloaryl or -S-heterocycloaryl.

Preferably Z is optionally: C _3-12 -cycloalkyl or C _3-12 -cycloalkoxy; wherein the alkyl moiety may optionally be replaced by any one or more of -N( _C0-10 -alkyl)( _C0-10 -alkyl), -CON( _C0-10 -alkyl)( _{C0 -10} -alkyl), -N(C _0-10 -alkyl)CO(C _0-10 -alkyl), -N(C _0-10 -alkyl) COO(C _0-10 -alkyl), -OCON(C _0-10 -alkyl)(C _0-10 -alkyl), halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -OC _0-10 -alkyl, C _6-18 -alkyl, -N -heterocycloaryl, -O-heterocycloaryl or -S-heterocycloaryl.

More preferably, Z is where p is any integer from 0 to 4; q - any integer from 0 to 4; p and q are not equal; R ₆ represents a substituting H element on one or more carbon atoms of the cycloalkyl; R ₆ is optionally C _1-6 -alkyl or C _3-6 -cycloalkyl, and s is an integer from 0 to 8; for example 0, 1, 2, 3, 4 and 5.

Preferably R ₆ is optionally: C _1-3 -alkyl.

More preferably, R ₅ is optionally -CH ₃ or -CH ₂ CH ₃ .

In preferred embodiments of the present invention, Z is optionally: C _4-10 -cycloalkyl, for example, , , , , , , , , , And .

More preferably, Z is .

R ₇ and R ₈ are each optionally: H, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-heterocycloaryl, substituted or unsubstituted heterocycloaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted amino, substituted or unsubstituted sulfo, or substituted or unsubstituted sulfonyl.

Preferably, R ₇ and R ₈ are each optionally H, halogen, C _1-3 alkyl, and -OC _0-2 alkyl.

More preferably, R ₇ and R ₈ are each optionally H or -CH ₃ .

The compound described in the present invention has the following structure:

where n is a positive integer from 1 to 4; preferably n is 1 or 2; in this case, the compound represented by the number III has the following structural formula:

R ₁ and R ₂ are each optionally: H, halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , C _1-10 linear or branched alkyl, C _3-10 -cycloalkyl, -OC _{0 -10} -alkyl, -N(C _0-10 -alkyl)(C _0-10 -alkyl), -O-heterocycloalkyl, -N-heterocycloalkyl, -S-heterocycloalkyl, C _6-18 -aryl, -N-heterocycloaryl , -S-heterocycloaryl or -O-heterocycloaryl, where H on the carbon atom can be replaced by groups such as deutero, hydroxy, halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , C _1-6 linear alkyl , -N(C _0-10 -alkyl)(C _0-10 -alkyl), -OC _0-10 -alkyl, C _3-10 -cycloalkyl, -O-heterocycloalkyl, -N-heterocycloalkyl, -S-heterocycloalkyl, C _6-18 -aryl (eg phenyl), -N-heterocycloaryl, -O-heterocycloaryl or -S-heterocycloaryl; wherein H on _C6-18 -aryl (eg, phenyl) or heterocycloaryl may be replaced by any one or more of halogen, _C1-4 linear alkyl, -N( _C0-10alkyl ) _SO2 ( C _0-10 -alkyl), -CON(C _0-10 -alkyl)(C _0-10 -alkyl), N-(C _0-10 -alkyl)CO(C _0-10 -alkyl), -N( C _0-10 -alkyl)COO(C _0-10 -alkyl), -OCON(C _0-10 -alkyl)(C _0-10 -alkyl), -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -N(C _0-10 -alkyl)(C _0-10 -alkyl), -OC _0-10 -alkyl, -N-heterocycloaryl, -O-heterocycloaryl or -S-heterocycloaryl, or where adjacent carbon atoms on C _6-18 -aryl (for example, phenyl) and heterocycloaryl form C _3-8 -cycloalkyl, -O-heterocycloalkyl, -N-heterocycloalkyl, -S-heterocycloalkyl or -N-heterocycloaryl, -O-heterocycloaryl, -S- heterocycloaryl; or the atoms R ₁ , R ₂ , S and N present between them form a heterocyclic ring; and preferably such a heterocyclic ring is a five-membered heterocycle or a six-membered heterocycle.

Preferably R ₁ is optionally: H, C _1-6 linear alkyl or C _3-6 cycloalkyl; and H on the carbon atom can be replaced by groups such as deutero, hydroxy, halogen, -CN, -OCF ₃ , -N(C _0-10 -alkyl)(C _0-10 -alkyl), -OC _0-4 -alkyl , C _3-10 -cycloalkyl, -O-heterocycloalkyl, -N-heterocycloalkyl, and also C _6-18 -aryl (for example, phenyl).

More preferably, R ₁ is optionally: H, -CH ₂ -, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ OCH _{3, ;}

R ₂ is optionally: C _1-6 linear alkyl, C _3-6 -cycloalkyl, C _3-8 -cycloalkoxy, -N(C _0-10 -alkyl)(C _0-10 -alkyl), C _{6- 18} -aryl (eg phenyl), as well as -N-heterocycloaryl; H on a carbon or nitrogen atom may be replaced by any one or more of such groups as deutero, hydroxy, halogen, -CN, OCH ₂ F, -OCHF ₂ , -OCF ₃ , C _1-3 linear alkyl, -N(C _0-10 -alkyl)(C _0-10 -alkyl), -OC _0-10 -alkyl, C _3-10 -cycloalkyl, -O-heterocycloalkyl, -N-heterocycloalkyl, C _6-18 -aryl (e.g. phenyl ), -N-heterocycloaryl, -O-heterocycloaryl or -S-heterocycloaryl; neighboring carbon atoms on phenyl or heterocycloaryl form C _3-8 -cycloalkyl, -O-heterocycloalkyl, -N-heterocycloalkyl, -S-heterocycloalkyl or -N-heterocycloaryl and -O-heterocycloaryl.

More preferably, R ₂ is optionally: -CH ₂ -,

In detailed embodiments of the present invention, the following specific compounds are provided:

The compound represented by general formula I also includes its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, metabolite, solvate or deuterated compound.

In one embodiment of the present invention, the stereoisomer of the compound represented by general formula I has the following structure:

In yet another embodiment of the present invention, a stereoisomer of the compound represented by the above general formula I has the following structure:

Detailed embodiments of the present invention provide a stereoisomer of this particular compound:

The compound represented by the general formula I in the present invention can be obtained by the following reaction route:

(1) dissolving compound 1 in solvent 1, adding triethylamine and p-toluenesulfonyl chloride, stirring at room temperature for 20-24 hours, concentrating, adding iodination reagent, heating to 60-70°C and stirring for 8-9 hours to obtain compound 2;

(2) dissolving compound 2 in solvent 2, adding sodium alkyl thiolate, allowing the reaction to proceed for 20-24 hours, filtering and concentrating to obtain compound 3;

(3) dissolving compound 3 in solvent 3, adding triethylamine and p-toluenesulfonyl chloride, stirring at room temperature for 20-24 hours and separating to obtain compound 4;

(4) dissolving compound 4 in solvent 4, adding metachloroperbenzoic acid (m-CPBA), allowing the reaction to proceed for 1-2 hours, extracting to collect the organic phase, washing with water and drying such organic phase, filtering and concentrating to obtain compound 5 ;

(5) dissolving compound 5 in solvent 5, adding iodobenzene diacetate (PhI(OAc) ₂ ) and ammonium carbamate, allowing the reaction to proceed for 30-35 minutes, concentrating under reduced pressure to obtain compound 6;

(6) dissolving compound 6 and polyaldehyde in solvent 6, heating to 90-95°C, allowing the reaction to proceed for 20-24 hours, concentrating, extracting to collect the organic phase, washing with water and drying such organic phase, filtering and concentrating with obtaining compound 7; and

(7) dissolving compound 7 and cesium carbonate (Cs ₂ CO ₃ ) in solvent 7, allowing the reaction to proceed at 40-50°C for 3-4 hours, filtering and concentrating to obtain the compound represented by the general formula I.

Solvents 1-7 in the above production step are each one or a combination of two or more of dichloromethane (DCM), acetone, tetrahydrofuran (THF), methyl alcohol and formic acid; preferably solvent 1 is DCM; solvent 2 - THF; solvent 3 - DCM; solvent 4 - THF; solvent 5 - methyl alcohol; solvent 6 - formic acid; and solvent 7 is a mixed solution of THF and methyl alcohol.

Preferably, the stirring time at room temperature in step (1) is 24 hours, and the iodizing agent is sodium iodide.

The duration of the reaction in step (2) is 24 hours.

The separation in step (3) is performed by separation using column chromatography.

After adding m-CPBA in step (4), the mixed material is reacted in an ice bath at 0°C for 1 hour; the reaction liquid is then quenched with saturated NaHCO ₃ solution, extracted with DCM, the organic layers are mixed, then washed with saturated saline solution, dried with anhydrous Na ₂ SO ₄ and finally filtered.

The polyaldehyde in step (6) is preferably paraformaldehyde; the reaction liquid is concentrated and then adjusted with saturated NaHCO ₃ to pH=7-8, extracted with ethyl acetate; wherein the organic layers are mixed, then washed with brine, dried with anhydrous Na ₂ SO ₄ and finally filtered.

The reaction temperature in step (7) is 40°C and the reaction time is 3 hours.

The present invention provides a pharmaceutical composition; wherein such a pharmaceutical composition contains a compound represented by the general formula I, and also contains a pharmaceutically acceptable excipient; wherein such excipient is optionally a carrier, a diluent, a binder, a lubricant and a wetting agent. Preferably, the pharmaceutical composition contains a therapeutically effective amount of a compound represented by general formula I. In some embodiments, the pharmaceutical composition may be used alone or in combination with other JAK inhibitors.

Preferably, the pharmaceutical composition can be administered to humans and/or animals.

The pharmaceutical composition is suitable for enteral or parenteral administration, in particular intravenous, intramuscular, intradermal and subcutaneous administration. Therefore, preferably, the pharmaceutical composition further includes an antioxidant, a buffering agent, a bacteriostatic agent and a solute making the drugs and blood of the subject and the like isotonic, as well as an aqueous and non-aqueous sterile suspension, which may include a suspending agent, a solubilizer, a thickening agent, stabilizer and preservative.

The compound described in the present invention can be obtained in pharmaceutical forms such as syrup, elixir, suspending agent, powder, granules, tablets, capsules, paste, aqueous solution, cream, ointment, lotion, gel, emulsion and the like.

The pharmaceutical preparation is preferably in unit dose form. In this form, the drug is divided into standard doses containing the appropriate amount of active ingredients. Said unit dosage form may be capsules, tablets or any dosage form; Moreover, such unit form may also be a packaged preparation, for example, tablets, capsules and powder packaged in a bottle or ampoule.

The amount of active ingredients in the specified portion form may vary or be adjusted from 0.1 mg to 1000 mg; Moreover, it is determined in accordance with the specific field of application and taking into account the effectiveness of the active substances. If necessary, the composition may further include other suitable therapeutic agents.

The present invention provides a method of using a compound represented by general formula I, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, metabolite, solvate or cooperative compound thereof in the preparation of a medicament for the treatment of a disease associated with Janus kinase-activated signal transporters and transcription activators (JAK-STAT).

The present invention provides a method of using a compound represented by general formula I, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, metabolite, solvate or deuterated compound thereof in the preparation of a medicament intended for the prevention and/or treatment of inflammatory or oncological diseases in humans and/or animals.

A method of using a compound represented by general formula I, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof in accordance with claim 1 of the formula in the preparation of a medicinal product intended for the prevention and/or treatment of inflammatory and oncological diseases in people and/or animals.

Preferably, said inflammatory diseases include rheumatoid arthritis, canine dermatitis, psoriasis, ulcerative colitis or Crohn's disease; and said cancer is myelofibrosis, polycythemia vera, essential thrombocythemia, chronic granulocytic leukemia, breast cancer, lung cancer and pancreatic cancer.

As used in the present invention, the term "C _0-10 -alkyl", C ₀ -alkyl means H. Therefore, C _0-10 -alkyl includes H, C ₁ -alkyl, C ₂ -alkyl, C ₃ -alkyl, C ₄ -alkyl, C ₅ -alkyl, C ₆ -alkyl, C ₇ -alkyl, C ₈ -alkyl, C ₉ -alkyl and C ₁₀ -alkyl.

As used herein, the term " _C3-10 -cycloalkyl" includes _C3 -cycloalkyl, _C4 -cycloalkyl, _C5 -cycloalkyl, _C6 -cycloalkyl, _C7 -cycloalkyl, _C8- cycloalkyl, _C9 -cycloalkyl. and C ₁₀ -cycloalkyl.

As used herein, the term “halogen” includes fluorine, chlorine, bromine and iodine.

The pharmaceutically acceptable salt described in the present invention includes an acid addition salt and an alkali addition salt.

Acid addition salt includes, but is not limited to, salts of inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid and phosphonic acid; as well as salts of organic acids, for example, aliphatic monocarboxylic acid and dicarboxylic acid, phenyl-paraffinic acid, hydroxyparaffinic acid, alkanedioic acid, aromatic acid, and salts of aliphatic and aromatic sulfonic acids. Therefore, such salts include, but are not limited to, sulfates, pyrosulfates, disulfates, sulfites, hydrosulfites, nitrates, phosphoric acid, dihydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, hydrochlorides, hydrobromides, iodates, acetates, propionates, caprylates , isobutylates, succinates, octanedicarboxylic acid, sebates, fumarates, maleates, mendelates, benzoates, chlorinated benzoates, methyl benzoates, binitrobenzoates, phthalates, benzenesulfonates, tosylates, phenylacetates, citrates, lactates, maleates, tartrates and mesylates, and also include amino acid salts , for example, arginine salts, gluconates, galacturonates and the like. The acid addition salt can be prepared in a conventional manner, namely by bringing the free alkaline form into contact with a sufficient amount of the acid required to form the salt. The specified salt form is brought into contact with alkali, as a result of which the form of free alkali is restored, and then the resulting free alkali is isolated in a traditional way.

An alkali addition salt and a metal or amine form alkali metal or alkaline earth metal hydroxides or forms containing organic amines. The sample used as a cationic metal includes, but is not limited to, sodium, potassium, magnesium and calcium. A sample containing suitable amines includes, but is not limited to, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1,2-diamine), N-methylglucosamine and procaine. The alkali addition salt can be prepared in a conventional manner, namely by bringing the free acid form into contact with a sufficient amount of alkali necessary to form the salt. This salt form can be brought into contact with an acid, resulting in the reduction of the free acid form, and then the resulting free acid will be isolated in a conventional manner.

The stereoisomer described in the present invention is presented in the form of enantiomers, diastereomers and geometric isomers. Some of the compounds described in the present invention contain cycloalkyl, which can be substituted on more than one carbon atom. In such a case, all their geometric forms, including cis-forms and trans-forms, as well as combinations thereof, are subject to legal protection under the present invention.

The solvate described in the present invention refers to the physical connection of the compound described in the present invention with one or more solvents. Such physical bonding involves varying degrees of ionic and covalent bonds, including hydrogen bonding. In some cases, said solvate can be separated, for example, by adding one or more solvent molecules to the lattice of the crystalline solid. The concept of “solvate” extends to solvates in the solution phase or separated solvates. Typical solvates include alcoholates, methylates, and the like. By “hydrate” we mean a solvate in which one or more solvent molecules is _H2O .

By prodrug as used herein is meant a form of the compound represented by general formula I that is suitable for administration to a patient, is not unduly toxic, does not cause irritant or allergic reactions, and exhibits efficacy when used as directed, including forms such as acetal, ester, and zwitterion. The prodrug is converted in vivo (eg, hydrolyzed in the blood) to obtain the above formula of the parent compound.

DETAILED DESCRIPTION

The technical solution used in the embodiments of the present invention will be described in detail and comprehensively; It is clear that the embodiments described herein provide only a partial picture and do not constitute an exhaustive list of embodiments of the present invention. All other embodiments obtained by those skilled in the art without inventive effort, but based on the above embodiments of the present invention, are subject to legal protection under the present invention.

Embodiment 1: Synthesis of T1

Stage 1:

1 (220 g, 1.29 mol) and MeOH (40 ml) were added to a 5 L one-neck flask, after which a tetrahydrofuran solution of methylamine (0.78 L, 1.55 mol and 2 M in THF) was added sequentially. tetraisopropyl titanate (733 g, 2.58 mol) and NaBH ₃ CN (162 g, 2.58 mol), stirred at room temperature for 18 hours, dried using a spin dryer and then subjected to column chromatography (petroleum ether conditions : ethyl acetate=1:1) to obtain a white oily substance, that is, the target product (135 g, yield: 56.5%). LCTMS: 186[M+H] ⁺

Stage 2:

Add 2 (70 g, 378 mmol) (product obtained in step 1), 3 (96.7 g, 315 mmol), potassium carbonate (86.9 g, 630 mmol) and DMF ( 300 ml), after which the reaction was carried out for 18 hours at 100°C. After adding ice water, the residual materials were vacuum filtered and the filter cake was dried to obtain a yellow solid, that is, the target product (136 g, yield: 94.6%). LCTMS: 457[M+H] ⁺

Stage 3:

4 (136 g, 298 mmol) (product obtained in step 2) and tetrahydrofuran (1.0 L) were added to a 2 L one-neck flask, then lithium borohydride (13.0 g, 596 mmol) was added in portions, then The reaction was carried out for 5 hours at 50°C. Methyl alcohol (20 ml) was added for quenching purposes, after which the mixture was poured into water and extracted with dichloromethane (1.0 L x 3), washed with brine (500 ml x 3) and dried with anhydrous sodium sulfate, and dried with centrifugal dryer to obtain a white solid, that is, the target product (75 g, yield: 60.8%). LCTMS: 415 [M+H]+

Stage 4:

5 (75 g, 181 mmol) (product obtained in step 3) and dichloromethane (750 ml) were added to a 2 L one-neck flask at 0°C, then TsCl (51.8 g, 272 mmol) and triethylamine ( 36.7 g, 362 mmol), after which the reaction was carried out for 3 hours at room temperature. The reaction liquid was washed with saturated saline, dried with anhydrous sodium sulfate, and dried using a centrifugal dryer to obtain a crude product (80 g, yield: 77.8%). LCTMS: 569 [M+H]+

Stage 5:

6 (80 g, 141 mmol) (product obtained in step 4), acetone (500 ml) and sodium iodide (42.2 g, 282 mmol) were added to a 1 L one-neck flask and heated with reflux, and then dried using a centrifugal dryer and subjected to column chromatography (petroleum ether:ethyl acetate=1:2) to obtain a yellow solid, that is, the target product (70 g, yield: 94.7%). LCTMS: 525 [M+H] ⁺

Stage 6:

7 (25 g, 47.7 mmol) (product obtained in step 5), tetrahydrofuran (200 ml) and sodium methyl mercaptide (6.69 g, 95.4 mmol) were added to a 1 L one-neck flask for 12 hours were subjected to reflux and then dried using a centrifugal dryer and subjected to column chromatography (petroleum ether:ethyl acetate=1:1) to obtain a yellow solid, that is, the target product (11.5 g, yield: 83.1%). LCTMS: 291 [M+H] ⁺

Stage 7:

8 (11.5 g, 39.6 mmol) (product obtained in step 6) and dichloromethane (110 ml) were added to a 500 L one-neck flask at 0°C, then TsCl (11.3 g, 59, 4 mmol) and triethylamine (8.0 g, 79.2 mmol), followed by reaction for 3 hours at room temperature. The reaction liquid was washed with brine, dried with anhydrous sodium sulfate, and then spin-dried to obtain a crude product (14.5 g). LCTMS: 445 [M+H]+

Stage 8:

9 (14.5 g, 32.65 mmol) (product obtained in step 7) and tetrahydrofuran (120 ml) were added to a 250 ml one-neck flask at 0°C; tetrahydrofuran solution of metachloroperbenzoic acid (5.63 g, 32.65 mmol) was added dropwise, after which the mixture was reacted for 30 minutes and the mixture was concentrated, then poured into ethyl acetate (100 ml), then washed successively with saturated sodium sulfite (50 ml × 3), sodium bicarbonate (50 ml × 3) and saline (50 ml × 3), dried with anhydrous sodium sulfate and dried using a centrifugal dryer, then subjected to column chromatography (under conditions of petroleum ether: ethyl acetate=1:2 ) to obtain a yellow solid, that is, the target product (7.0 g, yield: 46.6%). LCTMS: 461 [M+H]+

Stage 9:

Add 10 (7.0 g, 15.21 mmol) (product from step 8), dichloromethane (70 mL), PhI(OAc) ₂ (7.35 g, 22.82 mmol) to a 250 L one-neck flask. and ammonium carbonate (2.92 g, 30.42 mmol), then reacted at room temperature for 6 hours. The residual materials after filtration and concentration were poured into methyl alcohol and potassium carbonate was added, stirred for 30 minutes to achieve the desired concentration, and then subjected to column chromatography (ethyl acetate: methyl alcohol = 4:1 conditions) to obtain a white solid, that is, the target compound (3.0 g, yield: 41.5%). LCTMS: 474 [MH]+

Stage 10:

11 (485 mg, 1.02 mmol), tetrahydrofuran/methyl alcohol (5.0 mL) and cesium carbonate (665 mg, 2.04 mmol) were added to a 25 mL one-neck flask and heated at reflux for 12 hours. refrigerator, concentrated and poured into dichloromethane and brine, the organic phase was dried with anhydrous sodium sulfate, concentrated, and a white solid, i.e. product A (95 mg, yield: 29.0) was obtained using conventional and chiral methods. %). LCTMS:322 [M+H]+，H ¹ -NMR: ¹ H-NMR (400 MHz, DMSO) δ 11.83 (s, 1H), 8.15 (s, 1H), 7.20 (t, J =25.5 Hz, 2H), 6.60 (d, J =2.4 Hz, 1H), 4.64 (s, 1H), 3.38-3.28 (m, 2H), 3, 23 (s, 3H), 3.19 (s, 3H), 2.13-1.98 (m, 3H), 1.73 (s, 4H), 1.42-1.29 (m, 2H) and product B (85 mg, yield: 25.9%), LCTMS: 322 [M+H]+, H ¹ -NMR: ¹ H-NMR (400 MHz, DMSO) δ 11.79 (s, 1H), 8.14 (s, 1H), 7.28-7.00 (m, 2H), 6.59 (d, J=2.3 Hz, 1H), 4.64 (s, 1H), 3.28 (d, J=3.4 Hz, 2H), 3.19 (s, 6H), 2.14-1.96 (m, 3H), 1.72 (d, J=7.4 Hz, 4H) , 1.34 (dd, J=10.7, 5.7 Hz, 2H).

Embodiment 2: T2 Synthesis

Stage 1:

1 (220 g, 1.29 mol) and MeOH (40 ml) were added to a 5 L one-neck flask, after which a tetrahydrofuran solution of methylamine (0.78 L, 1.55 mol and 2 M in THF) was added sequentially. tetraisopropyl titanate (733 g, 2.58 mol) and NaBH ₃ CN (162 g, 2.58 mol), stirred at room temperature for 18 hours, dried using a spin dryer and then subjected to column chromatography (petroleum ether conditions : ethyl acetate=1:1) to obtain a white oily substance, that is, the target product (135 g, yield: 56.5%). LCTMS: 186[M+H] ⁺

Stage 2:

Add 2 (70 g, 378 mmol) (product obtained in step 1), 3 (96.7 g, 315 mmol), potassium carbonate (86.9 g, 630 mmol) and DMF ( 300 ml), after which the reaction was carried out for 18 hours at 100°C. After adding ice water, the residual materials were vacuum filtered and the filter cake was dried to obtain a yellow solid, that is, the target product (136 g, yield: 94.6%). LCTMS: 457[M+H] ⁺

Stage 3:

4 (136 g, 298 mmol) (product obtained in step 2) and tetrahydrofuran (1.0 L) were added to a 2 L one-neck flask, then lithium borohydride (13.0 g, 596 mmol) was added in portions, then The reaction was carried out for 5 hours at 50°C. Methyl alcohol (20 ml) was added for quenching purposes, after which the mixture was poured into water and extracted with dichloromethane (1.0 L x 3), washed with brine (500 ml x 3) and dried with anhydrous sodium sulfate, and dried with centrifugal dryer to obtain a white solid, that is, the target product (75 g, yield: 60.8%). LCTMS: 415 [M+H]+

Stage 4:

5 (75 g, 181 mmol) (product obtained in step 3) and dichloromethane (750 ml) were added to a 2 L one-neck flask at 0°C, then TsCl (51.8 g, 272 mmol) and triethylamine ( 36.7 g, 362 mmol), after which the reaction was carried out for 3 hours at room temperature. The reaction liquid was washed with saturated saline, dried with anhydrous sodium sulfate, and dried using a centrifugal dryer to obtain a crude product (80 g, yield: 77.8%). LCTMS: 569 [M+H]+

Stage 5:

6 (80 g, 141 mmol) (product obtained in step 4), acetone (500 ml) and sodium iodide (42.2 g, 282 mmol) were added to a 1 L one-neck flask and heated with reflux, and then dried using a centrifugal dryer and subjected to column chromatography (petroleum ether:ethyl acetate=1:2) to obtain a yellow solid, that is, the target product (70 g, yield: 94.7%). LCTMS: 525 [M+H] ⁺

Stage 6:

7 (25 g, 47.7 mmol) (product obtained in step 5), tetrahydrofuran (200 ml) and sodium methyl mercaptide (6.69 g, 95.4 mmol) were added to a 1 L one-neck flask for 12 hours were subjected to reflux and then dried using a centrifugal dryer and subjected to column chromatography (petroleum ether:ethyl acetate=1:1) to obtain a yellow solid, that is, the target product (11.5 g, yield: 83.1%). LCTMS: 291 [M+H] ⁺

Stage 7:

8 (11.5 g, 39.6 mmol) (product obtained in step 6) and dichloromethane (110 ml) were added to a 500 L one-neck flask at 0°C, then TsCl (11.3 g, 59, 4 mmol) and triethylamine (8.0 g, 79.2 mmol), followed by reaction for 3 hours at room temperature. The reaction liquid was washed with brine, dried with anhydrous sodium sulfate, and then spin-dried to obtain a crude product (14.5 g). LCTMS: 445 [M+H]+

Stage 8:

9 (14.5 g, 32.65 mmol) (product obtained in step 7) and tetrahydrofuran (120 ml) were added to a 250 ml one-neck flask at 0°C; tetrahydrofuran solution of metachloroperbenzoic acid (5.63 g, 32.65 mmol) was added dropwise, after which the mixture was reacted for 30 minutes and the mixture was concentrated, then poured into ethyl acetate (100 ml), then washed successively with saturated sodium sulfite (50 ml × 3), sodium bicarbonate (50 ml × 3) and saline (50 ml × 3), dried with anhydrous sodium sulfate and dried using a centrifugal dryer, then subjected to column chromatography (under conditions of petroleum ether: ethyl acetate=1:2 ) to obtain a yellow solid, that is, the target product (7.0 g, yield: 46.6%). LCTMS: 461 [M+H]+

Stage 9:

Add 10 (7.0 g, 15.21 mmol) (product from step 8), dichloromethane (70 mL), PhI(OAc) ₂ (7.35 g, 22.82 mmol) to a 250 L one-neck flask. , then TsCl (7.35 g, 22.82 mmol) and ammonium carbonate (2.92 g, 30.42 mmol) were added sequentially, followed by reaction for 6 hours at room temperature. The residual materials after filtration and concentration were poured into methyl alcohol and potassium carbonate was added, stirred for 30 minutes to achieve the desired concentration, and then subjected to column chromatography (ethyl acetate: methyl alcohol = 4:1 conditions) to obtain a white solid, that is, the target compound (3.0 g, yield: 41.5%). LCTMS: 474 [MH]+

Stage 10:

Add 11 (1.0 g, 2.10 mmol) (product from step 9), paraformaldehyde (379 mL, 4.20 mmol) and formic acid (8 mL) to a 25 L one-neck round bottom flask. The reaction was carried out for 48 hours at 100°C. The residual materials after concentration were poured into dichloromethane and 2N sulfuric acid; the aqueous phase was neutralized with sodium bicarbonate and extracted with dichloromethane (10 ml x 3), and the organic phase was dried with anhydrous sodium sulfate and concentrated to obtain a white solid, that is, the target product (500 mg, yield: 48.7%). LCTMS: 490 [M+H]+

Stage 11:

12 (500 mg, 1.02 mmol) (product obtained in step 10), tetrahydrofuran/methyl alcohol (5.0 mL) and cesium carbonate (665 mg, 2.04 mmol) were added to a 25 mL one-neck flask. refluxed for 12 hours, concentrated and poured into dichloromethane and brine, the organic phase was dried over anhydrous sodium sulfate, concentrated, and a white solid, i.e. product A, was obtained by conventional and chiral methods. 100 mg, yield: 29.8%). LCTMS:336 [M+H]+，H ¹ -NMR: ¹ H-NMR (400 MHz, DMSO) δ 11.60 (s, 1H), 8.09 (s, 1H), 7.20-7, 04 (m, 1H), 6.53 (s, 1H), 4.67 (s, 1H), 3.23-2.99 (m, 5H), 2.94 (m, 3H), 2.64 (m, 3H), 2.16-1.89 (m, 3H), 1.69 (m, 4H), 1.35-1.14 (m, 2H) and product B (80 mg, yield: 23 .4%), LCTMS:336 [M+H]+, H ¹ -NMR: ¹ H-NMR (400 MHz, DMSO) δ 11.60 (s, 1H), 8.09 (s, 1H), 7 .12 (dd, J =3.3, 2.5 Hz, 1H), 6.54 (s, 1H), 4.67 (s, 1H), 3.21-2.99 (m, 5H), 2.93 (s, 3H), 2.63 (s, 3H), 2.14-1.89 (m, 3H), 1.70 (m, 4H), 1.36-1.20 (m, 2H).

Embodiment 3: T3 Synthesis

Stage 1:

1 (220 g, 1.29 mol) and MeOH (40 ml) were added to a 5 L one-neck flask, after which a tetrahydrofuran solution of methylamine (0.78 L, 1.55 mol and 2 M in THF) was added sequentially. tetraisopropyl titanate (733 g, 2.58 mol) and NaBH ₃ CN (162 g, 2.58 mol), stirred at room temperature for 18 hours, dried using a spin dryer and then subjected to column chromatography (petroleum ether conditions : ethyl acetate=1:1) to obtain a white oily substance, that is, the target product (135 g, yield: 56.5%). LCTMS: 186[M+H] ⁺

Stage 2:

Add 2 (70 g, 378 mmol) (product obtained in step 1), 3 (96.7 g, 315 mmol), potassium carbonate (86.9 g, 630 mmol) and DMF ( 300 ml), after which the reaction was carried out for 18 hours at 100°C. After adding ice water, the residual materials were vacuum filtered and the filter cake was dried to obtain a yellow solid, that is, the target product (136 g, yield: 94.6%). LCTMS: 457[M+H] ⁺

Stage 3:

4 (136 g, 298 mmol) (product obtained in step 2) and tetrahydrofuran (1.0 L) were added to a 2 L one-neck flask, then lithium borohydride (13.0 g, 596 mmol) was added in portions, then The reaction was carried out for 5 hours at 50°C. Methyl alcohol (20 ml) was added for quenching purposes, after which the mixture was poured into water and extracted with dichloromethane (1.0 L x 3), washed with brine (500 ml x 3) and dried with anhydrous sodium sulfate, and dried with centrifugal dryer to obtain a white solid, that is, the target product (75 g, yield: 60.8%). LCTMS: 415 [M+H]+

Stage 4:

5 (75 g, 181 mmol) (product obtained in step 3) and dichloromethane (750 ml) were added to a 2 L one-neck flask at 0°C, then TsCl (51.8 g, 272 mmol) and triethylamine ( 36.7 g, 362 mmol), after which the reaction was carried out for 3 hours at room temperature. The reaction liquid was washed with saturated saline, dried with anhydrous sodium sulfate, and dried using a centrifugal dryer to obtain a crude product (80 g, yield: 77.8%). LCTMS: 569 [M+H]+

Stage 5:

6 (80 g, 141 mmol) (product obtained in step 4), acetone (500 ml) and sodium iodide (42.2 g, 282 mmol) were added to a 1 L one-neck flask and heated with reflux, and then dried using a centrifugal dryer and subjected to column chromatography (petroleum ether:ethyl acetate=1:2) to obtain a yellow solid, that is, the target product (70 g, yield: 94.7%). LCTMS: 525 [M+H] ⁺

Stage 6:

7 (25 g, 47.7 mmol) (product obtained in step 5), tetrahydrofuran (200 ml) and sodium methyl mercaptide (6.69 g, 95.4 mmol) were added to a 1 L one-neck flask for 12 hours were subjected to reflux and then dried using a centrifugal dryer and subjected to column chromatography (petroleum ether:ethyl acetate=1:1) to obtain a yellow solid, that is, the target product (11.5 g, yield: 83.1%). LCTMS: 291 [M+H] ⁺

Stage 7:

8 (11.5 g, 39.6 mmol) (product obtained in step 6) and dichloromethane (110 ml) were added to a 500 L one-neck flask at 0°C, then TsCl (11.3 g, 59, 4 mmol) and triethylamine (8.0 g, 79.2 mmol), followed by reaction for 3 hours at room temperature. The reaction liquid was washed with brine, dried with anhydrous sodium sulfate, and then spin-dried to obtain a crude product (14.5 g). LCTMS: 445 [M+H]+

Stage 8:

9 (14.5 g, 32.65 mmol) (product obtained in step 7) and tetrahydrofuran (120 ml) were added to a 250 ml one-neck flask at 0°C; tetrahydrofuran solution of metachloroperbenzoic acid (5.63 g, 32.65 mmol) was added dropwise, after which the mixture was reacted for 30 minutes and the mixture was concentrated, then poured into ethyl acetate (100 ml), then washed successively with saturated sodium sulfite (50 ml × 3), sodium bicarbonate (50 ml × 3) and saline (50 ml × 3), dried with anhydrous sodium sulfate and dried using a centrifugal dryer, then subjected to column chromatography (under conditions of petroleum ether: ethyl acetate=1:2 ) to obtain a yellow solid, that is, the target product (7.0 g, yield: 46.6%). LCTMS: 461 [M+H]+

Stage 9:

Add 10 (7.0 g, 15.21 mmol) (product from step 8), dichloromethane (70 mL), PhI(OAc) ₂ (7.35 g, 22.82 mmol) to a 250 L one-neck flask. and ammonium carbonate (2.92 g, 30.42 mmol), then reacted at room temperature for 6 hours. The residual mixture after filtration and concentration was poured into methyl alcohol and potassium carbonate was added, stirred for 30 minutes to achieve the desired concentration, and then subjected to column chromatography (ethyl acetate: methyl alcohol = 4:1 conditions) to obtain a white solid, that is, the target compound (3.0 g, yield: 41.5%). LCTMS: 474 [MH]+

Stage 10:

Add 11 (1.0 g, 2.10 mmol) (product obtained in step 9), triethyloxonium tetrafluoroborate (798 mg, 4.20 mmol), potassium carbonate (580 mg, 4.20 mmol) and dichloromethane (10 ml), after which the reaction was carried out at room temperature for 18 hours. After concentration, treatment was carried out in a chromatographic column (under conditions of ethyl acetate:methyl alcohol=1:1) to obtain a white solid, that is, the target compound (500 mg, yield: 47.3%). LCTMS: 504 [M+H]+

Stage 11:

12 (500 mg, 0.99 mmol) (product obtained in step 10), tetrahydrofuran/methyl alcohol (5.0 mL) and cesium carbonate (648 mg, 1.98 mmol) were added to a 25 mL one-neck flask. refluxed for 12 hours, concentrated and poured into dichloromethane and brine, the organic phase was dried over anhydrous sodium sulfate, concentrated, and a white solid, i.e. product A, was obtained by conventional and chiral methods. 75 mg, yield: 21.7%). LCTMS:350.1 [M+H]+, ¹ H-NMR (400 MHz, DMSO) δ 11.60 (s, 1H), 8.09 (s, 1H), 7.15-7.10 (m, 1H ), 6.53 (s, 1H), 4.66 (s, 1H), 3.23 (s, 3H), 3.12-2.96 (m, 4H), 2.93 (s, 3H) , 2.07 (t, J =14.7 Hz, 2H), 1.95 (d, J =3.2 Hz, 1H), 1.76-1.68 (m, 4H), 1.32- 1.23 (m, 2H), 1.08 (t, J =7.1 Hz, 3H) and product B (85 mg, yield: 24.6%), LCTMS:350.1 [M+H]+, ¹ H-NMR (400 MHz, DMSO) δ 11.60 (s, 1H), 8.09 (s, 1H), 7.12 (d, J =1.2 Hz, 1H), 6.53 (d, J =2.6 Hz, 1H), 4.67 (s, 1H), 3.19 (d, J =19.5 Hz, 3H), 3.12-2.96 (m, 4H), 2, 94 (d, J =5.2 Hz, 3H), 2.07 (t, J =14.9 Hz, 2H), 1.93 (d, J =17.4 Hz, 1H), 1.76- 1.68 (m, 4H), 1.27 (dd, J =14.6, 6.9 Hz, 2H), 1.09 (dd, J =7.2, 3.9 Hz, 3H).

Embodiment 4: T4 Synthesis

Stage 1:

1 (220 g, 1.29 mol) and MeOH (40 ml) were added to a 5 L one-neck flask, after which a tetrahydrofuran solution of methylamine (0.78 L, 1.55 mol and 2 M in THF) was added sequentially. tetraisopropyl titanate (733 g, 2.58 mol) and NaBH ₃ CN (162 g, 2.58 mol), stirred at room temperature for 18 hours, dried using a spin dryer and then subjected to column chromatography (petroleum ether conditions : ethyl acetate=1:1) to obtain a white oily substance, that is, the target product (135 g, yield: 56.5%). LCTMS: 186[M+H] ⁺

Stage 2:

Add 2 (70 g, 378 mmol) (product obtained in step 1), 3 (96.7 g, 315 mmol), potassium carbonate (86.9 g, 630 mmol) and DMF ( 300 ml), after which the reaction was carried out for 18 hours at 100°C. After adding ice water, the residual materials were vacuum filtered and the filter cake was dried to obtain a yellow solid, that is, the target product (136 g, yield: 94.6%). LCTMS: 457[M+H] ⁺

Stage 3:

4 (136 g, 298 mmol) (product obtained in step 2) and tetrahydrofuran (1.0 L) were added to a 2 L one-neck flask, then lithium borohydride (13.0 g, 596 mmol) was added in portions, then The reaction was carried out for 5 hours at 50°C. Methyl alcohol (20 ml) was added for quenching purposes, after which the mixture was poured into water and extracted with dichloromethane (1.0 L x 3), washed with brine (500 ml x 3) and dried with anhydrous sodium sulfate, and dried with centrifugal dryer to obtain a white solid, that is, the target product (75 g, yield: 60.8%). LCTMS: 415 [M+H]+

Stage 4:

5 (75 g, 181 mmol) (product obtained in step 3) and dichloromethane (750 ml) were added to a 2 L one-neck flask at 0°C, then TsCl (51.8 g, 272 mmol) and triethylamine ( 36.7 g, 362 mmol), after which the reaction was carried out for 3 hours at room temperature. The reaction liquid was washed with saturated saline, dried with anhydrous sodium sulfate, and dried using a centrifugal dryer to obtain a crude product (80 g, yield: 77.8%). LCTMS: 569 [M+H]+

Stage 5:

6 (80 g, 141 mmol) (product obtained in step 4), acetone (500 ml) and sodium iodide (42.2 g, 282 mmol) were added to a 1 L one-neck flask and heated with reflux, and then dried using a centrifugal dryer and subjected to column chromatography (petroleum ether:ethyl acetate=1:2) to obtain a yellow solid, that is, the target product (70 g, yield: 94.7%). LCTMS: 525 [M+H] ⁺

Stage 6:

7 (15 g, 28.62 mmol) (product obtained in step 5), tetrahydrofuran (120 ml) and sodium ethanethiolate (4.82 g, 57.24 mmol) were added to a 1 L one-neck flask over 12 hrs was subjected to reflux and then dried using a centrifugal dryer and subjected to column chromatography (petroleum ether:ethyl acetate=1:1) to obtain a yellow solid, that is, the target product (7.5 g, yield: 86.2%). LCTMS: 305 [M+H] ⁺

Stage 7:

8 (7.5 g, 39.6 mmol) (product obtained in step 6) and dichloromethane (80 ml) were added to a 500 L one-neck flask at 0°C, then TsCl (7.06 g, 37. 01 mmol) and triethylamine (5.0 g, 49.34 mmol), followed by reaction for 3 hours at room temperature. The reaction liquid was washed with saturated saline (50 ml×3), dried with anhydrous sodium sulfate, and dried using a spin dryer to obtain a crude product (5.5 g). LCTMS: 459 [M+H]+

Stage 8:

9 (2.6 g, 5.68 mmol) (product obtained in step 7) and tetrahydrofuran (30 ml) were added to a 250 ml one-neck flask at 0°C; tetrahydrofuran solution of metachloroperbenzoic acid (980 mg, 5.68 mmol) was added dropwise, after which the mixture was reacted for 30 minutes and the mixture was concentrated, then poured into ethyl acetate (30 ml), then washed successively with saturated sodium sulfite (20 ml × 3 ), sodium bicarbonate (20 ml × 3) and saline (20 ml × 3), dried with anhydrous sodium sulfate and dried using a centrifugal dryer, then subjected to column chromatography (petroleum ether:ethyl acetate=1:2) with obtaining a yellow solid, that is, the target product (2.0 g, yield: 74.3%). LCTMS: 475 [M+H]+

Stage 9:

Add 10 (2.0 g, 4.22 mmol) (product obtained in step 8), dichloromethane (20 ml), PhI(OAc) ₂ (2.04 g, 6.33 mmol) to a 250 L one-neck flask. , PhI(OAc) ₂ (2.04 g, 6.33 mmol) and ammonium carbonate (811 mg, 8.44 mmol), and then reacted at room temperature for 6 hours. The residual materials after filtration and concentration were poured into methyl alcohol and potassium carbonate was added, stirred for 30 minutes to achieve the desired concentration, and then subjected to column chromatography (ethyl acetate: methyl alcohol = 4:1 conditions) to obtain a white solid, that is, the target compound (1.2 g, yield: 58.1%). LCTMS: 488 [MH]+

Stage 10:

Add 11 (1.0 g, 2.04 mmol) (product from step 9), tetrahydrofuran/methyl alcohol (10 mL), and cesium carbonate (1.33 g, 4.08 mmol) to a 25 mL one-neck flask. , which were refluxed for 12 hours, concentrated and poured into dichloromethane and brine, the organic phase was dried over anhydrous sodium sulfate, concentrated, and a white solid was obtained by conventional and chiral methods, i.e. the product A (20 mg, yield: 2.9%). LCTMS:336 [M+H]+，H ¹ -NMR: ¹ H-NMR (400 MHz, DMSO) δ 11.61 (s, 1H), 8.09 (s, 1H), 7.13 (s, 1H), 6.54 (s, 1H), 4.67 (s, 1H), 3.90-3.83 (m, 1H), 3.17 (s, 3H), 3.06-2.93 (m, 4H), 2.12-2.01 (m, 3H), 1.73-1.70 (m, 4H), 1.31-1.22 (m, 5H) and product B (25 mg , yield: 3.7%), LCTMS: 336 [M+H]+, H ¹ -NMR: ¹ H-NMR (400 MHz, DMSO) δ 11.59 (s, 1H), 8.09 (s, 1H), 7.12 (dd, J =3.3, 2.6 Hz, 1H), 6.54 (s, 1H), 4.67 (s, 1H), 3.58 (s, 1H), 3.17 (s, 3H), 3.06-2.89 (m, 4H), 2.16-1.93 (m, 3H), 1.74-1.69 (m, 4H), 1. 25-1.23 (m, 5H).

Embodiment 5: T5 Synthesis

Stage 1:

1 (220 g, 1.29 mol) and MeOH (40 ml) were added to a 5 L one-neck flask, after which a tetrahydrofuran solution of methylamine (0.78 L, 1.55 mol and 2 M in THF) was added sequentially. tetraisopropyl titanate (733 g, 2.58 mol) and NaBH ₃ CN (162 g, 2.58 mol), stirred at room temperature for 18 hours, dried using a spin dryer and then subjected to column chromatography (petroleum ether conditions : ethyl acetate=1:1) to obtain a white oily substance, that is, the target product (135 g, yield: 56.5%). LCTMS: 186[M+H] ⁺

Stage 2:

Add 2 (70 g, 378 mmol) (product obtained in step 1), 3 (96.7 g, 315 mmol), potassium carbonate (86.9 g, 630 mmol) and DMF ( 300 ml), after which the reaction was carried out for 18 hours at 100°C. After adding ice water, the residual materials were vacuum filtered and the filter cake was dried to obtain a yellow solid, that is, the target product (136 g, yield: 94.6%). LCTMS: 457[M+H] ⁺

Stage 3:

4 (136 g, 298 mmol) (product obtained in step 2) and tetrahydrofuran (1.0 L) were added to a 2 L one-neck flask, then lithium borohydride (13.0 g, 596 mmol) was added in portions, then The reaction was carried out for 5 hours at 50°C. Methyl alcohol (20 ml) was added for quenching purposes, after which the mixture was poured into water and extracted with dichloromethane (1.0 L x 3), washed with brine (500 ml x 3) and dried with anhydrous sodium sulfate, and dried with centrifugal dryer to obtain a white solid, that is, the target product (75 g, yield: 60.8%). LCTMS: 415 [M+H]+

Stage 4:

5 (75 g, 181 mmol) (product obtained in step 3) and dichloromethane (750 ml) were added to a 2 L one-neck flask at 0°C, then TsCl (51.8 g, 272 mmol) and triethylamine ( 36.7 g, 362 mmol), after which the reaction was carried out for 3 hours at room temperature. The reaction liquid was washed with saturated saline, dried with anhydrous sodium sulfate, and dried using a centrifugal dryer to obtain a crude product (80 g, yield: 77.8%). LCTMS: 569 [M+H]+

Stage 5:

6 (80 g, 141 mmol) (product obtained in step 4), acetone (500 ml) and sodium iodide (42.2 g, 282 mmol) were added to a 1 L one-neck flask and heated with reflux, and then dried using a centrifugal dryer and subjected to column chromatography (petroleum ether:ethyl acetate=1:2) to obtain a yellow solid, that is, the target product (70 g, yield: 94.7%). LCTMS: 525 [M+H] ⁺

Stage 6:

Add 7 (1.1 g, 2.10 mmol) (product from step 5), cyclopropylmethanethiol (154 mg, 1.75 mmol), tetrahydrofuran (12 mL) and sodium hydride (140 mg) to a 50 mL one-neck flask , 3.50 mmol), then reacted at room temperature for 30 minutes, and then the mixture was refluxed for 12 hours, then dried using a spin dryer to obtain a yellow solid (1.2 g, crude product). LCTMS: 331 [M+H] ⁺

Stage 7:

8 (1.2 g, 3.63 mmol) (product from step 6) and dichloromethane (12 mL) were added to a 50 L one-neck flask at 0°C, then TsCl (831 mg, 4.36 mmol) was added sequentially ) and triethylamine (735 mg, 7.26 mmol), followed by reaction for 3 hours at room temperature. The reaction liquid was washed with saturated saline, dried with anhydrous sodium sulfate, and dried using a spin dryer to obtain a crude product (1.0 g). LCTMS: 485 [M+H]+

Stage 8:

9 (1.0 g, 2.07 mmol) (product obtained in step 7) and tetrahydrofuran (10 ml) were added to a 50 ml one-neck flask at 0°C; tetrahydrofuran solution of metachloroperbenzoic acid (713 mg, 4.13 mmol) was added dropwise, after which the mixture was reacted for 30 min and the mixture was concentrated, then poured into ethyl acetate (20 ml), then washed successively with saturated sodium sulfite (10 ml × 3 ), sodium bicarbonate (10 ml × 3) and saline (10 ml × 3), dried with anhydrous sodium sulfate and dried using a centrifugal dryer, then subjected to column chromatography (petroleum ether:ethyl acetate=1:2) with obtaining a yellow solid, that is, the target product (320 mg, yield: 30.9%). LCTMS: 501 [M+H]+

Stage 9:

10 (320 mg, 0.54 mmol) (product obtained in step 8), dichloromethane (5 ml), PhI(OAc) ₂ (309 mg, 0.96 mmol) and ammonium carbonate ( 123 mg, 1.28 mmol), after which the reaction was carried out at room temperature for 6 hours. The residual materials after filtration and concentration were poured into methyl alcohol and potassium carbonate was added, stirred for 30 minutes to achieve the desired concentration, and then subjected to column chromatography (ethyl acetate: methyl alcohol = 4:1 conditions) to obtain a white solid, that is, the target compound (300 mg, yield: 91.0%). LCTMS: 514 [MH]+

Stage 10:

11 (300 mg, 0.58 mmol), tetrahydrofuran/methyl alcohol (5.0 mL) and cesium carbonate (380 mg, 1.16 mmol) were added to a 25 mL one-neck flask and heated at reflux for 12 hours. refrigerator, concentrated and poured into dichloromethane and brine, the organic phase was dried over anhydrous sodium sulfate, concentrated, and a white solid, i.e. product A (4 mg, yield: 1.9) was obtained using conventional and chiral methods. %), LCTMS: 362.2 [M+H]+, ¹ H-NMR (400 MHz, EUOO) δ 8.12 (s, 1H), 7.14 (d, J =3.6 Hz, 1H) , 6.68 (d, J =3.6 Hz, 1H), 4.72 (s, 1H), 3.34 (s, 3H), 3.16 (d, J =7.1 Hz, 2H) , 2.08 (dd, J =28.6, 9.0 Hz, 3H), 1.90 (t, J =8.4 Hz, 4H), 1.72 (d, J =8.7 Hz, 2H), 1.35-1.21 (m, 5H), 0.80-0.74 (m, 2H), 0.52-0.45 (m, 2H); with the white solid being product B (5 mg, yield: 2.4%), LCHTMS 362.2 [M+H]+, ¹ H-NMR (400 MHz, ECOO) δ 8.11 (s, 1H) , 7.11 (d, J=3.6 Hz, 1H), 6.65 (d, J=3.6 Hz, 1H), 4.73 (d, 1H), 3.30 (d, J= 6.8 Hz, 3H), 3.15 (d, J=7.1 Hz, 2H), 2.08 (dd, J=28.8, 9.0 Hz, 3H), 1.90 (t, J=8.6 Hz, 4H), 1.72 (s, 2H), 1.41-1.15 (m, 3H), 0.81-0.71 (m, 2H), 0.49 (dd , J=7.6, 4.6 Hz, 2H); with the white solid being product C (12 mg, yield: 5.7%), LCTMS: 362.2 [M+H]+, ¹ H-NMR (400 MHz, ECOO) δ 8.10 (s, 1H ), 7.11 (d, J =3.6 Hz, 1H), 6.65 (d, J =3.6 Hz, 1H), 4.73 (s, 1H), 3.28 (s, 3H ), 3.22-3.09 (m, 4H), 2.30-2.12 (m, 3H), 1.84 (ddd, J = 15.7, 9.8, 3.2 Hz, 4H ), 1.46 (qd, J =13.0, 6.3 Hz, 2H), 1.21 (tdd, J =7.2, 6.4, 2.3 Hz, 1H), 0.79- 0.72 (m, 2H), 0.50-0.42 (m, 2H); wherein the white solid was product D (15 mg, yield: 7.2%), LCTMS: 362.2 [M+H]+, ¹ H-NMR (400 MHz, ECOO) δ 8.10 (s, 1H ), 7.11 (d, J =3.6 Hz, 1H), 6.65 (d, J =3.6 Hz, 1H), 4.73 (s, 1H), 3.28 (s, 3H ), 3.22-3.09 (m, 4H), 2.30-2.23 (m, 1H), 2.16 (dd, J =13.1, 3.1 Hz, 2H), 1, 92-1.78 (m, 4H), 1.46 (qd, J =13.0, 6.3 Hz, 2H), 1.25-1.17 (m, 1H), 0.79-0, 71 (m, 2H), 0.47 (td, J =4.7, 2.1 Hz, 2H).

Embodiment 6: T6 Synthesis

Stage 1:

1 (220 g, 1.29 mol) and MeOH (40 ml) were added to a 5 L one-neck flask, after which a tetrahydrofuran solution of methylamine (0.78 L, 1.55 mol and 2 M in THF) was added sequentially. tetraisopropyl titanate (733 g, 2.58 mol) and NaBH ₃ CN (162 g, 2.58 mol), stirred at room temperature for 18 hours, dried using a spin dryer and then subjected to column chromatography (petroleum ether conditions : ethyl acetate=1:1) to obtain a white oily substance, that is, the target product (135 g, yield: 56.5%). LCTMS: 186[M+H] ⁺

Stage 2:

Add 2 (70 g, 378 mmol) (product obtained in step 1), 3 (96.7 g, 315 mmol), potassium carbonate (86.9 g, 630 mmol) and DMF ( 300 ml), after which the reaction was carried out for 18 hours at 100°C. After adding ice water, the residual materials were vacuum filtered and the filter cake was dried to obtain a yellow solid, that is, the target product (136 g, yield: 94.6%). LCTMS: 457[M+H] ⁺

Stage 3:

4 (136 g, 298 mmol) (product obtained in step 2) and tetrahydrofuran (1.0 L) were added to a 2 L one-neck flask, then lithium borohydride (13.0 g, 596 mmol) was added in portions, then The reaction was carried out for 5 hours at 50°C. Methyl alcohol (20 ml) was added for quenching purposes, after which the mixture was poured into water and extracted with dichloromethane (1.0 L x 3), washed with brine (500 ml x 3) and dried with anhydrous sodium sulfate, and dried with centrifugal dryer to obtain a white solid, that is, the target product (75 g, yield: 60.8%). LCTMS: 415 [M+H]+

Stage 4:

5 (75 g, 181 mmol) (product obtained in step 3) and dichloromethane (750 ml) were added to a 2 L one-neck flask at 0°C, then TsCl (51.8 g, 272 mmol) and triethylamine ( 36.7 g, 362 mmol), after which the reaction was carried out for 3 hours at room temperature. The reaction liquid was washed with saturated saline, dried with anhydrous sodium sulfate, and dried using a centrifugal dryer to obtain a crude product (80 g, yield: 77.8%). LCTMS: 569 [M+H]+

Stage 5:

6 (80 g, 141 mmol) (product obtained in step 4), acetone (500 ml) and sodium iodide (42.2 g, 282 mmol) were added to a 1 L one-neck flask and heated with reflux, and then dried using a centrifugal dryer and subjected to column chromatography (petroleum ether:ethyl acetate=1:2) to obtain a yellow solid, that is, the target product (70 g, yield: 94.7%). LCTMS: 525 [M+H] ⁺

Stage 6:

8 (473 mg, 3.33 mmol) and DMF (5 ml) were added to a 50 ml one-neck flask, then sodium hydride (266 mg, 6.66 mmol) was added at 0°C and stirred at room temperature for 30 min, 7 (2.1 g, 4.0 mmol) (product obtained in step 5) was added, followed by reaction at room temperature for 12 hours. Water was added for quenching purposes, after which the mixture was extracted with ethyl acetate (1.0 L x 3), washed with brine (30 mL x 3) and dried with anhydrous sodium sulfate, and dried using a spin dryer, and then subjected to chromatography column (under conditions of dichloromethane:methyl alcohol=30:1) to obtain a white solid, that is, the target product (1.2 g, yield: 93.8%). LCTMS: 385 [M+H] ⁺

Stage 7:

9 (1.2 g, 3.12 mmol) (product from step 6) and dichloromethane (15 mL) were added to a 50 L one-neck flask at 0°C, then TsCl (893 mg, 4.69 mmol) was added sequentially ) and triethylamine (948 mg, 9.36 mmol), followed by reaction for 3 hours at room temperature. The reaction liquid was washed with saturated saline, dried with anhydrous sodium sulfate and dried using a centrifugal dryer, then subjected to column chromatography (petroleum ether:ethyl acetate=2:1) to obtain a white solid, that is, the target product (400 mg, yield: 23.8%). LCTMS: 539 [M+H]+

Stage 8:

10 (400 mg, 0.74 mmol) (product obtained in step 7) and tetrahydrofuran (4 ml) were added to a 25 ml one-neck flask at 0°C; tetrahydrofuran solution of metachloroperbenzoic acid (257 mg, 1.49 mmol) was added dropwise, after which the mixture was reacted for 30 minutes and the mixture was concentrated, then poured into ethyl acetate (10 ml), then washed successively with saturated sodium sulfite (10 ml × 3 ), sodium bicarbonate (10 ml × 3) and saline (10 ml × 3), dried with anhydrous sodium sulfate and dried using a centrifugal dryer, then subjected to column chromatography (petroleum ether:ethyl acetate=1:1) with obtaining a yellow solid, that is, the target product (300 mg, yield: 73.2%). LCTMS: 555 [M+H]+

Stage 9:

11 (300 mg, 0.54 mmol) (product obtained in step 8), methyl alcohol (5 ml), PhI(OAc) ₂ (261 mg, 0.81 mmol) and ammonium carbonate were added to a 25 L one-neck flask (104 mg, 1.08 mmol), after which the reaction was carried out at 60°C for 48 hours. The residual materials after filtration and concentration were poured into methyl alcohol and potassium carbonate was added, stirred for 30 minutes to achieve the desired concentration, and then subjected to column chromatography (ethyl acetate: methyl alcohol = 4:1 conditions) to obtain a white solid, that is, the target compound (276 mg, yield: 89.8%). LCTMS: 570 [M+H]+

Stage 10:

Add 12 (276 mg, 0.48 mmol) (product from step 9), tetrahydrofuran (3.0 mL), cesium carbonate (251 mg, 0.96 mmol) and tetrabutylammonium fluoride (251) to a 25 mL one-neck flask. mg, 0.96 mmol), which were refluxed for 12 hours, concentrated and poured into dichloromethane and brine, the organic phase being dried over anhydrous sodium sulfate and concentrated, then processed in the conventional manner and treated with a chiral solution (in column: DAICEL CHRAL OD (250 mm × 30 mm, 10 µm); gradient time: 20 min; conditions: 0.2% DEA, ethanol and hexane; flow rate: 18 ml/min; 75% ethanol) s obtaining a white solid, that is, the product - T6-A (8 mg, yield: 4.0%). LCTMS:416.2 [M+H]+, ¹ H-NMR (400 MHz, ECOO) δ 8.10 (s, 1H), 7.59-7.50 (m, 2H), 7.24-7 .15 (m, 2H), 7.10 (d, J =3.6 Hz, 1H), 6.64 (d, J =3.6 Hz, 1H), 4.71 (s, 1H), 4 .48 (dd, J =29.1, 13.5 Hz, 2H), 3.41-3.34 (m, 1H), 3.27 (d, J =10.9 Hz, 3H), 3. 22-3.17 (m, 1H), 2.60 (s, 1H), 2.09-1.98 (m, 2H), 1.91-1.83 (m, 4H), 1.68 ( d, J =8.4 Hz, 2H), 1.31 (s, 1H); product T6-B （27 mg, yield: 13.5%), LCTMS: 416.1 [M+H]+, ¹ H-NMR (400 MHz, ECOO) δ 8.09 (s, 1H), 7, 52 (dd, J =8.7, 5.3 Hz, 2H), 7.21-7.15 (m, 2H), 7.10 (d, J =3.6 Hz, 1H), 6.63 (d, J =3.6 Hz, 1H), 4.71 (s, 1H), 4.45 (q, J =13.6 Hz, 2H), 3.26 (s, 3H), 3.06 -2.98 (m, 2H), 2.23-2.19 (m, 1H), 2.16-2.08 (m, 2H), 1.88-1.77 (m, 4H), 1 .42-1.31 (m, 3H); product T6-C (28 mg, yield: 14.1%), LCTMS: 416.1 [M+H]+, ¹ H-NMR (400 MHz, EUOO) δ 8.09 (s, 1H), 7.55- 7.47 (m, 2H), 7.22-7.15 (m, 2H), 7.10 (d, J =3.6 Hz, 1H), 6.63 (d, J =3.6 Hz , 1H), 4.71 (s, 1H), 4.45 (q, J =13.6 Hz, 2H), 3.26 (s, 3H), 3.07-2.97 (m, 2H) , 2.21 (d, J =13.0 Hz, 1H), 2.16-2.07 (m, 2H), 1.89-1.76 (m, 4H), 1.49-1.26 (m, 3H).

Embodiment 7: T7 Synthesis

Stage 1:

1 (220 g, 1.29 mol) and MeOH (40 ml) were added to a 5 L one-neck flask, after which a tetrahydrofuran solution of methylamine (0.78 L, 1.55 mol and 2 M in THF) was added sequentially. tetraisopropyl titanate (733 g, 2.58 mol) and NaBH ₃ CN (162 g, 2.58 mol), stirred at room temperature for 18 hours, dried using a spin dryer and then subjected to column chromatography (petroleum ether conditions : ethyl acetate=1:1) to obtain a white oily substance, that is, the target product (135 g, yield: 56.5%). LCTMS: 186[M+H] ⁺

Stage 2:

Add 2 (70 g, 378 mmol) (product obtained in step 1), 3 (96.7 g, 315 mmol), potassium carbonate (86.9 g, 630 mmol) and DMF ( 300 ml), after which the reaction was carried out for 18 hours at 100°C. After adding ice water, the residual materials were vacuum filtered and the filter cake was dried to obtain a yellow solid, that is, the target product (136 g, yield: 94.6%). LCTMS: 457[M+H] ⁺

Stage 3:

4 (136 g, 298 mmol) (product obtained in step 2) and tetrahydrofuran (1.0 L) were added to a 2 L one-neck flask, then lithium borohydride (13.0 g, 596 mmol) was added in portions, then The reaction was carried out for 5 hours at 50°C. Methyl alcohol (20 ml) was added for quenching purposes, after which the mixture was poured into water and extracted with dichloromethane (1.0 L x 3), washed with brine (500 ml x 3) and dried with anhydrous sodium sulfate, and dried with centrifugal dryer to obtain a white solid, that is, the target product (75 g, yield: 60.8%). LCTMS: 415 [M+H]+

Stage 4:

5 (75 g, 181 mmol) (product obtained in step 3) and dichloromethane (750 ml) were added to a 2 L one-neck flask at 0°C, then TsCl (51.8 g, 272 mmol) and triethylamine ( 36.7 g, 362 mmol), after which the reaction was carried out for 3 hours at room temperature. The reaction liquid was washed with saturated saline, dried with anhydrous sodium sulfate, and dried using a centrifugal dryer to obtain a crude product (80 g, yield: 77.8%). LCTMS: 569 [M+H]+

Stage 5:

6 (80 g, 141 mmol) (product obtained in step 4), acetone (500 ml) and sodium iodide (42.2 g, 282 mmol) were added to a 1 L one-neck flask and heated with reflux, and then dried using a centrifugal dryer and subjected to column chromatography (petroleum ether:ethyl acetate=1:2) to obtain a yellow solid, that is, the target product (70 g, yield: 94.7%). LCTMS: 525 [M+H] ⁺

Stage 6:

Add 7 (1 g, 1.908 mmol) (product from step 5), 2-methyloxyethanethiol (263 mg, 2.862 mmol), dimethyl sulfoxide (15 mL) and potassium carbonate (395 mg, 2.862 mmol) to a 100 L one-neck flask. , after which the reaction was carried out at a temperature of 130°C overnight, and then dried using a centrifugal dryer and subjected to column chromatography (under conditions of petroleum ether: ethyl acetate = 1:1) to obtain a yellow solid, that is, the target product (438 mg, yield: 47%). LCTMS: 335 [M+H] ⁺

Stage 7:

8 (410 mg, 1.2289 mmol) (product obtained in step 6) and dichloromethane (10 ml) were added to a 100 L one-neck flask at 0°C, then TsCl (468 mg, 2.4478 mmol) was added sequentially and triethylamine (371 mg, 79.2 mmol) and reacted for 3 hours at room temperature. The reaction liquid was washed with saturated saline, dried with anhydrous sodium sulfate and dried using a centrifugal dryer, then separated by thin layer chromatography (petroleum ether:ethyl acetate=1:1) to obtain a white solid, that is, the target product (300 mg, yield : 50%). LCTMS: 489 [M+H]+

Stage 8:

9 (300 mg, 0.6135 mmol) (product obtained in step 7) and tetrahydrofuran (10 ml) were added to a 100 ml one-neck flask at 0°C; tetrahydrofuran solution of metachloroperbenzoic acid (106 mg, 0.6135 mmol) was added dropwise, after which the mixture was reacted for 30 min and the mixture was concentrated, then poured into ethyl acetate (20 ml), then washed successively with saturated sodium sulfite (50 ml × 3 ), sodium bicarbonate (50 ml × 3) and saline (50 ml × 3), dried with anhydrous sodium sulfate and dried using a centrifugal dryer, then subjected to thin layer chromatography (under conditions of dichloromethane: methyl alcohol=30:1) with obtaining a yellow solid, that is, the target product (200 mg, yield: 64.5%). LCTMS: 505 [M+H]+

Stage 9:

10 (200 mg, 0.3963 mmol) (product obtained in step 8), methyl alcohol (10 ml), PhI(OAc) ₂ (382.6 mg, 0.7926 mmol) and ammonium carbonate (192 mg, 1.1889 mmol), then reacted at room temperature for 6 hours. After concentration, treatment was carried out by thin layer chromatography (under conditions of dichloromethane:methyl alcohol=15:1) to obtain a white solid, that is, the target compound (145 mg, yield: 70.4%). LCTMS: 520 [MH]+

Stage 10:

Add 11 (145 mg, 0.2788 mmol) (product from step 9), tetrahydrofuran (5.0 mL), tetrahydrofuran solution TBAF (2.23 mL, 2.23 mmol, 1 mmol) to a 25 mL one-neck flask /ml), after which the reaction was carried out at 60°C for 12 hours, and then the mixture was concentrated to obtain a white solid (25 mg, 31%) using a traditional method. ¹ H-NMR (400 MHz, DMSO) δ 12.67 (s, 1H), 8.32 (s, 1H), 7.44 (s, 1H), 6.85 (s, 1H), 4.02 (s, 2H), 3.90-3.82 (m, 2H), 3.65 (d, J =5.8 Hz, 2H), 3.34 (s, 3H), 3.30 (s, 3H), 2.20 (s, 1H), 2.03 (dd, J =18.1, 10.7 Hz, 2H), 1.82 (s, 4H), 1.46 (s, 2H), 1.33-1.23 (m, 2H).

Embodiment 8: T8 Synthesis

Stage 1:

1 (220 g, 1.29 mol) and MeOH (40 ml) were added to a 5 L one-neck flask, after which a tetrahydrofuran solution of methylamine (0.78 L, 1.55 mol and 2 M in THF) was added sequentially. tetraisopropyl titanate (733 g, 2.58 mol) and NaBH ₃ CN (162 g, 2.58 mol), stirred at room temperature for 18 hours, dried using a spin dryer and then subjected to column chromatography (petroleum ether conditions : ethyl acetate=1:1) to obtain a white oily substance, that is, the target product (135 g, yield: 56.5%). LCTMS: 186[M+H] ⁺

Stage 2:

Add 2 (70 g, 378 mmol) (product obtained in step 1), 3 (96.7 g, 315 mmol), potassium carbonate (86.9 g, 630 mmol) and DMF ( 300 ml), after which the reaction was carried out for 18 hours at 100°C. After adding ice water, the residual materials were vacuum filtered and the filter cake was dried to obtain a yellow solid, that is, the target product (136 g, yield: 94.6%). LCTMS: 457[M+H] ⁺

Stage 3:

4 (136 g, 298 mmol) (product obtained in step 2) and tetrahydrofuran (1.0 L) were added to a 5 L one-neck flask, then lithium borohydride (13.0 g, 596 mmol) was added in portions, then The reaction was carried out for 5 hours at 50°C. Methyl alcohol (20 ml) was added for quenching purposes, after which the mixture was poured into water and extracted with dichloromethane (1.0 L x 3), washed with brine (500 ml x 3) and dried with anhydrous sodium sulfate, and dried with centrifugal dryer to obtain a white solid, that is, the target product (75 g, yield: 60.8%). LCTMS: 415 [M+H]+

Stage 4:

5 (75 g, 181 mmol) (product obtained in step 3) and dichloromethane (750 ml) were added to a 2 L one-neck flask at 0°C, then TsCl (51.8 g, 272 mmol) and triethylamine ( 36.7 g, 362 mmol), after which the reaction was carried out for 3 hours at room temperature. The reaction liquid was washed with saturated saline, dried with anhydrous sodium sulfate, and dried using a centrifugal dryer to obtain a crude product (80 g, yield: 77.8%). LCTMS: 569 [M+H]+

Stage 5:

6 (80 g, 141 mmol) (product obtained in step 4), acetone (500 ml) and sodium iodide (42.2 g, 282 mmol) were added to a 1 L one-neck flask and heated with reflux, and then dried using a centrifugal dryer and subjected to column chromatography (petroleum ether:ethyl acetate=1:2) to obtain a yellow solid, that is, the target product (70 g, yield: 94.7%). LCTMS: 525 [M+H] ⁺

Stage 6:

7 (15 g, 28.62 mmol) (product obtained in step 5), tetrahydrofuran (200 ml) and sodium ethanethiolate (4.82 g, 57.24 mmol) were added to a 500 ml one-neck flask over 12 hrs was subjected to reflux and then dried using a centrifugal dryer and subjected to column chromatography (petroleum ether:ethyl acetate=1:1) to obtain a yellow solid, that is, the target product (7.5 g, yield: 86.2%). LCTMS: 305 [M+H] ⁺

Stage 7:

8 (7.5 g, 24.67 mmol) (product obtained in step 6) and dichloromethane (80 ml) were added to a 250 L one-neck flask at 0°C, then TsCl (7.06 g, 37. 01 mmol) and triethylamine (5.0 g, 49.34 mmol), followed by reaction for 3 hours at room temperature. The reaction liquid was washed with saturated saline, dried with anhydrous sodium sulfate, and dried using a spin dryer to obtain a crude product (5.5 g). LCTMS: 459 [M+H]+

Stage 8:

9 (14.5 g, 32.65 mmol) (product obtained in step 7) and tetrahydrofuran (120 ml) were added to a 250 ml one-neck flask at 0°C; tetrahydrofuran solution of metachloroperbenzoic acid (5.63 g, 32.65 mmol) was added dropwise, after which the mixture was reacted for 30 minutes and the mixture was concentrated, then poured into ethyl acetate (100 ml), then washed successively with saturated sodium sulfite (50 ml × 3), sodium bicarbonate (50 ml × 3) and saline (50 ml × 3), dried with anhydrous sodium sulfate and dried using a centrifugal dryer, then subjected to column chromatography (under conditions of petroleum ether: ethyl acetate=1:2 ) to obtain a yellow solid, that is, the target product (7.0 g, yield: 46.6%). LCTMS: 461 [M+H]+

Stage 9:

10 (400 mg, 0.84 mmol) (product obtained in step 8), dichloromethane (5 ml), PhI(OAc) ₂ (408 mg, 1.27 mmol) and ammonium carbonate ( 161 mg, 1.68 mmol), after which the reaction was carried out at room temperature for 6 hours. After filtration and concentration, methyl alcohol was poured into the mixture and potassium carbonate was added, stirred for 30 minutes to achieve the desired concentration, and then subjected to column chromatography (ethyl acetate: methyl alcohol = 4:1 conditions) to obtain a white solid, then there is the target compound (400 mg, yield: 97.4%). LCTMS: 488 [MH]+

Stage 10:

11 (400 mg, 0.82 mmol) (product obtained in step 9), paraformaldehyde (147 ml, 1.64 mmol) and formic acid (4 ml) were added to a 25 L one-neck round bottom flask, then for 48 The reaction was carried out for hours at 100°C. The residual materials after concentration were poured into dichloromethane and 2N sulfuric acid; the aqueous phase was neutralized with sodium bicarbonate and extracted with dichloromethane (10 ml x 3), and the organic phase was dried with anhydrous sodium sulfate and concentrated to obtain a white solid, that is, the target product (170 mg, yield: 41.1%). LCTMS: 504 [M+H]+

Stage 11:

12 (170 mg, 0.34 mmol) (product obtained in step 10), tetrahydrofuran (2.0 ml) and tetrabutylammonium fluoride (177 mg, 0.68 mmol) were added to a 25 ml one-neck flask over 12 hours were refluxed, concentrated and poured into dichloromethane and brine, the organic phase was dried with anhydrous sodium sulfate and concentrated, then processed by conventional and chiral methods (in a column: DAICEL CHRAL IC (250 mm × 30 mm, 10 µm); gradient time: 20 min; under conditions: 0.2% DEA, ethanol and hexane; flow rate: 18 ml/min; 80% ethanol) to obtain a white solid, i.e. product-T8-A (20 mg , yield: 16.8%). LCTMS:350.2 [M+H]+，H ¹ -NMR: ¹ H-NMR (400 MHz, EUOO) δ 8.13 (s, 1H), 7.16 (d, J =3.6 Hz, 1H), 6.70 (d, J =3.6 Hz, 1H), 4.69 (s, 1H), 3.32-3.25 (m, 5H), 3.18 (dd, J =6 ,2, 1.9 Hz, 2H), 2.79 (s, 3H), 2.27-2.01 (m, 3H), 1.93-1.82 (m, 4H), 1.45 ( d, J =12.0 Hz, 2H), 1.37 (t, J =7.4 Hz, 3H), as well as product T8-B (30 mg, yield: 25.3%), LCTMS: 350, 2 [M+H]+, H ¹ -NMR: ¹ H-NMR (400 MHz, EUOO) δ 8.13 (s, 1H), 7.16 (d, J =3.6 Hz, 1H), 6 .70 (d, J =3.6 Hz, 1H), 4.69 (s, 1H), 3.27-3.21 (m, 3H), 3.11-3.10 (m, 2H), 3.18 (dd, J =6.2, 1.9 Hz, 2H), 2.79 (s, 3H), 2.19 (dd, J =24.0, 12.8 Hz, 2H), 2 .07 (s, 1H), 1.93-1.82 (m, 4H), 1.51-1.42 (m, 2H), 1.37 (t, J = 7.4 Hz, 3H).

Embodiment 9: JAK1 Enzymology Experiment

Experimental materials

JAK1 is a type of protein tyrosine kinase that can be purchased from Thermo (Part No.: PV4774). ATP was purchased from Thermo (cat. no.: PV4774), tofacitinib was purchased from Selleck (cat. no.: S5001), HTRF KinEASE-TK kit was purchased from Cisbio (cat. no.: 62TKOPEC ).

Experimental method

HTRF®KinEASE™-TK was a universal method for measuring tyrosine kinase activity using a substrate and a universal detection system. The reaction was carried out in a 384-well plate (Greiner brand, catalog no.: 784075), and the total reaction system was 20 μl/well. The reaction system mainly consisted of 1× kinase buffer solution, 5 mM MgCl ₂ , 0.625 mM EGTA, 0.06 μM SEB, 1 mM DTT, 0.01% Brij-35, 1 μM TK-subbiotin and 10 μM ATP. The compounds obtained in embodiments 1-8 and the control compound oclacitinib were continuously diluted with DMSO to 10 concentration points, after which 100 nL of each solution was transferred to a measuring plate for the experiment. After adding 19.76 nM JAk1, the reaction began, after 30 minutes at 25°C, a detection reagent (0.25 X TK antibody, 62.5 nM Streptavidin-XL665) was added to stop the reaction. After standing at room temperature for 60 minutes, a fluorescence resonance energy transfer (FRET) signal was read using a Spark 10M or Envision plate reader. (HTRF (Homogeneous Time Resolved Fluorescence) technology 665/615=665 nm signal value/615 nm signal value).

Data analysis

The 665/615 signal ratio was converted to a percentage inhibition ratio.

Inhibition coefficient, % = (max-sample)/(max-min)*100, where “min” denotes the ratio of signal values with a frequency of 665/615 for the control well without enzymes, “max” denotes the ratio of 665/615 signal values with a frequency for the control well with DMSO.

Result

Based on the experimental method described above, the IC50 measurements of the compound were given in the table below

Table 1. Test results for JAK1 enzyme activity

Compound Relative IC ₅₀ (nM) Oclacitinib 12.88 T1-A <100 T1-B <100 T2-A <100 T2-B 100<IC50<1000 T3-A 100<IC50<1000 T3-B <100 T4-A <100 T4-B 100<IC50<1000 T5-A 100<IC50<1000 T5-B 100<IC50<1000 T5C <100 T5-D <100 T6-A <100 T6-B <100 T6-C <100 T7 <100 T8-A <100 T8-B <100

Embodiment 10. Analysis of IL-2 and ConA-induced proliferation of peripheral blood mononuclear cells in dogs.

Experimental materials

Recombinant canine IL-2 protein (Cys147Ser) was purchased from R&D (cat. no.: 1815-CL-020/CF). Canine CD4 Alexa Fluor 647 conjugated antibodies were purchased from R&D (cat. no.: 1815-CL-020/CF), concanavalin A, obtained from Canavalia ensiformis, was purchased from Sigma. (Part No.: C5275-5MG). Oclacitinib maleate was purchased from AbMole Bioscience (Cat. No: M5827). Peripheral blood mononuclear cells were purchased from AllCells (Cat. No.: DPB-002).

Experimental method

Flow cytometry is a specific technology used to detect and measure the physical and chemical characteristics of a population of cells or a swarm of particles. Canine peripheral blood mononuclear cells were collected and stained with CFSE, and then the mononuclear cells (1x10*5 cells/well) were inoculated into a 96-well plate for incubation at 37°C for 1 hour in a 5％CO ₂ incubator. The appropriate concentration of compound (the compound had an initial concentration of 5 μM and was diluted threefold to 9%, with DMSO having a final concentration of 0.1%) was introduced into the appropriate wells, after 4 hours 50 ng/ µl of IL-2 and 1 µg/ml concanavalin A were incubated at 37°C in a 5％CO ₂ incubator for activation for 120 hours. Cells were then harvested and stained with CD4 Alexa Fluor 647-conjugated canine antibodies.

Samples containing cells were resuspended in staining buffer and injected into a flow cytometry device. When a cell suspension is passed through a flow cytometry device, the cell suspension flowing out of a small bell is aggregated toward the center by the fluid mechanics of the outer part of the liquid. Due to the formation of such a stream, cells successively pass through the laser beams, and only one at a time. When cells pass through laser beams, the detector detects scattered light from cells or particles. The front detector detected forward scatter (FSC), several side-mounted detectors detected side scatter (SB); and the fluorescence detector detected the fluorescent glow emitted by the stained cells or particles. Consequently, such cells could be divided into different cell populations based on different values of HBP and BR.

Data analysis

A single cell whose SSC-A and SSC-H showed a linear relationship was classified. CD4 + was located in a circle formed from subpopulations of lymphocytes. The average fold increase (MFG) of the CD4 ⁺ population was calculated.

Inhibition coefficient = (Compound UPC - Negative well UPC)/(Positive well UPC - Negative well UPC). In an inhibition rate graph, the X-axis indicates the concentration level and the Y-axis indicates the percentage of inhibition.

Inhibition rates were plotted to obtain the compound IC50. The results were presented in Table 2.

Table 2. Test results:

Compound Cellular IC50(nM) Oclacitinib 447.2 T1-A <1000 T1-B 1000<IC50<5000 T2-A <1000 T2-B <1000 T4-A 1000<IC50<5000 T5-C >5000 T5-D >5000

In conclusion, it should be pointed out that the above embodiments are used only to describe the technical solution presented by the present invention, but do not serve to indicate its limits. Even though the present invention has been described in detail with reference to the above embodiments, it should be understood by anyone skilled in the art that amendments may still be made to the technical solution presented in the above embodiments or to its specifications may still, in a certain part or in its entirety, become the subject of equivalent replacements; furthermore, such amendments or substitutions shall not deprive the corresponding technical solution of the essence and subject matter of the technical solutions implemented in the embodiments of the present invention.

Claims (52)

1. The compound represented by the general formula I, or a pharmaceutically acceptable salt or stereoisomer thereof where A represents C; R ₅ represents H; X represents R represents C _1-10 linear or branched alkyl; Y represents R ₃ and R ₄ represent H; m is any integer from 1 to 3, in particular 1, 2 or 3; Z represents C _3-12 -cycloalkyl; R ₁ and R ₂ are each optionally H, C _1-10 linear or branched alkyl, where the H on the carbon atom may be replaced by groups such as -N(C _0-10 -alkyl)(C _0-10 -alkyl) , -OC _0-10 -alkyl, C _3-10 -cycloalkyl, C _6-18 -aryl, -N-heterocycloaryl, -O-heterocycloaryl or -S-heterocycloaryl; where H on C _6-18 -aryl or heterocycloaryl can be replaced by a halogen group or C _1-4 linear alkyl; R ₇ and R ₈ each represent H. 2. The compound or its pharmaceutically acceptable salt or stereoisomer according to claim 1, characterized in that R represents C _1-10 linear alkyl; R ₁ is optionally H, C _1-6 linear alkyl; where H on the carbon atom can be replaced by groups such as -N(C _0-10 -alkyl)(C _0-10 -alkyl), -OC _0-4 -alkyl, C _3-10 -cycloalkyl and C _6-18 - aryl; R ₂ represents C _1-6 linear alkyl; H on the carbon atom may be replaced by the following groups, such as -N( _C0-10 -alkyl)( _C0-10 -alkyl), _-OC0-10 -alkyl, _C3-10- cycloalkyl or _C6-18 - aryl, -N-heterocycloaryl, -O-heterocycloaryl or -S-heterocycloaryl. 3. The compound or its pharmaceutically acceptable salt or stereoisomer according to claim 2, characterized in that R represents C _1-6 linear alkyl. 4. The compound or its pharmaceutically acceptable salt or stereoisomer according to claim 3, characterized in that Z is optionally C _4-10 -cycloalkyl, for example 5. The compound or its pharmaceutically acceptable salt or stereoisomer according to claim 4, characterized in that said compound has the following structural formula: where R ₁ is optionally H, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ and -CH ₂ CH ₂ OCH ₃ ; And R ₂ is optionally -CH ₃ -, 6. The compound or its pharmaceutically acceptable salt or stereoisomer according to claim 5, characterized in that said compound has the following characteristic structural formula: 7. A compound or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 1, characterized in that said stereoisomer has the following structure: 8. The compound or its pharmaceutically acceptable salt or stereoisomer according to claim 7, characterized in that said stereoisomer has the following structure: 9. A method for producing a compound represented by the general formula I according to claim 1, including the following reaction path: where the values of A, X, Y, Z, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₇ and R ₈ are defined in paragraph 1; (1) dissolving compound 1 in solvent 1, adding triethylamine and p-toluenesulfonyl chloride, stirring at room temperature for 20-24 hours, concentrating, adding iodizing reagent, heating to 60-70°C and stirring for 8-9 hours with obtaining compound 2; (2) dissolving compound 2 in solvent 2, adding sodium alkylthiolate, allowing the reaction to proceed for 20-24 hours, filtering and concentrating to obtain compound 3; (3) dissolving compound 3 in solvent 3, adding triethylamine and p-toluenesulfonyl chloride, stirring at room temperature for 20-24 hours and separating to obtain compound 4; (4) dissolving compound 4 in solvent 4, adding meta-chloroperbenzoic acid (m-CPBA), allowing the reaction to proceed for 1-2 hours, extracting to collect the organic phase, washing with water and drying such organic phase, filtering and concentrating to obtain connections 5; (5) dissolving compound 5 in solvent 5, adding iodobenzene diacetate (PhI(OAc) ₂ ) and ammonium carbamate, allowing the reaction to proceed for 30-35 minutes, concentrating under reduced pressure to obtain compound 6; (6) dissolving compound 6 and polyaldehyde in solvent 6, heating to 90-95°C, allowing the reaction to proceed for 20-24 hours, concentrating, extracting to collect the organic phase, washing with water and drying such an organic phase, filtering and concentrating with obtaining compound 7; and (7) dissolving compound 7 and cesium carbonate (Cs ₂ CO ₃ ) in solvent 7, allowing the reaction to proceed at 40-50°C for 3-4 hours, filtering and concentrating to obtain the compound represented by general formula I; wherein solvents 1-7 are optionally one or a combination of two or more of methylene chloride, acetone, tetrahydrofuran, methyl alcohol and formic acid. 10. A pharmaceutical composition having an inhibitory effect against JAK, wherein such pharmaceutical composition comprises an effective amount of a compound represented by general formula I, or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 1, and also includes a pharmaceutically acceptable excipient. 11. Use of a compound represented by general formula I, or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 1, in the preparation of a medicament intended for the treatment of a disease associated with the JAK-STAT signaling pathway. 12. The use of a compound represented by general formula I, or its pharmaceutically acceptable salt or stereoisomer according to claim 1, in the preparation of a medicinal product intended for the prevention and/or treatment of inflammatory or oncological diseases in humans and/or animals, where said inflammatory disease is rheumatoid arthritis, canine dermatitis, psoriasis, ulcerative colitis or Crohn's disease; and said cancer is myelofibrosis, polycythemia vera, essential thrombocythemia, chronic granulocytic leukemia, breast cancer, lung cancer and pancreatic cancer.