TWI830024B - Tri-heterocyclic compounds as jak inhibitors and applications thereof - Google Patents

Abstract

The invention relates to tri-heterocyclic compounds as JAK inhibitors,and applicationin preparing medicines for treating JAK1 or/and JAK2 related diseases. Specifically, it relates tocompounds represented by Formula (I) and the pharmaceutically acceptable salts thereof.

Description

Triheterocyclic compounds as JAK inhibitors and their applications

This invention claims the priority and rights of the Chinese Patent Application No. 202010501267.4 submitted to the National Intellectual Property Bureau of China on June 4, 2020, and the international application PCT/CN2020/132426 submitted to the National Intellectual Property Bureau of China on November 27, 2020. , the disclosure of the invention is incorporated herein by reference in its entirety.

The present invention relates to triheterocyclic compounds as JAK inhibitors and their application in preparing drugs for treating JAK1 or/and JAK2 related diseases. Specifically regarding the compound represented by formula (I') or a pharmaceutically acceptable salt thereof.

Janus kinases (JAKs) are cytoplasmic tyrosine kinases that transmit cytokine signals from membrane receptors to STAT transcription factors. The JAK family consists of four members, JAK1, JAK2, JAK3 and TYK2. The JAK-STAT pathway conducts extracellular signals from a variety of cytokines, growth factors, and hormones to the nucleus and is responsible for the expression of thousands of protein-coding genes. JAK-STAT intracellular signaling serves interferons, most interleukins, and a variety of cytokines and endocrine factors, such as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF, and PRL (Vainchenker W.E T al . (2008)).

JAK-1, JAK-2 and TYK-2 are expressed in cells of various tissues in the human body. JAK-3 is mainly expressed in cells of various hematopoietic tissues, mainly in bone marrow cells, thymocytes, NK cells and activated B lymphocytes. , in T lymphocytes. JAK1 has become a new target in the fields of immunity, inflammation, cancer and other diseases. A base mutation in the JAK2 gene in humans, JAK2V617F, is associated with primary polycythemia (PV), essential thrombocythemia (ET), and idiopathic myelofibrosis (IMF) in myeloproliferative diseases. , chronic myelogenous leukemia (CML), etc. are closely related to the occurrence. Mutations in JAK3 or γc can lead to severe combined immunodeficiency syndrome. Abnormal JAK3 activity manifests as a massive decrease in T cells and NK cells and loss of B cell function, seriously affecting the normal biological functions of the immune system. Based on its functional characteristics and special tissue distribution, JAK3 has become an attractive drug target for immune system-related diseases. In mice, loss of TYK2 function causes defects in the signaling pathways of multiple cytokine receptors, leading to viral infection, decreased antibacterial immunity, and increased possibility of lung infection (John J. O'Shea, 2004 , Nature Reviews Drug Discovery 3, 555-564). Different JAK family members selectively bind to different cytokine receptors, giving signaling specificity and thus exerting different physiological effects. This selective mode of action allows JAK inhibitors to be used in relatively specific applications. Disease treatment. For example, IL-2 or IL-4 receptors bind to JAK1 and JAK3 along with a common γ chain, while type I receptors with the same β chain bind to JAK2. Type I receptors using gp130 (glycoprotein 130) and type I receptors activated by heterodimeric cytokines preferentially bind JAK1/2 and TYK2. Type I receptors activated by hormone-like cytokines bind and activate JAK2 kinase. Type II receptors for interferons bind JAK1 and TYK2, whereas receptors of the IL-10 cytokine family bind JAK1/2 and TYK2. Various specific combinations of the above-mentioned cytokines and their receptors with JAK family members trigger different physiological effects and provide the possibility for the treatment of different diseases. JAK1 heterodimerizes with other JAKs to transduce cytokine-driven pro-inflammatory signaling. Therefore, inhibition of JAK1 and/or other JAKs is expected to have therapeutic benefit in a range of inflammatory diseases and other diseases driven by JAK-mediated signaling (Daniella M. Schwartz, 2017, Nature Reviews Drug Discovery 16, 843- 862.)

In one aspect, the invention provides a compound of formula (I') or a pharmaceutically acceptable salt thereof, Wherein, m is 1, 2, 3, 4 or 5; n is 1, 2, 3 or 4; each R ₁ is independently H, F, Cl, Br, I, CN, C _1-8 alkyl , C _1-8 alkoxy, C _1-8 alkyl S-, NH ₂ , C _1-8 alkyl NH-, (C _1-8 alkyl) ₂ N-, -COOH or -C(O) OC _1-8 alkyl, wherein the C _1-8 alkyl, C _1-8 alkoxy, C _1-8 alkyl S-, C _1-8 alkyl NH-, (C _1-8 alkyl ) ₂ N- or -C(O)OC _1-8 alkyl groups are independently optionally substituted by 1, 2, 3 or 4 R _a ; each R ₂ is independently H, F, Cl, Br, I, CN, NH ₂ , C _1-8 alkyl, C 1-8 alkoxy, C _1-8 alkyl S-, C _1-8 alkyl NH-, (C _1-8 alkyl) _{2 N} - or C _3-12 cycloalkyl; each R _a is independently H, F, Cl, Br, I, OH, CN or NH ₂ .

In some embodiments of the invention, m is 1, 2 or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1.

In some embodiments of the invention, n is 1, 2 or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1.

In some embodiments of the invention, m and n are both 1.

In some embodiments of the invention, the structural fragment for . In some embodiments, the above structural fragment is .

In some embodiments of the invention, the structural fragment for . In some embodiments, the above structural fragment is .

In some embodiments of the invention, each of the above R ₁ is independently H, F, Cl, Br, I, CN, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl Base S-, NH ₂ , C _1-6 alkyl NH-, (C _1-6 alkyl) ₂ N-, -COOH or -C(O)OC _1-6 alkyl, wherein the C _1-6 Alkyl, C _1-6 alkoxy, C _1-6 alkyl S-, C _1-6 alkyl NH-, (C _1-6 alkyl) ₂ N- or -C(O)OC _1-6 Alkyl groups are each independently optionally substituted with 1, 2, 3 or 4 R _a .

In some embodiments of the invention, each of the above R ₁ is independently H, F, Cl, Br, I, CN, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl S-, NH ₂ , C _1-6 alkyl NH- or (C _1-6 alkyl) ₂ N-, wherein the C _1-6 alkyl, C _1-6 alkoxy, C _1-6 Alkyl S-, C _1-6 alkyl NH- or (C _1-6 alkyl) ₂ N- are each independently optionally substituted with 1, 2, 3 or 4 R _a .

In some embodiments of the invention, each of the above R ₁ is independently H, F, Cl, Br, I, CN, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkyl Base S-, NH ₂ , C _1-3 alkyl NH-, (C _1-3 alkyl) ₂ N-, -COOH or -C(O)OC _1-3 alkyl, wherein the C _1-3 Alkyl, C _1-3 alkoxy, C _1-3 alkyl S-, C _1-3 alkyl NH-, (C _1-3 alkyl) ₂ N- or -C(O)OC _1-3 Alkyl groups are each independently optionally substituted with 1, 2, 3 or 4 R _a .

In some embodiments of the invention, each of the above R ₁ is independently H, F, Cl, Br, I, CN, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkyl S-, NH ₂ , C _1-3 alkyl NH- or (C _1-3 alkyl) ₂ N-, wherein the C _1-3 alkyl, C _1-3 alkoxy, C _1-3 Alkyl S-, C _1-3 alkyl NH- or (C _1-3 alkyl) ₂ N- are each independently optionally substituted with 1, 2, 3 or 4 R _a .

In some embodiments of the invention, each of the above R ₁ is independently H, F, Cl, Br, I, CN, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkyl S- or C _1-3 alkyl NH-, wherein the C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkyl S- or C _1-3 alkyl NH- are independently is optionally substituted by 1, 2, 3 or 4 _Ra .

In some embodiments of the invention, each of the above R ₁ is independently H, F, Cl, Br, I, CN, C _1-3 alkyl or C _1-3 alkoxy, wherein said C _{1 -3} alkyl or C _1-3 alkoxy are each independently optionally substituted with 1, 2, 3 or 4 R _a .

In some embodiments of the invention, each of the above R ₂ is independently H, F, Cl, Br, I, CN, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _{1 -6} alkyl S-, C _1-6 alkyl NH-, (C _1-6 alkyl) ₂ N- or C _3-10 cycloalkyl.

In some embodiments of the invention, each of the above R ₂ is independently H, F, Cl, Br, I, CN, NH ₂ , C _1-3 alkyl, C _1-3 alkoxy, C _{1 -3} alkyl S-, C _1-3 alkyl NH-, (C _1-3 alkyl) ₂ N- or C _3-6 cycloalkyl.

In some embodiments of the invention, each of the above R ₂ is independently H, F, Cl, Br, I, CN, NH ₂ , C _1-3 alkyl, C _1-3 alkoxy, C _{1 -3} alkyl S- or C _1-3 alkyl NH-.

In some embodiments, each R ₂ above is independently H, F, Cl, Br, I, CN, or NH ₂ .

In some embodiments of the invention, each of the above R ₂ is independently H, F, Cl, Br, I or CN.

In some embodiments of the invention, each of the above _Ra is independently F, Cl, Br, I or OH.

In some embodiments of the present invention, the above-mentioned compound of formula (I') or a pharmaceutically acceptable salt thereof is a compound of formula (I) or a pharmaceutically acceptable salt thereof, , where R ₁ is H, F, Cl, Br, I, CN, C _1-3 alkyl or C _1-3 alkoxy, wherein the C _1-3 alkyl and C _1-3 alkoxy Each R a is independently optionally substituted by 1, 2, 3 or 4 R _a ; R ₂ is H, F, Cl, Br, I or CN; Each R _a is independently H, F, Cl, Br, I Or OH.

In some embodiments of the invention, each of the above R ₁ is independently H, F, Cl, Br, I, CN, -CH ₃ , -CH ₂ CH ₃ or -OCH ₃ , wherein -CH ₃ , -CH ₂ CH ₃ and -OCH ₃ are each independently optionally substituted by 1, 2, 3 or 4 _Ra , and other variables are as defined in the present invention.

In some embodiments of the invention, each of the above R ₁ is independently H, F, Cl, Br, I, CN, -CH ₃ , -CH ₂ CH ₃ or -OCH ₃ , wherein -CH ₃ , -CH ₂ CH ₃ and -OCH ₃ are each independently optionally substituted by 1, 2 or 3 _Ra , and other variables are as defined in the present invention.

In some embodiments of the invention, each of the above R ₁ is independently H, F, Cl, Br, I, CN, -CH ₃ , -CH ₂ CH ₃ or -OCH ₃ , wherein -CH ₃ or -CH ₂ CH ₃ are each independently optionally substituted by 1, 2 or 3 R _a , and other variables are as defined in the present invention.

In some embodiments of the present invention, each of the above R _a is independently F, Cl, Br, I or OH, and other variables are as defined in the present invention.

In some embodiments of the present invention, each of the above R _a is independently F or OH, and other variables are as defined in the present invention.

In some embodiments of the invention, each of the above R ₁ is independently H, F, Cl, Br, I, CN, -CH ₃ , -CH ₂ CH ₃ or -OCH ₃ , wherein -CH ₃ or -CH ₂ CH ₃ are each independently optionally substituted by 1, 2 or 3 F or OH, and other variables are as defined in the present invention.

In some embodiments of the invention, each of the above R ₁ is independently H, F, Cl, Br, I, CN, -CH ₃ , -CF ₃ , -CH ₂ CH ₃ , -CH(OH)CH ₃ or -OCH ₃ , other variables are as defined in the present invention.

In some embodiments of the present invention, each of the above R ₁ is independently H, CN, -CH ₃ , -CF ₃ , -CH(OH)CH ₃ or -OCH ₃ , and other variables are as defined in the present invention.

In some embodiments of the invention, each of the above R ₁ is independently H, F, Cl, Br, I, CN, -CH ₃ , -CF ₃ , -CH ₂ CH ₃ or -OCH ₃ , and other variables As defined herein.

In some embodiments of the present invention, each of the above R ₁ is independently H, CN, -CH ₃ , -CF ₃ , -CH ₂ CH ₃ or -OCH ₃ , and other variables are as defined in the present invention.

In some embodiments of the present invention, each of the above R ₂ is independently F, Cl, Br, I or CN, and other variables are as defined in the present invention.

In some embodiments of the present invention, each of the above R ₂ is independently CN, and other variables are as defined in the present invention.

There are also some embodiments of the present invention that are derived from any combination of the above variables. In some embodiments of the present invention, the above-mentioned compound of formula (I') or a pharmaceutically acceptable salt thereof is a compound of formula (I'-A) or formula (I'-B) or a pharmaceutically acceptable salt thereof: Wherein, R ₁ , R ₂ , m or n are as defined in the present invention.

In some embodiments of the present invention, the above-mentioned compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (I-A) or formula (I-B) or a pharmaceutically acceptable salt thereof: Wherein, R ₁ or R ₂ is as defined in the present invention.

In some embodiments of the present invention, the compound of formula (I') or formula (I) or a pharmaceutically acceptable salt thereof has a compound structure of formula (I-1) , where R ₁ is as defined in the present invention.

In some embodiments of the present invention, the above-mentioned compound of formula (I-1) or a pharmaceutically acceptable salt thereof is a compound of formula (I-1-A) or formula (I-1-B) or a pharmaceutically acceptable salt thereof of salt: Wherein, R ₁ is as defined in the present invention.

On the other hand, the present invention also provides a compound of the following formula or a pharmaceutically acceptable salt thereof, or .

In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from or or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention also provides a pharmaceutical composition comprising the above compound of the present invention or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions of the present invention further include pharmaceutically acceptable excipients.

In another aspect, the present invention also provides the use of the above compounds or pharmaceutically acceptable salts thereof in the preparation of drugs for treating JAK1 and/or JAK2 related diseases.

In another aspect, the present invention also provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof in a drug for treating JAK1 and/or JAK2-related diseases.

In another aspect, the present invention also provides the above compounds or pharmaceutically acceptable salts thereof for treating JAK1 and/or JAK2 related diseases.

In another aspect, the present invention also provides a method for treating JAK1 and/or JAK2 related diseases, which includes administering a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof or a medicament thereof to a mammal, preferably a human, in need of the treatment. composition.

In the present invention, the above-mentioned JAK1 and/or JAK2-related diseases are selected from inflammatory diseases (such as arthritis) and the like.

The compound of the present invention shows good selective inhibition of JAK1 and/or JAK2 in the in vitro activity test of four kinase subtypes JAK1, JAK2, JAk3 and TYK2; it has good oral bioavailability in mice. Higher exposure is conducive to good in vivo drug effects.

Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear in the absence of a specific definition, but should be understood in its ordinary meaning. Where a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.

The dotted lines in the structural units or groups in the present invention ( ) represents a covalent bond.

When a substituent's bond is cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring. For example, structural unit It means that it can be substituted at any position of all rings, including but not limited to , , , or .

As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to a salt of a compound of the invention prepared from a compound having specific substituents found in the invention and a relatively non-toxic acid or base. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydriodic acid, phosphorous acid, etc.; and organic acid salts, including acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid and other similar acids; also includes amino acids (such as arginine, etc.) salts, as well as salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.

The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases. In general, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.

The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, ( R )- and ( S )-enantiomers, diastereomers, isomers, ( D )-isomers, ( L )-isomers, and their racemic mixtures and other mixtures, such as enantiomers or non-enantiomer-enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention. For example, those skilled in the art can understand that the compound of formula (I') of the present invention includes but is not limited to the compound of formula (I'-A) or formula (I'-B) and their mixtures in any ratio. Compounds of formula (I) include but are not limited to compounds of formula (I-A) or formula (I-B) and their mixtures in any ratio. Compounds of formula (I-1) of the present invention include, but are not limited to, compounds of formula (I- 1-A) or compounds of formula (I-1-B) and their mixtures in any proportion, etc.

Unless otherwise stated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of each other.

Unless otherwise stated, the term "cis-trans isomers" or "geometric isomers" refers to the inability of the double bonds or single bonds of the carbon atoms in the ring to rotate freely.

Unless otherwise stated, the term "diastereomer" refers to a stereoisomer in which the molecule has two or more stereocenters and the molecules are in a non-mirror image relationship.

Unless otherwise stated, "(+)" means right-handed, "(-)" means left-handed, and "(±)" means racemic.

Unless otherwise stated, use wedge-shaped solid line keys ( ) and wedge-shaped dotted keys ( ) represents the absolute configuration of a stereocenter, using a straight solid line key ( ) and straight dotted keys ( ) represents the relative configuration of the three-dimensional center, using a wavy line ( ) represents a wedge-shaped solid line key ( ) or wedge-shaped dotted key ( ), or use a tilde ( ) represents a straight solid line key ( ) and straight dotted keys ( ).

Unless otherwise stated, when there are double bond structures in the compound, such as carbon-carbon double bonds, carbon-nitrogen double bonds, and nitrogen-nitrogen double bonds, and each atom on the double bond is connected to two different substituents (including nitrogen atoms In a double bond, a lone pair of electrons on the nitrogen atom is regarded as a substituent connected to it), if a wavy line is used between the atom on the double bond and its substituent in the compound ( ) connection, it means the ( Z )-type isomer, ( E )-type isomer or a mixture of the two isomers of the compound. For example, the following formula (A) indicates that the compound exists as a single isomer of formula (A-1) or formula (A-2) or as two isomers of formula (A-1) and formula (A-2) exists in the form of a mixture; the following formula (B) indicates that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2) or in the form of both formula (B-1) and formula (B-2) Exists as a mixture of isomers. The following formula (C) indicates that the compound exists in the form of a single isomer of formula (C-1) or formula (C-2) or in the form of two isomers of formula (C-1) and formula (C-2) Exists in mixture form. (A) (A-1) (A-2) (B) (B-1) (B-2) (C) (C-1) (C-2)

Unless otherwise stated, the term "tautomer" or "tautomer form" means that at room temperature, isomers with different functional groups are in dynamic equilibrium and can quickly convert into each other. If tautomers are possible (eg in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as proton transfer tautomers) include interconversions through proton migration, such as keto-enol tautomers and imine-enamine tautomers. Allostery. Valence tautomers involve interconversions through the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the tautomerization between pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

Unless otherwise stated, the terms "enriched in an isomer", "enriched in an isomer", "enriched in an enantiomer" or "enriched in an enantiomer" refer to one of the isomers or enantiomers. The content of the isomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, Or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than Equal to 99.9%.

Unless otherwise stated, the term "isomer excess" or "enantiomer excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, then the excess (ee value) of the isomer or enantiomer is 80 %.

The optically active ( R )- and ( S )-isomers as well as the D and L isomers can be prepared by asymmetric synthesis or chiral reagents or other conventional techniques. If one desires to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliaries, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amine group) or an acidic functional group (such as a carboxyl group), it can form a diastereomeric salt with an appropriate optically active acid or base, and then use conventional methods known in the art to The diastereomers are resolved and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally combined with chemical derivatization methods (e.g. by amines to form carbamates).

The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, compounds can be labeled with radioactive isotopes such as tritium ( ^3H ), iodine-125 ( ^125I ) or C-14 ( ^14C ). For another example, deuterated drugs can be replaced by heavy hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce side effects and increase drug stability. , enhance efficacy, extend drug biological half-life and other advantages. All variations in the isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.

"Optional" or "optionally" means that the subsequently described event or condition may but need not occur, and that the description includes instances where the stated event or condition occurs and instances where the stated event or condition does not occur.

The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable of. When the substituent is oxygen (i.e. =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical achievability.

When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each instance is independent. Thus, for example, if a group is substituted by 0-2 R, then said group may optionally be substituted by up to two R's, with independent options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds.

When the number of a linking group is 0, such as -(CRR) ₀ -, it means that the linking group is a single bond.

When one of the variables is selected from a single bond, it means that the two groups it is connected to are directly connected. For example, when L in A-L-Z represents a single bond, it means that the structure is actually A-Z.

When a substituent is vacant, it means that the substituent does not exist. For example, when X in A-X is vacant, it means that the structure is actually A. When the listed substituent does not specify which atom it is connected to the substituted group through, the substituent can be bonded through any atom thereof. For example, a pyridyl group as a substituent can be bonded through any atom on the pyridine ring. A carbon atom is attached to the substituted group.

The term "alkyl" refers to a hydrocarbon group having the general formula C _n H _2n+1 . The alkyl group may be straight chain or branched. For example, the term "C _1-6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl , tertiary butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio groups have the same definitions as above.

Unless otherwise specified, the term "C _1-3 alkyl" is used to mean a straight-chain or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C _1-3 alkyl group includes C _1-2 and C _2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) . Examples of C _1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n -propyl and isopropyl), and the like.

The term "alkoxy" refers to "alkyl-O-". Unless otherwise specified, the term "C _1-3 alkoxy" means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through an oxygen atom. The C _1-3 alkoxy group includes C _1-2 , C _2-3 , C ₃ and C ₂ alkoxy groups, etc. Examples of C _1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

Unless otherwise specified, C _n-n+m or C _n -C _n+m includes any specific case of n to n+m carbons, for example, C _1-12 includes C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ , and C ₁₂ , also include any range from n to n+m, for example, C _1-12 includes C _1-3 , C _1-6 , C _1-9 , C _3-6 , C _3-9 , C _3-12 , C _6-9 , C _6-12 , and C _9-12 , etc.; for example, "C _1-6 " is means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. In the same way, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m. For example, 3-12-membered rings include 3-membered rings, 4-membered rings, 5-membered rings, 6-membered rings, 7-membered rings, 8-membered rings, 9-membered rings, 10-membered rings, 11-membered rings, and 12-membered rings also include any range from n to n+m, for example, 3-12-membered rings include 3-6-membered rings, 3-9 5-6-membered ring, 5-7-membered ring, 6-7-membered ring, 6-8-membered ring, 6-10-membered ring, etc.

The term "cycloalkyl" refers to a carbocyclic ring that is fully saturated and may exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is generally 3 to 10 membered. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl Alkyl etc.

The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, tetralin, and the like.

The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction, such as a nucleophilic substitution reaction. For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonate Ester, etc.; acyloxy group, such as acetyloxy group, trifluoroacetyloxy group, etc.

The term "protecting group" includes, but is not limited to, "amine protecting group", "hydroxy protecting group" or "thiol protecting group". The term "amine protecting group" refers to a protecting group suitable for preventing side reactions at the nitrogen position of an amine group. Representative amino protecting groups include, but are not limited to: formyl; carboxyl, such as alkyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert. Butoxycarbonyl (Boc); Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); Arylmethyl, such as benzyl (Bn), trityl ( Tr), 1,1-di-(4'-methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc. The term "hydroxyl protecting group" refers to a protecting group suitable for preventing side reactions of hydroxyl groups. Representative hydroxyl protecting groups include, but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; hydroxyl groups, such as alkyl groups (such as acetyl groups); arylmethyl groups, such as benzyl (Bn ), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and Tert-butyldimethylsilyl (TBS) and so on.

The term "treating" means administering a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with said disease, and includes: (i) To inhibit a disease or disease state, that is, to arrest its progression; (ii) Alleviation of a disease or disease condition, i.e. resolution of the disease or disease condition.

The term "prevent" means administering a compound or formulation of the invention to prevent a disease or one or more symptoms associated with said disease, including preventing the occurrence of a disease or disease state in a mammal, particularly when such disease or condition is present in a mammal. A mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

The terms "comprise" or "comprise" and their English variants such as compris or comprising should be understood in an open, non-exclusive sense, that is, "including but not limited to."

The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present invention or salts thereof and pharmaceutically acceptable excipients. The purpose of pharmaceutical compositions is to facilitate the administration to an organism of the compounds of the invention.

The term "pharmaceutically acceptable excipients" refers to those excipients that have no significant irritating effect on the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

The pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, Powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

Typical routes of administration of the compounds of the invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, and intravenous administration.

The pharmaceutical composition of the present invention can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulation methods, sugar-coated pill methods, grinding methods, emulsification methods, freeze-drying methods, etc.

In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present invention to be formulated into tablets, pills, lozenges, sugar-coated agents, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients.

Solid oral compositions may be prepared by conventional mixing, filling or tableting methods.

For example, it can be obtained by the following method: mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets Or sugar-coated core. Suitable excipients include but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.

The pharmaceutical compositions may also be suitable for parenteral administration as sterile solutions, suspensions or freeze-dried products in suitable unit dosage forms.

In all methods of administration of the compounds described herein, dosages of 0.01 to 200 mg/kg body weight are administered daily, in single or divided doses.

The structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, in single crystal X-ray diffractometer (SXRD), the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data. The light source is CuKα radiation. The scanning method is: After scanning and collecting relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure using the direct method (Shelxs97).

In some embodiments, the compounds of the present invention can be prepared by those skilled in the art of organic synthesis through the following steps: , where R ₁ is the same as the definition of the present invention.

The solvent used in the present invention is commercially available. The present invention adopts the following abbreviations: aq represents water; eq represents equivalent, equivalent amount; DCM represents dichloromethane; PE represents petroleum ether; EA represents ethyl acetate; DMF represents N, N-dimethylformamide; DMSO Represents dimethyl styrene; EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents methanol; Boc represents tert-butoxycarbonyl, which is an amine protecting group; AcOH or HOAc represents acetic acid; rt represents room temperature; THF represents tetrahydrofuran; TFA represents Trifluoroacetic acid; T _S represents p-toluenesulfonyl; TBS represents tert-butyldimethylsilyl; PMB represents p-phenylmethoxy; HPMC represents hydroxypropyl methylcellulose; PVP represents polyvinylpyrrolidone; SLS stands for sodium dodecyl sulfate; SBE-β-CD stands for sulfobutyl ether-β-cyclodextrin; TLC stands for thin layer chromatography; DMAP stands for 4-dimethylaminopyridine; DEA stands for diethylamine; ADDP stands for 1 ,1'-Azodimethyldipidine; TBAF represents tetrabutylammonium fluoride; TMSI represents trimethylsilyl iodide; DIEA represents N,N-diisopropylethylamine; TsOH represents p-toluenesulfonic acid; EDCI stands for 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; HOBt stands for 1-hydroxybenzotriazole; BSA stands for bovine serum albumin; EDTA stands for ethylenediaminetetraacetic acid ;BID stands for twice a day.

The present invention is described in detail through examples, which do not imply any adverse limitations to the present invention. The present invention has been described in detail herein, and its specific embodiments have also been disclosed. It is for those of ordinary skill in the technical field to which the present invention belongs to make the following detailed descriptions of the specific implementations of the present invention without departing from the spirit and scope of the present invention. Various changes and improvements will be apparent.

Example 1: Synthesis of Compounds 1A and 1B.

Step 1: To a suspension of sodium hydride (15.92 g, 398.08 mmol, 60% purity, 1.1 eq ) in DMF (200 mL) at 0°C, add (4-methoxyphenyl)methanol (50 g, 361.89 mmol, 45.05 mL, 1 eq ), after stirring for 0.5 hours, 3-bromopropyl-1-yne (59.19 g, 398.08 mmol, 42.89 mL, 1.1 eq ) was slowly added to the reaction system, and the resulting solution was stirred at 0°C Stir for 0.5 hours and 16 hours at 25°C. TLC (PE:EA =10:1) shows that the reaction is complete and a new main product is generated. Add saturated aqueous ammonium chloride solution (50 mL) and water to the reaction solution. The phase was extracted with ethyl acetate (500 mL*3), the combined organic phases were washed with water (200 mL*2) and brine (200 mL*1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was Purify by column chromatography (SiO ₂ , PE: EA =1:0 ~ 5:1) to obtain compound 1-2. MS (ESI) Calculated for C ₁₁ H ₁₂ O ₂ 176, Found 177 [M+H] ⁺ .

Step 2: To a solution of 5-bromo-2-iodo-pyridine (50 g, 176.12 mmol, 1 eq ) in THF (500 mL) at 25°C, compound 1-2 (34.14 g, 193.74 mmol, 25.00 mL, 1.1 eq ), copper iodide (3.35 g, 17.59 mmol, 0.1 eq ), piperidine (44.99 g, 528.36 mmol, 52.18 mL, 3 eq ) and dichlorobis(triphenylphosphine)palladium(II) (6.18 g, 8.80 mmol, 0.05 eq ), the reaction system was replaced with nitrogen three times, and the resulting solution was stirred at 25°C for 16 hours. TLC (PE: EA =10:1) showed that the reaction was complete and a new main product was generated. The reaction solution was filtered with diatomaceous earth to obtain the filtrate. After concentration under reduced pressure, the residue was dissolved in 800 mL of ethyl acetate, and then Wash with 300 mL water and 300 mL brine, then dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a residue that is passed through column chromatography (SiO ₂ , PE: EA =1:0 ~30:1) to obtain Compounds 1-3. ¹ H NMR (400 MHz, CCl3- d ) δ = 8.61 (d, J = 1.8 Hz, 1H), 7.75 (dd, J = 2.4, 8.4 Hz, 1H), 7.32 - 7.28 (m, 1H), 7.32 - 7.26 (m, 1H), 7.27 (s, 1H), 6.89 - 6.84 (m, 2H), 4.58 (s, 2H), 4.35 (s, 2H), 3.79 - 3.76 (m, 1H), 3.77 (s, 2H). MS (ESI) Calcd. for C ₁₆ H ₁₄ BrNO ₂ 332, found 334. MS (ESI) Calculated for C ₁₆ H ₁₄ BrNO ₂ 331, 333, Found 331M] ⁺ , 334M+H] ⁺ .

Step 3: Dissolve 2,4,6-trimethylbenzenesulfonate (972 mg, 4.52 mmol, 1.5 eq ) in dry DCM (15 mL) containing _{anhydrous NaSO} and incubate at 0 °C. Compound 1-3 (1 g, 3.01 mmol, 1 eq ) was added to the above mixture and stirred at 25°C for 16 hours. TLC (PE:EA=2:1) showed that a small amount of reaction raw materials remained and a new main product was formed. Then, while stirring at 0°C, 32 mL of methyl tert-butyl ether was slowly added to the system, and a large amount of off-white solid slowly precipitated. It was filtered and dried to obtain compound 1-4. MS (ESI) Calculated for C ₁₆ H ₁₆ BrN ₂ O ₂ 348, Found 348 [M] ⁺ .

Step 4: Add silver carbonate (10.07 g, 36.52 mmol, 1.66 mL, 2 eq ) to a solution of compound 1-4 (10 g, 18.27mmol, 1 eq ) in DMF (160 mL) at 25°C, and the resulting solution 40 Stir for 16 hours at ℃. LCMS showed that the reaction of the raw materials was complete and the product was generated. The reaction solution was filtered with diatomaceous earth to obtain the filtrate. After concentration under reduced pressure, the residue was dissolved in 200 mL of ethyl acetate, then washed with 100 mL of water and 100 mL of brine in sequence, and then the organic phase was washed with Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a residue that is passed through column chromatography (SiO ₂ , PE:EA=1:0~5:1) to obtain compound 1-5. ¹ H NMR (400 MHz, CCl3- d ) δ = 8.50 - 8.46 (m, 1H), 7.34 - 7.27 (m, 1H), 7.26 - 7.21 (m, 2H), 7.10 - 7.06 (m, 1H), 6.84 - 6.78 (m, 2H), 6.50 - 6.46 (m, 1H), 4.67 - 4.60 (m, 2H), 4.51 - 4.46 (m, 2H), 3.75 - 3.71 (m, 3H). MS (ESI) Calculated for C16H15BrN2O2 347, Found 348.8[M+H] ⁺ .

Step 5: Add compound 1-5 (4.7 g, 13.54 mmol, 1 eq ) and tert-butyl carbamate (1.9 g, 16.22 mmol, 1.2 eq ) in isoamyl alcohol (15 mL) and water (15 mL) at 25°C. mL), potassium hydroxide (1.63 g, 29.05 mmol, 2.15 eq ), 5-(di-tert-butylphosphonium)-1,3,5-triphenyl-1hydro-[1,4 ] dipyrazole (783.26 mg, 1.55 mmol, 0.1 eq ) and tris(dibenzylideneacetone)dipalladium (619.79 mg, 676.83 μmol, 0.05 eq ), the reaction system was replaced with nitrogen three times, and the resulting solution was stirred at 100°C After 2 hours, LCMS showed that the reaction of the raw materials was complete and the product was generated. The reaction solution was filtered with diatomaceous earth to obtain the filtrate. The filter cake was washed with 100 mL of ethyl acetate. The combined organic phase was washed with 100 mL of water and 100 mL of brine in sequence, and then the organic phase was washed with anhydrous water. Dry over sodium sulfate, filter, and concentrate under reduced pressure to obtain a residue that is purified by column chromatography (SiO ₂ , PE: EA=1:0~20:1) to obtain compound 1-6. MS (ESI) Calculated for C ₂₁ H ₂₅ N ₃ O ₄ 383, Found 384 [M+H] ⁺ .

Step 6: Add platinum dioxide (933.33 mg, 4.11 mmol, 0.1 eq) to a solution of compound 1-6 (4 g, 40.43 mmol, 1 eq ) in EtOH (60 mL) under nitrogen protection at 25°C. The reaction system was filled with H ₂ was replaced three times, and the resulting solution was stirred in H ₂ (3 MPa) at 70°C for 72 hours. LCMS showed that the reaction of the raw materials was complete and the product was generated. The reaction solution was filtered with diatomaceous earth to obtain a filtrate. After concentration under reduced pressure, compound 1-7 was obtained. MS (ESI) Calculated for C ₂₁ H ₂₉ N ₃ O ₄ 387, Found 388 [M+H] ⁺ .

Step 7: Add trifluoroacetic acid (12.33 g, 108.14 mmol, 8.00 mL, 10.85 eq ) to a solution of compound 1-7 (4 g, 10.32 mmol, 1 eq ) in DCM (40 mL) at 0°C, and the resulting solution After stirring at 25°C for 2 hours, LCMS showed that the reaction of the raw materials was complete and the product was generated. Compound 1-8 was obtained after concentration under reduced pressure. MS (ESI) Calcd. for C ₈ H ₁₃ N ₃ O 167, found 168 [M+H] ⁺ .

Step 8: To a solution of compound 1-9 (20 g, 131.08 mmol, 1 eq ) in DCM (50 mL), add p-toluenesulfonyl chloride (27.49 g, 144.19 mmol, 1.1 eq ) and DMAP ( 1.6 g, 13.11 mmol, 0.1 eq ) and triethylamine (19.9 g, 196,66 mmol, 27.37 mL). The resulting solution was stirred at 25°C for 16 hours. LCMS showed that the raw material reaction was complete. The solvent was removed under reduced pressure and saturated NaHCO was added. ₃ solution (50 mL), filtered, washed the filter cake with water, and dried to obtain product 1-10. MS (ESI) Calcd. for C ₁₄ H ₁₁ N ₂ ClSO ₂ 306, found 307 [M+H] ⁺ .

Step 9: Add tetrabutyl-ammonium nitrate (29.78 g, 97.81) dropwise to a solution of compound 1-10 (10 g, 32.60 mmol, 1 eq ) in DCM (50 mL) at -5°C. mmol, 3 eq ) in dichloromethane (50 mL), then slowly add trifluoroacetic anhydride (20.54 g, 97.79 mmol, 13.60 mL, 3 eq ) dropwise. The resulting solution was stirred at -5°C for 30 min, then moved to 25°C and stirred for 16 h. LCMS showed that the raw material reaction was complete. Extract with ethyl acetate (500 mL*3), and the combined organic phase was sequentially added with water (200 mL*2) and salt. Wash with water (200mL*1), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure, and recrystallize with dichloromethane to obtain product 1-11. MS (ESI) Calculated for C ₁₄ H ₁₀ N ₃ ClSO ₄ 351, Found 352 [M+H] ⁺ .

Step 10: Add N to a solution of compound 1-11 (4.2 g, 11.94 mmol, 1 eq ) and compound 1-8 (3.69 g, 13.12 mmol, 1.1 eq ) in isopropyl alcohol (50 mL) at 25°C. N-Diisopropylethylamine (15.43 g, 119.40 mmol, 20.8 mL, 10 eq ), the resulting solution was stirred at 90°C for 16 hours. LCMS showed that the raw material reaction was complete and the product was generated. The reaction solution was rotated and evaporated, and then added Water (500 mL), the aqueous phase was extracted with ethyl acetate (500 mL*3), the combined organic phases were washed with water (200 mL*2) and brine (200 mL*1) in sequence, dried over anhydrous sodium sulfate, filtered, and reduced pressure Concentrate, and the obtained residue is purified by column chromatography (SiO ₂ , DCM:MeOH=100:1~50:1) to obtain compound 1-12. MS (ESI) Calcd. for C ₂₂ H ₂₂ N ₆ O ₅ S 482, found 483 [M+H] ⁺ .

Step 11: Add palladium carbon (0.1 g, 10%) to a solution of compound 1-12 in methanol (20 mL) under nitrogen at 25°C, replace with hydrogen three times, and stir the resulting solution at 25°C for 16 hours. LCMS shows that the raw material When the reaction is complete and the product is generated, the reaction solution is filtered through diatomaceous earth to obtain a filtrate, which is concentrated under reduced pressure to obtain compound 1-13. MS (ESI) Calcd. for C ₂₂ H ₂₄ N ₆ O ₃ S 452, found 453 [M+H] ⁺ .

Step 12: Compound 1-13 (2 g, 4.42 mmol, 1 eq ) was dissolved in formic acid (10 mL). The resulting solution was stirred at 110°C for 16 hours. LCMS showed that the raw material reaction was complete and the product was generated. The reaction solution was rotated and evaporated to obtain Compounds 1-14. MS (ESI) Calculated for C ₂₄ H ₂₂ N ₆ O ₄ S 490, Found 491 [M+H] ⁺ .

Step 13: Add 10% aqueous sodium hydroxide solution (10 mL) dropwise to a solution of compound 1-14 (1.50 g, 3.06 mmol, 1 eq ) in methanol (10 mL) at 25°C, and stir the resulting solution at 25°C. After 4 hours, LCMS showed that the raw material reaction was complete and the product was generated. The reaction solution was neutralized with 10% dilute hydrochloric acid, the aqueous phase was extracted with dichloromethane (100 mL*3), and the combined organic phase was washed with saturated brine (100 mL*1). Rotation and evaporation gave compounds 1-15. MS (ESI) Calculated for C ₁₆ H ₁₆ N ₆ O 308, Found 309 [M+H] ⁺ .

Step 14: To compound 1-15 (1 g, 3.24 mmol, 1 eq ) in a mixed solvent of DCM (20 mL) and MeOH (2 mL), manganese dioxide (2.83 g, 32.6 mmol, 10 eq) was added ) The resulting solution was stirred at 65°C for 16 hours. LCMS showed that the raw material reaction was complete and the product was generated. The reaction solution was filtered with diatomaceous earth to obtain a filtrate, which was concentrated under reduced pressure to obtain compound 1-16. MS (ESI) Calculated for C ₁₆ H ₁₄ N ₆ O 306 , found 307[M+H] ⁺ .

Step 15: To a solution of compound 1-16 (0.39 g, 1.27 mmol, 1 eq ) in methanol (15 mL) was added hydroxylamine hydrochloride (106.99 mg, 1.66 mmol, 1.2 eq ) and sodium acetate (126.29 mg, 1.54 mmol, 1.2 eq ), and the resulting solution was stirred at 25°C for 0.5 hours. LCMS showed that the reaction of the raw materials was complete and the product was generated. The reaction solution was concentrated under reduced pressure to obtain a residue. The residue was diluted with 25 mL of saturated brine and extracted with THF (25 mL*3). The organic phase was dried with anhydrous sodium sulfate, filtered, Concentrate under reduced pressure to obtain compound 1-17. MS (ESI) Calculated for C ₁₆ H ₁₅ N ₇ O 321 , found 322[M+H] ⁺ .

Step 16: To a solution of compound 1-17 (0.35 g, 1.09 mmol, 1 eq ) in THF (15 mL) was added thiocarbonyldiimidazole (388.2 mg, 2.18 mmol, 2 eq ) at 25°C. The resulting solution was stirred at 25°C for 16 hours. LCMS showed that the raw material reaction was complete and the product was generated. Water (50 mL) was added to the reaction solution, the aqueous phase was extracted with dichloromethane (100 mL*3), and the combined organic phase was extracted with anhydrous It was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (SiO ₂ , DCM:MeOH =50:0~5:1) to obtain compound 1-18. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 11.91 (s, 1H), 8.62 (s, 1H), 8.22 (s, 1H), 7.50–7.48 (s, 1H), 6.92–6.88 (m, 1H), 5.53–5.20 (s, 1H), 4.84–4.80 (m, 1H), 4.73–4.67 (m, 1H), 3.34–3.32 (m, 2H), 3.02–2.49 (m, 2H). MS (ESI) Calculated for C ₁₆ H ₁₃ N ₇ 303 , Found 304[M+H] ⁺ .

Step 17: Chiral separation of compounds 1-18 (chiral column: Chiralcel OJ-3 50×4.6mm ID, 3μm; mobile phase: phase A is supercritical CO ₂ , phase B is MeOH (0.05%DEA) ); gradient: the content of B in A ranges from 5% to 40%; flow rate: 3mL/min; wavelength: 220nm; column temperature: 35°C; back pressure: 100Bar) to obtain compound 1A (retention time: 0.917 minutes) and compound 1B (Retention time: 2.790 minutes).

Compound 1A: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 11.91 (s, 1H), 8.62 (s, 1H), 8.22 (s, 1H), 7.50–7.48 (s, 1H), 6.92–6.88 (m, 1H), 5.53–5.20 (s, 1H), 4.84–4.80 (m, 1H), 4.73–4.67 (m, 1H), 3.34–3.32 (m, 2H), 3.02–2.49 (m, 2H) . C ₁₆ H ₁₃ N ₇ 303, measured value 304[M+H] ⁺ .

Example 2: Synthesis of Compounds 2A and 2B.

Step 1: Compound 1-13 (2.0 g, 4.40 mmol, 1 eq ) was dissolved in acetic acid (20 mL). The resulting solution was stirred at 120°C for 15 h. LCMS showed that the raw material reaction was complete and the product was generated. The reaction solution was rotated and evaporated to obtain Compound 2-1. MS (ESI) Calcd. for C ₂₆ H ₂₆ N ₆ O ₄ S 518, found 519 [M+H] ⁺ .

Step 2: To a solution of compound 2-1 (1.50 g, 2.89 mmol, 1 eq ) in methanol (10 mL), 10% aqueous sodium hydroxide solution (10 mL) was added dropwise at 25°C, and the resulting solution was stirred at 25°C. After 4 hours, LCMS showed that the raw material reaction was complete and the product was generated. The reaction solution was neutralized with 10% dilute hydrochloric acid, the aqueous phase was extracted with dichloromethane (100 mL*3), and the combined organic phase was washed with saturated brine (100 mL*1). Rotate and evaporate to obtain compound 2-2. MS (ESI) Calcd. for C ₁₇ H ₁₈ N ₆ O 322, found 323 [M+H] ⁺ .

Step 3: To compound 2-2 (1 g, 3.1 mmol, 1 eq ) in a mixed solvent of DCM (20 mL) and MeOH (2 mL), manganese dioxide (2.7 g, 31.0 mmol, 10 eq) was added ) The resulting solution was stirred at 65°C for 16 hours. LCMS showed that the reaction of the raw materials was complete and the product was generated. The reaction solution was filtered with diatomaceous earth to obtain the filtrate, which was concentrated under reduced pressure to obtain compound 2-3. MS (ESI) Calculated for C ₁₇ H ₁₆ N ₆ O 320, Found 321 [M+H] ⁺ .

Step 4: To a solution of compound 2-3 (0.5 g, 1.56 mmol, 1 eq ) in methanol (50 mL) was added hydroxylamine hydrochloride (119.3 mg, 1.54 mmol, 1.1 eq ) and sodium acetate (192.1 mg, 2.34 mmol, 1.5 eq ), the resulting solution was stirred at 25°C for 0.5 hours. LCMS showed that the reaction of the raw materials was complete and the product was generated. The reaction solution was concentrated under reduced pressure to obtain a residue. The residue was diluted with 25 mL of saturated brine and extracted with THF (25 mL*3). The organic phase was dried with anhydrous sodium sulfate, filtered, Concentrate under reduced pressure to obtain compound 2-4. MS (ESI) Calcd. for C ₁₇ H ₁₇ N ₇ O335 , found 336 [M+H] ⁺ .

Step 5: To a solution of compound 2-4 (0.35 g, 1.04 mmol, 1 eq ) in THF (15 mL) was added thiocarbonyldiimidazole (371.9 mg, 2.09 mmol, 2 eq ) at 25°C. The resulting solution was stirred at 25°C for 16 hours. LCMS showed that the raw material reaction was complete and the product was generated. Water (50 mL) was added to the reaction solution, and the aqueous phase was extracted with dichloromethane (100 mL*3). The combined organic phase was extracted with anhydrous sulfuric acid. The sodium was dried, filtered, and concentrated under reduced pressure, and the obtained residue was analyzed by preparative HPLC (column: Phenomenex Gemini-NX 80*40mm*3μm; mobile phase: [water (0.05% NH ₃ H ₂ O+10mM NH ₄ HCO ₃ )-ACN]; ACN: 17%-37%, 8min) to obtain compound 2-5. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 11.88 (s, 1H), 8.52 (s, 1H), 7.43 (s, 1H), 6.90 (s, 1H), 6.35–6.34 (m, 1H), 5.36–5.34 (m, 1H), 4.82–4.68 (m, 2H), 3.52–3.37 (m, 2H), 2.69–2.58 (m, 4H), 2.50–2.29 (m, 1H), MS (ESI) Calculated for C ₁₇ H ₁₅ N ₇ 317, Found 318[M+H] ⁺ .

Step 6: Chiral separation of 2-5 (chiral column: Chiralcel OJ-3 50×4.6mm ID, 3μm; mobile phase: phase A is supercritical CO ₂ , phase B is MEOH (0.05%DEA) ; Gradient: The content of B in A ranges from 5% to 40%; Flow rate: 3mL/min; Wavelength: 220nm; Column temperature: 35C; Back pressure: 100Bar) Compound 2A (retention time: 3.198 minutes) and compound 2B (retention time :3.947 minutes).

Example 3: Synthesis of Compounds 3A and 3B.

Step 1: Compound 1-13 (2 g, 4.40 mmol, 1 eq ) was dissolved in trifluoroacetic acid (10 mL). The resulting solution was stirred at 110°C for 16 h. LCMS showed that the raw material reaction was complete and the product was generated. The reaction solution was rotated and Evaporate to obtain compound 3-1. MS (ESI) Calculated for C ₂₆ H ₂₀ F ₆ N ₆ O ₄ S 626, Found 627 [M+H] ⁺ .

Step 2: Add 10% aqueous sodium hydroxide solution (10 mL) dropwise to a solution of compound 3-1 (1.50 g, 2.39 mmol, 1 eq ) in methanol (10 mL) at 25°C, and stir the resulting solution at 25°C. After 4 hours, LCMS showed that the raw material reaction was complete and the product was generated. The reaction solution was neutralized with 10% dilute hydrochloric acid, the aqueous phase was extracted with dichloromethane (100 mL*3), and the combined organic phase was washed with saturated brine (100 mL*1). Rotate and evaporate to obtain compound 3-2. MS (ESI) Calcd. for C ₁₇ H ₁₅ F ₃ N ₆ O 376, found 377 [M+H] ⁺ .

Step 3: To compound 3-2 (1 g, 2.7 mmol, 1 eq ) in a mixed solvent of DCM (20 mL) and MeOH (2 mL), manganese dioxide (2.3 g, 27.0 mmol, 10 eq) was added ) The resulting solution was stirred at 65°C for 16 hours. LCMS showed that the raw material reaction was complete and the product was generated. The reaction solution was filtered with diatomaceous earth to obtain a filtrate, which was concentrated under reduced pressure to obtain compound 3-3. MS (ESI) Calculated for C ₁₇ H ₁₃ F ₃ N ₆ O 374, Found 375 [M+H] ⁺ .

Step 4: To a solution of compound 3-3 (0.5 g, 1.34 mmol, 1 eq ) in methanol (50 mL) was added hydroxylamine hydrochloride (111.4 mg, 1.60 mmol, 1.1 eq ) and sodium acetate (131.5 mg, 1.60 mmol, 1.5 eq ), and the resulting solution was stirred at 25°C for 0.5 hours. LCMS showed that the reaction of the raw materials was complete and the product was generated. The reaction solution was concentrated under reduced pressure to obtain a residue. The residue was diluted with 25 mL of saturated brine and extracted with THF (25 mL*3). The organic phase was dried with anhydrous sodium sulfate, filtered, Concentrate under reduced pressure to obtain compound 3-4. MS (ESI) Calcd. for C ₁₇ H ₁₄ F ₃ N ₇ O 389, found 390 [M+H] ⁺ .

Step 5: To a solution of compound 3-4 (0.35 g, 0.89 mmol, 1 eq ) in THF (15 mL) was added thiocarbonyldiimidazole (320 mg, 1.80 mmol, 2 eq ) at 25°C. The resulting solution was stirred at 25°C for 16 hours. LCMS showed that the raw material reaction was complete and the product was generated. Water (50 mL) was added to the reaction solution, and the aqueous phase was extracted with dichloromethane (100 mL*3). The combined organic phase was extracted with anhydrous sulfuric acid. Nadine was dried, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (SiO ₂ , DCM:MeOH =50:0~5:1) to obtain compound 3-5. MS (ESI) calculated value C ₁₇ H ₁₂ F ₃ N ₇ O 371 , found value 372 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ )δ=12.34 (s,1H), 8.83 (s,1H), 7.59 –7.58(m,1H),6.96–6.93(s,1H), 6.32 (s,1H), 5.52 (s,1H),4.87–4.79 (m,2H), 3.14–3.02 (m, 2H), 2.73 –2.68 (m, 1H), 2.34–2.33(m,1H), MS (ESI) calculated value for C ₁₇ H ₁₂ F ₃ N ₇ 371 , found value 372[M+H] ⁺ .

Step 6: Pass 3-5 through chiral separation (chiral column: Chiralcel OJ-3 50×4.6mm ID, 3um; mobile phase: phase A is supercritical CO ₂ , phase B is MEOH (0.05%DEA) ; Gradient: the content of B in A ranges from 5% to 40%; flow rate: 3mL/min; wavelength: 220nm; column temperature: 35C; back pressure: 100Bar) to obtain compound 3A (retention time: 1.166 minutes) and compound 3B (retention Time: 1.339 minutes).

Example 4: Synthesis of Compound 4.

Step 1: Under nitrogen protection at -78°C, add n-butyllithium dropwise to a solution of tert-butyldimethyl (2-propynyloxy)silane (200 g, 1174.24 mmol) dissolved in tetrahydrofuran (2 L) (BuLi) in n-hexane (2.5 M, 427.54 mL), the reaction solution was stirred at -78°C for 30 minutes. Then, a solution of compound 4-1 (250 g, 971.7 mmol) in tetrahydrofuran (2 L) was added dropwise to the reaction liquid at -78°C. The reaction solution was reacted at -78°C for 3 hours. TLC (PE:EA=3:1) showed that the reaction was complete. The reaction solution was quenched with saturated amine chloride aqueous solution (2 L) and water (1 L), extracted with EA (2 L*3), and the combined reaction solution was Wash with saturated brine (2 L), dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain compound 4-2. ¹ H NMR (400MHz, CDCl ₃ )δ=5.11(br d, J =7.3 Hz, 1H), 4.48 (s,2H), 4.35-4.27 (m, 1H), 4.21 (q, J =7.2 Hz, 2H ), 2.80-2.59 (m, 2H), 2.30-2.13 (m, 1H), 1.98 (br dd, J =6.4, 14.2 Hz, 1H), 1.55 - 1.42 (s, 9H), 1.36-1.27 (m, 3H), 0.93 (s, 9H), 0.19-0.07 (s, 6H).

Step 2: Add hydrazine hydrate (34.71g, 1.03 mol, 98%) to a solution of compound 4-2 (400 g, 935.44 mmol) dissolved in DMF (3 L) under ice bath. The reaction was carried out at 25°C for 2 hours. LC-MS showed that the reaction was complete. The reaction solution was diluted with water (10L) and extracted with EA (2 L*2). The combined reaction solution was washed with saturated brine (2 L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Compound 4-3 was obtained. MS (ESI) Calculated for C ₂₁ H ₃₉ N ₃ O ₅ Si 441, Found 442 [M+H] ⁺ .

Step 3: To the solution of compound 4-3 (432 g, 978.18 mmol) in THF (3 L) under ice bath conditions, NaBH ₄ (77.71 g, 2.05 mol) was added in batches. Then methanol (0.6 L) was slowly added dropwise, and the reaction solution was stirred and reacted at 25°C for 12 hours. LC-MS showed that the reaction was complete. The reaction solution was quenched with saturated aqueous ammonium chloride solution (300 mL) in an ice bath, then diluted with water (2 L), extracted with EA (2 L*2), and the combined reaction solution was washed with saturated brine (2 L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and obtained compound 4-4 through column chromatography (SiO ₂ , DCM: MeOH = 50:1~20:1). MS (ESI) Calcd. for C ₁₉ H ₃₇ N ₃ O ₄ Si 399, found 400 [M+H] ⁺ .

Step 4: Add tributylphosphorus (340.24 g, 1.68 mol) to compound 4-4 (336g, 840.84 mmol) in tetrahydrofuran (4L) under ice bath conditions. The reaction solution was stirred in an ice bath for 30 minutes, and ADDP (424.31 g, 1.68 mol) was added to the reaction solution. The reaction solution was stirred and reacted at 20°C for 12 hours. LC-MS showed the reaction was complete. The reaction solution was diluted with water (2 L), extracted with EA (2 L*2), the combined reaction solution was washed with saturated brine (1.5 L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and passed through column chromatography (SiO ₂ , PE:EA =20:1 to 2:1) to obtain compound 4-5. MS (ESI) Calcd. for C ₁₉ H ₃₅ N ₃ O ₃ Si 381, found 382 [M+H] ⁺ .

Step 5: Add TBAF (1 M, 1.02 L, 1.02 mol) to a solution of compound 4-5 (390 g, 1.02 mol) dissolved in tetrahydrofuran (1 L) at room temperature. The reaction is carried out at 20°C. Reaction takes 1.5 hours. LC-MS showed the reaction was complete. The reaction solution was diluted with water (1 L), adjusted to pH=8 with saturated NaHCO ₃ aqueous solution, and extracted with EA (1 L*3). The combined reaction solution was washed with saturated brine (1 L), dried over anhydrous sodium sulfate, filtered and Concentrate under reduced pressure, and then dissolve the concentrated solution in ethyl acetate (1 L). HCl/EtOAc (4 M, 200 mL) is slowly added dropwise to the solution, and stirred for 1 hour. A white solid is formed. Filter to obtain compound 4- 6. MS (ESI) Calculated for C ₁₃ H ₂₁ N ₃ O ₃ 267, Found 268 [M+ H] ⁺ .

Step 6: Add manganese dioxide (37.40 g, 430.19 mmol) to a solution of compound 4-6 (11.5 g, 43.02 mmol) dissolved in DCM (150 mL) and MeOH (15 mL), replace with nitrogen three times, and then Stir at 65°C for 12 hours. LC-MS showed the reaction was complete. The reaction solution was filtered and concentrated to obtain compound 4-7. MS (ESI) Calcd. for C ₁₃ H ₁₉ N ₃ O ₃ 265, found 266 [M+H] ⁺ .

Step 7: To compound 4-7 (11 g, 41.46 mmol) dissolved in THF (150 mL), NH ₃ .H ₂ O (51.89 g, 414.61 mmol, 57.03 mL, 28% purity) and I ₂ (31.57 g, 124.38 mmol), the reaction solution was replaced with nitrogen three times, and then stirred at 25°C for 12 hours. LC-MS showed the reaction was complete. Add saturated sodium sulfite aqueous solution to the reaction solution to quench the reaction, add 20 mL of water to dilute, and then extract with ethyl acetate (50 mL*2). The organic phases were combined, washed with saturated brine (30 mL), dried over sodium sulfate, filtered, and concentrated to obtain the initial product. The initial product was purified by column chromatography (SiO ₂ , PE:EA =3:1) to obtain compound 4-8. MS (ESI) Calculated for C ₁₃ H ₁₈ N ₄ O ₂ 262, Found 263 [M+ H] ⁺ .

Step 8: To compound 4-8 (11 g, 41.94 mmol) dissolved in DCM (150 mL), TMSI (10.91 g, 54.52 mmol, 7.42 mL) was added at 0°C. The reaction solution was stirred at 0°C for 1 hour. TLC showed that the starting material disappeared and new products were formed. The reaction solution was concentrated under reduced pressure to obtain the hydroiodide salt of compound 4-9. MS (ESI) Calculated for C ₈ H ₁₀ N ₄ 162, Found 163 [M+H] ⁺ .

Step 9: Add DIEA (26.73 g, 206.82 mmol) to isopropyl alcohol (200 mL) in which compound 4-9 (12 g, 41.36 mmol, hydroiodide) and compound 1-11 (11.64 g, 33.09 mmol) were dissolved. , 36.0 mL). The reaction liquid was replaced with nitrogen three times, and then stirred at 90° C. for 12 hours. LC-MS showed the reaction was complete. The reaction solution was cooled, H ₂ O (200 mL) was added, filtered, and dried to obtain compound 4-10. MS (ESI) Calcd. for C ₂₂ H ₁₉ N ₇ SO ₄ 477, found 478 [M+H] ⁺ .

_Step 10: Add Fe (9.36 g, 167.54 mmol) and NH ₄ Cl (12.55 g, 234.56 mmol), replaced with nitrogen three times, and stirred at 100°C for 1 hour. LCMS showed the reaction was complete. The reaction solution was filtered, and the filtrate was diluted with H ₂ O (100 mL), and then extracted with ethyl acetate (150 mL*2). The filter cake was washed with DCM:MeOH (20:1, 100mL*3). The extract and filtrate were combined, dried over sodium sulfate, filtered, and concentrated to obtain compound 4-11. MS (ESI) Calcd. for C ₂₂ H ₂₁ N ₇ SO ₂ 447, found 448 [M+H] ⁺ .

Step 11: To a solution of compound 4-11 (150 mg, 335.19 μmol) and TsOH (5.8 mg, 33.52 μmol) in AcOH (5 mL) was added Tetramethoxymethane (456.4 mg, 3.35 mmol) . The reaction liquid was replaced with nitrogen three times and stirred at 50°C for 2 hours. LCMS showed the reaction was complete. The reaction solution was concentrated to remove the solvent, diluted with H ₂ O (5 mL), and extracted with dichloromethane (5 mL*3). The organic phases were combined, washed with saturated brine, dried over sodium sulfate, filtered, and concentrated to obtain 4-12. MS (ESI) calculated value C ₂₄ H ₂₁ N ₇ O ₃ S 487, measured value 488 [M+H] ⁺ .

Step 12: Dissolve compound 4-12 (180 mg, 369.21 μmol) in THF (10 mL), and then add TBAF (1 M, 738.4 μL). The reaction liquid was replaced with nitrogen three times and stirred at 70°C for 12 hours. LC-MS showed the reaction was complete. The reaction solution was concentrated, then diluted with NaHCO ₃ aqueous solution (15 mL), extracted with DCM (15 mL*3), the organic phases were combined, dried over sodium sulfate, filtered, and concentrated to obtain the initial product. The initial product was separated by preparative HPLC (Phenomenex Gemini NX 80*30mm*μm; mobile phase: [water (10 mM H ₄ HCO ₃ )-ACN]; B(ACN)%: 20%-50%, 9 min) to obtain the compound 4. MS (ESI) Calculated for C ₁₇ H ₁₅ N ₇ O 333, Found 334 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.72 (br s, 1H), 8.38 (br s, 1H), 7.42 (br s, 1H), 6.85 (br s, 1H), 6.71 (br s, 1H), 5.41 (br s, 1H), 4.69 (br s, 2H), 4.09 (br s, 3H), 3.05 (br s, 2H), 2.68 - 2.55 (m, 1H), 2.28 (br s, 1H ).

Example 5: Synthesis of Compound 5.

Step 1: Combine compound 4-11 (250 mg, 558.64 μmol, 1 eq ), (2R)-2-hydroxypropionic acid (221.41 mg, 1.68 mmol), EDCI (321.28 mg, 1.68 mmol) and HOBt (226.46 mg, 1.68 mmol) was dissolved in THF (10 mL), and then DIEA (361.00 mg, 2.79 mmol, 486.53μL) was added. The reaction solution was replaced with nitrogen three times, and then stirred at 20°C for 12 hours. LC-MS showed the reaction was complete. The reaction solution was diluted with H ₂ O (15 mL), and extracted with EA (15 mL*3). The organic phases were combined, washed with saturated brine, dried over sodium sulfate, filtered and concentrated to obtain compound 5-1. MS (ESI) Calcd. for C ₂₇ H ₂₇ N ₇ O ₅ S 561, found 562 [M+H] ⁺ .

Step 2: Dissolve compound 5-1 in AcOH (10 mL) and stir at 120°C for 0.5 hours. LCMS showed the reaction was complete. The reaction solution was diluted with water (15 mL) and extracted with ethyl acetate (15 mL*3). The organic phases were combined, washed with saturated brine, dried over sodium sulfate, filtered, and concentrated to obtain compound 5-2. MS (ESI) calculated value C ₂₇ H ₂₅ N ₇ O ₄ S 543, measured value 544 [M+H] ⁺ .

Step 3: Compound 5-2 (0.3 g, 551.88 μmol) was dissolved in MeOH (12 mL) and THF (3 mL), and then K ₂ CO ₃ (152.55 mg, 1.10 mmol) was added. The reaction liquid was replaced with nitrogen three times, and then stirred at 25° C. for 10 minutes. LC-MS showed the reaction was complete. The reaction solution was concentrated under reduced pressure to remove the solvent, diluted with H ₂ O (10 mL), and then extracted with DCM:MeOH (10:1, 10mL*3). The organic phases were combined, washed with saturated brine, and dried over sodium sulfate. Filter and concentrate to obtain compound 5-3. MS (ESI) Calcd. for C ₂₅ H ₂₃ N ₇ O ₃ S 501, found 502 [M+H] ⁺ .

Step 4: Dissolve compound 5-3 (150 mg, 299.07 μmol) in THF (5 mL), and then add TBAF (1 M, 598.1 μL). The reaction liquid was replaced with nitrogen three times and stirred at 70°C for 12 hours. LC-MS showed the reaction was complete. The reaction solution was concentrated, then diluted with NaHCO ₃ aqueous solution (15 mL), extracted with DCM (15 mL*3), the organic phases were combined, dried over sodium sulfate, filtered, and concentrated to obtain the initial product. The initial product was separated by preparative HPLC (Phenomenex Gemini NX 80*30mm*3μm; mobile phase: [water (10mM NH ₄ HCO ₃ )-ACN]; ACN%: 15%-45%, 9 min) to obtain compound 5. MS (ESI) Calculated for C ₁₈ H ₁₇ N ₇ O 347, Found 348 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ = 8.64 (s, 1H), 7.44 (br d, J =2.8 Hz, 1H), 6.74 (s, 1H), 6.35 (br s, 1H), 5.79 (br d, J =10.4 Hz, 1H), 5.41-5.29 (m, 1H), 4.99-4.90 (m, 2H), 4.84-4.76 (m, 1H), 3.31-3.22 (m, 1H), 3.18-3.07 ( m, 1H), 3.01-2.87 (m, 1H), 2.37 (br d, J =12.4 Hz, 1H), 1.82 (br d, J =6.3 Hz, 3H).

Example 6: Synthesis of Compound 6.

Step 1: Under nitrogen protection at -78°C, add n-butyl dimethyl (2-propynyloxy)silane (38.07 g, 223.49 mmol, 45.3 mL) dissolved in tetrahydrofuran (500 mL) dropwise. Butyllithium (BuLi) in n-hexane solution (2.5 M, 85.5 mL), the reaction solution was stirred at -78°C for 30 minutes. Then, a solution of compound 6-1 (50 g, 194.34 mmol) in tetrahydrofuran (500 mL) was added dropwise to the reaction solution at -78°C. The reaction solution was reacted at -78°C for 3 hours. TLC (PE:EA=3:1) showed that the reaction was complete. The reaction solution was quenched with saturated aqueous ammonium chloride solution (500 mL) and water (0.5L), extracted with EA (0.5 L*3), and the combined reaction solution was Wash with saturated brine (1 L), dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain compound 6-2.

Step 2: Add hydrazine hydrate (7.81 g, 231.52 mmol, 8.81 mL, 95% purity) to a solution of compound 6-2 (90 g, 210.47 mmol) dissolved in DMF (700 mL) at 0°C. ). The reaction was carried out at 25°C for 2 hours. LC-MS showed that the reaction was complete. The reaction solution was diluted with water (1L) and extracted with EA (1 L*2). The combined reaction solution was washed with H ₂ O (1L*3) and saturated brine (1L), and washed with anhydrous sulfuric acid. Dry over sodium, filter and concentrate under reduced pressure to obtain compound 6-3. MS (ESI) Calcd. for C ₂₁ H ₃₉ N ₃ O ₅ Si 441, found 442 [M+H] ⁺ .

Step 3: To a solution of compound 6-3 (432 g, 978.18 mmol) in THF (800 mL) at 0°C, NaBH ₄ (16.01 g, 423.20 mmol) was added in portions. Afterwards, methanol (200 mL) was slowly added dropwise, and the reaction solution was stirred and reacted at 25°C for 12 hours. LC-MS showed that the reaction was complete. The reaction solution was quenched with saturated aqueous ammonium chloride solution (300 mL) in an ice bath, then diluted with water (1 L), extracted with EA (1 L*2), and the combined reaction solution was washed with saturated brine (1 L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and passed through column chromatography (SiO ₂ , DCM: MeOH = 50:1~20:1) to obtain compound 6-4. MS (ESI) Calcd for C ₁₉ H ₃₇ N ₃ O ₄ Si 399, found 400 [M+H] ⁺ .

Step 4: To compound 6-4 (68 g, 170.17 mmol) in tetrahydrofuran (1.4L), add tributylphosphorus (68.86 g, 340.34 mmol, 84.0 mL) at 0°C. The reaction solution was stirred at 0°C for 30 minutes, and ADDP (85.87 g, 340.34 mmol) was added to the reaction solution. The reaction solution was stirred and reacted at 20°C for 12 hours. LC-MS showed the reaction was complete. Filter the reaction solution, dilute the filtrate with water (1 L), extract with EA (1 L*2), wash the combined reaction solution with saturated brine (1.5 L), dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure, and pass through a column Chromatography (SiO ₂ , PE:EA=20:1~2:1) gave compound 6-5. MS (ESI) Calculated for C ₁₉ H ₃₅ N ₃ O ₃ Si 381, Found 382 [M+H] ⁺ .

Step 5: Add TBAF (1 M, 230.62 mL) to a solution of compound 6-5 (80 g, 209.65 mmol) in tetrahydrofuran (800 mL) at room temperature, and react at 20 °C for 0.5 hours. . LC-MS showed the reaction was complete. The reaction solution was diluted with water (1 L) and extracted with EA (1 L*2). The combined reaction solution was washed with saturated brine (1 L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the initial product. Dissolve the obtained initial product in 800 mL EA, add 200 mL HCl/EA, stir for 1 hour, and precipitate 28 g of the initial product. Dissolve the initial product solution in 250 mL of water, adjust the pH to 8 with sodium bicarbonate, then extract with EA (300 mL*2), combine the organic compounds, and concentrate to obtain compound 6-6. MS (ESI) Calcd. for C ₁₃ H ₂₁ N ₃ O ₃ 267, found 268 [M+H] ⁺ .

Step 6: Add manganese dioxide (71.55 g, 822.97 mmol) to a solution of compound 6-6 (22 g, 82.30 mmol, 1 eq ) dissolved in DCM (300 mL) and MeOH (30 mL), and replace with nitrogen 3 times, and then stirred at 60°C for 12 hours. LCMS showed the reaction was complete. The reaction solution was filtered and concentrated to obtain compound 6-7. MS (ESI) Calculated for C ₁₃ H ₁₉ N ₃ O ₃ 265, Found 266 [M+H] ⁺ .

Step 7: To compound 6-7 (6 g, 22.62 mmol) dissolved in THF (90 mL), add NH ₃ .H ₂ O (28.31 g, 226.15 mmol, 31.11 mL, 28% purity) and I2 (17.22 g , 67.85 mmol, 13.7 mL), the reaction solution was replaced with nitrogen three times, and then stirred at 20°C for 12 hours. TLC showed the reaction was complete. Add saturated sodium sulfite aqueous solution to the reaction solution to quench the reaction, add 10 mL of water to dilute, and then extract with ethyl acetate (15 mL*2). The organic phases were combined, washed with saturated brine (15 mL), dried over sodium sulfate, filtered, and concentrated to obtain the initial product. The initial product was separated by column chromatography (SiO ₂ , PE:EA=3:1) and purified to obtain compound 6-8. MS (ESI) calculated value C ₁₃ H ₁₈ N ₄ O ₂ 262, measured value 263 [M+H] ⁺ .

Step 8: To compound 6-8 (10 g, 38.12 mmol) dissolved in DCM (100 mL), TMSI (9.92 g, 49.56 mmol, 6.8 mL) was added at 0°C. The reaction solution was stirred at 0°C for 1.5 hours. LCMS showed the reaction was complete. Add 100 mL EA to the reaction solution, and filter to obtain the hydroiodide salt of compound 6-9. MS (ESI) Calculated for C ₈ H ₁₀ N ₄ 162, Found 163 [M+H] ⁺ .

Step 9: To the dissolved compound 6-9 (7 g, 24.13 mmol, hydroiodide), 4-chloro-5-nitro-1-(p-toluenesulfonyl)pyrrole[2,3-b]pyridine (8.49 g, 24.13 mmol) of isopropyl alcohol (140 mL) was added to DIEA (9.36 g, 72.39 mmol, 12.6 mL). The reaction liquid was replaced with nitrogen three times, and then stirred at 90° C. for 12 hours. LCMS showed the reaction was complete. The reaction solution was cooled, H ₂ O (100 mL) was added, and a large amount of yellow solid precipitated, which was filtered and dried to obtain compound 6-10. MS (ESI) Calculated for C ₂₂ H ₁₉ N ₇ SO ₄ 477, Found 478 [M+H] ⁺ .

Step 10: Add Fe powder (8.19 g, 146.60 mmol) and NH ₄ Cl (10.98 g) to a solution of compound 6-10 (14 g, 29.32 mmol) dissolved in THF (168 mL) and H ₂ O (42 mL). , 205.24 mmol), stir at 90°C for 1 hour. LC-MS showed the reaction was complete. The reaction solution was filtered, and the filtrate was diluted with H ₂ O (100 mL), and then extracted with ethyl acetate (150 mL*2). The filter cake was washed with DCM:MeOH (20:1, 100mL*3). The extract and filtrate were combined, dried over sodium sulfate, filtered, and concentrated to obtain compound 6-11. MS (ESI) Calculated for C ₂₂ H ₂₁ N ₇ SO ₂ 447, Found 448 [M+H] ⁺ .

Step 11: Add tetramethyl orthocarbonate (304.23 mg, 2.23 mmol) to a solution of compound 6-11 (100 mg, 223.46 μmol) and TsOH (3.85 mg, 22.35 μmol) dissolved in AcOH (5 mL). The reaction liquid was replaced with nitrogen three times and stirred at 50°C for 12 hours. LC-MS showed the reaction was complete. The reaction solution was concentrated to remove the solvent, diluted with H ₂ O (5 mL), and extracted with DCM (5 mL*3). The organic phases were combined, washed with saturated brine (5 mL), dried over sodium sulfate, filtered, and concentrated to obtain compound 6-12. MS (ESI) Calculated for C ₂₄ H ₂₁ N ₇ O ₃ S 487, Found 488 [M+H] ⁺ .

Step 12: Dissolve compound 6-12 (100 mg, 205.11 μmol, 1 eq ) in THF (5 mL), and then add TBAF (1 M, 410.2 μL). The reaction liquid was replaced with nitrogen three times and stirred at 70°C for 12 hours. LC-MS showed the reaction was complete. The reaction solution was concentrated, then diluted with NaHCO ₃ aqueous solution (5 mL), extracted with DCM (5 mL*3), the organic phases were combined, dried over sodium sulfate, filtered, and concentrated to obtain the initial product. The initial product was separated by preparative HPLC (Phenomenex Gemini NX 80*30mm*3μm; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B (ACN)%: 20%-50%, 9min) to obtain the compound 6. MS (ESI) calculated value for C ₁₇ H ₁₅ N ₇ O 333, found value 334[M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.73 (br s, 1H), 8.38 (s, 1H), 7.43 (br s, 1H), 6.85 (s, 1H), 6.71(br s, 1H) , 5.41 (br s, 1H), 4.81 - 4.61 (m, 2H), 4.09 (s, 3H), 3.05 (br s, 2H), 2.64-2.54 (m, 2H).

Example 7: Synthesis of Compound 7.

Step 1: Dissolve compound 6-11 (150 mg, 335.19 μmol) and (2R)-2-hydroxypropionic acid (75.48 mg, 837.97 μmol) in THF (5 mL), and add EDCI (160.64 mg, 837.97 μmol) , HOBt (113.23 mg, 837.97 μmol), DIEA (129.96 mg, 1.01 mmol, 175.2 μL). The mixed solution was stirred at 20°C for 12 hours. LC-MS showed the reaction was complete. H ₂ O (15 mL) was added to the reaction solution, extracted with ethyl acetate (15 mL*3), the organic phases were combined, washed with saturated brine (15 mL), dried over sodium sulfate, filtered, and concentrated to obtain compound 7- 1. MS (ESI) Calculated for C ₂₅ H ₂₅ N ₇ O ₄ S 519, Found 520 [M+H] ⁺ .

Step 2: Dissolve compound 7-1 (200 mg, 384.93 μmol) in AcOH (4.20 g, 69.94 mmol, 4 mL), and stir at 120°C for 3 hours in a nitrogen atmosphere. LC-MS showed the reaction was complete. The reaction solution was concentrated, then diluted with NaHCO ₃ aqueous solution (5 mL), extracted with DCM (5 mL*3), the organic phases were combined, washed with saturated brine (15 mL), dried over sodium sulfate, filtered, and concentrated to obtain compound 7-2. MS (ESI) Calculated for C ₂₅ H ₂₃ N ₇ O ₃ S 501, Found 502 [M+H] ⁺ .

Step 3: Dissolve compound 7-2 (200 mg, 398.76 μmol) in THF (5 mL), and then add TBAF (1 M, 797.51 μL). The reaction liquid was replaced with nitrogen three times and stirred at 70°C for 12 hours. LC-MS showed the reaction was complete. The reaction solution was concentrated, then diluted with NaHCO ₃ aqueous solution (15 mL), extracted with DCM (15 mL*3), the organic phases were combined, dried over sodium sulfate, filtered, and concentrated to obtain the initial product. The initial product was separated by preparative HPLC (Phenomenex Gemini NX 80*30mm*3μm; mobile phase: [water (10mM NH ₄ HCO ₃ )-ACN]; B(ACN)%: 17%-47%, 9min) to obtain compound 7 . MS (ESI) Calculated for C ₁₈ H ₁₇ N ₇ O 347, Found 348 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.97 (br s, 1H), 8.62 (s, 1H), 7.60-7.34 (m, 1H), 6.92 (s, 1H), 6.31 (br s, 1H ), 5.80 (br d, J =7.0 Hz, 1H), 5.63 (br s, 1H), 5.23 (br s, 1H), 4.88-4.64 (m, 2H), 3.24 (br d, J =12.3 Hz, 1H), 3.09-2.88(m, 1H), 2.76-2.62 (m, 1H), 2.28 (br s, 1H), 1.67 (br d, J =6.4 Hz, 3H).

Bioactivity testing

Experimental Example 1: In vitro activity test of JAK1, JAK2, JAK3, and Tyk2 kinases

Experimental materials

Recombinant human JAK1, JAK2, JAK3 and Tyk2 proteases, main instruments and reagents are all provided by the British company Eurofins

Experimental methods

JAK2, JAK3, and TYK2 dilution: 20 mM 3-(N-morpholine)propanesulfonic acid (MOPS), 1 mM EDTA, 0.01% Brij-35.5% glycerol, 0.1% β-mercaptoethanol, 1 mg/mL BSA; JAK1 Dilution: 20 mM TRIS, 0.2 mM EDTA, 0.1% β-mercaptoethanol, 0.01% Brij-35.5% glycerol. All compounds were prepared as 100% DMSO solutions and brought to 50 times the final assay concentration. The test compound was diluted 3-fold with a final concentration of 9 concentrations from 10 μM to 0.001 μM. The content of DMSO in the detection reaction was 2%. A stock solution of this compound is added to the assay well as the first component of the reaction, then the remaining components are added following the protocol detailed for the assay below.

JAK1(h) enzyme reaction

JAK1(h) was incubated with 20mM Tris/HCl pH7.5, 0.2mM EDTA, 500μM MGEEPLYWSFPAKKK, 10mM magnesium acetate, and [γ- ^33P ]-ATP (activities and concentrations as needed). The reaction was started by adding the Mg/ATP mixture, and after incubation at room temperature for 40 minutes, the reaction was terminated by adding 0.5% phosphoric acid. Then 10 μL of the reaction was spotted on a P30 filter pad and washed three times with 0.425% phosphoric acid and once with methanol within 4 minutes, dried, and scintillation counted.

JAK2(h) enzyme reaction

JAK2(h) was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 100 μM KTFCGTPEYLAPEVRREPRILSEEEQEMFRDFDYIADWC, 10 mM magnesium acetate, and [γ- ³³ P]-ATP (activity and concentration as required). The reaction was started by adding the Mg/ATP mixture, and after incubation at room temperature for 40 minutes, the reaction was terminated by adding 0.5% phosphoric acid. Then 10 μL of the reaction was spotted on a P30 filter pad and washed three times with 0.425% phosphoric acid and once with methanol within 4 minutes, dried, and scintillation counted.

JAK3(h) enzyme reaction

JAK3(h) was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 500 μM GGEEEEYFELVKKKK, 10 mM magnesium acetate, and [γ- ³³ P]-ATP (activities and concentrations as required). The reaction was started by adding the Mg/ATP mixture, and after incubation at room temperature for 40 minutes, the reaction was terminated by adding 0.5% phosphoric acid. Then 10 μL of the reaction was spotted on a P30 filter pad and washed three times with 0.425% phosphoric acid and once with methanol within 4 minutes, dried, and scintillation counted.

TYK2(h) enzyme reaction

TYK2(h) was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 250 μM GGMEDIYFEFMGGKKK, 10 mM magnesium acetate, and [γ- ³³ P]-ATP (activity and concentration as required). The reaction was started by adding the Mg/ATP mixture, and after incubation at room temperature for 40 minutes, the reaction was terminated by adding 0.5% phosphoric acid. Then 10 μL of the reaction was spotted on a P30 filter pad and washed three times with 0.425% phosphoric acid and once with methanol within 4 minutes, dried, and scintillation counted.

data analysis

The IC ₅₀ results are analyzed by IDBS's XLFIT5 (205 formula), see Table 1 for details. Table 1. In vitro screening test results of compounds of the present invention compound JAK1 (IC ₅₀ ,nM) JAK2 (IC ₅₀ , nM) JAK3 (IC ₅₀ ,nM) TYK2 (IC ₅₀ , nM) 1A 1.3 27.0 30.8 35.8 2A <1 2 25 2 3A 3 62 217 57 4 0.9 7.0 27.3 50.3 5 9 250 576 231 6 2.3 70.2 73.8 130 7 0.3 53.9 38.4 12.4

Experimental Example 2: Pharmacokinetics (PK) Test

The clear solution obtained after dissolving the test compound [5% DMSO, 95% (12% SBE-β-CD)] was administered to male rats (SD) via tail vein injection and stomach tube gavage respectively (overnight fasting, 7 ~8 weeks old). After administration of the test compound, the intravenous injection group (1 mg/kg) was at 0.117, 0.333, 1, 2, 4, 7 and 24 hours, and the gastric tube feeding group (5 mg/kg) was at 0.25, 0.5, 1, 2 , 4, 8 and 24 hours, respectively, blood was collected from the mandibular vein and centrifuged to obtain plasma. The plasma concentration was measured using the LC-MS/MS method, and the relevant pharmacokinetic parameters were calculated using the noncompartmental model linear logarithmic trapezoidal method using WinNonlin™ Version 6.3 pharmacokinetic software. The test results are as follows: Table 2-1 PK test results of compounds 1A and 4 in rats PK parameters Compound 1A Compound 4 T _1/2 (hr) 1.35 3.65 C _max (nM) 2944 10152 AUC _0-inf (nM.hr) 8509 67786 bioavailability(%) 41.8% 119% Note: T _1/2 : half-life; C _max : peak concentration; AUC _0-inf : area under the plasma concentration-time curve from time 0 to extrapolation to infinity.

Experimental Example 3: In vivo efficacy study of adjuvant-induced arthritis (AIA) in rats

Experimental process: The rat adjuvant arthritis model was used to verify the arthritis treatment effect of the compound of the present invention. After female Lewis rats weighing 160-180 g were anesthetized with isoflurane, 0.1 ml of Mycobacterium tuberculosis suspension was injected subcutaneously into the left hind foot. After 13 days of modeling, the rats were divided into groups and given the corresponding test compounds. For example, rats were given different doses (see Table 3-2 for specific doses) of test compound 1A dissolved in [5% DMSO, 95% (12% SBE) -β-CD)] mixed solvent and administered orally to female Lewis rats twice a day (the number of test animals in each dose group was 10). Administration was continued for two weeks, during which the status of the rats was observed, foot volume swelling was recorded and scored. The scoring standards are shown in Table 3-1. Table 3-1. Clinical scoring criteria for arthritis Points clinical symptoms 0 No erythema or swelling 1 Red spots or mild redness and swelling near the tarsus or on the ankle or metatarsal bone, or redness and swelling on one of the toes 2 Mild erythema and swelling of the ankle and metatarsal bones, and redness, swelling and erythema of two or more toes 3 Moderate erythema and swelling of ankles, wrists, and metatarsals 4 Severe redness and swelling of ankles, wrists, metatarsals and toes

Experimental results: The two dose treatment groups of Compound 1A had a significant alleviation effect on the weight loss trend of animals caused by the disease, and the low and medium dose groups (3, 10 mg/kg) showed significant improvement from the 20th day compared with the solvent control group. Difference, showing good weight recovery effect. Compound 1A inhibited the increase in arthritis clinical scores and foot volume in a dose-dependent manner. Compound 1A 10mg/kg has the most obvious effect (starting from 15 days, there is a significant difference compared with the solvent control group). The average arthritis clinical score of this group dropped from a peak of 5.8 points on day 13 to 1.3 points at the end point of the experiment on day 27. Table 3-2 Area under the clinical score curve inhibition rate* compound Dosage(mg/kg) AUC (%) solvent control group 0 0 Compound 1A 3 49.8 10 60.3 *Note: Compared with the solvent control group, P<0.05 for each group (single-factor analysis of variation).

Experimental Example 4: In vivo efficacy study of collagen-induced arthritis (CIA) in rats

Experimental process: The rat collagen-induced arthritis model was used to verify the arthritis treatment effect of the compound of the present invention. Lewis rats were immunized, and the day of the first immunization was recorded as day 0, and subsequent days were marked in sequence. After Lewis rats were anesthetized with isoflurane, 50 μl of prepared collagen emulsion (containing 200 μg CII) was injected subcutaneously in the tail (2-3 cm from the tail base). On the 21st day, the same volume of collagen emulsion was injected into the tail in the same way. Mice in the normal group did not need to be immunized. On the 27th day of modeling, groups were divided into groups and given corresponding test compounds. For example, rats were given different doses (see Table 4-1 for specific doses. Test compound 4 was dissolved in [0.5%HPMC E5/0.5%PVP K30/0.2 %SLS in water] mixed solvent, and administered orally to female Lewis rats twice a day (the number of test animals in each dose group was 8). Administration was continued for 14 days, during which the status of the rats was observed, and foot volume and swelling were recorded. The situation is evaluated and scored. The scoring criteria are shown in Table 3-1.

Experimental results: Compound 4 showed a dose-dependent trend in reducing the clinical scores of arthritic rats at doses of 1 and 3 mg/kg BID, with a significant difference compared with the solvent control group. By the end of the 14th day of administration, The 3 mg/kg BID group reduced the clinical score of rats to zero (Table 4-1). At the same time, the degree of foot volume swelling also decreased in a dose-dependent manner. By the end of the 14th day of administration, there was a significant difference compared with the solvent control group. The 3 mg/kg BID group reduced the foot volume swelling of rats to 1.28 μL. The body weight of the treatment group also showed a dose-dependent recovery trend. By the end of the 14th day of administration, the body weight of the 3 mg/kg BID dose group returned to the level of the normal group. Table 4-1 Main parameters of in vivo efficacy study of CIA in rats* compound Dosage(mg/kg) Clinical score (on the 14th day of administration) Full volume (μL, on the 14th day of administration) Mean±S.E.M. Mean±S.E.M. normal group 0 0 1.298±0.022 solvent control group 0 13.20±0.82 2.096±0.064 dexamethasone group 0.1 0.00±0.00 1.224±0.042 Compound 4 1 0.38±0.16 1.324±0.040 3 0.00±0.00 1.280±0.012 *Note: Compared with the solvent control group, P<0.001 for each group (two-factor variation analysis).

without

Claims (30)

A compound of formula (I') or a pharmaceutically acceptable salt thereof,

Wherein, m is 1, 2, 3, 4 or 5; n is 1, 2, 3 or 4; each R ₁ is independently H, F, Cl, Br, I, CN, C _1-8 alkyl , C _1-8 alkoxy, C _1-8 alkyl S-, NH ₂ , C _1-8 alkyl NH-, (C _1-8 alkyl) ₂ N-, -COOH or -C(O) OC _1-8 alkyl, wherein the C _1-8 alkyl, C _1-8 alkoxy, C _1-8 alkyl S-, C _1-8 alkyl NH-, (C _1-8 alkyl ) ₂ N- or -C(O)OC _1-8 alkyl groups are independently optionally substituted by 1, 2, 3 or 4 R _a ; each R ₂ is independently H, F, Cl, Br, I, CN, NH ₂ , C _1-8 alkyl, C 1-8 alkoxy, C _1-8 alkyl S-, C _1-8 alkyl NH-, (C _1-8 alkyl) _{2 N} - or C _3-12 cycloalkyl; each R _a is independently H, F, Cl, Br, I, OH, CN or NH ₂ . The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein m is 1, 2 or 3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 1, 2 or 3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein m and n are 1 at the same time. The compound described in claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural fragment

for

. The compound described in claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural fragment

for

. The compound as described in claim 5 or 6 or a pharmaceutically acceptable salt thereof, wherein the structural fragment

for

;and/or, structure fragment

for

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R ₁ is independently H, F, Cl, Br, I, CN, C _1-6 alkyl, C _1-6 alkyl Oxygen, C _1-6 alkyl S-, NH ₂ , C _1-6 alkyl NH-, (C _1-6 alkyl) ₂ N-, -COOH or -C(O)OC _1-6 alkyl , wherein the C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl S-, C _1-6 alkyl NH-, (C _1-6 alkyl) ₂ N- or - C(O)OC _1-6 alkyl groups are each independently optionally substituted with 1, 2, 3 or 4 R _a . The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein each R ₁ is independently H, F, Cl, Br, I, CN, C _1-6 alkyl, C _1-6 alkyl Oxygen, C _1-6 alkyl S-, NH ₂ , C _1-6 alkyl NH- or (C _1-6 alkyl) ₂ N-, wherein the C _1-6 alkyl, C _1-6 Alkoxy, C _1-6 alkyl S-, C _1-6 alkyl NH- or (C _1-6 alkyl) ₂ N- are each independently optionally substituted by 1, 2, 3 or 4 R _a . The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein each R ₁ is independently H, F, Cl, Br, I, CN, C _1-3 alkyl, C _1-3 alkyl Oxygen, C _1-3 alkyl S-, NH ₂ , C _1-3 alkyl NH-, (C _1-3 alkyl) ₂ N-, -COOH or -C(O)OC _1-3 alkyl , wherein the C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkyl S-, C _1-3 alkyl NH-, (C _1-3 alkyl) ₂ N- or - C(O)OC _1-3 alkyl groups are each independently optionally substituted with 1, 2, 3 or 4 R _a . The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein each R ₁ is independently H, F, Cl, Br, I, CN, C _1-3 alkyl or C _1-3 alkyl Oxy group, wherein the C _1-3 alkyl or C _1-3 alkoxy group is independently optionally substituted by 1, 2, 3 or 4 R _a . The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R ₂ is independently H, F, Cl, Br, I, CN, NH ₂ , C _1-6 alkyl, C _{1 -6} alkoxy, C _1-6 alkyl S-, C _1-6 alkyl NH-, (C _1-6 alkyl) ₂ N- or C _3-10 cycloalkyl. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein each R ₂ is independently H, F, Cl, Br, I, CN, NH ₂ , C _1-3 alkyl, C _{1 -3} alkoxy, C _1-3 alkyl S- or C _1-3 alkyl NH-. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein each R ₂ is independently H, F, Cl, Br, I or CN. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein each R ₁ is independently H, F, Cl, Br, I, CN, C _1-3 alkyl, C _1-3 alkyl Oxygen, C _1-3 alkyl S-, NH ₂ , C _1-3 alkyl NH- or (C _1-3 alkyl) ₂ N-, wherein the C _1-3 alkyl, C _1-3 Alkoxy, C _1-3 alkyl S-, C _1-3 alkyl NH- or (C _1-3 alkyl) ₂ N- are each independently optionally substituted by 1, 2, 3 or 4 R _a ; and/or each R ₂ is independently H, F, Cl, Br, I, CN, NH ₂ , C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkyl S -, C _1-3 alkyl NH-, (C _1-3 alkyl) ₂ N- or C _3-6 cycloalkyl. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein each R ₁ is independently H, F, Cl, Br, I, CN, C _1-3 alkyl, C _1-3 alkyl Oxygen, C _1-3 alkyl S- or C _1-3 alkyl NH-, wherein said C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkyl S- or C _{1 -3} alkylNH- are each independently optionally substituted by 1, 2, 3 or 4 R _a ; and/or each R ₂ is independently H, F, Cl, Br, I, CN or NH ₂ . The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R _a is independently F, Cl, Br, I or OH. A compound of formula (I) or a pharmaceutically acceptable salt thereof

Wherein, R ₁ is H, F, Cl, Br, I, CN, C _1-3 alkyl or C _1-3 alkoxy, wherein the C _1-3 alkyl and C _1-3 alkoxy are either Choose to be replaced by 1, 2, 3 or 4 R _a ; R ₂ is H, F, Cl, Br, I or CN; each R _a is independently H, F, Cl, Br, I or OH. The compound of claim 1 or 18 or a pharmaceutically acceptable salt thereof, wherein each R ₁ is independently H, F, Cl, Br, I, CN, -CH ₃ , -CH ₂ CH ₃ or -OCH ₃ , wherein -CH ₃ , -CH ₂ CH ₃ and -OCH ₃ are optionally substituted by 1, 2, 3 or 4 _Ra . The compound of claim 1 or 18 or a pharmaceutically acceptable salt thereof, wherein each R ₁ is independently H, CN, -CH ₃ , -CF ₃ , -CH(OH)CH ₃ or -OCH ₃ . The compound of claim 1 or 18 or a pharmaceutically acceptable salt thereof, wherein each R _a is independently F, Cl, Br, I or OH. The compound of claim 1 or 18 or a pharmaceutically acceptable salt thereof, wherein each R ₂ is independently F, Cl, Br, I or CN. The compound of claim 1 or 18 or a pharmaceutically acceptable salt thereof, wherein each R ₁ is independently H, CN, -CH ₃ , -CF ₃ , -CH ₂ CH ₃ or -OCH ₃ ; wherein each R _a is independently F or OH; and/or wherein each R ₂ is independently CN. The compound described in claim 1 or a pharmaceutically acceptable salt thereof, selected from compounds of formula (I'-A) or formula (I'-B) or a pharmaceutically acceptable salt thereof

The compound as described in claim 1 or 18 or a pharmaceutically acceptable salt thereof, selected from compounds of formula (IA) or formula (IB) or a pharmaceutically acceptable salt thereof

The compound described in claim 1 or 18 or its pharmaceutically acceptable salt, the compound structure of which is the structure of formula (I-1)

, or, it is selected from formula (I-1-A) or formula (I-1-B) or a pharmaceutically acceptable salt thereof

. A compound of the following formula or a pharmaceutically acceptable salt thereof, wherein the compound is

The compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein the compound is

A pharmaceutical composition comprising the compound described in any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof. The use of a compound as described in any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 29 in the preparation of drugs for the treatment of JAK1 and/or JAK2 related diseases, Optionally, the disease is selected from an inflammatory disease.