Tricyclic heterocyclic compounds as JAK inhibitors and their applications

Abstract

A tricyclic heterocyclic compound as a JAK inhibitor and its use in the preparation of a medicament for treating JAK1 or / and JAK2 related diseases. Specifically, it relates to the compound shown by formula (Ⅰ') or a pharmaceutically acceptable salt thereof. #imgabs0#

Description

[0001] Cross - reference to related applications

[0002] This application claims the priority and benefits of Chinese Patent Application No. 201911180309.2 filed with the State Intellectual Property Office of China on November 27, 2019 and Chinese Patent Application No. 202010501267.4 filed with the State Intellectual Property Office of China on June 4, 2020. The disclosures of the said applications are incorporated herein by reference in their entireties. Technical field

[0003] This application relates to tricyclic heterocyclic compounds as JAK inhibitors and their use in the preparation of drugs for treating JAK1 - or / and JAK2 - related diseases. Specifically, it relates to the compounds of formula (I’) or their pharmaceutically acceptable salts. Background art

[0004] Janus kinases (JAKs) are cytoplasmic tyrosine kinases that can transmit cytokine signals from membrane receptors to STAT transcription factors. The JAK family contains 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. The JAK - STAT intracellular signal transduction serves interferon, 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)).

[0005] JAK-1, JAK-2, and TYK-2 are expressed in various tissue cells of the human body. JAK-3 is mainly expressed in various hematopoietic tissue cells, mainly present in bone marrow cells, thymocytes, NK cells, and activated B lymphocytes and T lymphocytes. JAK1 has become a novel target in the fields of diseases such as immunity, inflammation, and cancer. A base mutation JAK2V617F on the JAK2 gene in the human body is closely related to the occurrence of polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myelofibrosis (IMF), chronic myeloid leukemia (CML), etc. in myeloproliferative diseases. Mutations in JAK3 or γc can both lead to severe combined immunodeficiency. Abnormal JAK3 activity is manifested as a significant reduction in T cells and NK cells and the loss of B cell function, seriously affecting the normal biological functions of the immune system, etc. Based on its functional characteristics and special tissue distribution, JAK3 has become an extremely attractive drug target for immune system-related diseases. In mice, the loss of TYK2 function causes defects in the signal pathways of various cytokine receptors, thereby leading to a decline in virus infection, antibacterial immune function, and an increased possibility of lung infection, etc. (John J. O’Shea, 2004, Nature Reviews Drug Discovery 3, 555-564). Different JAK family members selectively bind to different cytokine receptors, endowing signal transduction specificity, thereby playing different physiological roles. This selective mode of action enables JAK inhibitors to be relatively specifically applied to disease treatment. For example, the IL-2 or IL-4 receptor together with the common γ chain binds to JAK1 and JAK3, while the type I receptor with the same β chain binds to JAK2. The type I receptor using gp130 (glycoprotein 130) and the type I receptor activated by heterodimeric cytokines preferentially bind to JAK1 / 2 and TYK2. The type I receptor activated by hormone-like cytokines binds and activates the JAK2 kinase. The type II receptor of interferon binds to JAK1 and TYK2, while the receptors of the IL-10 cytokine family bind to JAK1 / 2 and TYK2. The various specific bindings of the above cytokines and their receptors to JAK family members trigger different physiological effects, providing possibilities for the treatment of different diseases. Heterodimerize JAK1 with other JAKs to transduce cytokine-driven pro-inflammatory signal transduction. Therefore, it is expected that inhibiting JAK1 and / or other JAKs will be therapeutically beneficial for a series of inflammatory disorders and other diseases driven by JAK-mediated signal transduction (Daniella M. Schwartz, 2017, Nature Reviews Drug Discovery 16, 843-862). SUMMARY OF THE INVENTION

[0006] On the one hand, the present application provides a compound of formula (I’) or a pharmaceutically acceptable salt thereof,

[0007]

[0008] Among them,

[0009] m is 1, 2, 3, 4 or 5;

[0010] n is 1, 2, 3 or 4;

[0011] Each R1 is independently H, F, Cl, Br, I, CN, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylS-, NH2, C 1-8 alkylNH-, (C 1-8 alkyl)2N-, -COOH or -C(O)OC 1-8 alkyl, wherein the C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylS-, C 1-8 alkylNH-, (C 1-8 alkyl)2N- or -C(O)OC 1-8 alkyl is independently optionally substituted by 1, 2, 3 or 4 R a substituents;

[0012] Each R2 is independently H, F, Cl, Br, I, CN, NH2, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylS-, C 1-8 alkylNH-, (C 1-8 alkyl)2N- or C 3-12 cycloalkyl;

[0013] Each R a is independently H, F, Cl, Br, I, OH, CN or NH2.

[0014] In some embodiments of the present application, m is 1, 2 or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1.

[0015] In some embodiments of the present application, n is 1, 2 or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1.

[0016] In some embodiments of the present application, m and n are both 1 simultaneously.

[0017] In some embodiments of the present application, the structural fragment is In some embodiments, the above structural fragment is

[0018] In some embodiments of the present application, the structural fragment is In some embodiments, the above structural fragment is

[0019] In some embodiments of the present application, each of the above R1s is independently H, F, Cl, Br, I, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylS-, NH2, C 1-6 alkylNH-, (C 1-6 alkyl)2N-, -COOH or -C(O)OC 1-6 alkyl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylS-, C 1-6 alkylNH-, (C 1-6 alkyl)2N- or -C(O)OC 1-6 alkyl is independently optionally substituted by 1, 2, 3 or 4 R a substituents.

[0020] In some embodiments of the present application, each of the above R1s is independently H, F, Cl, Br, I, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylS-, NH2, C 1-6 alkylNH- or (C 1-6 alkyl)2N-, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylS-, C 1-6 alkylNH- or (C 1-6 alkyl)2N- is independently optionally substituted by 1, 2, 3 or 4 R a substituents.

[0021] In some embodiments of the present application, each of the above R1s is independently H, F, Cl, Br, I, CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylS-, NH2, C 1-3 alkylNH-, (C 1-3 alkyl)2N-, -COOH or -C(O)OC 1-3 alkyl, wherein the C 1-3 alkyl, C 1-3 alkoxy, C1-3 Alkyl S-, C 1-3 Alkyl NH-, (C 1-3 alkyl)2N- or -C(O)OC 1-3 The alkyl group is optionally substituted with 1, 2, 3 or 4 R a replace.

[0022] In some embodiments of the present application, each of the above R1 is independently H, F, Cl, Br, I, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkyl S-, NH2, C 1-3 Alkyl NH- or (C 1-3 alkyl)2N-, 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)2N- are each independently optionally substituted by 1, 2, 3 or 4 R a replace.

[0023] In some embodiments of the present application, each of the above R1 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- is optionally substituted with 1, 2, 3 or 4 R a replace.

[0024] In some embodiments of the present application, each of the above R1 is independently H, F, Cl, Br, I, CN, C 1-3 Alkyl or C 1-3 Alkoxy, wherein the C 1-3 Alkyl or C 1-3 The alkoxy groups are each independently optionally substituted with 1, 2, 3 or 4 R a replace.

[0025] In some embodiments of the present application, each of the above R2 is independently H, F, Cl, Br, I, CN, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6(alkyl)2N- or C 3-10 cycloalkyl.

[0026] In some embodiments of the present application, each of the above R2s is independently H, F, Cl, Br, I, CN, NH2, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylS-, C 1-3 alkylNH-, (C 1-3 alkyl)2N- or C 3-6 cycloalkyl.

[0027] In some embodiments of the present application, each of the above R2s is independently H, F, Cl, Br, I, CN, NH2, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylS- or C 1-3 alkylNH-.

[0028] In some embodiments, each of the above R2s is independently H, F, Cl, Br, I, CN or NH2.

[0029] In some embodiments of the present application, each of the above R2s is independently H, F, Cl, Br, I or CN.

[0030] In some embodiments of the present application, each of the above R a is independently F, Cl, Br, I or OH.

[0031] In some embodiments of the present application, the compound of formula (I’) or a pharmaceutically acceptable salt thereof is the compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0032]

[0033] wherein,

[0034] R1 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 each independently optionally substituted by 1, 2, 3 or 4 R a substituents;

[0035] R2 is H, F, Cl, Br, I or CN;

[0036] each R a is independently H, F, Cl, Br, I or OH.

[0037] In some embodiments of the present application, each of the above R1s is independently H, F, Cl, Br, I, CN, -CH3, -CH2CH3, or -OCH3, wherein the -CH3, -CH2CH3, and -OCH3 are each independently optionally substituted with 1, 2, 3, or 4 Rs a and the other variables are as defined in the present application.

[0038] In some embodiments of the present application, each of the above R1s is independently H, F, Cl, Br, I, CN, -CH3, -CH2CH3, or -OCH3, wherein the -CH3, -CH2CH3, and -OCH3 are each independently optionally substituted with 1, 2, or 3 Rs a and the other variables are as defined in the present application.

[0039] In some embodiments of the present application, each of the above R1s is independently H, F, Cl, Br, I, CN, -CH3, -CH2CH3, or -OCH3, wherein the -CH3 or -CH2CH3 is each independently optionally substituted with 1, 2, or 3 Rs a and the other variables are as defined in the present application.

[0040] In some embodiments of the present application, each of the above Rs a is independently F, Cl, Br, I, or OH, and the other variables are as defined in the present application.

[0041] In some embodiments of the present application, each of the above Rs a is independently F or OH, and the other variables are as defined in the present application.

[0042] In some embodiments of the present application, each of the above R1s is independently H, F, Cl, Br, I, CN, -CH3, -CH2CH3, or -OCH3, wherein the -CH3 or -CH2CH3 is each independently optionally substituted with 1, 2, or 3 Fs or OHs, and the other variables are as defined in the present application.

[0043] In some embodiments of the present application, each of the above R1s is independently H, F, Cl, Br, I, CN, -CH3, -CF3, -CH2CH3, -CH(OH)CH3, or -OCH3, and the other variables are as defined in the present application.

[0044] In some embodiments of the present application, each of the above R1s is independently H, CN, -CH3, -CF3, -CH(OH)CH3, or -OCH3, and the other variables are as defined in the present application.

[0045] In some embodiments of the present application, each of the above R1 is independently H, F, Cl, Br, I, CN, -CH3, -CF3, -CH2CH3 or -OCH3, and other variables are as defined in the present application.

[0046] In some embodiments of the present application, each of the above R1 is independently H, CN, -CH3, -CF3, -CH2CH3 or -OCH3, and other variables are as defined in the present application.

[0047] In some embodiments of the present application, each of the above R2 is independently F, Cl, Br, I or CN, and other variables are as defined in the present application.

[0048] In some embodiments of the present application, each of the above R2 is independently CN, and other variables are as defined in the present application.

[0049] In still some other embodiments of the present application, they are any combination of the above variables.

[0050] In some embodiments of the present application, the above 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:

[0051]

[0052] wherein, R1, R2, m or n are as defined in the present application.

[0053] In some embodiments of the present application, the above 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:

[0054]

[0055] wherein, R1 or R2 are as defined in the present application.

[0056] In some embodiments of the present application, the above compound of formula (I') or formula (I) or a pharmaceutically acceptable salt thereof has a structure of formula (I-1)

[0057]

[0058] wherein,

[0059] R1 is as defined in the present application.

[0060] In some embodiments of the present application, the above 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:

[0061]

[0062] Among them, R1 is as defined in the present application.

[0063] On the other hand, the present application also provides a compound of the following formula or a pharmaceutically acceptable salt thereof,

[0064]

[0065] In some embodiments of the present application, the above-mentioned compound or its pharmaceutically acceptable salt is selected from

[0066]

[0067] or a pharmaceutically acceptable salt thereof.

[0068] In yet another aspect, the present application also provides a pharmaceutical composition comprising the above-mentioned compound of the present application or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present application further includes pharmaceutically acceptable excipients.

[0069] In yet another aspect, the present application also provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating JAK1 and / or JAK2-related diseases.

[0070] In yet another aspect, the present application 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.

[0071] In yet another aspect, the present application also provides the above-mentioned compound or a pharmaceutically acceptable salt thereof for treating JAK1 and / or JAK2-related diseases.

[0072] In yet another aspect, the present application also provides a method for treating JAK1 and / or JAK2-related diseases, comprising administering a therapeutically effective amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to a mammal in need of such treatment, preferably a human.

[0073] In the present application, the above-mentioned JAK1 and / or JAK2-related diseases are selected from inflammatory disorders (such as arthritis), etc.

[0074] Technical effects

[0075] The compounds of the present application showed good selective inhibition of JAK1 and / or JAK2 in in vitro activity tests of four kinase subtypes, JAK1, JAK2, JAk3, and TYK2; they all had good oral bioavailability and relatively high exposure in mice, which was beneficial for producing good in vivo pharmacodynamic effects.

[0076] Definitions and explanations

[0077] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indefinite or unclear without a specific definition, but should be understood in its ordinary meaning. When a trade name appears in this application, it is intended to refer to the corresponding product or its active ingredient.

[0078] In the structural units or groups in this application, the dashed line (----) represents a covalent bond.

[0079] When the bond of a substituent cross-links to two atoms on a ring, such a substituent can be bonded to any atom on this ring. For example, the structural unit indicates that substitution can occur at any position of all rings, specifically including but not limited to

[0080] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0081] The term "pharmaceutically acceptable salt" refers to salts of the compounds of this application, prepared from compounds with specific substituents found in this application and relatively non-toxic acids or bases. When a compound of this application contains a relatively acidic functional group, a base addition salt can be obtained by contacting such a compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When a compound of this application contains a relatively basic functional group, an acid addition salt can be obtained by contacting such a compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, where the inorganic acids include, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, where the organic acids include, for example, 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, and methanesulfonic acid and similar acids; also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of this application contain both basic and acidic functional groups and can thus be converted into either base or acid addition salts.

[0082] The pharmaceutically acceptable salts of the present application can be synthesized from the parent compounds containing acid radicals or basic groups by conventional chemical methods. Generally, the preparation method of such salts is to react these compounds in the form of free acids or bases with stoichiometric appropriate bases or acids in water or organic solvents or a mixture of both.

[0083] The compounds of the present application may exist in specific geometric or stereoisomeric forms. The present application contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomer- or diastereomer-enriched mixtures, all of which mixtures are within the scope of the present application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and their mixtures are included within the scope of the present application. For example, those skilled in the art will understand that the compounds of formula (I') of the present application include, but are not limited to, the compounds of formula (I'-A) or formula (I'-B) and mixtures formed in any proportion thereof, the compounds of formula (I) of the present application include, but are not limited to, the compounds of formula (I-A) or formula (I-B) and mixtures formed in any proportion thereof, the compounds of formula (I-1) of the present application include, but are not limited to, the compounds of formula (I-1-A) or formula (I-1-B) and mixtures formed in any proportion thereof, etc.

[0084] Unless otherwise specified, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of each other.

[0085] Unless otherwise specified, the terms "cis-trans isomer" or "geometric isomer" are caused by the inability of double bonds or single bonds of ring carbon atoms to rotate freely.

[0086] Unless otherwise specified, the term "diastereoisomer" refers to stereoisomers that have two or more chiral centers and are not mirror images of each other.

[0087] Unless otherwise specified, "(+)" represents dextrorotation, "(-)" represents levorotation, and "(±)" represents racemic.

[0088] Unless otherwise specified, a solid wedge bond and a dashed wedge bond represent the absolute configuration of a stereocenter, a solid straight bond and a dashed straight bond represent the relative configuration of a stereocenter, and a wavy line represents a solid wedge bond or a dashed wedge bond or a wavy line represents a solid straight bond and a straight dashed line key

[0089] Unless otherwise specified, when a double bond structure is present in a compound, such as a carbon-carbon double bond, a carbon-nitrogen double bond, and a nitrogen-nitrogen double bond, and each atom on the double bond is connected to two different substituents (in the double bond containing a nitrogen atom, a lone pair of electrons on the nitrogen atom is regarded as one of the substituents it is connected to), if the atoms on the double bond in the compound and their substituents are connected by a wavy line it indicates the (Z)-isomer, (E)-isomer, or a mixture of the two isomers of the compound. For example, the following formula (A) indicates that the compound exists in the form of a single isomer of formula (A-1) or formula (A-2) or a mixture of the two isomers of formula (A-1) and formula (A-2); 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 a mixture of the two isomers of formula (B-1) and formula (B-2). 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 a mixture of the two isomers of formula (C-1) and formula (C-2).

[0090]

[0091]

[0092] Unless otherwise specified, the term "tautomer" or "tautomeric form" refers to different functional group isomers being in dynamic equilibrium at room temperature and being able to rapidly interconvert. If tautomers are possible (such as in solution), a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions carried out through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions carried out by the recombination of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between the two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0093] Unless otherwise specified, the terms "enriched in one isomer", "isomer-enriched", "enriched in one enantiomer", or "enantiomer-enriched" mean that the content of one isomer or enantiomer 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 or equal to 99.9%.

[0094] Unless otherwise specified, the terms "isomer excess" or "enantiomer excess" refer 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 isomer or enantiomer excess (ee value) is 80%.

[0095] Optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present application is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, in which the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with a suitable optically active acid or base, and then the diastereomers are resolved by conventional methods well known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which employs a chiral stationary phase and optionally in combination with chemical derivatization (such as formation of a carbamate from an amine).

[0096] The compounds of the present application may contain non-natural proportions of atomic isotopes on one or more atoms constituting the compound. For example, the compound can be labeled with a radioactive isotope, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). Also, for example, deuterium can be used to replace hydrogen to form a deuterated drug. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with the non-deuterated drug, the deuterated drug has advantages such as reducing toxic and side effects, increasing drug stability, enhancing efficacy, and prolonging the biological half-life of the drug. All isotopic compositions of the compounds of the present application, whether radioactive or not, are included within the scope of the present application.

[0097] "Optional" or "optionally" means that the subsequently described event or condition may, but need not, occur, and this description includes both the case where the described event or condition occurs and the case where the described event or condition does not occur.

[0098] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and variants of hydrogen, provided that the valence of the particular atom is normal and the resulting compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on an aromatic group. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary based on what is chemically achievable.

[0099] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0 - 2 R's, the group may optionally be substituted with up to two R's, and each R has independent options in each case. In addition, combinations of substituents and / or their variants are permitted only if such combinations result in a stable compound.

[0100] When the number of a linking group is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0101] When one of the variables is selected from a single bond, it means that the two groups it connects are directly linked. For example, when L in A - L - Z represents a single bond, it means that the structure is actually A - Z.

[0102] When a substituent is absent, it means that the substituent does not exist. For example, when X in A - X is absent, it means that the structure is actually A. When it is not specified which atom of an enumerated substituent is bonded to the group being substituted, such a substituent may be bonded through any of its atoms. For example, a pyridyl group as a substituent may be bonded to the group being substituted through any carbon atom on the pyridine ring.

[0103] The term "alkyl" refers to a hydrocarbon group having the general formula C n H 2n+1 Such alkyl groups can be straight-chain or branched-chain. 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, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl moieties (i.e., alkyl groups) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio groups have the same definition as above.

[0104] Unless otherwise specified, the term "C 1-3 alkyl" is used to denote a straight-chain or branched-chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 alkyl includes C 1-2 and C 2-3 alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine). Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0105] The term "alkoxy" means "alkyl-O-". Unless otherwise specified, the term "C 1-3 alkoxy" denotes those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule through an oxygen atom. The C 1-3 alkoxy includes C 1-2 , C 2-3 , C3, and C2 alkoxy, etc. Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc.

[0106] 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 C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 , and also includes any range within 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 " 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. Similarly, n-membered to n + m-membered means that the number of atoms in the ring is from n to n + m, for example, a 3-12 membered ring includes a 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and also includes any range within n to n + m, for example, a 3-12 membered ring includes a 3-6 membered ring, 3-9 membered ring, 5-6 membered ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, and 6-10 membered ring, etc.

[0107] The term "cycloalkyl" refers to a completely saturated carbocyclic ring that can exist as a monocyclic, bridged or spiro ring. Unless otherwise indicated, the carbocyclic ring is usually a 3- to 10-membered ring. 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, and the like.

[0108] The term "aryl" refers to an aromatic ring group of a fully carbon monocyclic or fused polycyclic having a conjugated π electron system. For example, aryl may have 6-20 carbon atoms, 6-14 carbon atoms or 6-12 carbon atoms. Non-limiting examples of aryl include, but are not limited to, phenyl, naphthyl, anthracenyl, and 1,2,3,4-tetrahydronaphthalene, and the like.

[0109] 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 (e.g., a nucleophilic substitution reaction). For example, representative leaving groups include trifluoromethanesulfonate; chlorine, bromine, iodine; sulfonate groups such as methanesulfonate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonate, and the like; acyloxy groups such as acetoxy, trifluoroacetoxy, and the like.

[0110] The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "mercapto protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to: formyl; acyl groups such as alkanoyl groups (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl groups such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups such as benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like. The term "hydroxy protecting group" refers to a protecting group suitable for preventing side reactions of the hydroxy group. Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl groups (such as acetyl); 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 the like.

[0111] The term "treatment" means administering the compounds or formulations described in the present application to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0112] (i) inhibiting a disease or disease state, i.e., curbing its development;

[0113] (ii) Alleviate a disease or disease state, even if the disease or disease state regresses.

[0114] The term "prevention" means administering the compounds or formulations described in this application to prevent a disease or one or more symptoms associated with the disease, including: preventing the occurrence of a disease or disease state in a mammal, especially when such a mammal is susceptible to the disease state but has not been diagnosed as having the disease state.

[0115] The words "comprise" or "comprising" and their English variants such as "comprises" or "comprising" should be understood in an open, non-exclusive sense, that is, "including but not limited to".

[0116] The compounds of this application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and equivalent substitution methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of this application.

[0117] The term "pharmaceutical composition" refers to a mixture of one or more compounds of this application or their salts and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compounds of this application to an organism.

[0118] The term "pharmaceutically acceptable excipient" refers to those excipients that have no obvious stimulatory effect on an 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.

[0119] The pharmaceutical compositions of this application can be prepared by combining the compounds of this application with suitable pharmaceutically acceptable excipients, and 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.

[0120] Typical routes of administering the compounds of this application or their pharmaceutically acceptable salts or their pharmaceutical compositions include but are not limited to oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

[0121] The pharmaceutical compositions of this application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugarcoating pill methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0122] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, syrups, suspensions, etc. for oral administration to a patient.

[0123] Solid oral compositions can 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 milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or dragee. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.

[0124] The pharmaceutical composition is also suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.

[0125] In all methods of administration of the compounds described herein, the daily dosage is 0.01 to 200 mg / kg body weight, in single or divided doses.

[0126] The structure of the compounds of the present application can be confirmed by conventional methods well known to those skilled in the art. If the present application relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the diffraction intensity data of the cultivated single crystal is collected with a Bruker D8 venture diffractometer, the light source is CuKα radiation, scanning mode: After scanning and collecting the relevant data, the crystal structure is further analyzed by the direct method (Shelxs97), and the absolute configuration can be confirmed.

[0127] In some embodiments, the compounds of the present application can be prepared by the methods of the following routes by those skilled in the art of organic synthesis:

[0128]

[0129] wherein R1 is as defined in the present application.

[0130] The solvents used in this application are commercially available. The following abbreviations are used in this application: aq represents water; eq represents equivalent; DCM represents dichloromethane; PE represents petroleum ether; EA represents ethyl acetate; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; 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; r.t. represents room temperature; THF represents tetrahydrofuran; TFA represents trifluoroacetic acid; Ts represents p-toluenesulfonyl; TBS represents tert-butyldimethylsilyl; PMB represents p-methoxybenzyl; HPMC represents hydroxypropyl methylcellulose; PVP represents polyvinylpyrrolidone; SLS represents sodium lauryl sulfate; SBE-β-CD represents sulfobutylether-β-cyclodextrin; TLC represents thin layer chromatography; DMAP represents 4-dimethylaminopyridine; DEA represents diethylamine; ADDP represents 1,1'-azodicarbonyl dipiperidine; TBAF represents tetrabutylammonium fluoride; TMSI represents trimethylsilyl iodide; DIEA represents N,N-diisopropylethylamine; TsOH represents p-toluenesulfonic acid; EDCI represents 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; HOBt represents 1-hydroxybenzotriazole; BSA represents bovine serum albumin; EDTA represents ethylenediaminetetraacetic acid; BID represents twice a day. Detailed Description of the Embodiments

[0131] This application is described in detail by way of examples, which does not mean any adverse limitation to this application. This application has been described in detail herein, and the specific embodiments thereof have also been disclosed. It will be obvious to those skilled in the art that various changes and improvements can be made to the specific embodiments of this application without departing from the spirit and scope of this application.

[0132] Example 1: Synthesis of Compounds 1A and 1B

[0133]

[0134] Step 1: At 0 °C, (4-methoxyphenyl)methanol (50 g, 361.89 mmol, 45.05 mL, 1 eq) was added to a suspension of sodium hydride (15.92 g, 398.08 mmol, 60% purity, 1.1 eq) in DMF (200 mL). After stirring for 0.5 h, 3-bromoprop-1-yne (59.19 g, 398.08 mmol, 42.89 mL, 1.1 eq) was slowly added to the reaction system. The resulting solution was stirred at 0 °C for 0.5 h and at 25 °C for 16 h. TLC (PE∶EA = 10∶1) showed that the reaction was complete and a new major product was formed. Saturated aqueous ammonium chloride solution (50 mL) was added to the reaction mixture. The aqueous phase was extracted with ethyl acetate (500 mL × 3). The combined organic phases were washed successively with water (200 mL × 2) and brine (200 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by column chromatography (SiO2, PE∶EA = 1∶0 - 5∶1) to give compound 1-2. MS (ESI) calcd for C 11 H 12 O2176, found 177 [M+H] + 。

[0135] Step 2: At 25 °C, compound 1-2 (34.14 g, 193.74 mmol, 25.00 mL, 1.1 eq), copper(I) 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) were added to a solution of 5-bromo-2-iodopyridine (50 g, 176.12 mmol, 1 eq) in THF (500 mL). The reaction system was purged with nitrogen three times. The resulting solution was stirred at 25 °C for 16 h. TLC (PE∶EA = 10∶1) showed that the reaction was complete and a new major product was formed. The reaction mixture was filtered through diatomaceous earth to obtain a filtrate, which was concentrated under reduced pressure. The residue was dissolved in 800 mL of ethyl acetate and then washed successively with 300 mL of water and 300 mL of brine. Then the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by column chromatography (SiO2, PE∶EA = 1∶0 - 30∶1) to give compound 1-3. 11H 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) calculated for C 16 H 14 BrNO2 332, found 334. MS (ESI) calculated for C 16 H 14 BrNO2 331, 333, found 331 M] + , 334 M+H] + .

[0136] Step 3: Dissolve ammonium 2,4,6-trimethylbenzenesulfonate (972 mg, 4.52 mmol, 1.5 eq) in DCM (15 mL) dried with anhydrous Na2SO4, then add compound 1-3 (1 g, 3.01 mmol, 1 eq) to the above mixture at 0 °C and stir at 25 °C for 16 h. TLC (PE∶EA = 2∶1) showed a small amount of the reaction raw material remaining and a new main product formed. Then, with stirring at 0 °C, slowly add 32 mL of tert-butyl methyl ether to the system, and a large amount of off-white solid slowly precipitated. Filter and dry to obtain compound 1-4. MS (ESI) calculated for C 16 H 16 BrN2O2 348, found 348 [M] + .

[0137] 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, 18.27 mmol, 1 eq) in DMF (160 mL) at 25 °C, and stir the resulting solution at 40 °C for 16 h. LCMS showed that the raw material reacted completely and the product was formed. The reaction solution was filtered through diatomaceous earth to obtain a filtrate. After concentration under reduced pressure, the residue was dissolved in 200 mL of ethyl acetate, then washed successively with 100 mL of water and 100 mL of brine, and then the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE∶EA = 1∶0 - 5∶1) to obtain compound 1-5. 11H 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) Calcd for C 16 H 15 BrN2O2347, Found 348.8 [M+H] + .

[0138] Step 5: To a mixture of compound 1-5 (4.7 g, 13.54 mmol, 1 eq), tert-butyl carbamate (1.9 g, 16.22 mmol, 1.2 eq) in isopentanol (15 mL) and water (15 mL) at 25 °C, potassium hydroxide (1.63 g, 29.05 mmol, 2.15 eq), 5-(di-tert-butylphosphino)-1,3,5-triphenyl-1H-[1,4]diazepine (783.26 mg, 1.55 mmol, 0.1 eq) and tris(dibenzylideneacetone)dipalladium(0) (619.79 mg, 676.83 μmol, 0.05 eq) were added successively. The reaction system was purged with nitrogen three times. The resulting solution was stirred at 100 °C for 2 h. LCMS showed that the raw materials were completely reacted and the product was formed. The reaction solution was filtered through diatomaceous earth to obtain a filtrate. The filter cake was washed with 100 mL of ethyl acetate. The combined organic phases were washed successively with 100 mL of water and 100 mL of brine, then the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE∶EA = 1∶0 - 20∶1) to obtain compound 1-6. MS (ESI) Calcd for C 21 H 25 N3O4383, Found 384 [M+H] + .

[0139] Step 6: To a solution of compound 1-6 (4 g, 40.43 mmol, 1 eq) in EtOH (60 mL) under nitrogen protection at 25 °C, platinum dioxide (933.33 mg, 4.11 mmol, 0.1 eq) was added. The reaction system was purged with H2 three times. The resulting solution was stirred at 70 °C under H2 (3 MPa) for 72 h. LCMS showed that the raw materials were completely reacted and the product was formed. The reaction solution was filtered through diatomaceous earth to obtain a filtrate, which was concentrated under reduced pressure to obtain compound 1-7. MS (ESI) Calcd for C 21 H 29 N3O4387, Found 388 [M+H] + .

[0140] 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. The resulting solution was stirred at 25 °C for 2 hours. LCMS showed that the raw material had completely reacted and the product was formed. After concentration under reduced pressure, compound 1-8 was obtained. MS (ESI) calculated value for C8H 13 N3O 167, found 168 [M+H] + .

[0141] Step 8: Add p-toluenesulfonyl chloride (27.49 g, 144.19 mmol, 1.1 eq), DMAP (1.6 g, 13.11 mmol, 0.1 eq) and triethylamine (19.9 g, 196.66 mmol, 27.37 mL) to a solution of compound 1-9 (20 g, 131.08 mmol, 1 eq) in DCM (50 mL) at 25 °C. The resulting solution was stirred at 25 °C for 16 hours. LCMS showed that the raw material had completely reacted. The solvent was removed under reduced pressure, saturated NaHCO3 solution (50 mL) was added, filtered, the filter cake was washed with water and dried to obtain product 1-10. MS (ESI) calculated value for C 14 H 11 N2ClSO2 306, found 307 [M+H] + .

[0142] Step 9: At -5 °C, add a solution of tetrabutylammonium nitrate (29.78 g, 97.81 mmol, 3 eq) in dichloromethane (50 mL) dropwise to a solution of compound 1-10 (10 g, 32.60 mmol, 1 eq) in DCM (50 mL), and then slowly add trifluoroacetic anhydride (20.54 g, 97.79 mmol, 13.60 mL, 3 eq). The resulting solution was stirred at -5 °C for 30 min, then transferred to 25 °C and stirred for 16 h. LCMS showed that the raw material had completely reacted. Extracted with ethyl acetate (500 mL * 3), the combined organic phases were washed successively with water (200 mL * 2) and brine (200 mL * 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Recrystallized from dichloromethane to obtain product 1-11. MS (ESI) calculated value for C 14 H 10 N3ClSO4 351, found 352 [M+H] + .

[0143] Step 10: At 25 °C, add N,N-diisopropylethylamine (15.43 g, 119.40 mmol, 20.8 mL, 10 eq) 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 isopropanol (50 mL). The resulting solution was stirred at 90 °C for 16 h. LCMS showed that the raw materials reacted completely and the product was formed. The reaction solution was concentrated by rotary evaporation, water (500 mL) was added, and the aqueous phase was extracted with ethyl acetate (500 mL × 3). The combined organic phases were washed successively with water (200 mL × 2) and brine (200 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by column chromatography (SiO2, DCM∶MeOH = 100∶1 to 50∶1) to obtain Compound 1-12. MS (ESI) calculated value for C 22 H 22 N6O5S 482, found 483 [M+H] + 。

[0144] Step 11: At 25 °C under nitrogen, add palladium on carbon (0.1 g, 10%) to a solution of Compound 1-12 in methanol (20 mL). The mixture was purged with hydrogen three times, and the resulting solution was stirred at 25 °C for 16 h. LCMS showed that the raw materials reacted completely and the product was formed. The reaction solution was filtered through diatomaceous earth to obtain a filtrate, which was concentrated under reduced pressure to obtain Compound 1-13. MS (ESI) calculated value for C 22 H 24 N6O3S452, found 453 [M+H] + 。

[0145] Step 12: Dissolve Compound 1-13 (2 g, 4.42 mmol, 1 eq) in formic acid (10 mL). The resulting solution was stirred at 110 °C for 16 h. LCMS showed that the raw materials reacted completely and the product was formed. The reaction solution was concentrated by rotary evaporation to obtain Compound 1-14. MS (ESI) calculated value for C 24 H 22 N6O4S 490, found 491 [M+H] + 。

[0146] Step 13: At 25 °C, add 10% aqueous sodium hydroxide solution (piece10 mL) dropwise to a solution of Compound 1-14 (1.50 g, 3.06 mmol, 1 eq) in methanol (10 mL). The resulting solution was stirred at 25 °C for 4 h. LCMS showed that the raw materials reacted completely and the product was formed. The reaction solution was neutralized with 10% dilute hydrochloric acid, and the aqueous phase was extracted with dichloromethane (100 mL × 3). The combined organic phases were washed with saturated brine (100 mL × 1) and concentrated by rotary evaporation to obtain Compound 1-15. MS (ESI) calculated value for C 16 H16 N6O 308, measured value 309 [M+H] + 。

[0147] Step 14: At 25 °C, manganese dioxide (2.83 g, 32.6 mmol, 10 eq) was added to a mixed solvent of DCM (20 mL) and MeOH (2 mL) of compound 1-15 (1 g, 3.24 mmol, 1 eq). The resulting solution was stirred at 65 °C for 16 hours. LCMS showed that the raw material had completely reacted and the product was formed. The reaction solution was filtered through diatomaceous earth to obtain a filtrate, which was concentrated under reduced pressure to obtain compound 1-16. MS (ESI) calculated value C 16 H 14 N6O 306, measured value 307 [M+H] + 。

[0148] Step 15: At 25 °C, hydroxylamine hydrochloride (106.99 mg, 1.66 mmol, 1.2 eq) and sodium acetate (126.29 mg, 1.54 mmol, 1.2 eq) were added to a methanol (15 mL) solution of compound 1-16 (0.39 g, 1.27 mmol, 1 eq). The resulting solution was stirred at 25 °C for 0.5 hour. LCMS showed that the raw material had completely reacted and the product was formed. The reaction solution was concentrated under reduced pressure to obtain a residue, which was diluted with 25 mL of saturated brine and extracted with THF (25 mL * 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1-17. MS (ESI) calculated value C 16 H 15 N7O 321, measured value 322 [M+H] + 。

[0149] Step 16: At 25 °C, thiocarbonyl diimidazole (388.2 mg, 2.18 mmol, 2 eq) was added to a THF (15 mL) solution of compound 1-17 (0.35 g, 1.09 mmol, 1 eq). The resulting solution was stirred at 25 °C for 16 hours. LCMS showed that the raw material had completely reacted and the product was formed. Water (50 mL) was added to the reaction solution, and the aqueous phase was extracted with dichloromethane (100 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, DCM∶MeOH = 50∶0 to 5∶1) to obtain compound 1-18. 11H NMR (400 MHz, DMSO-d6) 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 N7303, found 304 [M+H] + 。

[0150] Step 17: Compound 1-18 was subjected to chiral resolution (chiral column: Chiralcel OJ-350×4.6 mm I.D., 3 μm; mobile phase: phase A was supercritical CO2, phase B was MeOH (0.05% DEA); gradient: the content of B in A was from 5% to 40%; flow rate: 3 mL / min; wavelength: 220 nm; column temperature: 35 °C; back pressure: 100 Bar) to obtain compound 1A (retention time: 0.917 min) and compound 1B (retention time: 2.790 min). Compound 1A: 1 1H NMR (400 MHz, DMSO-d6) 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 N7303, found 304 [M+H] + 。

[0151] Example 2: Synthesis of Compounds 2A and 2B

[0152]

[0153] Step 1: Compound 1-13 (, 4.40 mmol, 1 eq) was dissolved in acetic acid (20 mL), and the resulting solution was stirred at 120 °C for 15 h. LCMS showed that the raw material had completely reacted and the product had formed. The reaction solution was concentrated to dryness to obtain compound 2-1. MS (ESI) calculated for C 26 H 26 N6O4S 518, found 519 [M+H] + 。

[0154] Step 2: A 10% aqueous sodium hydroxide solution (10 mL) was added dropwise to a solution of Compound 2-1 (1.50 g, 2.89 mmol, 1 eq) in methanol (10 mL) at 25 °C. The resulting solution was stirred at 25 °C for 4 hours. LCMS showed that the raw material had completely reacted and the product was formed. The reaction solution was neutralized with 10% dilute hydrochloric acid, and the aqueous phase was extracted with dichloromethane (100 mL * 3). The combined organic phases were washed with saturated brine (100 mL * 1) and concentrated in vacuo to obtain Compound 2-2. MS (ESI) calculated value for C 17 H 18 N6O 322, found 323 [M+H] + 。

[0155] Step 3: Manganese dioxide (2.7 g, 31.0 mmol, 10 eq) was added to a mixed solvent of Compound 2-2 (1 g, 3.1 mmol, 1 eq) in DCM (20 mL) and MeOH (2 mL) at 25 °C. The resulting solution was stirred at 65 °C for 16 hours. LCMS showed that the raw material had completely reacted and the product was formed. The reaction solution was filtered through diatomaceous earth to obtain a filtrate, which was concentrated under reduced pressure to obtain Compound 2-3. MS (ESI) calculated value for C 17 H[[ID=|12]] 16 N6O 320, found 321 [M+H] + 。

[0156] Step 4: Hydroxylamine hydrochloride (119.3 mg, 1.54 mmol, 1.1 eq) and sodium acetate (192.1 mg, 2.34 mmol, 1.5 eq) were added to a solution of Compound 2-3 (0.5 g, 1.56 mmol, 1 eq) in methanol (50 mL) at 25 °C. The resulting solution was stirred at 25 °C for 0.5 hour. LCMS showed that the raw material had completely reacted and the product was formed. The reaction solution was concentrated under reduced pressure to obtain a residue, which was diluted with 25 mL of saturated brine and extracted with THF (25 mL * 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound 2-4. MS (ESI) calculated value for C 17 H 17 N7O335, found 336 [M+H] + 。

[0157] Step 5: To a solution of compound 2-4 (0.35 g, 1.04 mmol, 1 eq) in THF (15 mL) at 25 °C was added thiocarbonyl diimidazole (371.9 mg, 2.09 mmol, 2 eq). The resulting solution was stirred at 25 °C for 16 h. LCMS showed that the raw material had completely reacted and the product was formed. Water (50 mL) was added to the reaction solution. The aqueous phase was extracted with dichloromethane (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by preparative HPLC (column: Phenomenex Gemini-NX 80*40 mm*3 μm; mobile phase:

[0158] [water (0.05% NH₃·H₂O + 10 mM NH₄HCO₃)-ACN]; ACN: 17% - 37%, 8 min), to obtain compound 2-5. 1 ¹H NMR (400 MHz, DMSO-d₆) 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 7317, found 318 [M + H] + .

[0159] Step 6: Compound 2-5 was subjected to chiral resolution (chiral column: Chiralcel OJ-350×4.6 mm I.D., 3 μm; mobile phase: phase A was supercritical CO₂, phase B was MeOH (0.05% DEA); gradient: the content of B in A was from 5% to 40%; flow rate: 3 mL / min; wavelength: 220 nm; column temperature: 35 °C; back pressure: 100 Bar) to obtain compound 2A (retention time: 3.198 min) and compound 2B (retention time: 3.947 min).

[0160] Example 3: Synthesis of Compounds 3A and 3B

[0161]

[0162]

[0163] 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 had completely reacted and the product was formed. The reaction solution was concentrated in vacuo to obtain Compound 3-1. MS (ESI) calculated value for C 26 H 20 F6N6O4S 626, found 627 [M+H] + 。

[0164] Step 2: A 10% aqueous sodium hydroxide solution (10 mL) was added dropwise to a solution of Compound 3-1 (1.50 g, 2.39 mmol, 1 eq) in methanol (10 mL) at 25 °C. The resulting solution was stirred at 25 °C for 4 h. LCMS showed that the raw material had completely reacted and the product was formed. The reaction solution was neutralized with 10% dilute hydrochloric acid, and the aqueous phase was extracted with dichloromethane (100 mL * 3). The combined organic phases were washed with saturated brine (100 mL * 1) and concentrated in vacuo to obtain Compound 3-2. MS (ESI) calculated value for C 17 H 15 F3N6O 376, found 377 [M+H] + 。

[0165] Step 3: Manganese dioxide (2.3 g, 27.0 mmol, 10 eq) was added to a mixed solvent of Compound 3-2 (1 g, 2.7 mmol, 1 eq) in DCM (20 mL) and MeOH (2 mL) at 25 °C. The resulting solution was stirred at 65 °C for 16 h. LCMS showed that the raw material had completely reacted and the product was formed. The reaction solution was filtered through diatomaceous earth to obtain a filtrate, which was concentrated under reduced pressure to obtain Compound 3-3. MS (ESI) calculated value for C 17 H 13 F3N6O 374, found 375 [M+H] + 。

[0166] Step 4: Hydroxylamine hydrochloride (111.4 mg, 1.60 mmol, 1.1 eq) and sodium acetate (131.5 mg, 1.60 mmol, 1.5 eq) were added to a solution of Compound 3-3 (0.5 g, 1.34 mmol, 1 eq) in methanol (50 mL) at 25 °C. The resulting solution was stirred at 25 °C for 0.5 h. LCMS showed that the raw material had completely reacted and the product was formed. The reaction solution was concentrated under reduced pressure to obtain a residue, which was diluted with 25 mL of saturated brine and extracted with THF (25 mL * 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound 3-4. MS (ESI) calculated value for C 17 H 14 F3N7O 389, found 390 [M+H] + 。

[0167] Step 5: To a solution of compound 3-4 (0.35 g, 0.89 mmol, 1 eq) in THF (15 mL) at 25 °C was added thiocarbonyl diimidazole (320 mg, 1.80 mmol, 2 eq). The resulting solution was stirred at 25 °C for 16 h. LCMS showed that the raw material had completely reacted and the product was formed. Water (50 mL) was added to the reaction solution, and the aqueous phase was extracted with dichloromethane (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by column chromatography (SiO2, DCM∶MeOH = 50∶0 to 5∶1) to obtain compound 3-5. MS(ESI) calculated value for C 17 H 12 F3N7O 371, found 372 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) 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 F3N7 371, found 372 [M+H] + 。

[0168] Step 6: Compound 3-5 was subjected to chiral resolution (chiral column: Chiralcel OJ-350×4.6 mm I.D., 3 μm; mobile phase: phase A was supercritical CO2, phase B was MeOH (0.05% DEA); gradient: the content of B in A was from 5% to 40%; flow rate: 3 mL / min; wavelength: 220 nm; column temperature: 35 °C; back pressure: 100 Bar) to obtain compound 3A (retention time: 1.166 min) and compound 3B (retention time: 1.339 min).

[0169] Example 4: Synthesis of Compound 4

[0170]

[0171] Step 1: Under nitrogen protection at -78 °C, a solution of n-butyllithium in hexane (2.5 M, 427.54 mL) was added dropwise to a solution of tert-butyldimethyl(2-propynyloxy)silane (200 g, 1174.24 mmol) in tetrahydrofuran (2 L). The reaction mixture 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 mixture at -78 °C. The reaction mixture was reacted at -78 °C for 3 hours. TLC (PE∶EA = 3∶1) showed that the reaction was complete. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (2 L) and water (1 L), extracted with EA (2 L * 3), the combined reaction mixture was washed with saturated brine (2 L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 4-2. 1 H NMR (400 MHz, CDCl3) 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).

[0172] Step 2: Under an ice bath, hydrazine hydrate (34.71 g, 1.03 mol, 98%) was added to a solution of compound 4-2 (400 g, 935.44 mmol) in DMF (3 L). The reaction was carried out at 25 °C for 2 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with water (10 L), extracted with EA (2 L * 2), the combined reaction mixture was washed with saturated brine (2 L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 4-3. MS (ESI) calculated value C 21 H 39 N3O5Si 441, found 442 [M+H] + 。

[0173] Step 3: Under ice bath conditions, NaBH4 (77.71 g, 2.05 mol) was added portionwise to a solution of compound 4-3 (432 g, 978.18 mmol) in THF (3 L). Then, methanol (0.6 L) was slowly added dropwise, and the reaction mixture was stirred at 25 °C for 12 h. LC-MS showed that the reaction was complete. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (300 mL) under ice bath conditions, then diluted with water (2 L), extracted with EA (2 L×2), the combined reaction mixture was washed with saturated brine (2 L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Compound 4-4 was obtained by column chromatography (SiO2, DCM∶MeOH = 50∶1 to 20∶1). MS (ESI) calculated value for C 19 H 37 N3O4Si 399, found 400 [M+H] + .

[0174] Step 4: Under ice bath conditions, tributylphosphine (340.24 g, 1.68 mol) was added to a solution of compound 4-4 (336 g, 840.84 mmol) in tetrahydrofuran (4 L). The reaction mixture was stirred at ice bath temperature for 30 min, and then ADDP (424.31 g, 1.68 mol) was added to the reaction mixture. The reaction mixture was stirred at 20 °C for 12 h. LC-MS showed that the reaction was complete. The reaction mixture was diluted with water (2 L), extracted with EA (2 L×2), the combined reaction mixture was washed with saturated brine (1.5 L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Compound 4-5 was obtained by column chromatography (SiO2, PE∶EA = 20∶1 to 2∶1). MS (ESI) calculated value for C 19 H 35 N3O3Si 381, found 382 [M+H] + .

[0175] Step 5: At room temperature, TBAF (1 M, 1.02 L, 1.02 mol) was added to a solution of compound 4-5 (390 g, 1.02 mol) in tetrahydrofuran (1 L). The reaction was carried out at 20 °C for 1.5 h. LC-MS showed that the reaction was complete. The reaction mixture was diluted with water (1 L), adjusted to pH = 8 with saturated aqueous NaHCO3 solution, extracted with EA (1 L×3), the combined reaction mixture was washed with saturated brine (1 L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Then, the concentrated solution was dissolved in ethyl acetate (1 L), and HCl / EtOAc (4 M, 200 mL) was slowly added dropwise to this solution. The mixture was stirred for 1 h, and a white solid was formed. The solid was filtered to obtain compound 4-6. MS (ESI) calculated value for C 13 H 21 N3O3 267, found 268 [M+H] +。

[0176] Step 6: To a solution of compound 4-6 (11.5 g, 43.02 mmol) in DCM (150 mL) and MeOH (15 mL), add manganese dioxide (37.40 g, 430.19 mmol). Replace the gas with nitrogen three times, and then stir at 65 °C for 12 hours. LC-MS shows that the reaction is complete. Filter the reaction solution and concentrate to obtain compound 4-7. MS (ESI) calculated value for C 13 H 19 N3O3 265, found 266 [M+H] + 。

[0177] Step 7: To a solution of compound 4-7 (11 g, 41.46 mmol) in THF (150 mL), add NH3.H2O (51.89 g, 414.61 mmol, 57.03 mL, 28% purity) and I2 (31.57 g, 124.38 mmol). Replace the gas with nitrogen three times, and then stir at 25 °C for 12 hours. LC-MS shows that the reaction is complete. Quench the reaction by adding saturated aqueous sodium sulfite solution, dilute with 20 mL of water, and then extract with ethyl acetate (50 mL × 2). Combine the organic phases, wash with saturated brine (30 mL), dry over sodium sulfate, filter, and concentrate to obtain the crude product. The crude product is purified by column chromatography (SiO2, PE∶EA = 3∶1) to obtain compound 4-8. MS (ESI) calculated value for C 13 H 18 N4O2 262, found 263 [M+H] + 。

[0178] Step 8: At 0 °C, add TMSI (10.91 g, 54.52 mmol, 7.42 mL) to a solution of compound 4-8 (11 g, 41.94 mmol) in DCM (150 mL). Stir the reaction solution at 0 °C for 1 hour. TLC shows that the starting material has disappeared and a new spot has formed. Concentrate the reaction solution under reduced pressure to obtain the hydroiodide salt of compound 4-9. MS (ESI) calculated value for C8H 10 N4 162, found 163 [M+H] + .

[0179] Step 9: To the isopropanol (200 mL) solution of dissolved Compound 4-9 (12 g, 41.36 mmol, hydroiodide) and Compound 1-11 (11.64 g, 33.09 mmol), add DIEA (26.73 g, 206.82 mmol, 36.0 mL). Replace the reaction solution with nitrogen three times, and then stir at 90 °C for 12 hours. LC-MS shows that the reaction is complete. Cool the reaction solution, add H2O (200 mL), filter, and dry to obtain Compound 4-10. MS (ESI) calculated value C 22 H 19 N7SO4477, measured value 478 [M+H] + 。

[0180] Step 10: To the solution of Compound 4-10 (16 g, 33.51 mmol) in THF (200 mL) and H2O (50 mL), add Fe (9.36 g, 167.54 mmol) and NH4C1 (12.55 g, 234.56 mmol). Replace with nitrogen three times and stir at 100 °C for 1 hour. LCMS shows that the reaction is complete. Filter the reaction solution, dilute the filtrate with H2O (100 mL), and then extract with ethyl acetate (150 mL * 2). Wash the filter cake with DCM∶MeOH (20∶1, 100 mL * 3). Combine the extract and the filtrate, dry over sodium sulfate, filter, and concentrate to obtain Compound 4-11. MS (ESI) calculated value C 22 H 21 N7SO2447, measured value 448 [M+H] + 。

[0181] Step 11: To the AcOH (5 mL) solution of dissolved Compound 4-11 (150 mg, 335.19 μmol) and TsOH (5.8 mg, 33.52 μmol), add tetramethyl orthocarbonate (456.4 mg, 3.35 mmol). Replace the reaction solution with nitrogen three times and stir at 50 °C for 2 hours. LCMS shows that the reaction is complete. Concentrate the reaction solution to remove the solvent, add H2O (5 mL) for dilution, and extract with dichloromethane (5 mL * 3). Combine the organic phases, wash with saturated brine, dry over sodium sulfate, filter, and concentrate to obtain 4-12. MS (ESI) calculated value C 24 H 21 N7O3S 487, measured value 488 [M+H] + 。

[0182] Step 12: Dissolve compound 4-12 (180 mg, 369.21 μmol) in THF (10 mL), then add TBAF (1 M, 738.4 μL). Replace the reaction solution with nitrogen three times and stir at 70 °C for 12 hours. LC-MS shows that the reaction is complete. Concentrate the reaction solution, then dilute it with aqueous NaHCO3 solution (15 mL), extract with DCM (15 mL * 3), combine the organic phases, dry over sodium sulfate, filter, and concentrate to obtain the crude product. The crude product is separated by preparative HPLC (Phenomenex Gemini NX 80 * 30 mm * μm; mobile phase: [water (10 mM H4HCO3)-ACN]; B (ACN)%: 20%-50%, 9 min) to obtain compound 4. MS (ESI) calculated value C 17 H 15 N7O 333, found 334 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ = 11.72 (br s, 1H), 8.38 (br s, 1H), 7.42 (br s, 1H), 6.85 (br s, 1H), 6.71 (brs, 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).

[0183] Example 5: Synthesis of Compound 5

[0184]

[0185] Step 1: Dissolve compound 4-11 (250 mg, 558.64 μmol, 1 eq), (2R)-2-hydroxypropanoic acid (221.41 mg, 1.68 mmol), EDCI (321.28 mg, 1.68 mmol) and HOBt (226.46 mg, 1.68 mmol) in THF (10 mL), then add DIEA (361.00 mg, 2.79 mmol, 486.53 μL). Replace the reaction solution with nitrogen three times, then stir at 20 °C for 12 hours. LC-MS shows that the reaction is complete. Dilute the reaction solution with H2O (15 mL) and extract with EA (15 mL * 3). Combine the organic phases, wash with saturated brine, dry over sodium sulfate, filter and concentrate to obtain compound 5-1. MS (ESI) calculated value C 27 H 27 N7O5S 561, found 562 [M+H] + 。

[0186] Step 2: Dissolve compound 5-1 in AcOH (10 mL) and stir at 120 °C for 0.5 h. LCMS shows that the reaction is complete. Dilute the reaction solution with water (15 mL) and extract with ethyl acetate (15 mL * 3). Combine the organic phases, wash with saturated brine, dry over sodium sulfate, filter, and concentrate to obtain compound 5-2. MS (ESI) calcd for C 27 H 25 N7O4S 543, found 544 [M+H] + 。

[0187] Step 3: Dissolve compound 5-2 (0.3 g, 551.88 μmol) in MeOH (12 mL) and THF (3 mL), then add K2CO3 (152.55 mg, 1.10 mmol). Flush the reaction solution with nitrogen three times and then stir at 25 °C for 10 min. LC-MS shows that the reaction is complete. Concentrate the reaction solution under reduced pressure to remove the solvent, dilute with H2O (10 mL), then extract with DCM∶MeOH (10∶1, 10 mL * 3). Combine the organic phases, wash with saturated brine, dry over sodium sulfate, filter, and concentrate to obtain compound 5-3. MS (ESI) calcd for C 25 H 23 N7O3S 501, found 502 [M+H] + 。

[0188] Step 4: Dissolve compound 5-3 (150 mg, 299.07 μmol) in THF (5 mL), then add TBAF (1 M, 598.1 μL). Flush the reaction solution with nitrogen three times and stir at 70 °C for 12 h. LC-MS shows that the reaction is complete. Concentrate the reaction solution, then dilute with aqueous NaHCO3 (15 mL) and extract with DCM (15 mL * 3). Combine the organic phases, dry over sodium sulfate, filter, and concentrate to obtain the crude product. The crude product is separated by preparative HPLC (Phenomenex Gemini NX 80*30mm*3μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; ACN%: 15%-45%, 9 min) to obtain compound 5. MS (ESI) calcd for C 18 H 17 N7O 347, found 348 [M+H] + 。 11H NMR (400 MHz, CD3OD) 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).

[0189] Example 6: Synthesis of Compound 6

[0190]

[0191] Step 1: Under nitrogen protection at -78 °C, a solution of n-butyllithium in hexane (2.5 M, 85.5 mL) was added dropwise to a solution of tert-butyldimethyl(2-propynyloxy)silane (38.07 g, 223.49 mmol, 45.3 mL) in tetrahydrofuran (500 mL). The reaction mixture 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 mixture at -78 °C. The reaction mixture was reacted at -78 °C for 3 hours. TLC (PE∶EA = 3∶1) showed that the reaction was complete. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (500 mL) and water (0.5 L), extracted with EA (0.5 L * 3), and the combined reaction mixture was washed with saturated brine (1 L), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound 6-2.

[0192] Step 2: At 0 °C, hydrazine hydrate (7.81 g, 231.52 mmol, 8.81 mL, 95% purity) was added to a solution of Compound 6-2 (90 g, 210.47 mmol) in DMF (700 mL). The reaction was carried out at 25 °C for 2 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with water (1 L), extracted with EA (1 L * 2), and the combined reaction mixture was washed with H2O (1 L * 3) and saturated brine (1 L), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound 6-3. MS (ESI) calculated value for C 21 H 39 N3O5Si 441, found 442 [M+H] + .

[0193] Step 3: At 0 °C, NaBH4 (16.01 g, 423.20 mmol) was added portionwise to a solution of compound 6-3 (432 g, 978.18 mmol) in THF (800 mL). Then, methanol (200 mL) was slowly added dropwise. The reaction mixture was stirred at 25 °C for 12 h, and LC-MS showed that the reaction was complete. The reaction mixture was quenched with saturated aqueous ammonium chloride (300 mL) under an ice bath condition, then diluted with water (1 L), 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, and purified by column chromatography (SiO2, DCM∶MeOH = 50∶1 to 20∶1) to obtain compound 6-4. MS (ESI) calculated value for C 19 H 37 N3O4Si 399, found 400 [M+H] + 。

[0194] Step 4: At 0 °C, tributylphosphine (68.86 g, 340.34 mmol, 84.0 mL) was added to a solution of compound 6-4 (68 g, 170.17 mmol) in tetrahydrofuran (1.4 L). The reaction mixture was stirred at 0 °C for 30 min, and then ADDP (85.87 g, 340.34 mmol) was added to the reaction mixture. The reaction mixture was stirred at 20 °C for 12 h. LC-MS showed that the reaction was complete. The reaction mixture was filtered, the filtrate was diluted with water (1 L), extracted with EA (1 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 purified by column chromatography (SiO2, PE∶EA = 20∶1 to 2∶1) to obtain compound 6-5. MS (ESI) calculated value for C 19 H 35 N3O3Si 381, found 382 [M+H] + 。

[0195] Step 5: At room temperature, TBAF (1 M, 230.62 mL) was added to a solution of compound 6-5 (80 g, 209.65 mmol) in tetrahydrofuran (800 mL). The reaction was carried out at 20 °C for 0.5 h. LC-MS showed that the reaction was complete. The reaction mixture was diluted with water (1 L), 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 a crude product. The obtained crude product was dissolved in 800 mL of EA, 200 mL of HCl / EA was added, and the mixture was stirred for 1 h to precipitate 28 g of a crude product. The crude product solution was added to 250 mL of water, the pH was adjusted to 8 with sodium bicarbonate, and then extracted with EA (300 mL × 2). The combined organic layers were concentrated to obtain compound 6-6. MS (ESI) calculated value for C 13 H21 N3O3 267, measured value 268 [M+H] + 。

[0196] Step 6: To a solution of compound 6-6 (22 g, 82.30 mmol, 1 eq) in DCM (300 mL) and MeOH (30 mL), add manganese dioxide (71.55 g, 822.97 mmol). Replace the gas with nitrogen three times, then stir at 60 °C for 12 hours. LCMS shows that the reaction is complete. Filter the reaction mixture and concentrate to obtain compound 6-7. MS (ESI) calculated value C 13 H 19 N3O3 265, measured value 266 [M+H] + 。

[0197] Step 7: To a solution of compound 6-7 (6 g, 22.62 mmol) in THF (90 mL), add NH3·H2O (28.31 g, 226.15 mmol, 31.11 mL, 28% purity) and I2 (17.22 g, 67.85 mmol, 13.7 mL). Replace the gas with nitrogen three times, then stir at 20 °C for 12 hours. TLC shows that the reaction is complete. Add saturated aqueous sodium sulfite solution to quench the reaction, add 10 mL of water to dilute, then extract with ethyl acetate (15 mL * 2). Combine the organic phases, wash with saturated brine (15 mL), dry over sodium sulfate, filter, and concentrate to obtain the crude product. The crude product is purified by column chromatography (SiO2, PE∶EA = 3∶1) to obtain compound 6-8. MS (ESI) calculated value C 13 H 18 N4O2 262, measured value 263 [M+H1 + 。

[0198] Step 8: At 0 °C, add TMSI (9.92 g, 49.56 mmol, 6.8 mL) to a solution of compound 6-8 (10 g, 38.12 mmol) in DCM (100 mL). Stir the reaction mixture at 0 °C for 1.5 hours. LCMS shows that the reaction is complete. Add 100 mL of EA to the reaction mixture, and filter to obtain the hydroiodide salt of compound 6-9. MS (ESI) calculated value C8H 10 N4 162, measured value 163 [M+H] + 。

[0199] Step 9: To the isopropanol (140 mL) solution dissolving compound 6-9 (7 g, 24.13 mmol, hydroiodide) and 4-chloro-5-nitro-1-(p-toluenesulfonyl)pyrrolo[2,3-b]pyridine (8.49 g, 24.13 mmol), add DIEA (9.36 g, 72.39 mmol, 12.6 mL). Replace the reaction solution with nitrogen three times, and then stir at 90 °C for 12 hours. LCMS shows that the reaction is complete. Cool the reaction solution, add H2O (100 mL), a large amount of yellow solid precipitates, filter, and dry to obtain compound 6-10. MS (ESI) calculated value C 22 H 19 N7SO4477, measured value 478 [M+H] + 。

[0200] Step 10: To the solution of compound 6-10 (14 g, 29.32 mmol) in THF (168 mL) and H2O (42 mL), add Fe powder (8.19 g, 146.60 mmol) and NH4C1 (10.98 g, 205.24 mmol), and stir at 90 °C for 1 hour. LC-MS shows that the reaction is complete. Filter the reaction solution, dilute the filtrate with H2O (100 mL), and then extract with ethyl acetate (150 mL * 2). Wash the filter cake with DCM∶MeOH (20∶1, 100 mL * 3). Combine the extraction solution and the filtrate, dry over sodium sulfate, filter, and concentrate to obtain compound 6-11. MS (ESI) calculated value C 22 H 21 N7SO2447, measured value 448 [M+H] + 。

[0201] Step 11: To the AcOH (5 mL) solution dissolving compound 6-11 (100 mg, 223.46 μmol) and TsOH (3.85 mg, 22.35 μmol), add tetramethyl orthocarbonate (304.23 mg, 2.23 mmol). Replace the reaction solution with nitrogen three times, and stir at 50 °C for 12 hours. LC-MS shows that the reaction is complete. Concentrate the reaction solution to remove the solvent, add H2O (5 mL) to dilute, and extract with DCM (5 mL * 3). Combine the organic phases, wash with saturated brine (5 mL), dry over sodium sulfate, filter, and concentrate to obtain compound 6-12. MS (ESI) calculated value C 24 H 21 N7O3S 487, measured value 488 [M+H] + 。

[0202] Step 12: Dissolve compound 6-12 (100 mg, 205.11 μmol, 1 eq) in THF (5 mL), then add TBAF (1 M, 410.2 μL). Replace the reaction solution with nitrogen three times and stir at 70 °C for 12 hours. LC-MS shows that the reaction is complete. Concentrate the reaction solution, then dilute it with aqueous NaHCO3 solution (5 mL), extract with DCM (5 mL * 3), combine the organic phases, dry over sodium sulfate, filter, and concentrate to obtain the crude product. The crude product is separated by preparative HPLC (Phenomenex Gemini NX 80 * 30 mm * 3 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B (ACN)%: 20%-50%, 9 min) to obtain compound 6. MS (ESI) calculated value C 17 H 15 N7O 333, found 334 [M + H] + 。 1 H NMR (400 MHz, DMSO-d6) 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).

[0203] Example 7: Synthesis of compound 7

[0204]

[0205] Step 1: Dissolve compound 6-11 (150 mg, 335.19 μmol) and (2R)-2-hydroxypropanoic acid (75.48 mg, 837.97 μmol) in THF (5 mL), 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). Stir the mixed solution at 20 °C for 12 hours. LC-MS shows that the reaction is complete. Add H2O (15 mL) to the reaction solution, extract with ethyl acetate (15 mL * 3), combine the organic phases, wash with saturated brine (15 mL), dry over sodium sulfate, filter, and concentrate to obtain compound 7-1. MS (ESI) calculated value C 25 H 25 N7O4S 519, found 520 [M + H] + 。

[0206] Step 2: Compound 7-1 (200 mg, 384.93 μmol) was dissolved in AcOH (4.20 g, 69.94 mmol, 4 mL) and stirred at 120°C for 3 hours under nitrogen. LC-MS showed that the reaction was complete. The reaction solution was concentrated, then diluted with aqueous NaHCO3 (5 mL), extracted with DCM (5 mL*3), and the organic phases were combined, washed with saturated brine (15 mL), dried over sodium sulfate, filtered, and concentrated to give compound 7-2. MS (ESI) calculated value: C 25 H 23 N7O3S 501, found 502 [M+H] + .

[0207] Step 3: Compound 7-2 (200 mg, 398.76 μmol) was dissolved in THF (5 mL), and then TBAF (1 M, 797.51 μL) was added. The reaction solution was replaced with nitrogen three times and stirred at 70°C for 12 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated, then diluted with NaHCO3 aqueous solution (15 mL), extracted with DCM (15 mL*3), and the organic phases were combined, dried over sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated by preparative HPLC (Phenomenex Gemini NX 80*30mm*3μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B(ACN)%: 17%-47%, 9min) to obtain compound 7. MS (ESI) calculated value C 18 H 17 N7O 347, found 348 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 11.97 (br s, 1H), 8.62 (s, 1H), 7.60-7.34 (m, 1H), 6.92 (s, 1H), 6.31 (brs, 1H), 5.80 (br d, J = 7.0Hz, 1H), 5.63 (br s, 1H), 5.23 (br s, 1H), 4.88-4.64 (m, 2H), 3.24 (br d, J=12.3Hz, 1H), 3.09-2.88 (m, 1H), 2.76-2.62 (m, 1H), 2.28 (br s, 1H), 1.67 (br d, J=6.4Hz, 3H).

[0208] Biological activity test

[0209] Experimental Example 1: In vitro activity test of JAK1, JAK2, JAK3, and Tyk2 kinases

[0210] Experimental Materials

[0211] The recombinant human JAK1, JAK2, JAK3, Tyk2 proteases, main instruments and reagents were all provided by Eurofins in the UK.

[0212] Experimental methods

[0213] Dilution of JAK2, JAK3 and TYK2: 20 mM 3-(N-morpholino)propanesulfonic acid (MOPS), 1 mM EDTA, 0.01% Brij-35, 5% glycerol, 0.1% β-mercaptoethanol, 1 mg / mL BSA; Dilution of JAK1: 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-fold the final assay concentration. The test compounds were serially diluted 3-fold to a final concentration range of 10 μM to 0.001 μM, with 9 concentrations in total, and the DMSO content in the assay reaction was 2%. The working stock solution of the compound was added as the first component of the reaction to the assay wells, and then the remaining components were added according to the protocol detailed below for the assay.

[0214] JAK1(h) enzyme reaction

[0215] JAK1(h) was incubated with 20 mM Tris / HCl pH 7.5, 0.2 mM EDTA, 500 μM MGEEPLYWSFPAKKK, 10 mM magnesium acetate and [γ- 33 p]-ATP (activity and concentration were determined as needed). The reaction was started by adding the Mg / ATP mixture. After incubation at room temperature for 40 minutes, the reaction was terminated by adding 0.5% phosphoric acid. Then 10 μL of the reaction mixture was spotted onto a P30 filter pad and washed three times with 0.425% phosphoric acid and once with methanol within 4 minutes, dried and counted by scintillation.

[0216] JAK2(h) enzyme reaction

[0217] 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 were determined as needed). The reaction was started by adding the Mg / ATP mixture. After incubation at room temperature for 40 minutes, the reaction was terminated by adding 0.5% phosphoric acid. Then 10 μL of the reaction mixture was spotted onto a P30 filter pad and washed three times with 0.425% phosphoric acid and once with methanol within 4 minutes, dried and counted by scintillation.

[0218] JAK3(h) enzyme reaction

[0219] 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 (activity and concentration were adjusted as needed). The reaction was initiated by adding the Mg / ATP mixture. After incubation at room temperature for 40 minutes, the reaction was terminated by adding 0.5% phosphoric acid. Then, 10 μL of the reaction mixture was spotted onto a P30 filter mat and washed three times with 0.425% phosphoric acid and once with methanol within 4 minutes, dried, and counted by scintillation.

[0220] TYK2(h) enzyme reaction

[0221] 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 were adjusted as needed). The reaction was initiated by adding the Mg / ATP mixture. After incubation at room temperature for 40 minutes, the reaction was terminated by adding 0.5% phosphoric acid. Then, 10 μL of the reaction mixture was spotted onto a P30 filter mat and washed three times with 0.425% phosphoric acid and once with methanol within 4 minutes, dried, and counted by scintillation.

[0222] Data analysis

[0223] IC 50 The results were analyzed using XLFIT5 (205 formula) from IDBS, as shown in Table 1.

[0224] Table 1. Results of in vitro screening tests of the compounds of this application

[0225]

[0226] Experimental Example 2: Pharmacokinetic (PK) test

[0227] The test compounds were dissolved to obtain clear solutions [5% DMSO, 95% (12% SBE-β-CD)] and were respectively administered to male Sprague-Dawley (SD) rats (fasted overnight, 7 - 8 weeks old) via tail vein injection and gavage. After administration of the test compounds, blood samples were collected from the mandibular vein at 0.117, 0.333, 1, 2, 4, 7, and 24 hours for the intravenous injection group (1 mg / kg), and at 0.25, 0.5, 1, 2, 4, 8, and 24 hours for the gavage group (5 mg / kg). Plasma was obtained after centrifugation. The plasma drug concentration was determined by LC-MS / MS, using WinNonlin TMVersion 6.3 pharmacokinetic software calculates relevant pharmacokinetic parameters using the non-compartmental model linear logarithmic trapezoidal method. The test results are as follows:

[0228] Table 2-1 PK test results of Compound 1A and 4 in rats

[0229] PK parameters Compound 1A Compound 4 <![CDATA[T 1 / 2 (hr)]]> 1.35 3.65 <![CDATA[C max (nM)]]> 2944 10152 <![CDATA[AUC 0-inf (nM.hr)]]> 8509 67786 Bioavailability (%) 41.8％ 119％

[0230] Note: T 1 / 2 : half-life; C max : peak concentration;

[0231] AUC 0-inf : area under the plasma concentration-time curve from time 0 to extrapolated to infinity.

[0232] Experimental Example 3: In vivo pharmacodynamic study of adjuvant-induced arthritis (AIA) in rats

[0233] Experimental procedure: The adjuvant arthritis model in rats was used to verify the anti-arthritis effect of the compounds of this application. Female Lewis rats weighing 160-180 g were anesthetized with isoflurane, and 0.1 ml of Mycobacterium tuberculosis suspension was injected subcutaneously into the left hind foot. Thirteen days after modeling, the rats were grouped and given the corresponding test compounds. For example, different doses (specific doses are shown in Table 3-2) of test compound 1A were dissolved in a mixed solvent of 【5% DMSO, 95% (12% SBE-β-CD)】 and orally administered to female Lewis rats twice a day (the number of test animals in each dose group was 10). The administration was continued for two weeks. During this period, the status of the rats was observed, the swelling of the foot volume was recorded and scored, and the scoring criteria are shown in Table 3-1.

[0234] Table 3-1. Clinical scoring criteria for arthritis

[0235] Score Clinical symptoms 0 No erythema and swelling 1 Erythema or mild swelling appears near the tarsal bone or in the ankle joint or metatarsal bone, or there is erythema and swelling on one toe 2 Slight erythema and swelling in the ankle joint and metatarsal bone, and there is swelling and erythema on two or more toes 3 Moderate erythema and swelling in the ankle, wrist joints and metatarsal bone 4 Severe swelling and erythema in all of the ankle, wrist joints, metatarsal bone and toes

[0236] Experimental results: The two-dose treatment groups of Compound 1A had a significant alleviating effect on the weight loss trend caused by the disease in animals. Moreover, significant differences were observed in the low- and medium-dose groups (3, 10 mg / kg) compared with the solvent control group from day 20, showing good weight recovery effects. Compound 1A inhibited the increase in arthritis clinical scores and foot volume, and this inhibitory effect was dose-dependent. The effect of Compound 1A at 10 mg / kg was the most obvious (significant differences were observed compared with the solvent control group from day 15). The average arthritis clinical score of this group decreased from the peak of 5.8 points on day 13 to 1.3 points at the end of the experiment on day 27.

[0237] Table 3-2 Inhibition rate of area under the clinical score curve*

[0238]

[0239] *Note: Compared with the solvent control group, P < 0.05 in each group (one-way ANOVA).

[0240] Experimental Example 4: In Vivo Pharmacodynamic Study of Collagen-Induced Arthritis (CIA) in Rats

[0241] Experimental procedure:

[0242] A rat collagen-induced arthritis model was used to verify the anti-arthritis effect of the compounds of this application. Lewis rats were immunized. The first immunization day was recorded as day 0, and the subsequent days were labeled in sequence. After anesthesia with isoflurane, 50 μL of the prepared collagen emulsion (containing 200 μg CII) was injected subcutaneously at the base of the tail (2-3 cm from the tail root). On day 21, the same volume of collagen emulsion was injected at the same site on the tail. The mice in the normal group did not need to be immunized. On the 27th day of modeling, the rats were grouped and given the corresponding test compounds. For example, different doses were given to the rats (the specific doses are shown in Table 4-1. The test compound 4 was dissolved in the mixed solvent of 【0.5% HPMC E5 / 0.5% PVP K30 / 0.2% SLS in water】 and orally administered to female Lewis rats twice a day (the number of test animals in each dose group was 8). The administration was continued for 14 days. During this period, the status of the rats was observed, and the swelling of the foot volume was recorded and scored. The scoring criteria are shown in Table 3-1.

[0243] Experimental results:

[0244] At the doses of 1 and 3 mg / kg BID, compound 4 showed a dose-dependent trend in reducing the clinical score of arthritic rats, with significant differences compared with the solvent control group. By the end of the 14th day of administration, the clinical score of the rats in the 3 mg / kg BID group dropped to zero (Table 4-1). At the same time, the degree of foot volume swelling also showed a dose-dependent trend of decrease, with significant differences compared with the solvent control group by the end of the 14th day of administration. The foot volume swelling of the rats in the 3 mg / kg BID group decreased to 1.28 μL. The body weight of the treatment group also showed a dose-dependent trend of recovery. By the end of the 14th day of administration, the body weight of the 3 mg / kg BID dose group recovered to the normal group level.

[0245] Table 4-1 Main Parameters of In Vivo Pharmacodynamic Study of CIA in Rats*

[0246]

[0247] *Note: Compared with the solvent control group, P < 0.001 in each group (two-way ANOVA). Sequence Listing <110> Chia Tai Tianqing Pharmaceutical Group Co., Ltd. <120> Tricyclic heterocyclic compounds as JAK inhibitors and their applications <130> FL066H2P1 <150> 201911180309.2 <151> 2019-11-27 <150> 202010501267.4 <151> 2020-06-04 <160> 4 <170> PatentIn version 3.5 <210> 1 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> 1 <400> 1 Met Gly Glu Glu Pro Leu Tyr Trp Ser Phe Pro Ala Lys Lys Lys 1 5 10 15 <210> 2 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> 2 <400> 2 Lys Thr Phe Cys Gly Thr Pro Glu Tyr Leu Ala Pro Glu Val Arg Arg 1 5 10 15 Glu Pro Arg Ile Leu Ser Glu Glu Glu Gln Glu Met Phe Arg Asp Phe 20 25 30 Asp Tyr Ile Ala Asp Trp Cys 35 <210> 3 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> 3 <400> 3 Gly Gly Glu Glu Glu Glu Tyr Phe Glu Leu Val Lys Lys Lys Lys 1 5 10 15 <210> 4 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> 4 <400> 4 Gly Gly Met Glu Asp Ile Tyr Phe Glu Phe Met Gly Gly Lys Lys Lys 1 5 10 15

Claims

1. A compound of formula (I’) or a pharmaceutically acceptable salt thereof, wherein, m is 1; n is 1 or 2; Each R1 is independently H, F, Cl, Br, I, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylS-, NH2, C 1-6 alkylNH-, (C 1-6 alkyl)2N-, -COOH or -C(O)OC 1-6 alkyl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylS-, C 1-6 alkylNH-, (C 1-6 alkyl)2N- or -C(O)OC 1-6 alkyl is each independently optionally substituted by 1, 2, 3 or 4 R a substituents; R2 is CN; Each R a is independently H, F, Cl, Br, I, OH, CN or NH2, respectively.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein n is 1.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the structural fragment is 4. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the structural fragment is 5. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein each R1 is independently H, F, Cl, Br, I, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylS-, NH2, C 1-6 alkylNH- or (C 1-6 alkyl)2N-, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylS-, C 1-6 alkylNH- or (C 1-6 alkyl)2N- - is each independently optionally substituted by 1, 2, 3 or 4 R a substituents.

6. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein each R1 is independently H, F, Cl, Br, I, CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylS-, NH2, C 1-3 alkylNH-, (C 1-3 alkyl)2N-, -COOH or -C(O)OC 1-3 alkyl, wherein the C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylS-, C 1-3 alkylNH-, (C 1-3 alkyl)2N- or -C(O)OC 1-3 alkyl is independently optionally substituted by 1, 2, 3 or 4 R a substituents.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein each R1 is independently H, F, Cl, Br, I, CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylS-, NH2, C 1-3 alkylNH- or (C 1-3 alkyl)2N-, wherein the C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylS-, C 1-3 alkylNH- or (C 1-3 alkyl)2N- is each independently optionally substituted by 1, 2, 3 or 4 R a substituents.

8. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein each R1 is independently H, F, Cl, Br, I, CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylS- or C 1-3 alkylNH-, wherein the C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylS- or C 1-3 alkylNH- is independently optionally substituted by 1, 2, 3 or 4 R a substituents.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R1 is independently H, F, Cl, Br, I, CN, C 1-3 alkyl or C 1-3 alkoxy, wherein the C 1-3 alkyl or C 1-3 alkoxy is each independently optionally substituted by 1, 2, 3 or 4 R a substituents.

10. The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from the compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein, R1 is H, F, Cl, Br, I, CN, C 1-3 alkyl or C 1-3 alkoxy, wherein said C 1-3 alkyl and C 1-3 alkoxy are optionally substituted by 1, 2, 3 or 4 R a substituents; R2 is CN; Each R a is independently H, F, Cl, Br, I or OH.

11. The compound according to claim 1 or 10, or a pharmaceutically acceptable salt thereof, wherein, Each R1 is independently H, F, Cl, Br, I, CN, -CH3, -CH2CH3 or -OCH3, where the -CH3, -CH2CH3 and -OCH3 are optionally substituted by 1, 2, 3 or 4 R a substituents.

12. The compound according to claim 1 or 10, or a pharmaceutically acceptable salt thereof, wherein each R1 is independently H, F, Cl, Br, I, CN, -CH3, -CH2CH3 or -OCH3, and wherein the -CH3, -CH2CH3 and -OCH3 are each independently optionally substituted with 1, 2 or 3 R a substituents.

13. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 10, wherein each R1 is independently H, F, Cl, Br, I, CN, -CH3, -CH2CH3 or -OCH3, and wherein the -CH3 or -CH2CH3 is independently optionally substituted with 1, 2 or 3 R a substituents.

14. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 10, wherein each R1 is independently H, F, Cl, Br, I, CN, -CH3, -CH2CH3 or -OCH3, wherein the -CH3 or -CH2CH3 is independently optionally substituted by 1, 2 or 3 F or OH.

15. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 10, wherein each R1 is independently H, F, Cl, Br, I, CN, -CH3, -CF3, -CH2CH3, -CH(OH)CH3 or -OCH3.

16. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 10, wherein each R1 is independently H, F, Cl, Br, I, CN, -CH3, -CF3, -CH2CH3 or -OCH3.

17. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 10, wherein each R1 is independently H, CN, -CH3, -CF3, -CH(OH)CH3 or -OCH3.

18. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 10, wherein each R1 is independently H, CN, -CH3, -CF3, -CH2CH3 or -OCH3.

19. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 10, wherein each R a is independently F, Cl, Br, I or OH, respectively.

20. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 10, wherein each R a is independently F or OH, respectively.

21. The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from the compounds of formula (I’-A) or a pharmaceutically acceptable salt thereof 22. The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from the compounds of formula (I’-B) or a pharmaceutically acceptable salt thereof, 23. The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from the compounds of formula (I-A) or a pharmaceutically acceptable salt thereof 24. The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from the compounds of formula (I-B) or a pharmaceutically acceptable salt thereof, 25. The compound or a pharmaceutically acceptable salt thereof according to claim 1, the compound structure of which is the structure of formula (I-1) 26. The compound or a pharmaceutically acceptable salt thereof according to claim 10, wherein the compound structure is of formula (I-1-A) or a pharmaceutically acceptable salt thereof 27. The compound or a pharmaceutically acceptable salt thereof according to claim 10, wherein the compound structure is formula (I-1-B) or a pharmaceutically acceptable salt thereof 28. A compound of the following formula or a pharmaceutically acceptable salt thereof, wherein, The compound is 29. A compound of the following formula or a pharmaceutically acceptable salt thereof, wherein, The compound is 30. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-29.

31. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-29, or the pharmaceutical composition according to claim 30, in the preparation of a medicament for the treatment of JAK1 and / or JAK2 related diseases.

32. The use according to claim 31, wherein the disease is selected from inflammatory disorders.

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