WO2021000785A1 - Pyrrolo[2,3-b]pyridine derivatives as selective inhibitors of janus kinase 1 - Google Patents

Abstract

Described in the present invention are pyrrolo[2,3-b]pyridine derivatives, the use thereof as selective inhibitors of Janus Kinase 1 (JAK1), and pharmaceutical compositions comprising same.

Description

Pyrrolo[2,3-b]pyridine derivatives as selective inhibitors of Janus kinase 1 Technical field

The present invention provides pharmaceutically active pyrrolo[2,3-b]pyridine compounds and analogs thereof. Such compounds can be used to inhibit Janus kinase (JAK), especially Janus kinase 1 (JAK1). The present invention also relates to compositions containing such compounds and methods for preparing such compounds, as well as methods for treating and preventing diseases mediated by JAK, especially JAK1.

Background technique

Cell communication is involved in regulating cell proliferation, maturation, differentiation, and apoptosis. Cell communication is closely related to the body’s metabolism, immunity, growth, development, reproduction and aging. Abnormal communication between cells can lead to metabolic disorders and immune loss , Tumors and many other diseases. JAK-STAT (Janus Kinase-signal Transducer and activator of transcription) signaling pathway is a group of signaling pathways ubiquitous in vertebrates. Many cytokines include: IFN family (IFN-α, IFN-β, IFN-ω, Limitin, IFN-γ, IL-10, IL-19, IL-20, IL-22); gp130 family (IL-6, IL-11, OSM, LIF, CNTF, NNT-1/BSF-3, G-CSF, CT-1, Leptin, IL-12, IL-23); γC family (IL-2, IL-7, TSLP, IL-9, IL-15, IL-21, IL-4, IL-13); IL -3 family (IL-3, IL-5, GM-CSF); single-chain family (EPO, GH, PRL, TPO); receptor tyrosine kinases (PDGF, CSF-1, HGF), etc. all pass this pathway Conduct signals. The JAK-STAT signaling pathway is related to a variety of hematological diseases, including but not limited to polycythemia, thrombocytosis, leukemia, and myelofibrosis. The JAK-STAT signaling pathway is also related to a variety of immune diseases, including but not limited to Rheumatoid arthritis, ankylosing spondylitis, lupus erythematosus, psoriasis, allergic dermatitis, ulcerative enteritis, hair loss, dry eye, etc. Therefore, the JAK-STAT signaling pathway has become an important target for a variety of blood-related diseases and autoimmune-related diseases. In addition, the JAK-STAT signaling pathway is also related to rejection during organ transplantation.

The Janus kinase family includes four types: JAK1, JAK2, JAK3 and TYK2. They play a central role in the signal transduction of the JAK-STAT signaling pathway. They activate each other and then interact with downstream STATs (STAT1, STAT2, STAT3, STAT4). , STAT5a, STAT5b and STAT6) proteins are phosphorylated to promote the formation of STAT protein dimers. STAT protein dimers can recognize specific DNA sequences and regulate the expression of specific genes. Small molecule Janus kinase inhibitors can effectively regulate the JAK-STAT signaling pathway and are potential drugs for the treatment of various blood-related diseases, autoimmune-related diseases and organ transplant rejection.

When Jenners kinase works, a specific type of cytokine usually interacts with its receptor, and then two or more JAKs are combined to phosphorylate different STAT proteins, such as IL-27 and IL-35. After binding to its receptor, STAT1, STAT3 or STAT4 is phosphorylated by the combination of JAK1 and JAK2 to achieve signal transduction; IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 After the receptor is bound, STAT1, STAT3, STAT5a, STAT5b or STAT6 are phosphorylated by the combination of JAK1 and JAK3, thereby achieving signal transduction; IL-6, IL-10, IL-11, IL-19, IL-20, IL-22 and IL-27 bind to their receptors through the combination of JAK1, JAK2 and TYK2 to phosphorylate STAT1, STAT2, STAT3, STAT4 or STAT5a, STAT5b, so as to realize signal transduction. JAK1 conducts the signal transmission of a variety of cytokines (especially interleukins) by combining with other JAK proteins. Therefore, JAK1 is closely related to the body's immunity. JAK2 is the only Jenus kinase known to be capable of signal transmission in combination with itself, IL-3, IL-5, GM-CSF, erythropoietin, thrombopoietin, granulocyte colony stimulating factor, growth hormone and thin After the protein binds to its receptor, STAT1, STAT3, STAT5a, STATb or STAT6 are phosphorylated by the combination of JAK2 and JAK2, thereby realizing signal transduction. Therefore, JAK2 is closely related to blood cells and bone marrow cells.

Due to the different division of labor of each JAK, JAK1, JAK3 and TYK2 are usually used as targets for immune-related diseases, while JAK2 is usually used as a target for blood-related diseases. Therefore, selective inhibition of different JAKs is useful for the treatment of specific JAK-STAT signaling pathways. Abnormal related diseases are particularly important. For example, selective inhibition of JAK1 kinase activity can effectively treat immune-related diseases or organ transplant rejection, and at the same time avoid inhibiting JAK2-dependent erythropoietin and thrombopoietin signal transduction, thereby avoiding anemia, etc. The occurrence of adverse reactions. Therefore, there is a great demand for the development of highly selective inhibitors with specific JAK, especially JAK1 relative to JAK2.

However, the kinase domains of the four JAKs have a high degree of homology, especially the homology of the amino acid residues in the active center, which brings great significance to the development of JAK inhibitors with good selectivity for specific JAKs. challenge. The homology comparison revealed that the glutamic acid residue at position 996 in the active center of the JAK1 kinase domain corresponds to the aspartic acid residue at position 939 of JAK2, the aspartic acid residue at position 912 of JAK3, and the aspartic acid residue at position 912 of TYK, respectively. The length of the side chain of the aspartic acid residue at position 996 and the side chain of the glutamic acid residue at position 996 of JAK1 is longer than that of other JAK corresponding aspartic acid residues. Therefore, the inhibitor can interact with the side chain of the glutamic acid residue at position 996 in JAK1 through positive and negative charges or hydrogen bonds, while not interacting with the aspartic acid side chains corresponding to other JAKs to achieve the effect of JAK1 Selective.

Summary of the invention

The following is the definition of each term or symbol used in this article:

symbol

Represents the connection point.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "alkyl" refers to a hydrocarbon group having a straight or branched chain or a combination thereof. The alkyl group may be a monovalent, divalent or cyclic alkyl group. Examples of monovalent alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, isohexyl and the like. Examples of divalent alkyl groups include:

Wait. Examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The term "cycloalkyl" refers to a saturated carbocyclic substituent containing 3 to about 20 carbon atoms, preferably 3 to 8 carbon atoms. The cycloalkyl group may be a monocyclic ring or a polycyclic ring. Such cycloalkyl groups include, for example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like, or polycyclic structures such as adamantyl and the like.

The term "heterocyclyl" refers to an unsaturated, saturated or partially saturated cyclic structure containing a total of 3 to 14 ring atoms. At least one ring atom is a heteroatom (ie, oxygen, nitrogen, or sulfur), and the remaining ring atoms are independently selected from carbon, oxygen, nitrogen, and sulfur. The heterocyclic group may be a monocyclic ring, which typically contains 3 to 7 ring atoms, more typically 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms. The heterocyclic group can also be 2 or 3 condensed rings. Examples of heterocyclic groups include azepanyl, diazacycloheptyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydropyranyl, benzodioxanyl Pentenyl, benzofuranyl, furanyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridazinyl, pyrimidinyl, pyrrolopyridyl, pyrazolyl, pyrazinyl, pyridyl, quinoline Group, tetrazolyl, thiazolidinyl, thiomorpholinyl, triazolyl, decyl etc.

The term "aryl" refers to an aromatic carbocyclic ring containing 6 to 14 carbon ring atoms. The term aryl encompasses monocyclic and polycyclic rings. Examples include phenyl, naphthyl, indenyl and the like.

The term "heteroaryl" refers to any mono-, di- or tricyclic ring system, in which at least one ring is a 5- or 6-membered aromatic ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, including any of the above Any bicyclic group in which a heteroaryl ring is fused to an aryl ring. Examples include: thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, azole, isoxazolyl, triazolyl, thiadiazolyl, diazolyl, tetrazolyl, thiatriazole Group, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, etc.

The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can be converted into each other through a low energy barrier. For example, proton tautomers (also called proton transfer tautomers) include interconversions through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversion through the recombination of some bonding electrons.

The symbol "C(O)" represents a carbonyl group, which can also be described as:

The symbol S(O) represents a sulfoxide group, which can also be described as:

The symbol S(O)2 represents a sulfone group, which can also be described as:

The symbol "C(OH)" can be described as:

If substituents are described as being "independently selected from" a group, then each substituent is selected independently of each other. Therefore, each substituent may be the same or different from the other substituents.

The term "pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and excipient. The purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredients and thus the biological activity.

The term "pharmaceutically acceptable salt" refers to the salt of the compound of the present invention, which is safe and effective when used in mammals, and has due biological activity.

The phrase "treatment" refers to alleviating symptoms associated with a disease, disorder, or condition, or suspending the further development or deterioration of those symptoms. Depending on the patient's disease and condition, the term "treatment" as used herein includes one or more curative, alleviating and preventive treatments. The compounds of the present invention can also be administered with other drugs and therapeutic agents.

The phrase "therapeutically effective" refers to the ability of an agent to prevent or ameliorate the severity of the disease, while avoiding the undesirable side effects typically associated with alternative treatments. The phrase "therapeutically effective" should be understood as equivalent to the phrase "effective for treatment, prevention or amelioration", both of which are intended to be competent for the amount of each agent used in the combination therapy, which can achieve the improvement of cancer, The severity of cardiovascular disease or pain and inflammation, as well as the morbidity target for each agent itself, while avoiding the undesirable side effects typically associated with alternative treatments.

Compound of the invention

The purpose of the present invention is to provide a compound of the structure represented by the general formula I or its tautomer, meso, racemate, enantiomer, diastereomer, and mixtures thereof Forms, and their pharmaceutically acceptable salts, as well as metabolites and metabolic precursors or prodrugs. The present invention provides a compound represented by formula I with the following structure:

R ^1, R ² and R ^{3 are} independently selected from hydrogen, deuterium, halo, ^{cyano, -NR a R b, -OR a} , -S (O) R a, -S (O) 2 R a, -NO _2. —C(O)OR ^a , —C(O)NR ^a R ^b , —NR ^a C(O)R ^b , —C(O)R ^a , —C(OH)R ^a R ^b , —NR ^a S(O) ₂ R ^b , -S(O) ₂ NR ^a R ^b , -CR ^a R ^b R ^c , -OCR ^a R ^b R ^c , -CH ₂ NR ^a R ^b , -CH ₂ OR ^a , —CH ₂ S(O)R ^a , —CH ₂ S(O) ₂ R ^a , —CH ₂ NO ₂ , —CH ₂ C(O)OR ^a , —CH ₂ CN, —CH ₂ C(O)NR ^a R ^b , -CH ₂ NR ^a C(O)R ^b , -CH ₂ C(O)R ^a , -CH ₂ C(OH)R ^a R ^b , -CH ₂ NR ^a S(O) ₂ R ^b , -CH ₂ S(O) ₂ NR ^a R ^b , -CH ₂ CR ^a R ^b R ^c , -CH ₂ OCR ^a R ^b R ^c , optionally substituted C1-3 alkyl, optionally substituted C2-3 alkenyl, optionally substituted C2-3 alkynyl;

A is a key or is —O—, —S—, —NR ⁴ —, —CR ⁴ R ⁵ —, —C(O)—, —S(O) ₂ —;

R ⁴ , R ⁵ , can be independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C1-3 alkyl;

Ring B is a C3-7 cycloalkyl group, a 3-7 membered heterocyclic group, a C5-7 aryl group, a 5-7 membered heteroaryl group, wherein the ring B is surrounded by one or more identical or different R ⁶ , R ^7. Replaced by R ⁸ and R ⁹ ;

R ⁶ , R ⁷ , R ⁸ , and R ⁹ can be independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, carbonyl, carboxyl, cyano, -CH ₂ OH, -CH ₂ NH ₂ , -CH ₂ NHCH ₃ , —CH ₂ C(O)OH, —CH ₂ CN, —NHCH ₃ , —N(CH ₃ ) ₂ , —NHCH ₂ CH ₃ , —C(O)NH ₂ , —C(O)NHCH ₃ , —C (O) NHCH ₂ CH ₃ , —S(O) ₂ NH ₂ , —S(O) ₂ NHCH ₃ , —S(O) ₂ NHCH ₂ CH ₃ , C1-3 alkyl;

X is a key or X is —O—, —S—, —NR ¹⁰ —, —CR ¹⁰ R ¹¹ —, —(CR ¹⁰ R ¹¹ ) _m —, —CR ¹⁰ R ¹¹ CR ¹² R ¹³ —, —C( O)—,—OCR ¹⁰ R ¹¹ —,—CR ¹⁰ R ¹¹ O—,—SCR ¹⁰ R ¹¹ —,—CR ¹⁰ R ¹¹ S—,—NR ¹⁰ CR ¹¹ R ¹² —,—CR ¹⁰ R ¹¹ NR ¹² —, —C(O)NR ¹⁰ —, —NR ¹⁰ C(O)—, —C(O)CR ¹⁰ R ¹¹ —, —CR ¹⁰ R ¹¹ C(O)—, —C(O)O—, —S(O) ₂ —, —S(O) ₂ NR ¹⁰ —, —NR ¹⁰ S(O) ₂ —, —S(O) ₂ CR ¹⁰ R ¹¹ —, —CR ¹⁰ R ¹¹ S(O) ₂ —, optionally substituted C2-3 alkenyl, optionally substituted C2-3 alkynyl;

R ¹⁰ , R ¹¹ , R ¹² , and R ¹³ can be independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, —CH ₂ OH, and optionally substituted C1-3 alkyl;

Y does not exist or is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 monocyclic alkyl, C6-14 bicyclic or tricyclic alkyl, 3-10 membered heteromonocyclic group, 6-14 membered heterobicyclic or tricyclic group, adamantane or its derivatives, C5-12 aryl, 5-12 membered heteroaryl, wherein Y is independently substituted by one or more of the following groups:

Deuterium, halogen, cyano, —NR ^a R ^b , —OR ^a , —S(O)R ^a , —S(O) ₂ R ^a , —NO ₂ , —C(O)OR ^a , —C(O )NR ^a R ^b , —NR ^a C(O)R ^b , —C(O)R ^a , —C(OH)R ^a R ^b , —NR ^a S(O) ₂ R ^b , —S(O) ₂ NR ^a R ^b , -CR ^a R ^b R ^c , -OCR ^a R ^b R ^c , -CH ₂ NR ^a R ^b , -CH ₂ OR ^a , -CH ₂ S(O)R ^a , -CH ₂ S (O) ₂ R ^a , —CH ₂ NO ₂ , —CH ₂ C(O)OR ^a , —CH ₂ CN, —CH ₂ C(O)NR ^a R ^b , —CH ₂ NR ^a C(O)R ^b , -CH ₂ C(O)R ^a , -CH ₂ C(OH)R ^a R ^b , -CH ₂ NR ^a S(O) ₂ R ^b , -CH ₂ S(O) ₂ NR ^a R ^b , —CH ₂ CR ^a R ^b R ^c , —CH ₂ OCR ^a R ^b R ^c , optionally substituted C1-3 alkyl, optionally substituted C2-3 alkenyl, optionally substituted C2-3 Alkynyl

Z is hydrogen, deuterium, halogen, cyano, —NR ¹⁴ R ¹⁵ , —OR ¹⁴ , —SR ¹⁴ , —S(O)R ¹⁴ , —S(O) ₂ R ¹⁴ , —NO ₂ , —C(O )R ¹⁴ , -C(O)OR ¹⁴ , -CR ¹⁴ R ¹⁵ CN, -C(O)NR ¹⁴ R ¹⁵ , -NR ¹⁴ C(O)R ¹⁵ , -C(OH)R ¹⁴ R ¹⁵ ,- NR ¹⁴ S(O) ₂ R ¹⁵ , -S(O) ₂ NR ¹⁴ R ¹⁵ , -CR ¹⁴ R ¹⁵ R ¹⁶ , -OCR ¹⁴ R ¹⁵ R ¹⁶ , -(CH ₂ ) _n R ¹⁴ , -(CH ₂ ) _n NR ¹⁴ R ¹⁵ , —(CH ₂ ) _n OR ¹⁴ , —(CH ₂ ) _n SR ¹⁴ , —(CH ₂ ) _n S(O)R ¹⁴ , —(CH ₂ ) _n S(O) ₂ R ¹⁴ , —(CH ₂ ) _n NO ₂ , —(CH ₂ ) _n C(O)R ¹⁴ , —(CH ₂ ) _n C(O)OR ¹⁴ , —(CH ₂ ) _n CN, —CHR ¹⁴ R ¹⁵ CN,—(CH ₂ ) _n CHR ¹⁴ R ¹⁵ CN,—(CH ₂ ) _n C(O)NR ¹⁴ R ¹⁵ ,—(CH ₂ ) _n NR ¹⁴ C(O)R ¹⁵ ,—(CH ₂ ) _n C(OH)R ¹⁴ R ¹⁵ 、—(CH ₂ ) _n NR ¹⁴ S(O) ₂ R ¹⁵ 、—(CH ₂ ) _n S(O) ₂ NR ¹⁴ R ¹⁵ 、—(CH ₂ ) _n CR ¹⁴ R ¹⁵ R ¹⁶ , —(CH ₂ ) _n OCR ¹⁴ R ¹⁵ R ¹⁶ , optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C5-12 aryl, 5-12 membered heteroaryl, wherein Z is independently optionally substituted by the following groups: deuterium, halogen, cyano, -NR ^a R ^b , —OR ^a , —SR ^a , —S(O)R ^a , —S(O) ₂ R ^a , —NO ₂ , —C(O)R ^a , —C(O)OR ^a , — C(O)NR ^a R ^b , —NR ^a C(O)R ^b , —C(OH)R ^a R ^b , —NR ^a S(O) ₂ R ^b , —S(O) ₂ NR ^a R ^b , —(CH ₂ ) _n R ^a R ^b , —CR ^a R ^b R ^c , —OCR ^a R ^b R ^c , optionally substituted C1-6 alkyl, optionally substituted C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C5-12 aryl, 5-12 membered heteroaryl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkyne base;

R ¹⁴ , R ¹⁵ , and R ¹⁶ can be selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, carboxy, optionally substituted C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered hetero Cycloalkyl, C5-12 aryl, 5-12 membered heteroaryl;

R ^a , R ^b and R ^c are each independently selected from hydrogen, deuterium, halogen, cyano, and optionally substituted C1-3 alkyl;

m is: 1, 2, 3;

n is: 1, 2, 3, 4.

In a preferred embodiment of the present invention, the compound represented by Formula I or its tautomer, meso, racemate, enantiomer, diastereomer, and The mixture form and the pharmaceutically acceptable salt thereof are the compound represented by the general formula II or the pharmaceutically acceptable salt thereof:

The definitions of A, B, X, Y, and Z are as defined in general formula I;

In another preferred embodiment of the present invention, the compound represented by formula I or its tautomers, mesosomes, racemates, enantiomers, diastereomers, And its mixture form, and its pharmaceutically acceptable salt, are the compound represented by general formula II or its pharmaceutically acceptable salt:

A is a bond or is: —O—, —S—, —NH—, —CH ₂ —;

B is selected from: imidazole, pyrazole, pyrrole, azetidine, pyrrolidine, pyrrolidone, imidazoline, piperidine, piperazine or the following structure:

X is a bond or X is: —O—, —S—, —NH—, —NCH ₃ —, —(CH ₂ ) _m —, —C(O)—, —CH ₂ O—, —CH ₂ S— , —CH ₂ NH—, —OCH ₂ —, —SCH ₂ —, —NHCH ₂ —;

The definitions of Y and Z are as defined in formula I;

m is: 1, 2, 3;

The wavy line represents the connection point between A and B.

In another preferred embodiment of the present invention, the compound represented by general formula I and general formula II or its tautomers, mesosomes, racemates, enantiomers, diastereomers Isomers, mixtures thereof, and pharmaceutically acceptable salts thereof are the compounds represented by the general formula III or their pharmaceutically acceptable salts:

B is selected from: imidazole, pyrazole, pyrrole, azetidine, pyrrolidine, pyrrolidone, imidazoline, piperidine, piperazine or the following structure:

The definitions of Y and Z are as defined in formula I;

In another preferred embodiment of the present invention, the compound represented by general formula I and general formula II or its tautomers, mesosomes, racemates, enantiomers, diastereomers Isomers, mixtures thereof, and pharmaceutically acceptable salts thereof are the compounds represented by the general formula III or their pharmaceutically acceptable salts:

B is: imidazole, pyrazole, pyrrole, azetidine, pyrrolidine, pyrrolidone, imidazoline, piperidine, piperazine;

The definitions of Y and Z are as defined in the general formula I;

In another preferred embodiment of the present invention, the compound represented by general formula I and general formula II or its tautomers, mesosomes, racemates, enantiomers, diastereomers Isomers, mixtures thereof, and pharmaceutically acceptable salts thereof are the compounds represented by the general formula III or their pharmaceutically acceptable salts:

B is imidazole, pyrazole, pyrrole, azetidine, pyrrolidine, pyrrolidone;

Y is the following structure:

Where C specifies the location connected to the following core parts:

The wavy line indicates the connection point;

The definition of Z is as defined in formula I;

In another preferred embodiment of the present invention, the compound represented by general formula I and general formula II or its tautomers, mesosomes, racemates, enantiomers, diastereomers The isomers, their mixture forms, and their pharmaceutically acceptable salts are the compounds represented by the general formula III or their pharmaceutically acceptable salts:

B is imidazole, pyrazole, pyrrole, azetidine, pyrrolidine, pyrrolidone;

Y is the following structure:

Where C specifies the location connected to the following core parts:

The wavy line indicates the connection point;

In another preferred embodiment of the present invention, the compound represented by general formula I and general formula II or its tautomers, mesosomes, racemates, enantiomers, diastereomers The isomers, their mixture forms, and their pharmaceutically acceptable salts are the compounds represented by the general formula III or their pharmaceutically acceptable salts:

B is pyrrole, pyrazole or imidazole;

Y is:

Where C specifies the location connected to the following core parts:

The wavy line indicates the connection point;

The definition of Z is as defined by formula I;

In another preferred embodiment of the present invention, the compound represented by general formula I and general formula II or its tautomers, mesosomes, racemates, enantiomers, diastereomers The isomers, their mixture forms, and their pharmaceutically acceptable salts are the compounds represented by the general formula III or their pharmaceutically acceptable salts:

B is pyrrole, pyrazole or imidazole;

Y is:

Z is hydrogen, deuterium, halogen, hydroxyl, amino, carboxyl, cyano, methyl, —(CH ₂ ) _n CH ₃ , —CH(CH ₃ ) ₂ , —C(CH ₃ ) ₃ , —(CH ₂ ) _n CH(CH ₃ ) ₂ , —(CH ₂ ) _n C(CH ₃ ) ₃ , —(CH ₂ ) _m CH(CH ₃ )(CH ₂ ) _n CH ₃ , —C(O)CH ₃ , —C (O)(CH ₂ ) _n CH ₃ , -C(O)CH(CH ₃ ) ₂ , -C(O)C(CH ₃ ) ₃ , -C(O)CH(CH ₃ )CH ₂ CH ₃ , —OCH ₃ , —O(CH ₂ ) _n CH ₃ , —OCH(CH ₃ ) ₂ , —OC(CH ₃ ) ₃ , —OCH(CH ₃ )CH ₂ CH ₃ , —SCH ₃ , —S(CH ₂ ) _n CH ₃ , —SCH(CH ₃ ) ₂ , —SC(CH ₃ ) ₃ , —SCH(CH ₃ )CH ₂ CH ₃ , —(CH ₂ ) _n NH ₂ , —NHCH ₃ , —N(CH ₃ ) ₂ , —(CH ₂ ) _n NHCH ₃ , —(CH ₂ ) _n N(CH ₃ ) ₂ , —C(O)NH ₂ , —C(O)NHCH ₃ , —C(O)N(CH ₃ ) ₂ , -C(O)(CH ₂ ) _n NH ₂ , -C(O)(CH ₂ ) _n NHCH ₃ , -C(O)(CH ₂ ) _n N(CH ₃ ) ₂ , -S(O ) ₂ CH ₃ , —S(O) ₂ (CH ₂ ) _n CH ₃ , —S(O) ₂ CH(CH ₃ ) ₂ , —S(O) ₂ C(CH ₃ ) ₃ , —S(O) ₂ CH(CH ₃ )CH ₂ CH ₃ , —S(O) ₂ (CH ₂ ) _n CH(CH ₃ ) ₂ , —S(O) ₂ (CH ₂ ) _n C(CH ₃ ) ₃ , —S( O) ₂ (CH ₂ ) _n CH(CH ₃ )CH ₂ CH ₃ , —S(O) ₂ NH ₂ , —S(O) ₂ NHCH ₃ , —S(O) ₂ N(CH ₃ ) ₂ , — S(O) ₂ (CH ₂ ) _n NH ₂ , -S(O) ₂ (CH ₂ ) _n NHCH ₃ , -S(O) ₂ (CH ₂ ) _n N(CH ₃ ) ₂ , -CH ₂ F, —CHF ₂ , —CF ₃ , —C(O)CH ₂ F, —C(O)CHF ₂ , —C(O)CF ₃ , —S(O) ₂ CH ₂ F, —S(O) ₂ CHF ₂ , —S(O) ₂ CF ₃ , —(CH ₂ ) _n CH ₂ F, —(CH ₂ ) _n CHF ₂ , —(CH ₂ ) _n CF ₃ , —C(O )(CH ₂ ) _n CH ₂ F, -C(O)(CH ₂ ) _n CHF ₂ , -C(O)(CH ₂ ) _n CF ₃ , -S(O) ₂ (CH ₂ ) _n CH ₂ F , -S(O) ₂ (CH ₂ ) _n CHF ₂ , -S(O) ₂ (CH ₂ ) _n CF ₃ , -CH(CH ₃ )CH ₂ F, -CH(CH ₃ )CHF ₂ , -CH (CH ₃ )CF ₃ , -C(O)CH(CH ₃ )CH ₂ F, -C(O)CH(CH ₃ )CHF ₂ , -C(O)CH(CH ₃ )CF ₃ , -S( O) ₂ CH(CH ₃ )CH ₂ F, —S(O) ₂ CH(CH ₃ )CHF ₂ , —S(O) ₂ CH(CH ₃ )CF ₃ , —(CH ₂ ) _n OH, —( CH ₂ ) _n C(O)OH, —C(O)(CH ₂ ) _n OH, —S(O) ₂ (CH ₂ ) _n OH, —CH(CH ₃ )OH, —CH(CH ₃ )CH ₂ OH, —CH(CH ₃ )C(O)OH, —CH(CH ₃ )CH ₂ C(O)OH, —(CH ₂ ) _n CN, —C(CH ₃ ) ₂ CN, —CH(CH ₃ )CN, —(CH ₂ ) _n C(CH ₃ ) ₂ CN, —(CH ₂ ) _n CH(CH ₃ )CN, —C(O)(CH ₂ ) _n CN, —S(O) ₂ ( CH ₂ ) _n CN, -C(O)C(CH ₃ ) ₂ CN, -C(O)CH(CH ₃ )CN, -S(O) ₂ C(CH ₃ ) ₂ CN, -S(O) ₂ CH(CH ₃ )CN or the following structure:

Where C specifies the location connected to the following core parts:

Where D specifies the location connected to the following core parts:

The wavy line indicates the connection point;

m is 1, 2, 3;

n is: 1, 2, 3, 4.

In yet another preferred embodiment of the present invention, the compound represented by general formula I, general formula II and general formula III or its tautomer, meso, racemate, enantiomer, Diastereoisomers, mixtures thereof, and pharmaceutically acceptable salts thereof are selected from the following compounds:

Or its pharmaceutically acceptable salt.

The pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base salts thereof.

Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include, but are not limited to: acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, Camphorsulfonate, citrate, cyclic sulfonate, ethanedisulfonate, ethanesulfonate, formate, fumarate, gluconate, gluconate, glucuronate, Hexafluorophosphate, hydroxybenzoyl benzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate , Maleate, malonate, methanesulfonate, methylsulfate, naphthalate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitic acid Salt, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, toluenesulfonic acid Salt, trifluoroacetate and hydroxynaphthoate, etc.

Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum salt, arginine salt, benzathine penicillin salt, calcium salt, choline salt, diethylamine salt, diethanolamine salt, glycinate, lysine salt, magnesium salt, meglumine salt, ethanolamine salt, Potassium, sodium, tromethamine and zinc salts.

Drug combination:

The pharmaceutically acceptable salt of the compound of the present invention can be prepared by one or more of the following three methods: 1. The compound is reacted with a desired acid or base; 2. The desired acid or base is used, starting from a suitable precursor of the compound Remove the acid or base unstable protective group, or open a suitable cyclic precursor such as lactone or lactam; 3. React with a suitable acid or base or use a suitable ion exchange column to convert a salt of the compound Into another salt. All three reactions are usually carried out in solution. The resulting salt can be precipitated out and collected by filtration or can be recovered by evaporation of the solvent. The degree of ionization in the obtained salt can vary from complete ionization to almost no ionization.

The present invention also provides a composition for treating or ameliorating a variety of JAK-related diseases, which can be prepared by mixing one or more of the compounds described herein, or a pharmaceutically acceptable salt or tautomer thereof, and a pharmaceutically acceptable carrier , Excipients, adhesives, diluents, etc. The pharmaceutical composition of the present invention can be prepared by methods well known in the art, including but not limited to conventional granulation, mixing, dissolving, encapsulating, freeze-drying, emulsification or grinding. The composition includes but is not limited to the form of granules, powders, tablets, syrups, suppositories, injections, emulsions, elixirs, suspensions or solutions. The composition of the present invention can be formulated for various administration routes, such as oral administration, transmucosal administration, rectal administration, topical administration or subcutaneous administration, and intrathecal, intravenous, intramuscular, intraperitoneal, nasal Intraocular, intraocular or intraventricular injection. The compounds of the invention may also be administered locally rather than systemically.

For oral, oral and sublingual administration, powders, suspensions, granules, tablets, pills and capsules are acceptable solid dosage forms. These can be prepared, for example, by mixing one or more compounds of the invention or a pharmaceutically acceptable salt or tautomer thereof with at least one additive or excipient such as starch or other additives. Suitable additives or excipients include, but are not limited to, sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, sorbitol, starch, agar, alginate, chitin, chitosan, pectin, Gum tragacanth, gum arabic, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymer compounds or glycerides, methyl cellulose and hydroxypropyl methyl cellulose, etc. Optionally, the oral dosage form may contain other components that facilitate administration, such as inert diluents, or lubricants such as magnesium stearate, or preservatives such as p-hydroxybenzoic acid or sorbic acid, or antioxidants such as ascorbic acid , Tocopherol or cysteine, disintegrant, binder, thickener, buffer, sweetener, flavoring or fragrance. In addition, dyes or pigments can be added for identification. The tablets and pills can be further processed with suitable coating materials known in the art.

Liquid dosage forms for oral administration include, but are not limited to, emulsions, syrups, elixirs, suspensions, slurries, and solutions, which may contain inert diluents such as water. Sterile liquids, such as but not limited to oil, water, alcohol, and combinations thereof, can be used to prepare pharmaceutical preparations into liquid suspensions or solutions. For oral or parenteral administration, pharmaceutically suitable surfactants, suspending agents or emulsifiers can be added.

The compounds can also be administered topically, (intradermal) subcutaneously or transdermally to the skin or mucosa. The preparations used for this purpose include, but are not limited to, gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, glutinous rice paper capsules, transplants Inclusions, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid paraffin, petrolatum, glycerin, polyethylene glycol and propylene glycol.

The compound can also be administered through the nose, and the pharmaceutical preparation can be a spray or aerosol, which contains a suitable solvent and optionally other compounds, such as but not limited to stabilizers, antimicrobial agents, antioxidants, pH regulators, Surfactants, bioavailability modifiers and combinations thereof. Propellants used for aerosols may include compressed air, nitrogen, carbon dioxide, or hydrocarbon-based low-boiling solvents.

Injectable dosage forms usually include aqueous suspensions or oily suspensions, which can be prepared using suitable dispersing or wetting agents and suspending agents. The injectable form may be in the solution phase, or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or excipients include sterile water, Ringer's solution or isotonic saline solution. Alternatively, sterile oils can be used as solvents or suspending agents. Generally, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, monoglycerides, diglycerides, or triglycerides.

For rectal administration, the pharmaceutical preparation may be in the form of suppositories, ointments, enemas, tablets or creams, which release the compound in the intestinal tract, sigmoid flexure or rectum. Rectal suppositories are prepared by mixing one or more compounds of the invention, or pharmaceutically acceptable salts or tautomers of the compounds, and acceptable excipients such as cocoa butter or polyethylene glycol. It is a solid phase at normal storage temperature and a liquid phase at a temperature suitable for releasing the drug in the body such as in the rectum. Oils can also be used in the preparation of soft gelatin type preparations and suppositories. In the preparation of a suspension formulation, water, physiological saline, aqueous dextrose and related sugar solutions, and glycerin can be administered, and the formulation may also include a suspending agent such as gum, carbomer, methylcellulose, and hydroxypropyl. Base cellulose or carboxymethyl cellulose, as well as buffers and preservatives.

The composition of the invention may also include, for example, micelles or liposomes or other encapsulated forms, or may be administered in an extended release form to provide an extended storage or delivery effect. Therefore, the pharmaceutical preparation can be compressed into granules or cylinders, can be implanted intramuscularly or subcutaneously, as a depot injection or as an implant such as a stent. Such implants can use known substances, such as silicone and biodegradable polymers.

The composition may contain, for example, from about 0.1% by weight to about 90% or more of the active substance, depending on the method of administration. When the composition includes dosage units, each unit may contain, for example, about 0.1 to 500 mg or more of the active ingredient. For example, the dosage used for adult treatment can be, for example, about 0.1 to 1000 mg/day, depending on the route of administration and frequency of administration.

The specific dosage can be adjusted according to the conditions of JAK-related diseases, the subject's age, weight, general health, gender and diet, dosing interval, dosing route, excretion rate, and drug combination. Any of the aforementioned dosage forms containing an effective amount are within the scope of routine experimentation, and therefore, are within the scope of the present invention. Generally, the total daily dose may typically be about 1 mg/kg/day to about 500 mg/kg/day, administered in a single dose or in divided doses. Typically, the dose for humans can be about 5 mg to about 100 mg/day, given in a single dose or in multiple doses. The therapeutically effective dose or amount can vary according to the route of administration and dosage form.

Pharmaceutical formulations of JAK inhibitors, the compounds of the present invention or in combination with one or more additional agents, the additional agents may include, but are not limited to cyclosporin A, rapamycin, tacrolimus, Sirolimus, everolimus, azathioprine, buquina, deoxyspergualin, leflunomide, aspirin, paracetamol, ibuprofen, naproxen, piroxicam, methotrexate, anti Inflammatory steroids (such as prednisolone or dexamethasone) and so on. These combinations can be administered as the same or separate dosage forms, via the same or different routes of administration, and comply with the same or different dosing schedules of standard pharmaceutical practice.

treatment method:

In one embodiment, the invention provides a method of treating or preventing a disease associated with JAK1 in a subject, which comprises administering to the subject an effective amount of one or more of the compounds described herein, such as Mammals, that is, human or non-human mammals. The JAK-related diseases may be related to JAK1. Suitable non-human subjects that can be treated include domesticated or wild animals, companion animals, such as dogs and cats. In one embodiment, the compound is administered in a pharmaceutically acceptable form, optionally in a pharmaceutically acceptable carrier.

JAK/STAT signaling is related to the regulation of many immune response abnormalities, such as: arthritis, asthma, hair loss, diabetes, certain eye diseases, inflammation, allergies, enteritis, allergies or diseases, psoriasis, transplant rejection. The diseases that can benefit from JAK1 inhibition are discussed in more detail below.

In some embodiments, the methods and compositions of the invention cover the treatment of connective tissue and joint diseases including but not limited to: arthritis, rheumatoid arthritis, juvenile arthritis, juvenile arthritis, psoriatic arthritis, vertebral arthritis, Connective tissue or joint diseases such as ankylosing spondylitis, tendinitis and bursitis, lumbar arthropathy.

In some embodiments, the methods and compositions of the invention cover the treatment of skin or hair related diseases including but not limited to: allergic dermatitis, skin itching, acne, acne, rosacea, lupus erythematosus, pemphigus, psoriasis, hair loss , Alopecia areata, etc.

In some embodiments, the methods and compositions of the invention cover the treatment of diseases including but not limited to: ulcerative enteritis, Crohn’s disease, ulcerative colitis, proctitis, asthma, rhinitis, hay fever, dry eye disease, uveitis , Keratitis, type I diabetes, multiple sclerosis autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture’s disease, sympathetic ophthalmia/organ transplant rejection, etc.

Description of the drawings

Figure 1: Taking Example 65 as an example, the effect of promoting hair growth experiment, respectively on the day of administration, 14 days, 21 days and 28 days. The picture shows 10-week-old C57 mice shaved their backs and then divided them into groups. Using the method of smearing on the right half of the body, the mice were smeared and administered at an interval of 12 hours in the morning and evening. The ointment contained 2% of the compound in the example. The blank control group is only an emulsifier and does not contain any of the compounds in the examples.

Specific implementation method

Chemical synthesis:

Unless otherwise stated in the following examples, the reagents, starting materials, and solvents used in the following examples were purchased from commercial suppliers (for example, Aldrich, Fluka, Sigma, etc.) and can be used without additional purification.

Implementation examples:

Example 1:

Step a: Under the protection of nitrogen, mix 1 (3.68.g, 15.9mmol), benzyltriethylammonium chloride (0.91g, 3.97mmol) and potassium hydroxide (2.67g, 47.7mmol) in a 100ml round bottom flask Suspended in dichloromethane (50ml) and stirred at room temperature for 1 hour. Then p-toluenesulfonyl chloride (3.62g, 19.1mmol) was added and stirring continued for 3 hours. After the reaction was completed, it was quenched by adding water, the pH was adjusted to 8 with saturated ammonium chloride solution, and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water and brine, and then dried over anhydrous sodium sulfate, filtered and concentrated to obtain 5.39 g (88%, purity>98%) of white solid 2. ¹ H NMR(400MHz,CDCl3)δ8.50(s,1H), 8.05(d,J=8.2Hz,2H), 7.77(dd,J=4.0,0.4Hz,1H), 7.29(d,J=8.8 Hz, 2H), 6.67 (dd, J = 4.0, 0.8 Hz, 1H), 2.38 (s, 3H). ¹³ C NMR (50MHz, CDCl3) δ 147.2, 146.2, 146.1, 136.7, 135.2, 130.2, 128.6, 128.4, 123.9, 115.9, 104.0, 22.1.

Step b: Under the protection of nitrogen, add 2 (1.0g, 2.6mmol) in a 100ml round bottom flask, and heat cyclohexylamine (2.57g, 26mmol) to 140°C for 2 hours, then cool to room temperature and quench with water. The water layer Extract with dichloromethane. The combined organics were washed with water and brine, and then dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel chromatography with methanol/dichloromethane (1:50) to obtain 2.2 g (84%, Purity>98%) white solid 3. ¹ H NMR(400MHz,CDCl ₃ )δ8.17(s,1H), 8.03(d,J=8.2Hz,2H), 7.51(d,J=4.0Hz,1H), 7.25(d,J=8.2Hz ,2H),6.56(d,J=4.0Hz,1H),5.00(d,J=7.8Hz,1H),3.83-3.71(m,1H),2.36(s,3H),2.10-2.01(m, 2H),1.84–1.75(m,2H),1.71–1.62(m,1H),1.48–1.21(m,5H). ¹³ C NMR(101MHz,CDCl ₃ )δ147.8,146.2,145.1,144.0,135.3,129.6 ,128.2,123.28,108.5,104.4,101.9,52.5,33.9,25.4,24.5,21.7.

Step c: Under the protection of nitrogen, in a 50ml round-bottom flask, 3 (0.9g, 2mmol), pyrazole pinacol boron ester (0.78g, 4mmol), potassium carbonate (1.1g, 8mmol) and tetratriphenyl Phosphine palladium (0.11g, 0.1mmol) was added to 1,4-dioxane (20ml) and stirred at 120°C for 24 hours. Then it was cooled to room temperature, quenched with water, and extracted with dichloromethane. The combined organics were washed with water and brine, and then dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel chromatography with methanol/dichloromethane (1:20) to obtain 0.35 g (80%, Purity>98%) white solid 4. ¹ H NMR(400MHz,CDCl ₃ )δ8.06(d,J=8.4Hz,2H),7.95(s,1H),7.72(br,2H),7.52(d,J=4.2Hz,1H),7.25 (d,J=8.4Hz,2H), 6.60(d,J=4.2Hz,1H), 4.70(d,J=7.2Hz,1H), 3.74(m,1H), 2.37(s,3H), 2.10 --2.02(m,2H),1.75-1.57(m,3H),1.45-1.04(m,5H). ¹³ C NMR(101MHz,CDCl ₃ )δ147.8,146.2,145.19,143.9,135.3,129.6,128.1,123.2 ,119.1,108.5,104.5,102.7,101.9,52.5,33.9,25.4,24.5,21.6.

Step d: Under the protection of nitrogen, 4 (1g, 2.3mmol) and potassium hydroxide (0.16g, 2.9mmol) were dissolved in methanol (5ml) in a 20ml round bottom flask and stirred at 45°C for 5 hours. Then it was cooled to room temperature, filtered, and washed with a small amount of cold methanol and ice water to obtain 0.58 g (89%, purity >99%) of white solid 5. ¹ H NMR (400MHz, CDCl ₃ ) δ 10.31 (s, 1H), 8.11 (s, 1H), 7.75 (br, 2H), 7.10 (d, J = 3.2 Hz, 1H), 6.50 (d, J = 3.6Hz, 1H), 4.99 (d, J = 8.0 Hz, 1H), 4.08–3.89 (m, 1H), 2.18 (t, J = 16.6 Hz, 2H), 1.87–1.62 (m, 5H), 1.52– 1.21 (m, 6H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 149.2, 144.6, 144.1, 121.8, 120.2, 106.6, 103.4, 100.3, 98.2, 52.5, 34.2, 25.6, 24.7.

Example 2:

The pyrrole pinacol borane ester was used instead of pyrazole pinacol borane ester, and the operation of steps c and d was the same as in Example 1, and 0.51 g (91%, purity>99%) of white solid 7 was obtained. ¹ H NMR (400MHz, CDCl ₃ ) δ 10.18 (s, 1H), 8.21 (s, 1H), 7.10 (d, J = 3.6 Hz, 1H), 6.71 (t, J = 2.4 Hz, 1H), 6.56 –6.53(m,1H),6.50(d,J=3.6Hz,1H), 6.16(dd,J=2.4,1.6Hz,1H), 4.99(d,J=8.0Hz,1H),4.08–3.89( m,1H), 2.18(t,J=16.6Hz,2H), 1.87–1.62(m,5H), 1.52–1.21(m,6H). ¹³ C NMR(101MHz,CDCl ₃ )δ149.3,144.5,144.0, 124.8, 123.4, 121.7, 120.2, 113.2, 106.6, 103.4, 100.3, 98.2, 98.1, 52.5, 34.2, 25.6, 24.7.

Example 3:

Substituting (S)-3-amino-1-benzylpiperidine for cyclohexylamine, the steps a, b, c, and d are the same as in Example 1, and 0.69 g (92%, purity >99%) of a white solid compound is obtained 10. ¹ H NMR (400MHz, CDCl ₃ ) δ 10.26 (s, 1H), 8.20 (s, 1H), 7.80 (br, 2H), 7.20-7.35 (m, 5H), 7.11 (d, J = 3.6 Hz, 1H), 6.52(d,J=3.2Hz,1H),3.51-3.40(m,3H),2.80-2.75(m,2H),2.61-2.56(m,2H),2.24-2.16(m,2H) ,1.71-1.63(m,2H). ¹³ C NMR(101MHz, CDCl ₃ ) δ149.4,144.7,144.1,138.6,128.8,128.4,127.2,121.9,120.4,106.7,103.4,100.2,98.1,58.5,54.7,52.3 ,50.1,36.7,20.8.

Example 4-12:

(R)-3-amino-1-benzylpiperidine, 4-amino-1-benzylpiperidine, (S)-3-amino-1-benzylpyrrolidine and (R)-3-amino -1-benzylpyrrolidine replaces cyclohexylamine to synthesize the corresponding intermediate with compound 2 through step b, and then react with pyrazole pinacol boron ester or pyrrol pinacol boron ester through step c, and finally remove it through step d The protective group synthesis of the compounds in Examples 4-12, the specific operation is the same as that in Example 3, and the corresponding compounds obtained are as follows:

Example 13:

Step e: Suspend compound 10 (0.75 g, 2.0 mmol) in 10 ml water and 1 ml formic acid in a 100 ml round bottom flask at room temperature, and add 0.1 g of 10% palladium on carbon in portions. Then the temperature was raised to 50°C and stirring was continued for 8 hours. The reaction was cooled to room temperature, basified, and extracted with 1-butanol. The combined organics were filtered and concentrated, and the obtained residue was purified by silica gel chromatography with methanol/dichloromethane (1:20) to obtain 0.42 g (75%, purity >99%) of 20 as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ 10.28 (s, 1H), 8.22 (s, 1H), 7.82 (br, 2H), 7.11 (d, J = 3.2 Hz, 1H), 6.51 (d, J = 3.2Hz, 1H), 3.48-3.39 (m, 1H), 2.88-2.79 (m, 2H), 2.73-2.65 (m, 2H), 2.25-2.16 (m, 2H), 1.71-1.64 (m, 2H) . ¹³ C NMR (101MHz, CDCl ₃ ) δ149.3, 144.7, 144.0, 121.8, 120.4, 106.3, 103.1, 100.2, 98.3, 57.5, 51.3, 50.4, 36.3, 20.7.

Examples 14-22:

Using the compound in Example 4-12 (Compound 11-19) as an intermediate, the compound in Example 14-22 was synthesized through step e. The specific operation was the same as that in Example 13, and the corresponding compound was obtained as shown below:

Example 23-416:

The compounds in Examples 23-414 fall into one of the following general formulas:

Preparation of Intermediate IVA1-IVB8:

The compounds in Examples 3-12 (compounds 10-19) were passed through steps f and e to obtain the corresponding intermediates IVA1-IVB5. Take the preparation process of IVA1 as an example:

Step f: Under nitrogen protection, 10 (0.75g, 2.0mmol) was dissolved in 20ml tetrahydrofuran in a 50ml round bottom flask at 0°C and stirred for 10 minutes. Sodium hydride (0.15 g, 6.0 mmol) was slowly added in batches and stirring was continued for 1 hour. Slowly add triisopropylsilyl chloride dropwise, and stir overnight at 60°C after dropping. The reaction was cooled to room temperature, poured into ice water to quench, and extracted with ether. Alkalize and extract with 1-butanol. The combined organics were filtered and concentrated, and the obtained residue was purified by silica gel chromatography with petroleum ether/ethyl acetate (100:1-100:2) to obtain 1.26g (92%, purity>99%) of a white solid compound 30. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.16 (s, 1H), 7.69 (s, 1H), 7.20-7.35 (m, 5H), 7.11 (d, J = 3.6 Hz, 1H), 6.61 (s, 1H), 6.52(d,J=3.2Hz,1H),3.51-3.40(m,3H),2.80-2.75(m,2H),2.61-2.56(m,2H),2.24-2.16(m,2H) ,1.71-1.63(m,2H),1.51-1.40(m,6H),1.15-1.08(m,36H). ¹³ C NMR(101MHz,CDCl ₃ )δ149.4,144.8,144.1,138.2,128.1,128.4,126.9 ,121.9,120.4,106.3,103.4,100.2,97.9,58.1,54.2,52.3,50.1,36.7,20.8,18.0,17.9,11.9,11.7.

Step e: Dissolve compound 30 (1.37g, 2.0mmol) in 20ml methanol in a 100ml round bottom flask at room temperature, add 0.1g 10% palladium on carbon in portions, and slowly add amine formate (0.63g, 10.0mmol). The temperature was then raised to 50°C and stirring continued overnight. The reaction was cooled to room temperature and extracted with ethyl acetate. The combined organics were filtered and concentrated, and the obtained residue was purified by silica gel chromatography with petroleum ether/ethyl acetate (10:1-5:1) to obtain 0.96g (81%, purity>99%) of a white solid compound 31 (Intermediate IV A1). ¹ H NMR (400MHz, CDCl ₃ ) δ 8.20 (s, 1H), 7.71 (s, 1H), 7.19 (d, J = 3.2 Hz, 1H), 6.63 (s, 1H), 6.51 (d, J = 3.2Hz,1H),3.56-3.44(m,3H),2.81-2.75(m,2H),2.62-2.57(m,2H),2.24-2.15(m,2H),1.70-1.62(m,2H) ,1.50-1.43(m,6H),1.12-1.06(m,36H). ¹³ C NMR(101MHz,CDCl ₃ )δ149.4,144.8,144.2,122.0,120.1,106.4,103.1,100.1,97.7,57.1,52.3, 50.3, 36.4, 20.7, 18.0, 17.8, 11.9, 11.7.

Using the compounds in Examples 4-12 (compounds 11-19) as raw materials, intermediates IV A2, IV A3, IV A4, IV A5, IV B1, IV B2, IV B3 were prepared in the same manner as above intermediate IV A1 , IV B4 and IV B5:

1.01 g (88%, purity>99%) of compound 32 (Intermediate IV A2) was obtained as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.20 (s, 1H), 7.71 (s, 1H), 7.19 (d, J = 3.2 Hz, 1H), 6.63 (s, 1H), 6.51 (d, J = 3.2Hz,1H),3.56-3.44(m,3H),2.81-2.75(m,2H),2.62-2.57(m,2H),2.24-2.15(m,2H),1.70-1.62(m,2H) ,1.50-1.43(m,6H),1.12-1.06(m,36H). ¹³ C NMR(101MHz, CDCl ₃ )δ149.3,144.6,144.1,122.2,120.0,106.1,103.1,100.2,97.8,57.1,52.1, 50.0, 36.4, 20.7, 18.0, 17.9, 11.9, 11.6.

1.04 g (89%, purity >99%) of compound 33 (Intermediate IV A3) was obtained as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.20 (s, 1H), 7.70 (s, 1H), 7.19 (d, J = 3.2 Hz, 1H), 6.63 (s, 1H), 6.51 (d, J = 3.2Hz,1H),3.57-3.44(m,1H),2.61-2.55(m,2H),2.52-2.47(m,2H),1.91-1.82(m,2H),1.72-1.63(m,2H) ,1.50-1.43(m,6H),1.12-1.06(m,36H). ¹³ C NMR(101MHz, CDCl ₃ )δ149.4,144.8,144.2,122.0,120.1,106.4,103.1,100.1,97.7,52.7,49.3, 33.4, 18.2, 17.8, 11.9, 11.7.

0.98 g (85%, purity >99%) of white solid compound 34 (Intermediate IV A4) was obtained. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.20 (s, 1H), 7.70 (s, 1H), 7.19 (d, J = 3.2 Hz, 1H), 6.63 (s, 1H), 6.51 (d, J = 3.2Hz,1H),3.43-3.31(m,1H),2.71-2.65(m,2H),2.51-2.39(m,2H),1.91-1.82(m,1H),1.72-1.63(m,1H) , 1.51-1.43 (m, 6H), 1.11-1.04 (m, 36H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 149.4, 144.8, 144.2, 122.0, 120.1, 106.4, 103.1, 100.1, 97.7, 57.3, 51.7, 49.8, 36.7, 18.2, 17.7, 11.9, 11.7.

Obtained 0.99 g (85%, purity>99%) of white solid compound 35 (Intermediate IV A5). ¹ H NMR (400MHz, CDCl ₃ ) δ 8.23 (s, 1H), 7.71 (s, 1H), 7.18 (d, J = 3.2 Hz, 1H), 6.62 (s, 1H), 6.50 (d, J = 3.2Hz, 1H), 3.51-3.43 (m, 1H), 2.79-2.66 (m, 2H), 2.50-2.37 (m, 2H), 1.90-1.81 (m, 1H), 1.73-1.63 (m, 1H) , 1.53-1.43 (m, 6H), 1.10-1.03 (m, 36H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 149.5, 144.5, 144.1, 122.2, 120.0, 106.1, 102.1, 99.9, 97.6, 57.1, 51.2, 49.6, 36.1, 18.5, 18.0, 11.9, 11.6.

0.95 g (82%, purity >99%) of compound 36 (Intermediate IV A6) was obtained as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.24 (s, 1H), 7.70 (s, 1H), 7.19 (d, J = 3.2 Hz, 1H), 6.61 (s, 1H), 6.51 (d, J = 3.2Hz,1H),3.41-3.35(m,1H),3.23-3.15(m,1H),2.61-2.49(m,2H),2.46-2.32(m,2H),1.53-1.43(m,6H) ,1.10-1.03(m,36H). ¹³ C NMR(101MHz, CDCl ₃ ) δ149.5,144.5,144.1,122.2,120.0,106.1,102.1,99.9,97.6,53.1,44.2,40.6,38.1,18.4,18.1,11.9 , 11.7.

0.95 g (86%, purity >99%) of compound 37 (Intermediate IV A7) was obtained as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.21 (s, 1H), 7.69 (s, 1H), 7.17 (d, J = 3.2 Hz, 1H), 6.60 (s, 1H), 6.50 (d, J = 3.2Hz,1H),4.09-3.97(m,1H),3.51-3.42(m,2H), 3.10-3.01(m,2H), 2.48-2.40(m,2H),2.33-2.24(m,1H) , 2.10(d,J=5.6Hz,3H)1.51-1.41(m,6H),1.09-1.03(m,36H). ¹³ C NMR(101MHz,CDCl ₃ )δ149.3,144.2,144.0,122.1,120.1,106.8 ,101.9,99.7,97.4,52.1,49.3,45.2,40.6,38.1,22.6,18.2,18.0,11.8,11.7.

1.05 g (91%, purity >99%) of compound 38 (Intermediate IV A8) was obtained as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.25 (s, 1H), 7.72 (s, 1H), 7.21 (d, J = 3.2 Hz, 1H), 6.62 (s, 1H), 6.53 (d, J = 3.2Hz, 1H), 4.01-3.92 (m, 1H), 3.51-3.43 (m, 2H), 2.78-2.63 (m, 2H), 2.23-2.10 (m, 2H), 1.51-1.44 (m, 6H) , 1.12-1.06 (m, 36H). 13 C NMR (101MHz, CDCl 3) δ149.4,144.6,144.5,123.1,120.1,119.3,106.1,102.6,99.9,97.3,57.5,53.3,50.3,36.4,21.7 (d ,J=216Hz),18.5,18.4,11.8,11.3.

0.98 g (83%, purity >99%) of compound 39 (Intermediate IV B1) was obtained as a white solid. ¹ H NMR(400MHz,CDCl ₃ )δ8.23(s,1H), 7.12(d,J=3.6Hz,1H), 6.72(t,J=2.4Hz,1H), 6.58–6.53(m,1H) , 6.52 (d, J = 3.6 Hz, 1H), 6.19 (dd, J = 2.4, 1.6 Hz, 1H), 4.99 (d, J = 8.0 Hz, 1H), 4.11-4.02 (m, 1H), 3.54- 3.46(m,2H),2.81-2.73(m,2H),2.62-2.57(m,2H),2.21-2.11(m,2H),1.70-1.63(m,2H),1.51-1.44(m,6H) ), 1.12-1.06 (m, 36H). ¹³ C NMR (101MHz, CDCl ₃ ) δ149.3,144.7,144.8,123.8,120.1,119.7,107.4,103.1,100.9,99.3,57.5,53.3,50.3,36.4,21.7, 18.5, 18.4, 11.8, 11.3.

0.96 g (81%, purity >99%) of white solid compound 40 (Intermediate IV B2) was obtained. ¹ H NMR(400MHz,CDCl ₃ )δ8.23(s,1H), 7.13(d,J=3.6Hz,1H), 6.71(t,J=2.4Hz,1H), 6.59–6.53(m,1H) , 6.52 (d, J = 3.6 Hz, 1H), 6.18 (dd, J = 2.4, 1.6 Hz, 1H), 5.00 (d, J = 8.0 Hz, 1H), 4.10-4.01 (m, 1H), 3.54- 3.44(m,2H),2.81-2.71(m,2H),2.63-2.56(m,2H),2.22-2.13(m,2H),1.71-1.63(m,2H),1.51-1.44(m,6H) ), 1.12-1.06 (m, 36H). ¹³ C NMR (101MHz, CDCl ₃ ) δ149.3,144.5,144.6,123.4,120.1,119.8,107.3,103.1,100.7,99.2,57.4,53.1,50.3,36.4,21.7, 18.5, 18.4, 11.7, 11.3.

0.93 g (79%, purity >99%) of compound 41 (Intermediate IV B3) was obtained as a white solid. ¹ H NMR(400MHz,CDCl ₃ )δ8.17(s,1H), 7.10(d,J=3.6Hz,1H), 6.69(t,J=2.4Hz,1H), 6.56–6.51(m,1H) ,6.48(d,J=3.6Hz,1H),6.16(dd,J=2.4,1.6Hz,1H), 4.96(d,J=8.0Hz,1H),3.55-3.44(m,1H),2.61- 2.53(m,2H),2.52-2.44(m,2H),1.91-1.82(m,2H),1.72-1.63(m,2H),1.50-1.43(m,6H),1.12-1.06(m,36H) ). ¹³ C NMR (101MHz, CDCl ₃ ) δ148.9,144.1,144.3,123.6,120.0,119.8,107.2,103.0,101.0,99.3,57.1,49.1,33.1,18.0,17.8,11.8,11.6.

0.92 g (81%, purity >99%) of compound 42 (Intermediate IV B4) was obtained as a white solid. ¹ H NMR(400MHz,CDCl ₃ )δ8.21(s,1H), 7.12(d,J=3.6Hz,1H), 6.70(t,J=2.4Hz,1H), 6.53–6.49(m,1H) ,6.45(d,J=3.6Hz,1H),6.17(dd,J=2.4,1.6Hz,1H),5.00(d,J=8.0Hz,1H),3.44-3.33(m,1H),2.72- 2.64 (m, 2H), 2.50-2.41 (m, 2H), 1.91-1.81 (m, 1H), 1.72-1.63 (m, 1H), 1.51-1.43 (m, 6H), 1.11-1.04 (m, 36H) ). ¹³ C NMR (101MHz, CDCl ₃ ) δ149.3,144.5,144.6,123.4,120.1,119.8,107.3,103.1,100.7,99.2,57.3,51.7,49.8,36.7,18.7,18.5,11.8,11.3.

0.93 g (82%, purity >99%) of compound 43 (Intermediate IV B5) was obtained as a white solid. ¹ H NMR(400MHz, CDCl ₃ )δ8.20(s,1H), 7.11(d,J=3.6Hz,1H), 6.69(t,J=2.4Hz,1H), 6.55–6.49(m,1H) ,6.46(d,J=3.6Hz,1H),6.13(dd,J=2.4,1.6Hz,1H),4.99(d,J=8.0Hz,1H),3.43-3.31(m,1H),2.72- 2.63(m,2H),2.52-2.43(m,2H),1.93-1.86(m,1H),1.71-1.63(m,1H),1.50-1.43(m,6H),1.11-1.04(m,36H) ). ¹³ C NMR (101MHz, CDCl ₃ ) δ149.4,144.5,144.5,123.4,120.1,119.6,107.1,103.3,100.5,99.1,57.1,51.4,49.2,36.5,18.6,18.4,11.8,11.3.

Obtained 0.96 g (89%, purity >99%) of white solid compound 44 (Intermediate IV B6). ¹ H NMR(400MHz,CDCl ₃ )δ8.20(s,1H), 7.12(d,J=3.2Hz,1H), 6.70(t,J=2.8Hz,1H), 6.53–6.45(m,1H) , 6.46(d,J=3.2Hz,1H), 6.16(dd,J=2.8,1.6Hz,1H), 3.40-3.35(m,1H),3.26-3.15(m,1H), 2.60-2.47(m , 2H), 2.43-2.32 (m, 2H), 1.52-1.43 (m, 6H), 1.12-1.03 (m, 36H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 149.3, 144.4, 144.1, 122.0, 120.2, 119.6, 106.2, 102.3, 100.5, 97.6, 53.2, 44.1, 40.6, 38.1, 18.4, 18.1, 11.8, 11.7.

0.95 g (86%, purity>99%) of compound 45 (Intermediate IV B7) was obtained as a white solid. ¹ H NMR(400MHz,CDCl ₃ )δ8.21(s,1H), 7.17(d,J=3.2Hz,1H), 6.72(t,J=2.8Hz,1H), 6.53–6.42(m,1H) ,6.48(d,J=3.2Hz,1H),6.19(dd,J=2.8,1.6Hz,1H),4.10-3.97(m,1H),3.52-3.41(m,2H),3.13-3.01(m ,2H),2.45-2.38(m,2H),2.31-2.22(m,1H), 2.12(d,J=5.6Hz,3H) 1.51-1.40(m,6H),1.09-1.02(m,36H) . ¹³ C NMR (101MHz, CDCl ₃ ) δ149.3,144.2,144.0,122.1,120.1,119.3,106.1,102.2,100.2,97.6,52.2,49.1,45.3,40.2,38.1,22.2,18.4,18.0,11.9,11.6.

1.05 g (91%, purity>99%) of compound 46 (Intermediate IV B8) was obtained as a white solid. ¹ H NMR(400MHz,CDCl ₃ )δ8.23(s,1H), 7.19(d,J=3.2Hz,1H), 6.71(t,J=2.8Hz,1H), 6.58–6.50(m,1H) ,6.45(d,J=3.2Hz,1H),6.11(dd,J=2.8,1.6Hz,1H),4.10–3.99(m,1H),3.51-3.43(m,2H),2.77-2.62(m , 2H), 2.21-2.10 (m, 2H), 1.52-1.41 (m, 6H), 1.13-1.06 (m, 36H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 149.5, 144.7, 144.3, 123.2, 120.2, 119.1, 106.2, 102.4, 100.1, 97.2, 57.2, 52.1, 50.1, 36.2, 21.5 (d, J = 216Hz), 18.3, 18.1, 11.7, 11.3.

Example 23-332:

The following general methods are used to obtain the compounds in Examples 23-325 from the key intermediates IV A1-IV B5

Example 23:

Step g: Under the protection of nitrogen, at 0℃, add compound 31 (1.19g, 2.0mmol and sodium hydride (0.096g, 4.0mmol) in 20ml tetrahydrofuran and stir for 10 minutes, then add iodomethane (0.29g, 2mmol) After dropping, stir at room temperature for 3 hours. Add water to quench the reaction and extract with dichloromethane. The combined organics are filtered and concentrated, and the resulting residue is chromatographed on silica gel with petroleum ether/ethyl acetate (20:1-10: 1) Purification, to obtain 1.1g (90%, purity>99%) of white solid compound 47. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.31 (s, 1H), 7.72 (s, 1H), 7.14 (d ,J=3.2Hz,1H),6.66(s,1H),6.53(d,J=3.2Hz,1H),3.56-3.48(m,3H),2.82-2.71(m,2H),2.66-2.57( m,2H),2.41(s,3H),1.72-1.62(m,2H),1.50-1.43(m,6H),1.12-1.06(m,36H). ¹³ C NMR(101MHz, CDCl ₃ )δ172. 5,149.3,144.6,144.1,122.1,120.2,106.1,102.5,100.1,97.1,57.0,52.2,50.0,46.9,36.3,20.6,18.0,17.8,11.9,11.7.

Step h: Under nitrogen protection, dissolve compound 47 (1.22g, 2.0mmol) in 20ml tetrahydrofuran in a 50ml round bottom flask, add tetrabutylammonium fluoride (1M THF solution 4.8ml, 4.8mmol), and stir at room temperature overnight. After the reaction, it was quenched by adding water and extracted with dichloromethane. The combined organics were filtered and concentrated, and the resulting residue was purified by silica gel chromatography with dichloromethane/methanol (10:1) to obtain 0.58 g (90%, purity >99%) of compound 48 as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ 10.31 (s, 1H), 8.22 (s, 1H), 7.80 (br, 2H), 7.16 (d, J = 3.6 Hz, 1H), 6.52 (d, J = 3.6Hz, 1H), 3.54-3.44 (m, 3H), 2.81-2.73 (m, 2H), 2.62-2.56 (m, 2H), 2.45 (s, 3H), 2.20-2.14 (m, 2H), 1.70 -1.61 (m, 2H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 172.7, 149.2, 144.7, 144.2, 121.9, 120.1, 106.2, 103.1, 100.3, 97.5, 56.9, 52.1, 50.3, 46.9, 36.2, 21.1,20.4 .

Example 143:

Step g: Under the protection of nitrogen, at 0℃, add compound 31 (1.19g, 2.0mmol and triethylamine (0.4g, 4.0mmol) in 20ml of dichloromethane) and stir for 10 minutes, then add acetyl chloride (0.24 g, 3mmol), after the dropping, stirred at room temperature for 3 hours. The reaction was quenched by adding water and extracted with dichloromethane. The combined organics were filtered and concentrated, and the resulting residue was chromatographed on silica gel with petroleum ether/ethyl acetate (20:1 -10:1) purification, to obtain 1.2g (91%, purity>99%) of white solid compound 49. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.21 (s, 1H), 7.72 (s, 1H), 7.19(d,J=3.2Hz,1H),6.62(s,1H),6.50(d,J=3.2Hz,1H),3.51-3.43(m,3H),2.82-2.75(m,2H),2.62 -2.56(m,2H),2.26(s,3H),1.70-1.62(m,2H),1.50-1.43(m,6H),1.12-1.06(m,36H). ¹³ C NMR(101MHz, CDCl ₃ )δ172.5,149.3,144.7,144.1,122.1,120.2,106.1,102.9,100.1,97.1,57.0,52.2,50.0,36.3,21.1,20.6,18.0,17.8,11.9,11.7.

Step h: Under nitrogen protection, dissolve compound 49 (1.27g, 2.0mmol) in 20ml tetrahydrofuran in a 50ml round bottom flask, add tetrabutylammonium fluoride (1M THF solution 4.8ml, 4.8mmol), stir at room temperature overnight. After the reaction, it was quenched by adding water and extracted with dichloromethane. The combined organics were filtered and concentrated, and the residue obtained was purified by silica gel chromatography with dichloromethane/methanol (10:1) to obtain 0.58 g (90%, purity >99%) of a white solid compound as Example 143 In the compound. ¹ H NMR (400MHz, CDCl ₃ ) δ 10.31 (s, 1H), 8.22 (s, 1H), 7.76 (br, 2H), 7.16 (d, J = 3.6 Hz, 1H), 6.50 (d, J = 3.6Hz, 1H), 3.54-3.44 (m, 3H), 2.90 (s, 3H), 2.80-2.73 (m, 2H), 2.60-2.56 (m, 2H), 2.26 (s, 3H), 2.21-2.14 (m,2H),1.70-1.62(m,2H). ¹³ C NMR(101MHz, CDCl ₃ )δ172.5,149.9,145.0,144.1,122.1,120.1,106.3,103.3,100.2,97.8,57.2,52.1,50.3, 36.2, 21.1,20.6.

Example 203:

Under the protection of nitrogen, compound 31 (1.19g, 2mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.31g, 2mmol) and ethyl cyanoacetate were sequentially combined in a 100ml round bottom flask. The ester (0.68g, 6mmol) was dissolved in 20ml ethanol and stirred at 45°C for 12 hours. The reaction was cooled to room temperature, ethanol was removed under reduced pressure, the residue was dissolved in ethyl acetate, washed with water, brine, and concentrated. The residue obtained was purified by silica gel chromatography with methanol/dichloromethane (1:20) to obtain 0.9g ( 86%, purity>99%) white solid compound 50. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.20 (s, 1H), 7.71 (s, 1H), 7.11 (d, J = 3.6 Hz, 1H), 6.61 (s, 1H), 6.46 (d, J = 3.6Hz, 1H), 3.47-3.40 (m, 3H), 2.86-2.73 (m, 2H), 2.73-2.61 (m, 2H), 2.21-2.11 (m, 2H), 1.74-1.66 (m, 2H) ,1.50-1.41(m,6H),1.12-1.04(m,36H). ¹³ C NMR(101MHz, CDCl ₃ )δ 166.8, 149.1, 144.5, 144.0, 135.3, 121.1, 120.1, 106.2, 103.6, 100.1, 98.2, 57.3, 51.1, 50.6, 36.2, 25.3, 20.8, 18.0, 17.8, 11.9, 11.7.

Step h: Under nitrogen protection, dissolve compound 50 (1.34g, 2.0mmol) in 20ml tetrahydrofuran in a 50ml round bottom flask, add tetrabutylammonium fluoride (1M THF solution 4.8ml, 4.8mmol), and stir at room temperature overnight. After the reaction, it was quenched by adding water and extracted with dichloromethane. The combined organics were filtered and concentrated, and the obtained residue was purified by silica gel chromatography with dichloromethane/methanol (10:1) to obtain 0.58 g (80%, purity >99%) of a white solid. ¹ H NMR(400MHz,CDCl ₃ )δ10.31(s,1H), 8.20(s,1H), 7.71(s,1H), 7.58(br,2H), 7.13(d,J=3.6Hz,1H) ,6.61(s,1H),6.48(d,J=3.6Hz,1H),3.44-3.34(m,3H),2.87-2.72(m,2H),2.70-2.60(m,2H),2.20-2.11 (m, 2H), 1.73-1.62 (m, 2H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 166.9, 148.9, 144.3, 144.2, 135.1, 121.2, 120.1, 106.1, 103.3, 100.0, 98.1, 57.2, 51.0, 50.4, 36.3, 25.2, 20.9.

Example 233:

Step g: Under the protection of nitrogen, at 0℃, add 31 (1.19g, 2.0mmol and triethylamine (0.4g, 4.0mmol) in 20ml of dichloromethane and stir for 10 minutes, then add methanesulfonyl chloride (0.34 g, 3mmol), after the dropping, stirred at room temperature for 3 hours. The reaction was quenched by adding water and extracted with dichloromethane. The combined organics were filtered and concentrated, and the resulting residue was chromatographed on silica gel with petroleum ether/ethyl acetate (20:1 -10:1) purification, to obtain 1.2g (89%, purity>99%) of white solid compound 51. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.21 (s, 1H), 7.70 (s, 1H), 7.19(d,J=3.2Hz,1H),6.62(s,1H),6.51(d,J=3.2Hz,1H),3.55-3.44(m,3H),2.91(s,3H),2.81-2.75 (m,2H),2.62-2.57(m,2H),2.24-2.15(m,2H),1.70-1.62(m,2H),1.50-1.43(m,6H),1.12-1.06(m,36H) . ¹³ C NMR (101MHz, CDCl ₃ ) δ 149.3, 144.7, 144.2, 122.1, 120.0, 106.1, 102.9, 100.1, 97.1, 57.0, 52.2, 50.0, 43.6, 36.3, 20.7, 18.0, 17.8, 11.9, 11.7.

Step h: Under nitrogen protection, dissolve 51 (1.37g, 2.0mmol) in 20ml of tetrahydrofuran in a 50ml round bottom flask, add tetrabutylammonium fluoride (1M THF solution 4.8ml, 4.8mmol), and stir overnight at room temperature . After the reaction, it was quenched by adding water and extracted with dichloromethane. The combined organics were filtered and concentrated, and the residue obtained was purified by silica gel chromatography with dichloromethane/methanol (10:1) to obtain 0.61 g (82%, purity >99%) of a white solid compound as Example 233 In the compound. ¹ H NMR (400MHz, CDCl ₃ ) δ 10.31 (s, 1H), 8.22 (s, 1H), 7.83 (br, 2H), 7.70 (s, 1H), 7.16 (d, J = 3.6 Hz, 1H) ,6.62(s,1H),6.50(d,J=3.6Hz,1H),3.54-3.44(m,3H),2.90(s,3H),2.80-2.73(m,2H),2.60-2.56(m ,2H),2.21-2.14(m,2H),1.70-1.62(m,2H). ¹³ C NMR (101MHz, CDCl ₃ )δ149.7,144.9,144.2,122.2,120.1,106.5,103.3,100.2,97.9,57.2 , 52.1, 50.3, 43.6, 36.2, 20.6.

Example 373:

Step g: Under the protection of nitrogen, at 0℃, add 36 (1.16g, 2.0mmol and triethylamine (0.4g, 4.0mmol) in 20ml dichloromethane) and stir for 10 minutes, then add propionyl chloride (0.28g , 3mmol), stirred at room temperature for 3 hours after dropping. The reaction was quenched by adding water and extracted with dichloromethane. The combined organics were filtered and concentrated. The residue obtained was chromatographed on silica gel with petroleum ether/ethyl acetate (20:1- 10:1) Purification, to obtain 1.2g (91%, purity>99%) of white solid compound 51. ¹ H NMR (400MHz, CDCl ₃ ) δ ¹ H NMR (400MHz, CDCl ₃ ) δ 8.24 (s, 1H ), 7.70 (s, 1H), 7.19 (d, J = 3.2 Hz, 1H), 6.61 (s, 1H), 6.51 (d, J = 3.2 Hz, 1H), 3.41-3.35 (m, 1H), 3.23 -3.15(m,1H),2.61-2.49(m,2H),2.46-2.32(m,2H),2.26(q,J=7.2Hz,2H)1.53-1.43(m,6H),1.15(t, J = 7.2Hz, 3H), 1.10-1.03 (m, 36H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 173.2, 149.5, 144.5, 144.1, 122.2, 120.0, 106.1, 102.1, 99.9, 97.6, 53.1, 44.2, 40.6,38.1,27.5,18.3,18.0,11.9,11.7,9.1.

Step h: Under the protection of nitrogen, dissolve 52 (1.27g, 2.0mmol) in 20ml tetrahydrofuran in a 50ml round bottom flask, add tetrabutylammonium fluoride (1M THF solution 4.8ml, 4.8mmol), and stir overnight at room temperature . After the reaction, it was quenched by adding water and extracted with dichloromethane. The combined organics were filtered and concentrated, and the residue obtained was purified by silica gel chromatography with dichloromethane/methanol (10:1) to obtain 0.58 g (90%, purity >99%) of a white solid compound as Example 373 In the compound. ¹ H NMR (400MHz, CDCl ₃ ) δ ¹ H NMR (400MHz, CDCl ₃ ) δ 10.31 (s, 1H), 8.24 (s, 1H), 7.83 (br, 2H), 7.70 (s, 1H), 7.19 (d,J=3.2Hz,1H),6.61(s,1H),6.51(d,J=3.2Hz,1H),3.41-3.35(m,1H),3.23-3.15(m,1H), 2.61 2.49(m,2H),2.46-2.32(m,2H), 2.26(q,J=7.2Hz,2H), 1.15(t,J=7.2Hz,3H). ¹³ C NMR(101MHz,CDCl ₃ )δ173 .1,149.2,144.3,144.0,122.1,120.1,106.0,102.2,99.9,97.6,53.2,44.1,40.6,38.3,27.2,9.1.

Example 403

Under the protection of nitrogen, in a 100ml round bottom flask, compound 37 (1.21g, 2mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.31g, 2mmol) and ethyl cyanoacetic acid The ester (0.68g, 6mmol) was dissolved in 20ml ethanol and stirred at 45°C for 12 hours. The reaction was cooled to room temperature, ethanol was removed under reduced pressure, the residue was dissolved with ethyl acetate, washed with water, brine, and concentrated. The residue obtained was purified by silica gel chromatography with methanol/dichloromethane (1:20) to obtain 1.28 g ( 84%, purity>99%) white solid compound 53. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.24 (s, 1H), 7.71 (s, 1H), 7.19 (d, J = 3.2 Hz, 1H), 6.62 (s, 1H), 6.53 (d, J ＝3.2Hz,1H),3.51-3.40(m,3H),2.83-2.72(m,2H),2.71-2.60(m,2H),2.21-2.11(m,2H),2.12(d,J=5.6 Hz, 3H), 1.74-1.66 (m, 2H), 1.50-1.41 (m, 6H), 1.12-1.04 (m, 36H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 166.8, 149.1, 144.5, 144.0, 135.3 ,121.1,120.1,113.2,106.2,103.6,100.1,99.2,57.2,51.3,50.2,36.1,25.3,22.2,20.8,18.0,17.8,11.9,11.7.

Step h: Under nitrogen protection, dissolve compound 53 (1.35g, 2.0mmol) in 20ml tetrahydrofuran in a 50ml round bottom flask, add tetrabutylammonium fluoride (1M THF solution 4.8ml, 4.8mmol), and stir at room temperature overnight. After the reaction, it was quenched by adding water and extracted with dichloromethane. The combined organics were filtered and concentrated, and the residue obtained was purified by silica gel chromatography with dichloromethane/methanol (10:1) to obtain 0.62 g (86%, purity >99%) of a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ 10.31 (s, 1H), 8.23 (s, 1H), 7.80 (br, 2H), 7.63 (s, 1H), 7.16 (d, J = 3.2 Hz, 1H) ,6.61(d,J=3.6Hz,1H),6.53(d,J=3.2Hz,1H),3.51-3.43(m,3H),2.80-2.73(m,2H),2.62-2.56(m,2H) ),2.21-2.14(m,2H),1.70-1.62(m,2H). ¹³ C NMR(101MHz,CDCl ₃ )δ166.3,149.2,144.4,144.1,135.2,121.2,119.8,113.2,106.3,103.4,100.1 ,98.9,57.1,51.7,50.1,43.6,36.2,22.1,20.6.

The following are the structure, preparation method and mass spectrometry characterization data of Example 3-416:

Example number	general formula	R group	Preparation	m/zESI+(M+H) +
3	IV A1	-Benzyl	b,c,d	373.2117
4	IV A2	-Benzyl	b,c,d	373.2131
5	IV A3	-Benzyl	b,c,d	373.2187
6	IV A4	-Benzyl	b,c,d	359.1929
7	IV A5	-Benzyl	b,c,d	359.1912
8	IV B1	-Benzyl	b,c,d	372.2167
9	IV B2	-Benzyl	b,c,d	372.2153
10	IV B3	-Benzyl	b,c,d	372.2147
11	IV B4	-Benzyl	b,c,d	358.2031
12	IV B5	-Benzyl	b,c,d	358.2091
13	IV A1	-H	e	283.1681
14	IV A2	-H	e	283.1675
15	IV A3	-H	e	283.1671
16	IV A4	-H	e	269.1450
17	IV A5	-H	e	269.1443
18	IV B1	-H	e	282.1720
19	IV B2	-H	e	282.1731
20	IV B3	-H	e	282.1719
twenty one	IV B4	-H	e	268.1562
twenty two	IV B5	-H	e	268.1553
twenty three	IV A1	-CH 3	g,h	297.1772
twenty four	IV A2	-CH 3	g,h	297.1768
25	IV A3	-CH 3	g,h	297.1732
26	IV A4	-CH 3	g,h	283.1661
27	IV A5	-CH 3	g,h	283.1655
28	IV B1	-CH 3	g,h	296.1822
29	IV B2	-CH 3	g,h	296.1831
30	IV B3	-CH 3	g,h	296.1832
31	IV B4	-CH 3	g,h	282.1647
32	IV B5	-CH 3	g,h	282.1635
33	IV A1	-CH 2 CH 3	g,h	311.1951
34	IV A2	-CH 2 CH 3	g,h	311.1946
35	IV A3	-CH 2 CH 3	g,h	311.1981
36	IV A4	-CH 2 CH 3	g,h	297.1782
37	IV A5	-CH 2 CH 3	g,h	297.1741

38	IV B1	-CH 2 CH 3	g,h	310.2021
39	IV B2	-CH 2 CH 3	g,h	310.2027
40	IV B3	-CH 2 CH 3	g,h	310.2012
41	IV B4	-CH 2 CH 3	g,h	296.1833
42	IV B5	-CH 2 CH 3	g,h	296.1827
43	IV A1	-CH 2 CH 2 CH 3	g,h	325.2118
44	IV A2	-CH 2 CH 2 CH 3	g,h	325.2130
45	IV A3	-CH 2 CH 2 CH 3	g,h	325.2134
46	IV A4	-CH 2 CH 2 CH 3	g,h	311.1947
47	IV A5	-CH 2 CH 2 CH 3	g,h	311.1951
48	IV B1	-CH 2 CH 2 CH 3	g,h	324.2191
49	IV B2	-CH 2 CH 2 CH 3	g,h	324.2183
50	IV B3	-CH 2 CH 2 CH 3	g,h	324.2141
51	IV B4	-CH 2 CH 2 CH 3	g,h	310.2021
52	IV B5	-CH 2 CH 2 CH 3	g,h	310.2031
53	IV A1	-CH(CH 3 ) 2	g,h	325.2119
54	IV A2	-CH(CH 3 ) 2	g,h	325.2121
55	IV A3	-CH(CH 3 ) 2	g,h	325.2161
56	IV A4	-CH(CH 3 ) 2	g,h	311.1971
57	IV A5	-CH(CH 3 ) 2	g,h	311.1964
58	IV B1	-CH(CH 3 ) 2	g,h	324.2145
59	IV B2	-CH(CH 3 ) 2	g,h	324.2137
60	IV B3	-CH(CH 3 ) 2	g,h	324.2141
61	IV B4	-CH(CH 3 ) 2	g,h	310.2033
62	IV B5	-CH(CH 3 ) 2	g,h	310.2014
63	IV A1	-CH 2 CN	g,h	322.1731
64	IV A2	-CH 2 CN	g,h	322.1742
65	IV A3	-CH 2 CN	g,h	322.1741
66	IV A4	-CH 2 CN	g,h	308.1566
67	IV A5	-CH 2 CN	g,h	308.1548
68	IV B1	-CH 2 CN	g,h	321.1742
69	IV B2	-CH 2 CN	g,h	321.1755
70	IV B3	-CH 2 CN	g,h	321.1761
71	IV B4	-CH 2 CN	g,h	307.1643
72	IV B5	-CH 2 CN	g,h	307.1631
73	IV A1	-CH 2 F	g,h	315.1782
74	IV A2	-CH 2 F	g,h	315.1771
75	IV A3	-CH 2 F	g,h	315.1752
76	IV A4	-CH 2 F	g,h	301.1545
77	IV A5	-CH 2 F	g,h	301.1546
78	IV B1	-CH 2 F	g,h	314.1732
79	IV B2	-CH 2 F	g,h	314.1740
80	IV B3	-CH 2 F	g,h	314.1728
81	IV B4	-CH 2 F	g,h	300.1546
82	IV B5	-CH 2 F	g,h	300.1552
83	IV A1	-CHF 2	g,h	333.1671
84	IV A2	-CHF 2	g,h	333.1658
85	IV A3	-CHF 2	g,h	333.1651
86	IV A4	-CHF 2	g,h	319.1401
87	IV A5	-CHF 2	g,h	319.1420
88	IV B1	-CHF 2	g,h	332.1642

89	IV B2	-CHF 2	g,h	332.1650
90	IV B3	-CHF 2	g,h	332.1646
91	IV B4	-CHF 2	g,h	318.1557
92	IV B5	-CHF 2	g,h	318.1541
93	IV A1	-CF 3	g,h	351.1542
94	IV A2	-CF 3	g,h	351.1509
95	IV A3	-CF 3	g,h	351.1521
96	IV A4	-CF 3	g,h	337.1351
97	IV A5	-CF 3	g,h	337.1342
98	IV B1	-CF 3	g,h	350.1546
99	IV B2	-CF 3	g,h	350.1551
100	IV B3	-CF 3	g,h	350.3619
101	IV B4	-CF 3	g,h	336.1417
102	IV B5	-CF 3	g,h	336.1423
103	IV A1	-Cyclobutyl	g,h	337.2119
104	IV A2	-Cyclobutyl	g,h	337.2141
105	IV A3	-Cyclobutyl	g,h	337.4401
106	IV A4	-Cyclobutyl	g,h	323.1918
107	IV A5	-Cyclobutyl	g,h	323.1921
108	IV B1	-Cyclobutyl	g,h	336.2129
109	IV B2	-Cyclobutyl	g,h	336.2130
110	IV B3	-Cyclobutyl	g,h	336.2143
111	IV B4	-Cyclobutyl	g,h	322.2017
112	IV B5	-Cyclobutyl	g,h	322.2031
113	IV A1	-Cyclobutyl methyl	g,h	351.2218
114	IV A2	-Cyclobutyl methyl	g,h	351.2251
115	IV A3	-Cyclobutyl methyl	g,h	351.2216
116	IV A4	-Cyclobutyl methyl	g,h	337.2132
117	IV A5	-Cyclobutyl methyl	g,h	337.2114
118	IV B1	-Cyclobutyl methyl	g,h	350.2319
119	IV B2	-Cyclobutyl methyl	g,h	350.2331
120	IV B3	-Cyclobutyl methyl	g,h	350.2331
121	IV B4	-Cyclobutyl methyl	g,h	336.2134
122	IV B5	-Cyclobutyl methyl	g,h	336.2136
123	IV A1	-Cyclopentyl	g,h	351.2254
124	IV A2	-Cyclopentyl	g,h	351.2234
125	IV A3	-Cyclopentyl	g,h	351.2243
126	IV A4	-Cyclopentyl	g,h	337.2132
127	IV A5	-Cyclopentyl	g,h	337.2146
128	IV B1	-Cyclopentyl	g,h	350.2371
129	IV B2	-Cyclopentyl	g,h	350.2354
130	IV B3	-Cyclopentyl	g,h	350.2341
131	IV B4	-Cyclopentyl	g,h	336.2117
132	IV B5	-Cyclopentyl	g,h	336.2124
133	IV A1	-Cyclopentylmethyl	g,h	365.2440
134	IV A2	-Cyclopentylmethyl	g,h	365.2434
135	IV A3	-Cyclopentylmethyl	g,h	365.4721
136	IV A4	-Cyclopentylmethyl	g,h	351.2243
137	IV A5	-Cyclopentylmethyl	g,h	351.2231
138	IV B1	-Cyclopentylmethyl	g,h	364.2431
139	IV B2	-Cyclopentylmethyl	g,h	364.2434

140	IV B3	-Cyclopentylmethyl	g,h	364.2461
141	IV B4	-Cyclopentylmethyl	g,h	350.2350
142	IV B5	-Cyclopentylmethyl	g,h	350.2341
143	IV A1	-C(O)CH 3	g,h	325.1728
144	IV A2	-C(O)CH 3	g,h	325.1733
145	IV A3	-C(O)CH 3	g,h	325.1732
146	IV A4	-C(O)CH 3	g,h	311.1551
147	IV A5	-C(O)CH 3	g,h	311.1539
148	IV B1	-C(O)CH 3	g,h	324.1751
149	IV B2	-C(O)CH 3	g,h	324.1744
150	IV B3	-C(O)CH 3	g,h	324.1736
151	IV B4	-C(O)CH 3	g,h	310.1672
152	IV B5	-C(O)CH 3	g,h	310.1666
153	IV A1	-C(O)CH 2 CH 3	g,h	339.1942
154	IV A2	-C(O)CH 2 CH 3	g,h	339.1928
155	IV A3	-C(O)CH 2 CH 3	g,h	339.1927
156	IV A4	-C(O)CH 2 CH 3	g,h	325.1745
157	IV A5	-C(O)CH 2 CH 3	g,h	325.1748
158	IV B1	-C(O)CH 2 CH 3	g,h	338.1942
159	IV B2	-C(O)CH 2 CH 3	g,h	338.1927
160	IV B3	-C(O)CH 2 CH 3	g,h	338.1927
161	IV B4	-C(O)CH 2 CH 3	g,h	234.1746
162	IV B5	-C(O)CH 2 CH 3	g,h	324.1735
163	IV A1	-C(O)CH(CH 3 ) 2	g,h	353.2043
164	IV A2	-C(O)CH(CH 3 ) 2	g,h	353.2059
165	IV A3	-C(O)CH(CH 3 ) 2	g,h	353.2047
166	IV A4	-C(O)CH(CH 3 ) 2	g,h	339.1907
167	IV A5	-C(O)CH(CH 3 ) 2	g,h	339.1921
168	IV B1	-C(O)CH(CH 3 ) 2	g,h	352.2119
169	IV B2	-C(O)CH(CH 3 ) 2	g,h	352.2140
170	IV B3	-C(O)CH(CH 3 ) 2	g,h	352.2161
171	IV B4	-C(O)CH(CH 3 ) 2	g,h	338.1937
172	IV B5	-C(O)CH(CH 3 ) 2	g,h	338.1941
173	IV A1	-C(O)CH 2 F	g,h	343.1629
174	IV A2	-C(O)CH 2 F	g,h	343.1638
175	IV A3	-C(O)CH 2 F	g,h	343.1617
176	IV A4	-C(O)CH 2 F	g,h	329.1440
177	IV A5	-C(O)CH 2 F	g,h	329.1431
178	IV B1	-C(O)CH 2 F	g,h	342.1728
179	IV B2	-C(O)CH 2 F	g,h	342.1731
180	IV B3	-C(O)CH 2 F	g,h	342.1737
181	IV B4	-C(O)CH 2 F	g,h	328.1543
182	IV B5	-C(O)CH 2 F	g,h	328.1536
183	IV A1	-C(O)CH(CH 3 )F	g,h	357.1834
184	IV A2	-C(O)CH(CH 3 )F	g,h	357.1826
185	IV A3	-C(O)CH(CH 3 )F	g,h	357.1842
186	IV A4	-C(O)CH(CH 3 )F	g,h	343.1629
187	IV A5	-C(O)CH(CH 3 )F	g,h	343.1635
188	IV B1	-C(O)CH(CH 3 )F	g,h	356.1851
189	IV B2	-C(O)CH(CH 3 )F	g,h	356.1855
190	IV B3	-C(O)CH(CH 3 )F	g,h	356.1827

191	IV B4	-C(O)CH(CH 3 )F	g,h	342.1731
192	IV B5	-C(O)CH(CH 3 )F	g,h	342.1723
193	IV A1	-C(O)CHF 2	g,h	361.1565
194	IV A2	-C(O)CHF 2	g,h	361.1570
195	IV A3	-C(O)CHF 2	g,h	361.1551
196	IV A4	-C(O)CHF 2	g,h	347.1425
197	IV A5	-C(O)CHF 2	g,h	347.1436
198	IV B1	-C(O)CHF 2	g,h	360.1636
199	IV B2	-C(O)CHF 2	g,h	360.1627
200	IV B3	-C(O)CHF 2	g,h	360.1644
201	IV B4	-C(O)CHF 2	g,h	346.1432
202	IV B5	-C(O)CHF 2	g,h	346.1455
203	IV A1	-C(O)CH 2 CN	g,h	336.1528
204	IV A2	-C(O)CH 2 CN	g,h	336.1547
205	IV A3	-C(O)CH 2 CN	g,h	336.1552
206	IV A4	-C(O)CH 2 CN	g,h	322.1342
207	IV A5	-C(O)CH 2 CN	g,h	322.1329
208	IV B1	-C(O)CH 2 CN	g,h	349.1742
209	IV B2	-C(O)CH 2 CN	g,h	349.1747
210	IV B3	-C(O)CH 2 CN	g,h	349.1723
211	IV B4	-C(O)CH 2 CN	g,h	321.1455
212	IV B5	-C(O)CH 2 CN	g,h	321.1469
213	IV A1	-Cyclobutyl formyl	g,h	365.2037
214	IV A2	-Cyclobutyl formyl	g,h	365.2043
215	IV A3	-Cyclobutyl formyl	g,h	365.2051
216	IV A4	-Cyclobutyl formyl	g,h	351.1935
217	IV A5	-Cyclobutyl formyl	g,h	351.1943
218	IV B1	-Cyclobutyl formyl	g,h	364.2132
219	IV B2	-Cyclobutyl formyl	g,h	364.2145
220	IV B3	-Cyclobutyl formyl	g,h	364.2118
221	IV B4	-Cyclobutyl formyl	g,h	350.1933
222	IV B5	-Cyclobutyl formyl	g,h	350.1945
223	IV A1	-Cyclopentylformyl	g,h	379.2243
224	IV A2	-Cyclopentylformyl	g,h	379.2231
225	IV A3	-Cyclopentylformyl	g,h	379.2218
226	IV A4	-Cyclopentylformyl	g,h	365.2049
227	IV A5	-Cyclopentylformyl	g,h	365.2034
228	IV B1	-Cyclopentylformyl	g,h	378.2234
229	IV B2	-Cyclopentylformyl	g,h	378.2241
230	IV B3	-Cyclopentylformyl	g,h	378.2241
231	IV B4	-Cyclopentylformyl	g,h	364.2117
232	IV B5	-Cyclopentylformyl	g,h	364.2130
233	IV A1	-S(O) 2 CH 3	g,h	361.1453
234	IV A2	-S(O) 2 CH 3	g,h	361.1446
235	IV A3	-S(O) 2 CH 3	g,h	361.1442
236	IV A4	-S(O) 2 CH 3	g,h	347.1227
237	IV A5	-S(O) 2 CH 3	g,h	347.1258
238	IV B1	-S(O) 2 CH 3	g,h	360.1428
239	IV B2	-S(O) 2 CH 3	g,h	360.1436
240	IV B3	-S(O) 2 CH 3	g,h	360.1463
241	IV B4	-S(O) 2 CH 3	g,h	346.1323

242	IV B5	-S(O) 2 CH 3	g,h	346.1342
243	IV A1	-S(O) 2 CH 2 CH 3	g,h	375.1525
244	IV A2	-S(O) 2 CH 2 CH 3	g,h	375.1531
245	IV A3	-S(O) 2 CH 2 CH 3	g,h	375.1523
246	IV A4	-S(O) 2 CH 2 CH 3	g,h	361.1435
247	IV A5	-S(O) 2 CH 2 CH 3	g,h	361.1461
248	IV B1	-S(O) 2 CH 2 CH 3	g,h	374.1638
249	IV B2	-S(O) 2 CH 2 CH 3	g,h	374.1647
250	IV B3	-S(O) 2 CH 2 CH 3	g,h	374.1634
251	IV B4	-S(O) 2 CH 2 CH 3	g,h	360.1442
252	IV B5	-S(O) 2 CH 2 CH 3	g,h	360.1441
253	IV A1	-S(O) 2 CH 2 CH 2 CH 3	g,h	389.1739
254	IV A2	-S(O) 2 CH 2 CH 2 CH 3	g,h	389.1740
255	IV A3	-S(O) 2 CH 2 CH 2 CH 3	g,h	389.1726
256	IV A4	-S(O) 2 CH 2 CH 2 CH 3	g,h	375.1561
257	IV A5	-S(O) 2 CH 2 CH 2 CH 3	g,h	375.1560
258	IV B1	-S(O) 2 CH 2 CH 2 CH 3	g,h	388.1753
259	IV B2	-S(O) 2 CH 2 CH 2 CH 3	g,h	388.1748
260	IV B3	-S(O) 2 CH 2 CH 2 CH 3	g,h	388.1754
261	IV B4	-S(O) 2 CH 2 CH 2 CH 3	g,h	374.1671
262	IV B5	-S(O) 2 CH 2 CH 2 CH 3	g,h	374.1687
263	IV A1	-S(O) 2 CH(CH 3 ) 2	g,h	389.1762
264	IV A2	-S(O) 2 CH(CH 3 ) 2	g,h	389.1749
265	IV A3	-S(O) 2 CH(CH 3 ) 2	g,h	389.1743
266	IV A4	-S(O) 2 CH(CH 3 ) 2	g,h	375.1549
267	IV A5	-S(O) 2 CH(CH 3 ) 2	g,h	375.1551
268	IV B1	-S(O) 2 CH(CH 3 ) 2	g,h	388.1745
269	IV B2	-S(O) 2 CH(CH 3 ) 2	g,h	388.1737
270	IV B3	-S(O) 2 CH(CH 3 ) 2	g,h	388.1742
271	IV B4	-S(O) 2 CH(CH 3 ) 2	g,h	374.1628
272	IV B5	-S(O) 2 CH(CH 3 ) 2	g,h	374.1643
273	IV A1	-S(O) 2 CH 2 F	g,h	379.1328
274	IV A2	-S(O) 2 CH 2 F	g,h	379.1322
275	IV A3	-S(O) 2 CH 2 F	g,h	379.1352
276	IV A4	-S(O) 2 CH 2 F	g,h	365.1121
277	IV A5	-S(O) 2 CH 2 F	g,h	365.1136
278	IV B1	-S(O) 2 CH 2 F	g,h	378.1336
279	IV B2	-S(O) 2 CH 2 F	g,h	378.1341
280	IV B3	-S(O) 2 CH 2 F	g,h	378.1345
281	IV B4	-S(O) 2 CH 2 F	g,h	364.1247
282	IV B5	-S(O) 2 CH 2 F	g,h	364.1231
283	IV A1	-S(O) 2 CH(CH 3 )F	g,h	393.1438
284	IV A2	-S(O) 2 CH(CH 3 )F	g,h	393.1436
285	IV A3	-S(O) 2 CH(CH 3 )F	g,h	393.1438
286	IV A4	-S(O) 2 CH(CH 3 )F	g,h	379.1351
287	IV A5	-S(O) 2 CH(CH 3 )F	g,h	379.1360
288	IV B1	-S(O) 2 CH(CH 3 )F	g,h	392.1527
289	IV B2	-S(O) 2 CH(CH 3 )F	g,h	392.1530
290	IV B3	-S(O) 2 CH(CH 3 )F	g,h	392.1543
291	IV B4	-S(O) 2 CH(CH 3 )F	g,h	378.1334
292	IV B5	-S(O) 2 CH(CH 3 )F	g,h	378.1345

293	IV A1	-S(O) 2 CHF 2	g,h	397.1243
294	IV A2	-S(O) 2 CHF 2	g,h	397.1231
295	IV A3	-S(O) 2 CHF 2	g,h	397.1247
296	IV A4	-S(O) 2 CHF 2	g,h	383.1045
297	IV A5	-S(O) 2 CHF 2	g,h	383.1047
298	IV B1	-S(O) 2 CHF 2	g,h	396.1233
299	IV B2	-S(O) 2 CHF 2	g,h	396.1228
300	IV B3	-S(O) 2 CHF 2	g,h	386.1256
301	IV B4	-S(O) 2 CHF 2	g,h	382.1145
302	IV B5	-S(O) 2 CHF 2	g,h	382.1153
303	IV A1	-S(O) 2 CH 2 CN	g,h	386.1349
304	IV A2	-S(O) 2 CH 2 CN	g,h	386.1355
305	IV A3	-S(O) 2 CH 2 CN	g,h	386.1345
306	IV A4	-S(O) 2 CH 2 CN	g,h	372.1237
307	IV A5	-S(O) 2 CH 2 CN	g,h	372.1263
308	IV B1	-S(O) 2 CH 2 CN	g,h	385.1462
309	IV B2	-S(O) 2 CH 2 CN	g,h	385.1470
310	IV B3	-S(O) 2 CH 2 CN	g,h	385.1451
311	IV B4	-S(O) 2 CH 2 CN	g,h	371.1275
312	IV B5	-S(O) 2 CH 2 CN	g,h	371.1279
313	IV A1	-Cyclobutylsulfonyl	g,h	401.1721
314	IV A2	-Cyclobutylsulfonyl	g,h	401.1729
315	IV A3	-Cyclobutylsulfonyl	g,h	491.1728
316	IV A4	-Cyclobutylsulfonyl	g,h	387.1542
317	IV A5	-Cyclobutylsulfonyl	g,h	387.1533
318	IV B1	-Cyclobutylsulfonyl	g,h	400.1745
319	IV B2	-Cyclobutylsulfonyl	g,h	400.1734
320	IV B3	-Cyclobutylsulfonyl	g,h	400.1731
321	IV B4	-Cyclobutylsulfonyl	g,h	386.1627
322	IV B5	-Cyclobutylsulfonyl	g,h	386.1643
323	IV A1	-Cyclopentylsulfonyl	g,h	415.1832
324	IV A2	-Cyclopentylsulfonyl	g,h	415.1842
325	IV A3	-Cyclopentylsulfonyl	g,h	415.1837
326	IV A4	-Cyclopentylsulfonyl	g,h	401.1729
327	IV A5	-Cyclopentylsulfonyl	g,h	401.1721
328	IV B1	-Cyclopentylsulfonyl	g,h	414.1928
329	IV B2	-Cyclopentylsulfonyl	g,h	414.1911
330	IV B3	-Cyclopentylsulfonyl	g,h	414.1928
331	IV B4	-Cyclopentylsulfonyl	g,h	400.1753
332	IV B5	-Cyclopentylsulfonyl	g,h	400.1747
333	IV A6	-Methylsulfonyl	g,h	346.1228
334	IV B6	-Methylsulfonyl	g,h	345.1306
335	IV A6	-Ethylsulfonyl	g,h	360.1413
336	IV B6	-Ethylsulfonyl	g,h	359.1407
337	IV A6	-Propylsulfonyl	g,h	374.1519
338	IV B6	-Propylsulfonyl	g,h	373.1611
339	IV A6	-Butylsulfonyl	g,h	388.1717
340	IV B6	-Butylsulfonyl	g,h	387.1712
341	IV A6	-Isopropylsulfonyl	g,h	374.1517
342	IV B6	-Isopropylsulfonyl	g,h	373.1610
343	IV A6	-Cyclopropylsulfonyl	g,h	372.1415

344	IV B6	-Cyclopropylsulfonyl	g,h	371.1403
345	IV A6	-Cyclopropylmethylsulfonyl	g,h	386.1521
346	IV B6	-Cyclopropylmethylsulfonyl	g,h	385.1611
347	IV A6	-Cyclopropylethylsulfonyl	g,h	400.1725
348	IV B6	-Cyclopropylethylsulfonyl	g,h	399.1713
349	IV A6	-Cyclobutylsulfonyl	g,h	386.1523
350	IV B6	-Cyclobutylsulfonyl	g,h	385.1619
351	IV A6	-Cyclobutyl Methanesulfonyl	g,h	400.1723
352	IV B6	-Cyclobutyl Methanesulfonyl	g,h	399.1715
353	IV A6	-3-Epoxybutylsulfonyl	g,h	388.1341
354	IV B6	-3-Epoxybutylsulfonyl	g,h	387.1433
355	IV A6	-3-Epoxybutyl methylsulfonyl	g,h	402.1521
356	IV B6	-3-Epoxybutyl methylsulfonyl	g,h	401.1512
357	IV A6	-2-N-Methyl-pyrrolesulfonyl	g,h	411.1532
358	IV B6	-2-N-Methyl-pyrrolesulfonyl	g,h	410.1527
359	IV A6	-2-N-Methyl-pyrazolesulfonyl	g,h	412.1420
360	IV B6	-2-N-Methyl-pyrazolesulfonyl	g,h	411.1519
361	IV A6	-S(O) 2 CH 2 CF 3	g,h	414.1153
362	IV B6	-S(O) 2 CH 2 CF 3	g,h	413.1144
363	IV A6	-S(O) 2 (CH 2 ) 2 CF 3	g,h	428.1228
364	IV B6	-S(O) 2 (CH 2 ) 2 CF 3	g,h	427.1309
365	IV A6	-S(O) 2 (CH 2 ) 3 CF 3	g,h	442.1437
366	IV B6	-S(O) 2 (CH 2 ) 3 CF 3	g,h	441.1425
367	IV A6	-S(O) 2 CH 2 CN	g,h	371.1212
368	IV B6	-S(O) 2 CH 2 CN	g,h	370.1209
369	IV A6	-S(O) 2 (CH 2 ) 2 CN	g,h	385.1344
370	IV B6	-S(O) 2 (CH 2 ) 2 CN	g,h	384.1431
371	IV A6	-Acetyl	g,h	310.1519
372	IV B6	-Acetyl	g,h	309.1603
373	IV A6	-Propionyl	g,h	324.1728
374	IV B6	-Propionyl	g,h	323.1711
375	IV A6	-Butyryl	g,h	338.1928
376	IV B6	-Butyryl	g,h	337.1910
377	IV A6	-Isobutyryl	g,h	338.1943
378	IV B6	-Isobutyryl	g,h	337.1929
379	IV A6	-Cyclopropanoyl	g,h	336.1733
380	IV B6	-Cyclopropanoyl	g,h	335.1713
381	IV A6	-Cyclopropylacetyl	g,h	350.1934
382	IV B6	-Cyclopropylacetyl	g,h	349.1914
383	IV A6	-Cyclobutyryl	g,h	350.1943
384	IV B6	-Cyclobutyryl	g,h	349.1934
385	IV A6	-Cyclobutanyl	g,h	364.2045
386	IV B6	-Cyclobutanyl	g,h	363.2137
387	IV A6	-3-Epoxybutylsulfonyl	g,h	352.1640
388	IV B6	-3-Epoxybutylsulfonyl	g,h	351.1741
389	IV A6	-3-Epoxybutyl methylsulfonyl	g,h	366.1834
390	IV B6	-3-Epoxybutyl methylsulfonyl	g,h	365.1944
391	IV A6	-C(O)CH 2 CF 3	g,h	378.1436
392	IV B6	-C(O)CH 2 CF 3	g,h	378.1426
393	IV A6	-C(O)(CH 2 ) 2 CF 3	g,h	392.1639
394	IV B6	-C(O)(CH 2 ) 2 CF 3	g,h	391.1640

395	IV A6	-C(O)CH 2 CN	g,h	335.1537
396	IV B6	-C(O)CH 2 CN	g,h	334.1528
397	IV A6	-C(O)(CH 2 ) 2 CN	g,h	349.1730
398	IV B6	-C(O)(CH 2 ) 2 CN	g,h	348.1712
399	IV A6	-CH 2 CN	g,h	307.1536
400	IV B6	-CH 2 CN	g,h	306.1627
401	IV A6	-CH 2 CF 3	g,h	350.1535
402	IV B6	-CH 2 CF 3	g,h	349.1516
403	IV A7	-C(O)CH 2 CN	g,h	363.1843
404	IV B7	-C(O)CH 2 CN	g,h	362.1914
405	IV A7	-C(O)CH 2 CF 3	g,h	406.1731
406	IV B7	-C(O)CH 2 CF 3	g,h	405.1813
407	IV A8	-C(O)CH 2 CN	g,h	385.1538
408	IV B8	-C(O)CH 2 CN	g,h	384.1519
409	IV A8	-C(O)CH 2 CF 3	g,h	428.1447
410	IV B8	-C(O)CH 2 CF 3	g,h	427.1438
411	IV A8	-CH 2 CN	g,h	357.1546
412	IV B8	-CH 2 CN	g,h	356.1628
413	IV A8	-CH 2 CF 3	g,h	371.1730
414	IV B8	-CH 2 CF 3	g,h	370.1721
415	To	-C(O)CH2CN	g,h	367.1628
416	To	-C(O)CH2CN	g,h	366.1610

Determination of IC50:

In IRStide peptide (5FAM-KKSRGDYMTMQID) of JAK1 substrate to JAKtide peptide (FITC-KGGEEEEYFELVKK) of JAK2 and JAK3 substrate, containing the ATP 0.1mM, MgCl 20mM of _{2, 2%} DMSO, 50mM phosphate buffer Add recombinant JAK1, JAK2 or JAK3 to the pH 7.0 solution system for reaction, and then use high performance liquid chromatography to determine the amount of phosphorylation of the substrate to determine the IC50 range of the compound. "+++++" means IC50 is less than 50nM, "++++" means IC50 is between 50nM and 200nM, "+++" means IC50 is between 200nM and 500nM, "++" means IC50 is between Between 500nM and 1000nM, "+" means IC50 is above 1000nM, blank means no inhibitory effect.

Example number	JAK1IC 50	JAK2IC 50	JAK3IC 50
1	+++++	++++	++++
2	+++++	++++	++++
3	+++++	++++	++++
4	+++++	++++	+++
5	+++++	++++	++++
6	+++++	++++	++++
7	+++++	++++	++++
8	+++++	++++	++++
9	+++++	++++	++++
10	+++++	++++	++++
11	+++++	+++	++++
12	+++++	++++	++++
13	+++++	++++	+++
14	+++++	++++	++++
15	+++++	++++	++++
16	+++++	++++	++++

17	+++++	++++	++++
18	+++++	++++	+++
19	+++++	++++	++++
20	+++++	++++	++++
twenty one	++++	+++	++++
twenty two	+++++	++++	++++
twenty three	+++++	++++	++++
twenty four	+++++	++++	++++
25	+++++	++++	++++
26	+++++	++++	++++
27	+++++	++++	++++
28	+++++	++++	++++
29	+++++	+++	++++
30	+++++	++++	++++
31	+++++	++++	++++
32	+++++	++++	++++
33	+++++	++++	++++
34	+++++	++++	++++
35	+++++	++++	++++
36	+++++	++++	++++
37	+++++	++++	++++
38	+++++	++++	++++
39	+++++	++++	++++
40	+++++	++++	++++
41	+++++	++++	++++
42	+++++	++++	++++
43	+++++	++++	++++
44	+++++	++++	++++
45	+++++	+++++	++++
46	+++++	++++	++++
47	+++++	++++	++++
48	+++++	++++	++++
49	+++++	++++	++++
50	+++++	++++	++++
51	+++++	++++	++++
52	+++++	++++	++++
53	++++	++++	+++
54	+++++	++++	+++
55	+++++	++++	++++
56	+++++	++++	++++
57	+++++	++++	++++
58	+++++	++++	++++
59	+++++	++++	++++
60	+++++	++++	++++
61	+++++	++++	++++
62	+++++	++++	++++
63	+++++	++++	++++

64	+++++	++++	++++
65	+++++	+++++	+++++
66	+++++	++++	++++
67	+++++	++++	++++
68	+++++	++++	++++
69	+++++	++++	++++
70	+++++	++++	++++
71	+++++	++++	++++
72	+++++	+++	+++
73	+++++	++++	++++
74	+++++	++++	++++
75	+++++	++++	++++
76	+++++	++++	++++
77	+++++	++++	++++
78	+++++	++++	++++
79	++++	++++	+++
80	+++++	++++	++++
81	+++++	++++	++++
82	++++	+++	++++
83	+++++	++++	++++
84	+++++	++++	++++
85	+++++	++++	++++
86	+++++	++++	++++
87	+++++	++++	++++
88	++++	+++	++++
89	+++++	++++	++++
90	+++++	++++	++++
91	+++++	++++	++++
92	+++++	++++	++++
93	+++++	++++	++++
94	+++++	++++	++++
95	+++++	++++	++++
96	+++++	++++	++++
97	+++++	++++	++++
98	+++++	++++	++++
99	+++++	++++	++++
100	+++++	++++	+++
101	+++++	++++	++++
102	+++++	++++	++++
103	+++++	++++	++++
104	+++++	++++	++++
105	+++++	++++	+++
106	+++++	++++	++++
107	+++++	++++	++++
108	+++++	++++	++++
109	+++++	++++	++++
110	+++++	++++	++++

111	+++++	++++	++++
112	+++++	++++	++++
113	+++++	++++	+++
114	+++++	++++	++++
115	+++++	++++	++++
116	+++++	++++	++++
117	+++++	++++	++++
118	+++++	++++	++++
119	+++++	++++	++++
120	+++++	++++	++++
121	+++++	++++	++++
122	+++++	++++	++++
123	+++++	++++	+++
124	+++++	++++	++++
125	+++++	++++	++++
126	+++++	++++	++++
127	++++	++++	++++
128	+++++	++++	++++
129	+++++	++++	+++
130	+++++	++++	++++
131	+++++	++++	++++
132	+++++	++++	++++
133	+++++	++++	++++
134	+++++	++++	++++
135	+++++	+++	++++
136	+++++	++++	++++
137	+++++	++++	++++
138	+++++	++++	++++
139	+++++	++++	++++
140	+++++	++++	++++
141	++++	++++	+++
142	+++++	++++	++++
143	+++++	++++	++++
144	+++++	++++	++++
145	+++++	++++	++++
146	+++++	++++	++++
147	+++++	++++	++++
148	+++++	++++	++++
149	+++++	++++	++++
150	+++++	++++	++++
151	+++++	++++	++++
152	+++++	++++	+++
153	+++++	++++	++++
154	++++	++++	++++
155	+++++	++++	++++
156	+++++	++++	++++
157	+++++	++++	++++

158	+++++	++++	++++
159	+++++	+++	++++
160	+++++	++++	++++
161	+++++	++++	++++
162	+++++	+++++	++++
163	+++++	++++	++++
164	+++++	++++	++++
165	+++++	++++	++++
166	++++	+++	++++
167	+++++	++++	++++
168	+++++	++++	++++
169	+++++	++++	++++
170	+++++	++++	++++
171	+++++	++++	++++
172	+++++	++++	++++
173	+++++	++++	++++
174	+++++	++++	++++
175	+++++	++++	++++
176	+++++	++++	++++
177	+++++	++++	++++
178	+++++	++++	++++
179	+++++	++++	++++
180	+++++	++++	++++
181	+++++	++++	++++
182	+++++	++++	++++
183	+++++	+++++	++++
184	+++++	++++	++++
185	+++++	++++	++++
186	+++++	++++	++++
187	+++++	++++	++++
188	+++++	++++	++++
189	+++++	++++	++++
190	+++++	++++	+++++
191	+++++	++++	++++
192	+++++	++++	++++
193	+++++	++++	++++
194	+++++	+++	++++
195	+++++	++++	++++
196	+++++	++++	++++
197	+++++	++++	++++
198	++++	++++	++++
199	+++++	++++	++++
200	+++++	++++	++++
201	+++++	++++	++++
202	++++	++++	++++
203	+++++	++++	++++
204	+++++	+++	++++

205	+++++	++++	++++
206	+++++	++++	++++
207	+++++	++++	++++
208	+++++	++++	++++
209	+++++	++++	++++
210	+++++	++++	++++
211	+++++	++++	++++
212	+++++	++++	++++
213	+++++	+++	++++
214	+++++	++++	++++
215	+++++	++++	++++
216	+++++	++++	++++
217	+++++	++++	++++
218	+++++	++++	++++
219	+++++	++++	++++
220	+++++	+++	++++
221	+++++	++++	+++
222	+++++	++++	+++
223	+++++	++++	++++
224	+++++	++++	++++
225	+++++	++++	++++
226	+++++	++++	+++
227	+++++	++++	++++
228	+++++	++++	++++
229	+++++	++++	++++
230	+++++	++++	++++
231	+++++	+++	+++
232	+++++	++++	++++
233	+++++	++++	++++
234	+++++	++++	++++
235	+++++	++++	++++
236	+++++	+++	++++
237	+++++	++++	++++
238	+++++	++++	+++
239	+++++	++++	++++
240	+++++	++++	++++
241	+++++	++++	++++
242	+++++	++++	++++
243	+++++	++++	++++
244	+++++	++++	+++
245	+++++	++++	++++
246	+++++	++++	++++
247	+++++	++++	++++
248	+++++	++++	++++
249	+++++	++++	++++
250	+++++	++++	++++
251	+++++	++++	+++

252	+++++	++++	++++
253	+++++	++++	++++
254	+++++	++++	++++
255	+++++	++++	++++
256	+++++	++++	++++
257	+++++	++++	++++
258	+++++	+++	++++
259	+++++	++++	++++
260	+++++	++++	++++
261	+++++	++++	++++
262	+++++	++++	++++
263	++++	++++	+++
264	+++++	++++	++++
265	+++++	++++	++++
266	+++++	++++	++++
267	+++++	++++	++++
268	+++++	++++	++++
269	+++++	++++	++++
270	+++++	++++	++++
271	++++	++++	++++
272	+++++	++++	++++
273	+++++	++++	+++++
274	+++++	++++	+++
275	+++++	++++	++++
276	+++++	+++	++++
277	+++++	++++	++++
278	+++++	++++	++++
279	+++++	++++	++++
280	+++++	++++	++++
281	+++++	++++	++++
282	+++++	++++	++++
283	+++++	++++	+++
284	+++++	++++	++++
285	+++++	++++	++++
286	+++++	++++	++++
287	+++++	++++	+++
288	+++++	+++++	++++
289	+++++	++++	++++
290	+++++	++++	++++
291	+++++	++++	++++
292	+++++	++++	++++
293	+++++	++++	++++
294	++++	++++	+++
295	+++++	++++	++++
296	+++++	++++	++++
297	+++++	++++	++++
298	+++++	++++	++++

299	+++++	++++	+++
300	+++++	++++	++++
301	+++++	+++++	++++
302	+++++	++++	++++
303	+++++	++++	++++
304	+++++	++++	++++
305	+++++	++++	++++
306	+++++	+++	+++
307	+++++	++++	++++
308	+++++	++++	++++
309	+++++	+++	++++
310	+++++	++++	++++
311	+++++	++++	+++
312	+++++	++++	++++
313	+++++	++++	++++
314	+++++	++++	+++
315	+++++	+++	++++
316	+++++	++++	++++
317	+++++	++++	++++
318	+++++	++++	++++
319	+++++	++++	++++
320	+++++	++++	++++
321	+++++	++++	++++
322	+++++	++++	++++
323	+++++	++++	++++
324	+++++	++++	++++
325	+++++	++++	++++
326	+++++	++++	++++
327	+++++	++++	++++
328	+++++	+++	++++
329	+++++	++++	++++
330	+++++	++++	+++
331	+++++	++++	++++
332	+++++	+++	+++
333	+++++	++++	++++
334	++++	+++	+++
335	++++	+++	+++
336	+++++	++++	++++
337	+++++	++++	++++
338	+++++	+++	++++
339	+++++	+++	++++
340	+++++	++++	+++
341	+++++	++++	+++
342	+++++	++++	++++
343	+++++	++++	+++
344	+++++	+++	+++
345	+++++	++++	++++

346	+++++	++++	++++
347	+++++	++++	++++
348	+++++	++++	++++
349	+++++	++++	++++
350	+++++	++++	+++
351	+++++	++++	+++
352	+++++	++++	++++
353	++++	+++	+++
354	++++	+++	+++
355	+++++	++++	++++
356	+++++	++++	++++
357	+++++	+++	++++
358	+++++	++++	++++
359	+++++	++++	++++
360	+++++	+++	+++
361	+++++	++++	++++
362	+++++	++++	++++
363	+++++	+++	++++
364	+++++	++++	++++
365	+++++	++++	+++
366	+++++	++++	++++
367	+++++	++++	++++
368	+++++	++++	+++
369	+++++	+++	++++
370	+++++	+++	++++
371	+++++	++++	++++
372	+++++	++++	++++
373	+++++	++++	++++
374	+++++	++++	++++
375	+++++	++++	+++
376	+++++	++++	+++
377	+++++	+++	+++
378	+++++	++++	++++
379	+++++	++++	++++
380	+++++	++++	++++
381	+++++	+++	+++
382	+++++	+++	+++
383	+++++	++++	++++
384	+++++	++++	++++
385	+++++	+++	+++
386	+++++	++++	++++
387	+++++	++++	++++
388	+++++	+++	+++
389	+++++	++++	++++
390	+++++	++++	+++
391	+++++	++++	++++
392	+++++	++++	++++

393	+++++	+++	+++
394	+++++	++++	++++
395	+++++	++++	++++
396	+++++	++++	++++
397	+++++	++++	++++
398	+++++	++++	++++
399	+++++	++++	++++
400	+++++	++++	++++
401	+++++	++++	++++
402	+++++	++++	++++
403	+++++	++++	++++
404	+++++	++++	++++
405	+++++	++++	++++
406	+++++	+++	++++
407	+++++	+++	++++
408	+++++	++++	++++
409	+++++	+++	++++
410	+++++	+++	+++
411	+++++	++++	++++
412	+++++	++++	++++
413	+++++	+++	++++
414	+++++	+++	++++
415	+++++	++++	++++
416	+++++	++++	++++

Mouse collagen induced arthritis model:

Eight-week-old male DBA/1 mice were selected and subcutaneously immunized with 50 micrograms of type II chicken collagen emulsified in complete Freund’s adjuvant, and added 50 micrograms emulsified in incomplete Freund’s adjuvant 21 days later. Type II chicken collagen. Observe and record from the 42nd day. Using the scoring method: 1 point, normal; 2 points, 1 joint swelling; 3 points, more than one joint swelling, but not all joints accumulated; 4 points, the entire paw is severely swollen or rigid. The scores of each paw are added to obtain the total score of mouse arthritis. After the model was successfully established, the mice were gavaged with the compound or physiological saline at a dose of 5 mg/kg, 12 hours apart in the morning and evening, and the mice’s arthritis score was scored two weeks after the administration. The compound has obvious therapeutic effect on mouse arthritis.

Compound group	Arthritis score
Blank control group	1
Saline control group	3.7
Example 1	2.6
Example 33	2.1
Example 63	2.4
Example 65	2.7
Example 93	2.3
Example 98	2.7
Example 143	2.6
Example 203	2.0
Example 219	2.2
Example 305	2.4
Example 339	2.2
Example 403	2.1

Experiment to promote hair growth:

The compound of the invention was added to the emulsifier to make a 2% ointment. The blank control was the emulsifier paste without the compound. The backs of 10-week-old C57 mice were selected and then divided into groups. Methods: The mice were smeared and administered at an interval of 12 hours in the morning and evening, and then the average time for the appearance of dark spots on the skin of each group of mice was observed, and half of the hair was long for the entire time. The results showed that the mice in the administration group showed black plaques and a small amount of hair growth on the coated part at about 12 days. The black plaques spread and expanded over time and more hairs grew. The mice were on average At about 32 days, the hair on the right side of the body with the medicine was long and full, while the left half of the body did not change. The blank control group showed black patches on the back at about 36 days, and in the next three The hair around the entire back is long and full, and the results show that the compound of the present invention has obvious hair growth promoting effect.

Compound group	Average time of appearance of black patches (days)	Average length of half bristle hair (days)
Blank control	36.5
Example 1	12.3	31.5
Example 2	11.5	30.8
Example 33	13.3	32.0
Example 35	12	29.5
Example 65	11.2	32.3
Example 95	11.5	32.5
Example 118	12.5	31.8
Example 190	12.8	34
Example 211	11.8	29.8
Example 309	13.5	33.2
Example 339	12.0	31.5
Example 403	12.5	31.0

Claims (21)

1. A compound of the structure represented by the general formula I or its tautomer, meso, racemate, enantiomer, diastereomer, and mixture forms thereof, and pharmacological properties thereof Salt used:

   

   R ^1, R ² and R ^{3 are} independently selected from hydrogen, deuterium, halo, ^{cyano, -NR a R b, -OR a} , -S (O) R a, -S (O) 2 R a, -NO _2. —C(O)OR ^a , —C(O)NR ^a R ^b , —NR ^a C(O)R ^b , —C(O)R ^a , —C(OH)R ^a R ^b , —NR ^a S(O) ₂ R ^b , -S(O) ₂ NR ^a R ^b , -CR ^a R ^b R ^c , -OCR ^a R ^b R ^c , -CH ₂ NR ^a R ^b , -CH ₂ OR ^a , —CH ₂ S(O)R ^a , —CH ₂ S(O) ₂ R ^a , —CH ₂ NO ₂ , —CH ₂ C(O)OR ^a , —CH ₂ CN, —CH ₂ C(O)NR ^a R ^b , -CH ₂ NR ^a C(O)R ^b , -CH ₂ C(O)R ^a , -CH ₂ C(OH)R ^a R ^b , -CH ₂ NR ^a S(O) ₂ R ^b , -CH ₂ S(O) ₂ NR ^a R ^b , -CH ₂ CR ^a R ^b R ^c , -CH ₂ OCR ^a R ^b R ^c , optionally substituted C1-3 alkyl, optionally substituted C2-3 alkenyl, optionally substituted C2-3 alkynyl;

   A is a key or is —O—, —S—, —NR ⁴ —, —CR ⁴ R ⁵ —, —C(O)—, —S(O) ₂ —;

   R ⁴ , R ⁵ , can be independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C1-3 alkyl;

   Ring B is a C3-7 cycloalkyl group, a 3-7 membered heterocyclic group, a C5-7 aryl group, a 5-7 membered heteroaryl group, wherein the ring B is defined by one or more identical or different R ⁶ , R ⁷ , R ⁸ , R ⁹ substitution;

   R ⁶ , R ⁷ , R ⁸ , and R ⁹ can be independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, carbonyl, carboxyl, cyano, -CH ₂ OH, -CH ₂ NH ₂ , -CH ₂ NHCH ₃ , —CH ₂ C(O)OH, —CH ₂ CN, —NHCH ₃ , —N(CH ₃ ) ₂ , —NHCH ₂ CH ₃ , —C(O)NH ₂ , —C(O)NHCH ₃ , —C (O) NHCH ₂ CH ₃ , —S(O) ₂ NH ₂ , —S(O) ₂ NHCH ₃ , —S(O) ₂ NHCH ₂ CH ₃ , C1-3 alkyl;

   X is a key or X is —O—, —S—, —NR ¹⁰ —, —CR ¹⁰ R ¹¹ —, —(CR ¹⁰ R ¹¹ ) _m —, —CR ¹⁰ R ¹¹ CR ¹² R ¹³ —, —C( O)—,—OCR ¹⁰ R ¹¹ —,—CR ¹⁰ R ¹¹ O—,—SCR ¹⁰ R ¹¹ —,—CR ¹⁰ R ¹¹ S—,—NR ¹⁰ CR ¹¹ R ¹² —,—CR ¹⁰ R ¹¹ NR ¹² —, —C(O)NR ¹⁰ —, —NR ¹⁰ C(O)—, —C(O)CR ¹⁰ R ¹¹ —, —CR ¹⁰ R ¹¹ C(O)—, —C(O)O—, —S(O) ₂ —, —S(O) ₂ NR ¹⁰ —, —NR ¹⁰ S(O) ₂ —, —S(O) ₂ CR ¹⁰ R ¹¹ —, —CR ¹⁰ R ¹¹ S(O) ₂ —, optionally substituted C2-3 alkenyl, optionally substituted C2-3 alkynyl;

   R ¹⁰ , R ¹¹ , R ¹² , and R ¹³ can be independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, —CH ₂ OH, and optionally substituted C1-3 alkyl;

   Y does not exist or is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 monocyclic alkyl, C6-14 bicyclic or tricyclic alkyl, 3-10 membered heteromonocyclic group, 6-14 membered heterobicyclic or tricyclic group, adamantane or its derivatives, C5-12 aryl, 5-12 membered heteroaryl, wherein Y is independently substituted by one or more of the following groups:

   Deuterium, halogen, cyano, —NR ^a R ^b , —OR ^a , —S(O)R ^a , —S(O) ₂ R ^a , —NO ₂ , —C(O)OR ^a , —C(O )NR ^a R ^b , —NR ^a C(O)R ^b , —C(O)R ^a , —C(OH)R ^a R ^b , —NR ^a S(O) ₂ R ^b , —S(O) ₂ NR ^a R ^b , -CR ^a R ^b R ^c , -OCR ^a R ^b R ^c , -CH ₂ NR ^a R ^b , -CH ₂ OR ^a , -CH ₂ S(O)R ^a , -CH ₂ S (O) ₂ R ^a , —CH ₂ NO ₂ , —CH ₂ C(O)OR ^a , —CH ₂ CN, —CH ₂ C(O)NR ^a R ^b , —CH ₂ NR ^a C(O)R ^b , -CH ₂ C(O)R ^a , -CH ₂ C(OH)R ^a R ^b , -CH ₂ NR ^a S(O) ₂ R ^b , -CH ₂ S(O) ₂ NR ^a R ^b , —CH ₂ CR ^a R ^b R ^c , —CH ₂ OCR ^a R ^b R ^c , optionally substituted C1-3 alkyl, optionally substituted C2-3 alkenyl, optionally substituted C2-3 Alkynyl

   Z is hydrogen, deuterium, halogen, cyano, —NR ¹⁴ R ¹⁵ , —OR ¹⁴ , —SR ¹⁴ , —S(O)R ¹⁴ , —S(O) ₂ R ¹⁴ , —NO ₂ , —C(O )R ¹⁴ , -C(O)OR ¹⁴ , -CR ¹⁴ R ¹⁵ CN, -C(O)NR ¹⁴ R ¹⁵ , -NR ¹⁴ C(O)R ¹⁵ , -C(OH)R ¹⁴ R ¹⁵ ,- NR ¹⁴ S(O) ₂ R ¹⁵ , —S(O) ₂ NR ¹⁴ R ¹⁵ , —CR ¹⁴ R ¹⁵ R ¹⁶ , —OCR ¹⁴ R ¹⁵ R ¹⁶ , —(CH ₂ ) _n R ¹⁴ —, —(CH ₂ ) _n NR ¹⁴ R ¹⁵ , —(CH ₂ ) _n OR ¹⁴ , —(CH ₂ ) _n SR ¹⁴ , —(CH ₂ ) _n S(O)R ¹⁴ , —(CH ₂ ) _n S(O) ₂ R ¹⁴ , —(CH ₂ ) _n NO ₂ , —(CH ₂ ) _n C(O)R ¹⁴ , —(CH ₂ ) _n C(O)OR ¹⁴ , —(CH ₂ ) _n CN, —CHR ¹⁴ R ¹⁵ CN,—(CH ₂ ) _n CHR ¹⁴ R ¹⁵ CN,—(CH ₂ ) _n C(O)NR ¹⁴ R ¹⁵ ,—(CH ₂ ) _n NR ¹⁴ C(O)R ¹⁵ ,—(CH ₂ ) _n C(OH)R ¹⁴ R ¹⁵ , —(CH ₂ ) _n NR ¹⁴ S(O) ₂ R ¹⁵ , —(CH ₂ ) _n S(O) ₂ NR ¹⁴ R ¹⁵ , —(CH ₂ ) _n CR ¹⁴ R ¹⁵ R ¹⁶ , —(CH ₂ ) _n OCR ¹⁴ R ¹⁵ R ¹⁶ , optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl , C3-12 cycloalkyl, 3-12 membered heterocyclyl, C5-12 aryl, 5-12 membered heteroaryl, wherein Z is independently optionally substituted by the following groups: deuterium, halogen, cyano, — NR ^a R ^b , —OR ^a , —SR ^a , —S(O)R ^a , —S(O) ₂ R ^a , —NO ₂ , —C(O)R ^a , —C(O)OR ^a , —C(O)NR ^a R ^b , —NR ^a C(O)R ^b , —C(OH)R ^a R ^b , —NR ^a S(O) ₂ R ^b , —S(O) ₂ NR ^a R ^b , —(CH ₂ ) _n R ^a R ^b , —CR ^a R ^b R ^c , —OCR ^a R ^b R ^c , optionally substituted C1-6 alkyl, optionally substituted C3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C5-12 aryl, 5-12 membered heteroaryl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkyne base;

   R ¹⁴ , R ¹⁵ , and R ¹⁶ can be selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, carboxy, optionally substituted C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered hetero Cycloalkyl, C5-12 aryl, 5-12 membered heteroaryl;

   R ^a , R ^b and R ^c are each independently selected from hydrogen, deuterium, halogen, cyano, and optionally substituted C1-3 alkyl;

   m is: 1, 2, 3;

   n is: 1, 2, 3, 4.
2. The compound represented by the general formula I according to claim 1, or its tautomer, meso, racemate, enantiomer, diastereomer, and mixtures thereof, And a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula II or a pharmaceutically acceptable salt thereof:

   

   The definitions of A, B, X, Y, and Z are as defined in claim 1.
3. The compound according to claim 1-2 or its tautomers, mesosomes, racemates, enantiomers, diastereomers, and mixtures thereof, and pharmacologically The salt used is a compound represented by the general formula II or a pharmaceutically acceptable salt thereof:

   A is a bond or is: —O—, —S—, —NH—, —CH ₂ —;

   B is selected from: imidazoline, piperidine, piperazine or the following structure:

   

   X is a bond or X is: —O—, —S—, —NH—, —NCH ₃ —, —(CH ₂ ) _m —, —C(O)—, —CH ₂ O—, —CH ₂ S— , —CH ₂ NH—, —OCH ₂ —, —SCH ₂ —, —NHCH ₂ —;

   The definitions of Y and Z are as defined in claim 1;

   m is: 1, 2, 3;

   The wavy line represents the connection point between A and B.
4. The compound according to claims 1-3 or its tautomers, mesosomes, racemates, enantiomers, diastereomers, and mixtures thereof, and pharmacologically The salt used is a compound represented by the general formula III or a pharmaceutically acceptable salt thereof:

   

   Wherein B is defined as defined in claim 3;

   The definitions of Y and Z are as defined in claim 1.
5. The compound according to claims 1-4 or its tautomers, mesosomes, racemates, enantiomers, diastereomers, and mixtures thereof, and pharmacologically The salt used is a compound represented by the general formula III or a pharmaceutically acceptable salt thereof:

   B is: imidazoline, piperidine, piperazine;

   The definitions of Y and Z are as defined in claim 1.
6. The compound according to claims 1 to 5 or its tautomer, meso, racemate, enantiomer, diastereomer, and mixture forms thereof, and pharmacologically thereof The salt used is a compound represented by the general formula III or a pharmaceutically acceptable salt thereof:

   B is;

   Y is the following structure:

   

   Where C specifies the location connected to the following core parts:

   

   The wavy line indicates the connection point;

   The definition of Z is as defined in claim 1.
7. The compound according to claims 1-6 or its tautomers, mesosomes, racemates, enantiomers, diastereomers, and mixtures thereof, and pharmacologically The salt used is the compound shown in III or its pharmaceutically acceptable salt:

   B is;

   Y is the following structure:

   

   

   Wherein C is designated to be connected to the following core part as defined in claim 6, wherein the wavy line represents the connection point;

   The definition of Z is as defined in claim 1.
8. The compound according to claims 1-7 or its tautomers, mesosomes, racemates, enantiomers, diastereomers, and mixtures thereof, and pharmaceutically acceptable The salt used is the compound shown in III or its pharmaceutically acceptable salt:

   B is pyrrole, pyrazole or imidazole;

   Y is:

   

   Wherein C is designated to be connected to the following core part as defined in claim 6, wherein the wavy line represents the connection point;

   The definition of Z is as defined in the general formula (I).
9. The compound according to claims 1-8 or its tautomers, mesosomes, racemates, enantiomers, diastereomers, and mixtures thereof, and pharmacologically The salt used is the compound shown in III or its pharmaceutically acceptable salt:

   B is pyrrole, pyrazole or imidazole;

   Wherein Y is defined as defined in claim 8;

   Z is hydrogen, deuterium, halogen, hydroxyl, amino, carboxyl, cyano, methyl, —(CH ₂ ) _n CH ₃ , —CH(CH ₃ ) ₂ , —C(CH ₃ ) ₃ , —(CH ₂ ) _n CH(CH ₃ ) ₂ , —(CH ₂ ) _n C(CH ₃ ) ₃ , —(CH ₂ ) _m CH(CH ₃ )(CH ₂ ) _n CH ₃ , —C(O)CH ₃ , —C (O)(CH ₂ ) _n CH ₃ , -C(O)CH(CH ₃ ) ₂ , -C(O)C(CH ₃ ) ₃ , -C(O)CH(CH ₃ )CH ₂ CH ₃ , —OCH ₃ , —O(CH ₂ ) _n CH ₃ , —OCH(CH ₃ ) ₂ , —OC(CH ₃ ) ₃ , —OCH(CH ₃ )CH ₂ CH ₃ , —SCH ₃ , —S(CH ₂ ) _n CH ₃ , —SCH(CH ₃ ) ₂ , —SC(CH ₃ ) ₃ , —SCH(CH ₃ )CH ₂ CH ₃ , —(CH ₂ ) _n NH ₂ , —NHCH ₃ , —N(CH ₃ ) ₂ , —(CH ₂ ) _n NHCH ₃ , —(CH ₂ ) _n N(CH ₃ ) ₂ , —C(O)NH ₂ , —C(O)NHCH ₃ , —C(O)N(CH ₃ ) ₂ , -C(O)(CH ₂ ) _n NH ₂ , -C(O)(CH ₂ ) _n NHCH ₃ , -C(O)(CH ₂ ) _n N(CH ₃ ) ₂ , -S(O ) ₂ CH ₃ , —S(O) ₂ (CH ₂ ) _n CH ₃ , —S(O) ₂ CH(CH ₃ ) ₂ , —S(O) ₂ C(CH ₃ ) ₃ , —S(O) ₂ CH(CH ₃ )CH ₂ CH ₃ , -S(O) ₂ (CH ₂ ) _n CH(CH ₃ ) ₂ , -S(O) ₂ (CH ₂ ) _n C(CH ₃ ) ₃ , -S( O) ₂ (CH ₂ ) ₂ CH(CH ₃ )CH ₂ CH ₃ , —S(O) ₂ NH ₂ , —S(O) ₂ NHCH ₃ , —S(O) ₂ N(CH ₃ ) ₂ , — S(O) ₂ (CH ₂ ) _n NH ₂ , -S(O) ₂ (CH ₂ ) _n NHCH ₃ , -S(O) ₂ (CH ₂ ) _n N(CH ₃ ) ₂ , -CH ₂ F, —CHF ₂ , —CF ₃ , —C(O)CH ₂ F, —C(O)CHF ₂ , —C(O)CF ₃ , —S(O) ₂ CH ₂ F, — S(O) ₂ CHF ₂ , -S(O) ₂ CF ₃ , -(CH ₂ ) _n CH ₂ F, -(CH ₂ ) _n CHF ₂ , -(CH ₂ ) _n CF ₃ , -C(O) (CH ₂ ) _n CH ₂ F, -C(O)(CH ₂ ) _n CHF ₂ , -C(O)(CH ₂ ) _n CF ₃ , -S(O) ₂ (CH ₂ ) _n CH ₂ F, -S(O) ₂ (CH ₂ ) _n CHF ₂ , -S(O) ₂ (CH ₂ ) _n CF ₃ , -CH(CH ₃ )CH ₂ F, -CH(CH ₃ )CHF ₂ , -CH( CH ₃ )CF ₃ , -C(O)CH(CH ₃ )CH ₂ F, -C(O)CH(CH ₃ )CHF ₂ , -C(O)CH(CH ₃ )CF ₃ , -S(O ) ₂ CH(CH ₃ )CH ₂ F, —S(O) ₂ CH(CH ₃ )CHF ₂ , —S(O) ₂ CH(CH ₃ )CF ₃ , —(CH ₂ ) _n OH, —(CH ₂ ) _n C(O)OH, —C(O)(CH ₂ ) _n OH, —S(O) ₂ (CH ₂ ) _n OH, —CH(CH ₃ )OH, —CH(CH ₃ )CH ₂ OH, —CH(CH ₃ )C(O)OH, —CH(CH ₃ )CH ₂ C(O)OH, —(CH ₂ ) _n CN, —C(CH ₃ ) ₂ CN, —CH(CH ₃ )CN, —(CH ₂ ) _n C(CH ₃ ) ₂ CN, —(CH ₂ ) _n CH(CH ₃ )CN, —C(O)(CH ₂ ) _n CN, —S(O) ₂ (CH ₂ ) _n CN, -C(O)C(CH ₃ ) ₂ CN, -C(O)CH(CH ₃ )CN, -S(O) ₂ C(CH ₃ ) ₂ CN, -S(O) ₂ CH(CH ₃ )CN may have the following structure:

   

   Where D specifies the location connected to the following core parts:

   

   The wavy line indicates the connection point;

   m is: 1, 2, 3;

   n is: 1, 2, 3, 4.
10. The compound according to claims 1-9 or its tautomers, mesoisomers, racemates, enantiomers, diastereomers, and mixtures thereof, and pharmaceutically acceptable The salt used is selected from the following compounds:

    

    

    

    

    

    

    

    

    

    

    

    

    

    Or its pharmaceutically acceptable salt.
11. A pharmaceutical or veterinary composition comprising the compound of general formula I according to any one of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
12. A pharmaceutical or veterinary composition comprising the compound of general formula II according to any one of claims 2-3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
13. A pharmaceutical or veterinary composition comprising the compound of formula III according to any one of claims 4-9 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
14. A pharmaceutical or veterinary composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claim 10 and a pharmaceutically acceptable carrier.
15. A method for treating a disease mediated by Jenners kinase in a subject, wherein the method comprises administering to the subject a certain amount of the compound of general formula I according to any one of claim 1 or A pharmaceutically acceptable salt thereof, wherein the amount of the compound is effective for treating diseases mediated by Janus kinase.
16. A method for treating a disease mediated by Jenners kinase in a subject, wherein the method comprises administering to the subject a certain amount of the formula II of any one of claims 2-3 A compound or a pharmaceutically acceptable salt thereof, wherein the amount of the compound is effective for the treatment of diseases mediated by Janus kinase.
17. A method for treating a disease mediated by Janus kinase in a subject, wherein the method comprises administering to the subject a certain amount of the formula III according to any one of claims 4-9 A compound or a pharmaceutically acceptable salt thereof, wherein the amount of the compound is effective for the treatment of diseases mediated by Janus kinase.
18. A method for treating a disease mediated by Janus kinase in a subject, wherein the method comprises administering to the subject a certain amount of the compound according to any one of claims 10 or a pharmaceutically acceptable compound thereof Salt, wherein the amount of the compound is effective for treating diseases mediated by Janus kinase.
19. The method of claim, wherein said Jenners kinase-mediated joint or connective tissue related diseases include but are not limited to: arthritis, rheumatoid arthritis, juvenile arthritis, juvenile arthritis, psoriatic arthritis, vertebral joints Inflammation, ankylosing spondylitis, tendinitis and bursitis, lumbar arthropathy, etc.
20. The method of claim, wherein the skin or hair-related diseases mediated by Janus kinase include but are not limited to: allergic dermatitis, skin pruritus, acne, acne, rosacea, lupus erythematosus, corpus sores, psoriasis, Hair loss, alopecia areata, etc.
21. The method of claim, wherein the other diseases mediated by Jenus kinase include but are not limited to: ulcerative enteritis, Crohn’s disease, ulcerative colitis, proctitis, asthma, rhinitis, hay fever, dry eye disease, grapevine Meningitis, keratitis, type I diabetes, multiple sclerosis, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture’s disease, sympathetic ophthalmia, organ transplant rejection, etc.

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