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:

代表连接点。 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:

等。环状烷基的实例包括环丙基、环丁基、环戊基、环己基等。

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)

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. 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. 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. 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. 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. 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. 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. 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). 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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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