Spirocyclic jak inhibitors, pharmaceutical compositions containing the same, and uses thereof

Abstract

The present application relates to a kind of spiro JAK inhibitor, pharmaceutical composition containing it and its application.It is specifically related to the compound as shown in formula I or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate, also related to the pharmaceutical composition of the compound and its as JAK inhibitor, and in the medical use for preparing the drug for preventing and / or treating the disease related to JAK, especially JAK1.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and in particular relates to a spirocyclic JAK inhibitor, a pharmaceutical composition containing the same, and applications thereof. Background Art

[0002] Protein kinases (PKs) are a group of enzymes that regulate a variety of important biological processes, constituting one of the largest enzyme families in humans. These biological processes include, among others, the phosphorylation of proteins, lipids, sugars, nucleosides, and other cellular metabolites catalyzed by cellular kinases, and playing a key role in all aspects of eukaryotic cell physiology. Abnormal kinase activity has been implicated in many human diseases, including cancer, autoimmune diseases, and inflammatory diseases.

[0003] Janus kinases (JAKs) are cytoplasmic tyrosine kinases that transduce cytokine signals from membrane receptors to STAT transcription factors, playing an important role in cytokine signaling. The JAK family includes four members: JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). JAKs typically associate with cytokine receptors in pairs as homodimers or heterodimers. Cytokines bind to their receptors, causing the receptor molecules to dimerize. The receptor-coupled JAKs approach each other and become activated through reciprocal phosphorylation of tyrosine residues. The JAK family transmits cytokine-mediated signals into cells via the JAK-STAT (signal transducer and activator of transcription) pathway.

[0004] Signal transducers and activators of transcription (STATs) are a group of cytoplasmic proteins that bind to the DNA in the regulatory regions of target genes. As downstream substrates of JAKs, STATs can be activated by tyrosine phosphorylation in response to external signals and subsequently translocate to the cell nucleus to regulate gene transcription. When cytokines bind to their receptors, JAK family members autophosphorylate and / or transphosphorylate each other, leading to phosphorylation of STATs, which then translocate to the cell nucleus to regulate transcription.

[0005] Many abnormal immune responses, such as allergy, asthma, (allogeneic) transplant rejection, autoimmune diseases such as rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, myeloproliferative disorders, and hematological malignancies such as leukemia and lymphoma, are all regulated by the JAK / STAT signaling pathway.

[0006] Research indicates that blocking signal transduction at the JAK kinase level offers promising therapeutic approaches for inflammatory diseases, autoimmune diseases, myeloproliferative disorders, and cancer. JAK kinase inhibition also contributes to the treatment of skin immune disorders such as psoriasis and skin sensitization. Already marketed are Pfizer's toficitinib, used to treat rheumatoid arthritis, and Incyte's ruxolitinib, used to treat myelofibrosis and acute graft-versus-host disease.

[0007] However, some of the currently available JAK enzyme inhibitors also have some obvious toxic side effects. For example, some JAK inhibitors are prone to cause the following side effects: infection, including pneumonia, viral infection (such as herpes zoster infection), bacterial infection, actinomycete infection (mycobacterial infection), fungal infection, decreased immunity (such as NK cell reduction) and anemia. In the United States, some even receive black box warnings due to some serious side effects. These serious side effects include, for example, acute tuberculosis, invasive fungal infection, bacterial infection, and some lymphomas or other tumors. Studies have shown that currently available JAK inhibitors often have inhibitory activity on both JAK1 and JAK3, and most of these side effects are related to the inhibition of JAK3 activity.

[0008] However, studies have shown that JAKs family kinases are responsible for regulating numerous signaling pathways. Because JAK1 and JAK3 are components of the common γ-chain cytokine receptor complex, the development of inhibitors with high selectivity for JAK1 is very difficult.

[0009] JAK1 plays a key role in regulating biological responses and is widely expressed and associated with several major cytokine receptor families. It participates in signal transduction through members of the IL-2 receptor gamma subunit family (IL-2, IL-4, IL-7R, IL-9R, IL-15R, and IL-21R), the IL-4 receptor family (IL-4R, IL-13R), the gp130 receptor family, and class II cytokine receptors (including the IL-10 receptor family and both type I and type II IFN receptor families).

[0010] In summary, there is an urgent need to develop inhibitors of Janus kinase or related kinases, especially

[0011] JAK1 has highly selective inhibitors. Summary of the Invention

[0012] The present invention provides an inhibitor of JAK or related kinases, in particular an inhibitor with high selectivity for JAK1.

[0013] In a first aspect, the present invention provides a compound represented by formula I or a stereoisomer or optical isomer, a pharmaceutically acceptable salt, a prodrug or a solvate thereof.

[0014]

[0015] Where,

[0016] R1, R2 and R3 are each independently selected from the following substituted or unsubstituted groups: H, D, halogen, amino, nitro, hydroxyl, cyano, carboxyl, sulfone, sulfoxide, amide, sulfonamide, ester, formyl, formamide, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl; wherein the substitution refers to the substitution of one or more R a replace;

[0017] Or R1 and R2 together with the atoms to which they are attached constitute the following substituted or unsubstituted groups: 5-6 membered aryl or heteroaryl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl; wherein the substitution refers to the substitution of one or more R a replace;

[0018] B is independently selected from the group consisting of: a bond, -(CH2) r -、C(=O)、NR b 、C(=O)O-、 -(CH2) p -R c , O, S, SO, SO2; R c Selected from: C(=O)O-, Among them, R b Independently selected from the group consisting of H, C1-C6 alkyl;

[0019] Among them, -(CH2) r - and -(CH2) p - The H atoms in the may be optionally replaced by one or more R a replace;

[0020] C is selected from the following substituted or unsubstituted groups: H, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl; wherein the substitution refers to the substitution of one or more R a replace;

[0021] r and p are each independently 1, 2, 3, or 4;

[0022] m, n, k and l are each independently 0, 1, 2, or 3, and m+n≥1, k+l≥1;

[0023] The H in the moiety may optionally be replaced by one or more R a replace;

[0024] Among them, each R a independently selected from the group consisting of halogen, amino, nitro, hydroxyl, mercapto, cyano, carboxyl, sulfone, sulfoxide, amide, sulfonamide, ester, formyl, formamide, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, and C6-C12 aryl, substituted or unsubstituted; wherein R a The substitution described in refers to substitution by one or more groups selected from the group consisting of halogen, amino, nitro, hydroxy, thiol, cyano, carboxyl, sulfone, sulfoxide, amide, sulfonamide, ester, formyl, formamide, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl and C6-C12 aryl.

[0025] In another preferred embodiment, the compound represented by Formula I or its stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates,

[0026]

[0027] Where,

[0028] R1, R2 and R3 are each independently selected from the following substituted or unsubstituted groups: H, D, halogen, amino, nitro, hydroxyl, cyano, carboxyl, sulfone, sulfoxide, amide, sulfonamide, ester, formyl, formamide, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl; wherein the substitution refers to the substitution of one or more R a replace;

[0029] Or R1 and R2 together with the atoms to which they are attached constitute the following substituted or unsubstituted groups: 5-6 membered aryl or heteroaryl, 3-10 membered heterocyclic group, C3-C10 cycloalkyl; wherein the substitution refers to the substitution of one or more R a replace;

[0030] B is independently selected from the group consisting of: a bond, -(CH2) r -、C(=O)、NR b、C(=O)O-、 -(CH2) p -R c , O, S, SO, SO2; R c Selected from: C(=O)O-, Among them, R b Independently selected from the group consisting of H, C1-C6 alkyl;

[0031] Among them, -(CH2) r - and -(CH2) p - The H atoms in the may be optionally replaced by one or more R a replace;

[0032] C is selected from the following groups: substituted or unsubstituted: C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl; wherein, the substitution refers to the substitution of one or more R a replace;

[0033] r and p are each independently 1, 2, 3, or 4;

[0034] m, n, k and l are each independently 0, 1, 2, or 3, and m+n≥1, k+l≥1;

[0035] The H in the moiety may optionally be replaced by one or more R a replace;

[0036] Among them, each R a independently selected from the group consisting of halogen, amino, nitro, hydroxyl, mercapto, cyano, carboxyl, sulfone, sulfoxide, amide, sulfonamide, ester, formyl, formamide, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, and C6-C12 aryl, substituted or unsubstituted; wherein R a The substitution described in refers to substitution by one or more groups selected from the group consisting of halogen, amino, nitro, hydroxy, thiol, cyano, carboxyl, sulfone, sulfoxide, amide, sulfonamide, ester, formyl, formamide, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl and C6-C12 aryl.

[0037] In another preferred embodiment, each R aindependently selected from the group consisting of halogen, amino, nitro, hydroxy, mercapto, cyano, carboxyl, sulfone, sulfoxide, amide, sulfonamide, ester, formyl, formamide, C1-C6 alkyl, halogenated C1-C6 alkyl, (CH2) t G, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl and C6-C12 aryl, wherein t is 1, 2 or 3; G is selected from: 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl and C6-C12 aryl.

[0038] In another preferred embodiment, the compound or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate, Some selected from:

[0039] Where q is 0, 1, 2, 3, 4 or 5;

[0040] R a The definition of is as above.

[0041] In another preferred embodiment, the compound or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate has a structure shown in Formula II:

[0042]

[0043] Where q is 0, 1, 2, 3, 4 or 5;

[0044] R1, R2, R3, R a , B and C are defined as above.

[0045] In another preferred embodiment, the compound or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate, B is selected from the following groups: C(=O)O-, Among them, R b As stated above in the definition.

[0046] In another preferred embodiment, the compound or its stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates, C is selected from the following groups: 3-8 membered heterocycloalkyl, C3-C8 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl; wherein the substitution refers to the substitution of one or more R a replace;

[0047] R a The definition of is as above.

[0048] In another preferred embodiment, C is selected from the following substituted or unsubstituted groups: cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperazinyl, piperidinyl, morpholinyl, phenyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, furanyl, thiazolyl, pyrrolyl, indolyl, naphthyl, wherein the substitution refers to the substitution of one or more R a Replacement; R a The definition of is as above.

[0049] In another preferred embodiment, Selected from:

[0050]

[0051] Where q is 0, 1, 2, 3, 4 or 5;

[0052] R a The definition of is as above.

[0053] In another preferred embodiment, B is selected from: -NH-, -NH-C(=O)-, optionally, each hydrogen in the above group is substituted by a C1-C6 alkyl group.

[0054] In another preferred embodiment, C is selected from: H, methoxy, phenyl, methyl, ethyl, thiazolyl, pyridyl, cyclopropyl, pyrazinyl, cyclohexyl, benzothiophenyl, benzofuranyl, pyrimidinyl, naphthyl, cyclobutyl, cyclopentyl, cycloheptyl; wherein, optionally, C is substituted by a substituent selected from the following: fluorine, chlorine, bromine, nitro, cyano, hydroxyl, ethynyl, methyl, methoxy, methylformate, trifluoromethyl, phenyl, aminosulfonyl (or sulfonamide).

[0055] In another preferred embodiment, C is selected from: H, methoxy, phenyl, methyl, ethyl, Cyclopropyl, Cyclohexyl, naphthyl, cyclobutyl, cyclopentyl, cycloheptyl; wherein, optionally, C is substituted by a substituent selected from the group consisting of fluorine, chlorine, bromine, nitro, cyano, hydroxy, ethynyl, methyl, methoxy, methylformyl, trifluoromethyl, phenyl, aminosulfonyl (or sulfonamide).

[0056] In another preferred embodiment, C is selected from: H, methyl, methoxy, Phenyl,

[0057]

[0058]

[0059] In another preferred embodiment, R1 is hydrogen.

[0060] In another preferred embodiment, R2 is hydrogen.

[0061] In another preferred embodiment, R3 is hydrogen.

[0062] In another preferred embodiment, Selected from

[0063] In another preferred embodiment, the compound has a structure shown in Formula II:

[0064]

[0065] Where q is 0, 1, 2, 3, 4 or 5;

[0066] R1, R2, R3, R a , B and C are defined as above.

[0067] In another preferred embodiment, each C1-C6 alkyl group is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl.

[0068] In another preferred embodiment, each C1-C6 alkoxy group is independently selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, and tert-butoxy.

[0069] In another preferred embodiment, each C2-C6 alkenyl group is independently selected from vinyl, propenyl, and allyl.

[0070] In another preferred embodiment, each C2-C6 alkynyl group is independently selected from ethynyl and propynyl.

[0071] In another preferred embodiment, each 3-10 membered heterocycloalkyl group is independently selected from tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophene, tetrahydropyranyl, piperazinyl, piperidinyl, and morpholinyl.

[0072] In another preferred embodiment, each C3-C10 cycloalkyl group is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0073] In another preferred embodiment, each 5-12 membered heteroaryl group is independently selected from pyrrolyl, furyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, indolyl, benzothienyl, and benzofuranyl.

[0074] In another preferred embodiment, each C6-C12 aryl group is independently selected from phenyl and naphthyl.

[0075] In another preferred embodiment, in Formula I, R1, R2, R3, R a , B and C are specific groups corresponding to the specific compounds in the examples.

[0076] In another preferred embodiment, the compound or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate is selected from the following group:

[0077]

[0078]

[0079]

[0080]

[0081]

[0082] In another preferred embodiment, the compound of formula I is selected from the compounds shown in the examples.

[0083] In a second aspect, the present invention provides a pharmaceutical composition comprising the compound described in the first aspect or its stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates; and a pharmaceutically acceptable carrier.

[0084] In another preferred embodiment, the pharmaceutical composition further comprises a drug selected from the following group:

[0085] PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009 or biosimilars of the above drugs), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, veltuzumab,Tositumomab, 131I-tositumomab, ibritumomab tiuxetan, 90Y-ibritumomab tiuxetan, 90In-ibritumomab tiuxetan, ibritumomab tiuxetan, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as ceritinib, alectinib, brigatinib, lorlatinib, ocatinib), PI3K inhibitors (such as idelalisib, duvelisib, dactolisib, Tas Elisib, Bimiralisib, Omipalisib, Buparlisib, etc.), BTK inhibitors (such as Ibrutinib, Tirabrutinib, Acalabrutinib, Zambutinib, Vecabrutinib, etc.), EGFR inhibitors (such as afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, canertinib, saputinib, Naquotinib, pyrotinib, rolactinib, osimertinib, etc.), VEGFR inhibitors (such as Soratinib, Fenib, Pazopanib, Regorafenib, Selumetinib, Ningetinib, Cabozantinib, Sunitinib, Donafenib, etc.), HDAC inhibitors (such as Givinostat, Tucidinostat, Vorinostat, Fimepinostat, Droxinostat, Entinostat, Dacilast, Quisinostat, Tecodeinaline, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, Milciclib, Tri laciclib, Lerociclib, etc.), MEK inhibitors (such as selumetinib (AZD6244), trametinib (GSK1120212), PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040), etc.), mTOR inhibitors (such as vistusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.), or a combination thereof.

[0086] In a third aspect, the present invention provides a method for preparing a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound described in the first aspect of the present invention or its stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates to form a pharmaceutical composition.

[0087] In another preferred embodiment, the compound of the present invention can be prepared into powders, tablets, granules, capsules, solutions, emulsions, suspensions, and the like.

[0088] In another preferred embodiment, the pharmaceutical composition is used to treat or prevent diseases related to the activity or expression of JAK kinase.

[0089] In another preferred embodiment, the pharmaceutical composition is used as a JAK kinase inhibitor, preferably as a JAK1 kinase inhibitor.

[0090] In a fourth aspect, the present invention provides a use of the compound described in the first aspect or its stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates for preparing a drug or pharmaceutical composition for treating or preventing diseases related to the activity or expression of JAK kinase.

[0091] In another preferred embodiment, the disease is selected from the following groups: cancer, myeloproliferative disease, inflammation, immune disease, organ transplantation, viral disease, cardiovascular disease or metabolic disease, human or animal autoimmune disease, rheumatoid arthritis, skin disease, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, myasthenia gravis, psoriasis.

[0092] The cancer is selected from the group consisting of prostate cancer, kidney cancer, liver cancer, breast cancer, lung cancer, thyroid cancer, Kaposi's sarcoma, giant lymphoproliferation, pancreatic cancer, leukemia, lymphoma, and multiple myeloma.

[0093] In another preferred embodiment, the disease related to the activity or expression level of the JAK kinase is a JAK1-related disorder.

[0094] Wherein, the JAK1-related disorder is preferably selected from the group consisting of type I diabetes, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease and alopecia areata.

[0095] In another preferred embodiment, there is provided a use of the compound according to the first aspect or its stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates for preparing a drug or pharmaceutical composition for inhibiting JAK kinase activity; wherein the JAK kinase is preferably JAK1 kinase.

[0096] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0097] Figure 1 It is a spirocyclic JAK inhibitor having a structure shown in Formula I of the present invention. DETAILED DESCRIPTION

[0098] Through extensive and in-depth research, the inventors unexpectedly discovered a new JAK inhibitor with a novel structure, excellent biological activity, and exceptional selectivity against JAK1. Specifically, the compounds of the present invention have an average selectivity improvement of approximately 10-fold (most compounds have an increase of approximately 20-100-fold) in selectivity, as represented by the JAK2 / JAK1 ratio, the JAK3 / JAK1 ratio, or the TYK2 / JAK1 ratio. Consequently, the side effects associated with JAK3 inhibition in the compounds of the present invention are significantly reduced, while safety is significantly improved. This is the basis for the present invention.

[0099] the term

[0100] In the present invention, unless otherwise specified, the terms used have the general meanings commonly known to those skilled in the art.

[0101] When describing a substituent using a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. That is, when the linking group -L1- listed in the present invention does not specify its connection direction, its connection direction can be connected in the same direction as the reading order from left to right, or in the opposite direction to the above direction. For example, The connecting group -L1- is -CD-, if -CD- connects ring A and ring B in the same direction as reading from left to right to form If -CD- connects ring A and ring B in the opposite direction to the above direction, it will form

[0102] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0103] As used herein, when used in reference to a specific recited value, the term "about" means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0104] As used herein, the terms "comprising" or "including" may be open, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0105] As used herein, the term "alkyl" includes straight or branched chain alkyl groups. For example, C1-C6 alkyl groups represent straight or branched chain alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like.

[0106] As used herein, the term "alkenyl" includes straight or branched alkenyl groups. For example, C2-C6 alkenyl refers to a straight or branched alkenyl group having 2 to 6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or the like.

[0107] As used herein, the term "alkynyl" includes straight or branched chain alkynyl groups. For example, C2-C6 alkynyl refers to a straight or branched chain alkynyl group having 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, or the like.

[0108] As used herein, the term "cycloalkyl" refers to a cyclic alkyl group (saturated or containing double bonds) containing a specific number of carbon atoms, such as "C3-C10 cycloalkyl" refers to a cycloalkyl group having 3-10 (preferably 3, 4, 5, 6, 7, or 8) carbon atoms. It can be a monocyclic ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or similar groups. It can also be a bicyclic ring, such as a bridged ring or spiro ring. In the present invention, cycloalkyl is intended to include substituted cycloalkyl groups.

[0109] As used herein, the term "C1-C6 alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms; having the formula C1-C6 alkyl-O- or -C1-C5 alkyl-O-C1-C5 alkyl (e.g., -CH2-O-CH2CH3,

[0110] -CH2-O-(CH2)2CH3, -CH2CH2-O-CH2CH3) structure, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, etc.

[0111] As used herein, "heterocyclyl" refers to a saturated or partially saturated cyclic group having a heteroatom selected from N, S and O, and "3-10 membered heterocyclyl" refers to a saturated or partially saturated cyclic group having 3-10 atoms and 1-3 atoms thereof being a heteroatom selected from the group consisting of N, S and O. In the present invention, heterocyclyl and heterocycloalkyl have the same meaning and are used interchangeably. They may be monocyclic or bicyclic, such as a bridged ring or a spirocyclic form. 3-10 membered heterocyclyl (alkyl) groups are preferably 3-8 membered heterocyclyl (alkyl) groups, more preferably 6-8 membered heterocyclyl (alkyl) groups. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl and pyrrolidinyl groups.

[0112] As used herein, "aryl" refers to an aromatic ring group containing no heteroatoms in the ring. "C6-C12 aryl" refers to an aromatic ring group containing no heteroatoms in the ring and having 6 to 12 carbon atoms. The aryl group may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is the aryl ring. Examples include phenyl (i.e., a six-membered aromatic ring) and naphthyl. The six-membered aryl group is also intended to include six-membered aryl and 5-6-membered cycloalkyl groups and six-membered aryl and 5-6-membered heterocycloalkyl groups. C6-C12 aryl is preferably C6-C10 aryl. The aryl group may be optionally substituted or unsubstituted.

[0113] As used herein, "heteroaryl" refers to a cyclic aromatic group having 1-3 heteroatoms selected from the group consisting of N, S, and O. "5-12 membered heteroaryl" refers to a cyclic aromatic group having 5-12 atoms, 1-3 of which are heteroatoms selected from the group consisting of N, S, and O. It may be a single ring or a fused ring. Specific examples include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2,4)-triazolyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring connected to the parent structure is the heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, amide, sulfonamide, formyl, formamido, carboxyl, and carboxylate groups, among others.

[0114] As used herein, "halogen" or "halogen atom" refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl, and Br.

[0115] In the present invention, the term "amido" refers to a group with the structure -CONRR', wherein R and R' can independently represent hydrogen, alkyl, cycloalkyl, aryl, or heterocyclic radicals, as defined above. R and R' can be the same or different in the dialkylamine fragment. Examples of amido include, but are not limited to, -CONH2, -CONHCH3, -CONHCH2CH3, -CON(CH3)2, -CONHcyclopropyl, -CONHcyclobutyl, -CONHcyclopentyl, -CONHcyclohexyl, -CONCH3cyclopropyl, -CONCH3cyclobutyl, -CONCH3cyclopentyl, and -CONCH3cyclohexyl.

[0116] In the present invention, the term "sulfonamide" refers to a group with the structure -SO2NRR', wherein R and R' can independently represent hydrogen, alkyl, cycloalkyl, aryl, or heterocyclic groups, as defined above. R and R' can be the same or different in the dialkylamine segment. Examples of sulfonamide include, but are not limited to, -SO2NH2, -SO2NHCH3, -SO2NHCH2CH3, -SO2N(CH3)2, -SO2NHcyclopropyl, -SO2NHcyclobutyl, -SO2NHcyclopentyl, -SO2NHcyclohexyl, -SO2NCH3cyclopropyl, -SO2NCH3cyclobutyl, -SO2NCH3cyclopentyl, and -SO2NCH3cyclohexyl.

[0117] In the present invention, the term "formyl" refers to a group containing -CHO.

[0118] In the present invention, the term "carboxamide group" refers to a The group of carboxamido is also intended to include substituted carboxamido groups having the formula wherein R each independently represents hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl, as defined above. Each R may be the same or different.

[0119] In the present invention, "amino" refers to a group having the structure -N-RR', where R and R' independently represent hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic radical, as defined above, and R and R' may be the same or different. Examples of amino groups include, but are not limited to, -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, -NHcyclopropyl, -NHcyclobutyl, -NHcyclopentyl, -NHcyclohexyl, -NCH3cyclopropyl, -NCH3cyclobutyl, -NCH3cyclopentyl, and -NCH3cyclohexyl.

[0120] In the present invention, "sulfoxide" refers to a group having -S(O)-R, where R independently represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, as defined above. Examples of sulfoxide include, but are not limited to, -S(O)-CH3, -S(O)-CH2CH3, and -S(O)-CH(CH3)2.

[0121] In the present invention, "sulfone group" refers to a group having -S(O)2-R, where R independently represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group, as defined above. Examples of sulfone groups include, but are not limited to: -S(O)2-CH3, -S(O)2-CH2CH3, and -S(O)2-CH(CH3)2.

[0122] In the present invention, "ester group" refers to a group having a -C(O)-OR or RC(O)-O- structure, wherein R independently represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group, as defined above. Examples of ester groups include, but are not limited to, -C(O)-O-CH3, -C(O)-O-CH2CH3, -C(O)-O-CH2CH2CH3, -C(O)-O-CH(CH3)2, -OC(O)-CH3, -OC(O)-CH2CH3, -OC(O)-CH2CH2CH3, and -OC(O)-CH(CH3)2.

[0123] In the present invention, the term "substituted" refers to the replacement of one or more hydrogen atoms on a specific group with a specific substituent. The specific substituent is the substituent described above or the substituent appearing in the examples. Unless otherwise specified, a substituted group may have a substituent selected from the specific group at any substitutable position of the group, and the substituent may be the same or different at each position. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible.

[0124] Unless otherwise specified as "substituted or unsubstituted", the groups described in the present invention may be substituted by substituents selected from the following groups: deuterium, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, and C6-C12 aryl.

[0125] In the present invention, the term "plurality" independently refers to 2, 3, 4, or 5.

[0126] Unless otherwise specified, the structural formulas described herein are intended to include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformers)): for example, R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, etc. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformers) are all within the scope of the present invention.

[0127] As used herein, the term "tautomer" refers to structural isomers of different energies that can interconvert across a low energy barrier. For example, proton tautomers (i.e., prototropy) include interconversion via proton migration, such as 1H-indazole and 2H-indazole. Valence tautomers include interconversion via reorganization of some of the bonding electrons.

[0128] As used herein, the term "solvate" refers to a complex in which the compound of the present invention is coordinated with solvent molecules to form a specific ratio.

[0129] Active ingredient

[0130] As used herein, "compounds of the present invention" refers to compounds represented by Formula I, and also includes stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates of the compounds of Formula I.

[0131] The compound of formula I of the present invention has the following structure,

[0132]

[0133] wherein R1, R2, R3, B, C, m, n, k and l are as defined above.

[0134] Preferably, the compound of formula I has the structure of formula II,

[0135]

[0136] Where, R1, R2, R3, R a , q, B and C are defined as above.

[0137] Preferably, in formula I-II, B is selected from the following groups: C(=O)O-, Among them, R b The definition of is as above.

[0138] Preferably, in formula I-II, C is selected from the following groups: substituted or unsubstituted: 3-8 membered heterocycloalkyl, C3-C8 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl; preferably, C is selected from the following groups: substituted or unsubstituted: cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperazinyl, piperidinyl, morpholinyl, phenyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, furanyl, thiazolyl, pyrrolyl, indolyl, naphthyl, wherein the substitution refers to the substitution of one or more R a replace;

[0139] R a The definition of is as above.

[0140] The salts that may be formed by the compounds of the present invention also fall within the scope of the present invention. Unless otherwise indicated, the compounds of the present invention are understood to include their salts. The term "salt" as used herein refers to acidic or basic salts formed with inorganic or organic acids and bases. In addition, when the compound of the present invention contains a basic fragment, it includes but is not limited to pyridine or imidazole, and contains an acidic fragment, including but not limited to carboxylic acid, the zwitterions ("inner salts") that may be formed are included within the scope of the term "salt". Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in separation or purification steps during the preparation process. The compounds of the present invention may form salts, for example, compound I reacts with a certain amount, such as an equivalent amount, of an acid or base, salts out in a medium, or is obtained by freeze-drying in an aqueous solution.

[0141] The compounds of the present invention contain basic moieties, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids. Typical acids that can form salts include acetates (e.g., acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipates, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphor, camphorsulfonate, cyclopentanepropionate, diglycolate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide,

[0014] Examples of the present invention include, for example, hydroxyethylsulfonates, lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonate), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g., 3-phenylpropionate), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (e.g., with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as p-toluenesulfonate, dodecanoates, and the like.

[0142] Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases. Typical base-forming salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts formed with organic bases (e.g., organic amines), such as benzathine, dicyclohexylamine, hepamine (salt formed with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butylamine, and salts formed with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups can react with halide quaternary ammonium salts, such as small molecular alkyl halides (such as chlorides, bromides and iodides of methyl, ethyl, propyl and butyl), dialkyl sulfates (such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and dipentyl sulfate), long chain halides (such as chlorides, bromides and iodides of decyl, dodecyl, tetradecyl and tetradecyl), aralkyl halides (such as benzyl and phenyl bromide), etc.

[0143] Prodrugs and solvates of the compounds of the present invention are also encompassed. The term "prodrug" herein refers to a compound that undergoes chemical transformation via metabolic or chemical processes to produce a compound, salt, or solvate of the present invention when used to treat a relevant disease. The compounds of the present invention include solvates, such as hydrates.

[0144] The compounds, salts or solvates of the present invention may exist in tautomeric forms (such as amides and imino ethers). All such tautomers are part of the present invention.

[0145] All stereoisomers of the compounds (e.g., those that may exist due to asymmetric carbon atoms for various substitutions), including enantiomeric and diastereomeric forms, are contemplated by the present invention. Individual stereoisomers of the compounds of the present invention may not exist with other isomers (e.g., as a pure or substantially pure optical isomer having a particular activity), or may be mixtures, such as racemates, or mixtures with all other stereoisomers or portions thereof. The chiral centers of the present invention have either S or R configurations, as defined by the 1974 recommendations of the International Union of Pure and Applied Chemistry (IUPAC). Racemic forms can be resolved by physical methods, such as fractional crystallization, or by crystallization of diastereomers derived from them, or by separation by chiral column chromatography. Individual optical isomers can be obtained from the racemate by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by recrystallization.

[0146] The compounds of the present invention, obtained by sequential preparation, isolation, and purification, are described in the text to a concentration of 90% or greater by weight, for example, 95% or greater, or 99% or greater ("very pure" compounds). Such "very pure" compounds of the present invention are also considered part of the present invention.

[0147] All configurational isomers of the compounds of the present invention are encompassed, whether in mixture, pure or very pure form. The definition of the compounds of the present invention includes both cis (Z) and trans (E) olefin isomers, as well as cis and trans isomers of carbocyclic and heterocyclic rings.

[0148] Throughout the specification, groups and substituents may be chosen to provide stable fragments and compounds.

[0149] Specific functional groups and chemical term definitions are detailed below. For the purposes of this invention, chemical elements are referred to in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th The definitions of specific functional groups are consistent with those in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito, 1999, which is incorporated by reference in its entirety.

[0150] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures, and other mixtures. Additionally, asymmetric carbon atoms may represent substituents, such as alkyl groups. All isomers and mixtures thereof are encompassed by the present invention.

[0151] According to the present invention, mixtures of isomers can contain various ratios of isomers. For example, mixtures containing only two isomers can have the following ratios: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. All ratios of isomers are within the scope of the present invention. Similar ratios, as well as ratios for more complex mixtures of isomers, are readily understood by those skilled in the art and are also within the scope of the present invention.

[0152] The present invention also includes isotopically labeled compounds that are equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms having a different atomic mass or mass number. Examples of isotopes of the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, such as 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates thereof, which contain isotopes or other isotopic atoms of the above compounds are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as 3 H and 14 Radioisotopes of C are also included and are useful in tissue distribution experiments of drugs and substrates. 3 H and carbon-14, i.e. 14 C, their preparation and detection are relatively easy. It is the first choice among isotopes. In addition, heavier isotope substitutions such as deuterium, i.e. 2 H, due to its excellent metabolic stability, has advantages in certain therapeutics, such as increasing half-life in vivo or reducing dosage, and therefore, may be preferred in some cases. Isotopically labeled compounds can be prepared using conventional methods by replacing readily available isotopically labeled reagents with non-isotopic reagents using the protocols disclosed in the examples.

[0153] If a synthesis of a specific enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, followed by separation of the resulting diastereomeric mixture and removal of the chiral auxiliary to obtain the pure enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed with a suitable optically active acid or base, followed by separation by conventional means such as fractional crystallization or chromatography to obtain the pure enantiomer.

[0154] As described herein, the compounds of the present invention may be substituted with any number of substituents or functional groups to expand their scope. Generally, the term "substituted," whether preceded or followed by the term "optionally," in formulas of the present invention including substituents, refers to the replacement of a hydrogen radical with a substituent of the specified structure. When multiple positions in a particular structure are substituted with multiple substituents of the specified structure, the substituents may be the same or different at each position. As used herein, the term "substituted" includes all permissible substitutions in organic compounds. Broadly speaking, permissible substituents include acyclic, cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. For example, heteroatoms of nitrogen may be substituted with hydrogen or any of the permissible organic compounds described above to supplement their valences. Furthermore, the present invention is not intended to limit the permissible substitutions in any way to organic compounds. The present invention recognizes that combinations of substituents and variables are advantageous for providing stable compounds for the treatment of diseases. As used herein, the term "stable" refers to compounds that are stable and maintain the structural integrity of the compound over a period of time sufficient to be detected, preferably over a period of time sufficient to be effective, as used herein for the purposes described above.

[0155] The metabolites of the compounds and pharmaceutically acceptable salts thereof involved in the present application, as well as prodrugs that can be converted into the structures of the compounds and pharmaceutically acceptable salts involved in the present application and in vivo, are also included in the claims of the present application.

[0156] Preparation method of compound

[0157] The following schemes and examples describe methods for preparing compounds of Formula I. Starting materials and intermediates were purchased from commercial sources, prepared by known procedures, or described otherwise. In some cases, the order in which the steps of the reaction schemes are performed may be altered to facilitate the reaction or to avoid unwanted side reaction products.

[0158] Typically, in the preparation process, each reaction is carried out in an inert solvent at room temperature to reflux temperature (e.g., 0°C to 150°C, preferably 10°C to 100°C), and the reaction time is typically 0.1 to 60 hours, preferably 0.5 to 48 hours.

[0159] Preferably, the compounds of the present invention can be prepared by the following steps:

[0160] In an inert solvent (such as DCM, DMF, etc.), in the presence of a catalyst (such as HATU, potassium carbonate, etc.), compound I' reacts to obtain compound I

[0161]

[0162] Where,

[0163] R1, R2, R3, m, n, k and l are as defined above;

[0164] R is selected from the following substituted or unsubstituted groups: C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl;

[0165] B' is selected from the following groups: amino, hydroxyl, carboxyl, sulfonic acid, CO-O-R', -CO-NH-R';

[0166] C' is selected from: amino, hydroxyl, carboxyl, sulfonic acid, CO-O-R', -CO-NH-R';

[0167] wherein R' is selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocyclyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, and C6-C12 aryl;

[0168] The substitution refers to substitution by one or more groups selected from the following groups: halogen, amino, nitro, hydroxyl, thiol, cyano, carboxyl, sulfone, sulfoxide, amide, sulfonamide, ester, formyl, formamide, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl and C6-C12 aryl.

[0169] The starting materials and reagents used in the synthesis methods of the compounds of the present invention can be purchased commercially or synthesized by methods reported in the literature.

[0170] Pharmaceutical compositions and methods of administration

[0171] Since the compounds of the present invention have excellent JAK kinase inhibitory activity, the compounds of the present invention or their stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates, as well as pharmaceutical compositions containing the compounds of the present invention as the main active ingredient, can be used to prevent and / or treat (stabilize, alleviate or cure) JAK kinase-related diseases (e.g., skin diseases, rheumatoid arthritis, multiple sclerosis, type I diabetes, psoriatic arthritis, juvenile arthritis, Crohn's disease, myasthenia gravis, cancer (including prostate cancer, kidney cancer, liver cancer, breast cancer, lung cancer, thyroid cancer, Kaposi's sarcoma, giant lymphoproliferation, pancreatic cancer, leukemia, lymphoma or multiple myeloma, etc.)).

[0172] The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention and a pharmaceutically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-200 mg per dose. Preferably, "one dose" is one capsule or tablet.

[0173] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0174] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration methods include (but are not limited to): oral administration, parenteral administration (intravenous administration, intramuscular administration, or subcutaneous administration).

[0175] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0176] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0177] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0178] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0179] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0180] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0181] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (eg, JAK inhibitors).

[0182] When administered in combination, the pharmaceutical composition further comprises one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds (e.g., JAK inhibitors). One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compounds (e.g., JAK inhibitors) can be used simultaneously, separately, or sequentially with the compound of the present invention to prevent and / or treat diseases related to the activity or expression of JAK kinases.

[0183] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0184] The main advantages of the present invention are:

[0185] 1. The compounds of the present invention have novel structures and excellent JAK kinase inhibitory effects;

[0186] 2. The compounds of the present invention can act as JAK kinase inhibitors, especially as highly selective inhibitors of JAK1.

[0187] 3. The compounds of the present invention have good pharmacokinetic properties and efficacy, such as better drugability, low toxicity and side effects, and good bioavailability.

[0188] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which no specific conditions are specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0189] Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial channels.

[0190] Example

[0191] Common materials and test methods:

[0192] The synthetic methods of the compounds of the present invention are shown in the following schemes, methods and examples. The starting materials are commercially available or can be prepared according to known methods in the art or as described herein. The compounds of the present invention can be illustrated by the specific examples shown below. However, these specific examples should not be construed as being the only types of the present invention. These examples further describe the preparation of the compounds of the present invention in detail. Those skilled in the art will readily appreciate that known variations of conditions and processes can be used to prepare these compounds.

[0193] All temperatures are in degrees Celsius unless otherwise stated.

[0194] The percentages for yield are all by mass.

[0195] All parts are by volume and all percentages are by volume unless otherwise indicated.

[0196] Preparative thin layer chromatography (PTLC) was performed on 20 x 20 cm plates (500 micron thick silica gel). Silica gel chromatography was performed using a Biotage flash chromatography system.

[0197] 1 H NMR was performed on a Bruker Ascend™ 400 spectrometer at 400 MHz and 298 K, and the chemical shifts (ppm) of the residual protons in the deuterated reagent are given as references:

[0198] CDCl3δ=7.26ppm, CD3ODδ=3.30ppm, DMSO-d6δ=2.50ppm

[0199] LCMS chromatography was performed using an Agilent Technologies 1260 linked 6100 quadrupole spectrometer. The LC mobile phase consisted of 0.1% formic acid in water (A) and 0.1% formic acid in acetonitrile (B), with an eluent gradient of: 0-95% B over 0-5.5 minutes, 95% B over 5.5-6 minutes, and 0% B over 6-8 minutes. A 50 mm × 2.1 mm × 3.5 μm SB-Aq capillary column was used.

[0200] Mass spectra (MS) were measured by electrospray ionization mass spectrometry (ESI).

[0201] HPLC mass spectrometry analysis conditions:

[0202] LC1:

[0203] Column: SB-Aq 50mm×2.1mm×3.5μm;

[0204] Temperature: 40℃;

[0205] Eluent: 100:0 to 5:95 v / v 0.1% formic acid-water / 0.1% formic acid-acetonitrile, 8 min;

[0206] Flow rate: 1.0 mL / min, injection 5 μL;

[0207] Detection: VWD, 210nm & 254nm;

[0208] MS: mass range 100-100 amu; positive ion electrospray ionization.

[0209] Abbreviations:

[0210] AcOH = acetic acid

[0211] Alk is an alkyl group

[0212] AR is an aryl group

[0213] Boc = tert-butyloxycarbonyl

[0214] bs = broad peak

[0215] CH2Cl2=dichloromethane

[0216] d = bimodal

[0217] dd = doublet

[0218] DBU=1,8-diazabicyclo[5.4.0]undec-7-ene

[0219] DCM = dichloromethane

[0220] DMF=N,N-dimethylformamide

[0221] DMSO = dimethyl sulfoxide EA = ethyl acetate

[0222] ESI = Electrospray Ionization

[0223] Et = Ethyl

[0224] EtOAc = ethyl acetate

[0225] EtOH = ethanol h = hours

[0226] HOAc = acetic acid

[0227] LiOH = lithium hydroxide m = multiple

[0228] Me = methyl

[0229] MeCN = acetonitrile

[0230] MeOH = methanol

[0231] MgSO4 = magnesium sulfate

[0232] min = minutes

[0233] MS = Mass Spectrometry

[0234] NaCl = sodium chloride

[0235] NaOH = Sodium Hydroxide

[0236] Na2SO4=Sodium sulfate

[0237] NMR = Nuclear Magnetic Resonance Spectroscopy PE = Petroleum Ether

[0238] PG = Protecting Group

[0239] Ph = phenyl rt = room temperature s = singlet t = triplet

[0240] TFA = trifluoroacetic acid

[0241] THF = Tetrahydrofuran

[0242] Synthesis of Example 1A1:

[0243]

[0244] Step 1: ethyl 2-(1,4-dioxaspiro[4.5]dec-8-ylidene)acetate (A1-2)

[0245] Under nitrogen, 1,4-cyclohexanedione monoethylene glycol ketal (A1-1, 10.0 g, 64.0 mmol) was added to anhydrous THF (100 ml) and stirred on ice for 5 min. Sodium hydroxide (3.07 g, 76.8 mmol, 60% dispersion in mineral oil) was added portionwise and stirred on ice for 0.5 h. Then, a THF solution of triethyl phosphonoacetate (14.78 g, 65.9 mmol) in 50 ml was slowly added. After the mixture was allowed to warm to room temperature, stirring was continued for 2 h. After TLC confirmed the reaction was complete, the reaction was quenched with water, the THF was concentrated, and extraction with EA was performed. The organic layer was collected, dried over anhydrous sodium sulfate, and the EA was concentrated to obtain crude ethyl 2-(1,4-dioxaspiro[4.5]decan-8-ylidene)acetate (A1-2, 14.38 g, yellow liquid, which was used directly in the next step without purification. 1 H NMR (400MHz, CDCl3) δ5.69 (s, 1H), 4.17 (q, J = 8.0Hz, 2H), 4.00 (s, 4H), 3.04 -3.01(m,2H),2.42-2.39(m,2H),1.82-1.77(m,4H),1.30(t,J=8.0Hz,3H).

[0246] Step 2: ethyl 2-(8-nitromethyl-1,4-dioxaspiro[4.5]dec-8-yl)acetate (A1-3)

[0247] Ethyl 2-(1,4-dioxaspiro[4.5]dec-8-ylidene)acetate (A1-2, 14.38 g, 63.6 mmol) was added to THF (100 ml), followed by tetrabutylammonium fluoride (18.29 g, 70 mmol, 70 mL, 1 M in THF) and nitromethane (5.82 g, 95.40 mmol). The temperature was raised to 80°C and the reaction was stirred for 16 hours. After TLC confirmed the reaction was complete, the THF was concentrated, and EA and deionized water were added. The liquids were separated by extraction. The organic layer was dried over anhydrous sodium sulfate, and the EA was concentrated to afford crude ethyl 2-(8-(nitromethyl)-1,4-dioxaspiro[4.5]dec-8-ylidene)acetate (A1-3, 16.68 g, yellow liquid, which was used directly in the next step without purification. 1HNMR (400MHz, CDCl3) δ4.75 (s, 2H), 4.21-4.15 (q, J = 8.0Hz, 2H), 3.97 (s, 4H), 2.58 (s, 2H), 1.74-1.72 (m, 8H), 1.31-1.25 (m, 3H).

[0248] Step 3: 1,4-dioxa-10-azadispiro[4.2.4 8 .2 5 ]Tetradecan-11-one (A1-4)

[0249] 2-(8-Nitromethyl-1,4-dioxaspiro[4.5]dec-8-yl)acetic acid ethyl ester (A1-3, 16.68 g) was added to methanol (150 ml), and then Raney nickel was added. Hydrogen was introduced and the reaction was carried out at 45°C for 48 hours. After the reaction was completed as monitored by LCMS, the reaction was filtered and the methanol was concentrated to obtain 1,4-dioxa-10-azabisspiro[4.2.4 8 .2 5 ]Tetradecan-11-one (A1-4, 11.98 g, crude) was used in the next step without purification. 1 H NMR (400MHz, CDCl3) δ5.65(s,1H),3.97(s,4H),3.22(s,2H),2.26(s,2H),1.77-1.74(m,4H),1.69-1.66(m,4H).

[0250] Step 4: 1,4-dioxa-10-azaspiro[4.2.4 8 .2 5 ]Tetradecane (A1-5)

[0251] Nitrogen protection, 1,4-dioxa-10-azadispiro[4.2.4 8 .2 5 ]Tetradecan-11-one (A1-4, 2 g, 9.47 mmol) was added to dry THF (30 ml) and stirred for 5 min. Borane THF solution (47.4 ml, 47.4 mmol, 1 M) was slowly added, the temperature was raised to 70 ° C, and stirred for 16 h. After LCMS confirmed that the reaction was complete, it was cooled to room temperature, methanol was slowly added to quench, and the solvent was concentrated to obtain oily 1,4-dioxa-10-azaspiro[4.2.4 8 .2 5 ]Tetradecane (A1-5, 1.8 g, crude) was used in the next step without purification.

[0252] Step 5: 10-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,4-dioxa-10-azaspiro[4.2.4 8 .25 ]Tetradecane (A1-6)

[0253] 1,4-dioxa-10-azaspiro[4.2.4 8 .2 5 ]Tetradecane (A1-5, 1.8 g, 9.13 mmol) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.4 g, 9.13 mmol) were added to DMF (30 ml), and N,N-diisopropylethylamine (2.36 g, 18.3 mmol) was added, the temperature was raised to 100 ° C, and stirred for 16 h. After LCMS confirmed that the reaction was complete, it was cooled to room temperature, filtered, the filter cake was collected, and dried under reduced pressure to obtain an off-white solid 10-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,4-dioxa-10-azaspiro[4.2.4 8 .2 5 ]Tetradecane (A1-6, 2.26 g, crude) was used in the next step without purification. 1 H NMR (400MHz, CDCl3) δ10.16(br,1H),8.33(s,1H),7.05(d,J=3.48Hz,1H),6.59(d,J =3.52Hz,1H),3.99–3.96(m,6H),3.73(s,2H),2.00–1.92(m,2H),1.78–1.71(m,8H).

[0254] Step 6: 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-aza-spiro[4.5]decan-8-one (A1-7)

[0255] 10-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,4-dioxa-10-azaspiro[4.2.4 8 .2 5 ]Tetradecane (A1-6, 2.26 g, 7.20 mmol) was added to THF (30 ml), concentrated hydrochloric acid (10 ml) was added dropwise, and the mixture was stirred at room temperature for 16 h. After LCMS confirmed that the reaction was complete, 6 mol / L NaOH solution was added dropwise to adjust the pH to 7-8, and the mixture was filtered, the filter cake was collected, and dried under reduced pressure to obtain an off-white solid 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-aza-spiro[4.5]decan-8-one (A1-7, 1.89 g, crude), which was used directly in the next step without purification. 1H NMR (400MHz, CDCl3) δ10.63(br,1H),8.35(s,1H),7.09(d,J=4Hz,1H),6.61(d,J=4.0Hz,1H) ,4.05(s,2H),3.89(s,2H),2.48(t,J=8.0Hz,4H),2.12(t,J=8.0Hz,2H),2.07–1.96(m,4H).

[0256] Step 7: 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[4.5]dec-8-amine (A1)

[0257] 2-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[4.5]decan-8-one (A1-7, 1 g, 3.70 mmol) was added to anhydrous ethanol (30 ml), followed by a 7 mol / L NH3 solution in MeOH (29.6 ml, 0.21 mol) and isopropyl titanate (2.1 g, 7.40 mmol). The mixture was stirred at room temperature for 6 h. Sodium borohydride (210 mg, 5.56 mmol) was then added portionwise and stirring continued for 16 h. After LCMS confirmed the reaction was complete, aqueous ammonia (17 ml) was added to quench the reaction. The mixture was stirred at room temperature for 15 min, filtered, and the filtrate was collected. After concentration, EA was added and stirred for 10 min. The filter cake was collected and dried under vacuum to afford A1 (900 mg) as an off-white solid. MS (ESI) m / z: calcd 272.19 (M+H), found 272.10; 1 H NMR (400 MHz, DMSO- d6 )δ11.55(br,1H),8.06(s,1H),7.09(d,J=3.32Hz,1H),6.57(s,1H),3.79(s,2H),3.49(s,2H),2.7 1-2.68(m,1H),1.87(s,2H),1.72-1.69(m,2H),1.64-1.61(m,2H),1.43(s,2H),1.33-1.27(m,2H).

[0258] Example 2 Synthesis of N-(2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[4.5]dec-8-yl)acetamide (A2):

[0259]

[0260] Under nitrogen protection, 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[4.5]dec-8-amine (A1, 4 mg, 14.8 μmol) was added to MeCN (1 ml), followed by sodium bicarbonate (2 mg, 23.8 μmol). The mixture was cooled to 0°C and stirred for 5 min. A solution of acetyl chloride (1.1 mg, 14.8 μmmol) in MeCN was then added dropwise, and stirring was continued on ice for 1 h. After LCMS confirmed the reaction was complete, the MeCN was concentrated, and the residue was purified on a preparative plate to afford A2 (3 mg, 64.9% yield) as a white solid. MS (ESI) m / z: calcd 314.20 (M+H), found 314.00; 1 H NMR (400 MHz, MeOH- d4 )δ8.08(s,1H),7.10(d,J=3.56Hz,1H),6.71(d,J=3.56Hz,1H),3.91(br,2H),3.73-3.63(m,3H),2.06- 2.04(m,2H),1.95(s,3H),1.88-1.85(m,2H),1.79-1.75(m,2H),1.65-1.59(m,2H),1.53-1.45(m,2H).

[0261] Example 3 Synthesis of N-(2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[4.5]dec-8-yl)benzenesulfonamide (A3):

[0262]

[0263] Under nitrogen protection, 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[4.5]dec-8-amine (A1, 10 mg, 36.9 μmol) was added to DMF (2 ml) and stirred to dissolve. Potassium carbonate (6.1 mg, 44.2 μmol) was added, followed by a solution of benzenesulfonyl chloride (7.8 mg, 44.2 μmol) in DMF (0.5 ml) and stirred at room temperature for 1 hour. After LCMS confirmed the reaction was complete, EA and deionized water were added for extraction. The organic phase was collected, the EA was concentrated, and the residue was purified by reverse phase column to obtain A3 (5 mg, 33.1% yield) as a white solid. MS (ESI) m / z: calcd 412.18 (M+H), found 412.20; 1 H NMR (400 MHz, DMSO- d6)δ12.65(br,1H),8.27(d,J=8.0Hz,1H),7.84(d,J=8.0Hz,2H),7.71(d,J=8.0Hz,1H),7.66-7.58(m,3H),7.43(br,1H ),6.88(br,1H),3.99(br,1H),3.63(br,3H),3.02(br,1H),1.92-1.85(m,2H),1.61-1.59(m,4H),1.39-1.32(m,4H).

[0264] Example 4 Synthesis of N-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[4.5]dec-8-yl)-3-bromo-5-nitrobenzamide (A4):

[0265]

[0266] Under nitrogen, 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[4.5]decan-8-amine (A1, 15 mg, 55.3 μmol) and 3-bromo-5-nitrobenzoic acid (13.5 mg, 55.3 μmol) were added to a mixture of DCM (2 ml) and DMF (0.5 ml). HATU (21 mg, 55.3 μmol) was then added, and the mixture was stirred on ice for 5 min. Then, a solution of N,N-diisopropylethylamine (7.1 mg, 55.3 μmol) in DCM (1 ml) was added dropwise, and the mixture was stirred on ice for 0.5 h. After LCMS confirmed the reaction was complete, dichloromethane and deionized water were added. The organic layer was collected, dried over anhydrous NaSO, and the DCM was concentrated. The residue was purified by reverse-phase column chromatography to afford A4 (11 mg, 40.0% yield) as a white solid. MS(ESI)m / z:calcd 499.11, 501.11(M+H), found 499.21, 501.22; 1 H NMR (400 MHz, DMSO- d6 )δ12.66(br,1H),8.74(d,J=8.0Hz,1H),8.66-8.65(m,1H),8.56(d,J=1.48Hz,1H),8.49-8.48(m,1H),8 .30(d,J=4.0Hz,1H),7.45(s,1H),6.94(s,1H),4.04-3.87(m,5H),2.05-1.75(m,6H),1.59-1.52(m,4H).

[0267] Referring to the experimental steps of Examples 2 to 4, different acylating agents were used to obtain Examples 5-75, as shown in Table 1 below.

[0268] Table 1

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283] Example 76 Synthesis of N-(2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[3.3]hept-6-yl)-2-chloro-4-nitrobenzamide (76)

[0284]

[0285] Step 1: 6-oxo-2-azaspiro[3.3]heptane (A76-01)

[0286] 2-Boc-6-oxo-2-azaspiro[3.3]heptane (200 mg, 0.95 mmol) was added to DCM (2 mL), and trifluoroacetic acid (2 mL) was added under nitrogen. The mixture was stirred at room temperature for 3.0 h. After LCMS confirmed the reaction was complete, the reaction solution was directly spin-dried to give 6-oxo-2-azaspiro[3.3]heptane trifluoroacetate (A76-01, 215 mg, crude) as a yellow oil, which was used directly in the next step without purification. MS (ESI) m / z: calcd 112.07 (M+H), found 112.14.

[0287] Step 2: 6-oxo-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[3.3]heptane (A76-02)

[0288] 6-Oxo-2-azaspiro[3.3]heptane trifluoroacetate (A76-01, 215 mg, 0.95 mmol) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (148 mg, 0.96 mmol) were added to N-methylpyrrolidone (4 ml), followed by potassium carbonate (900 mg, 6.5 mmol). The mixture was heated to 80°C and stirred for 14 h. After LCMS confirmed the reaction was complete, the mixture was cooled to room temperature and filtered. The filter cake was collected and dried under reduced pressure to afford 6-oxo-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[3.3]heptane (A76-02, 40 mg, crude) as an off-white solid, which was used directly in the next step without purification.

[0289] Step 3: 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[3.3]hept-6-amine (A76-03)

[0290] 6-Oxo-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[3.3]heptane (A76-02, 40 mg, 0.18 mmol) was added to anhydrous ethanol (2 ml), and then 7 mol / L NH3 in MeOH solution (2 ml, 14 mmol) and isopropyl titanate (105 mg, 0.37 mmol) were added. The mixture was stirred at room temperature for 6 h. Sodium borohydride (67 mg, 1.8 mmol) was added and stirring was continued for 16 h. After LCMS confirmed the reaction was complete, aqueous ammonia (2 mL) was added to quench the reaction, and the mixture was stirred at room temperature for 15 min. The mixture was filtered and the filtrate was collected. After concentration, EA was added for dissolution, the mixture was filtered and the filtrate was collected and dried under reduced pressure to afford 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[3.3]hept-6-amine (A76-03, 35 mg, crude) as a pale yellow oil, which was used in the next step without further treatment. MS (ESI) m / z: calcd 229.13 (M+H), found 229.10.

[0291] Step 4: N-(2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[3.3]hept-6-yl)-4-chloro-2-nitrobenzamide (A76)

[0292] 2-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[3.3]hept-6-amine (A76-03, 35 mg, 0.15 mmol) and 4-chloro-2-nitrobenzoic acid (30 mg, 0.15 mmol) were added to DMF (1 ml), followed by HATU (57 mg, 0.15 mmol). The mixture was stirred on ice for 5 min, followed by the dropwise addition of a solution of N,N-diisopropylethylamine (19.35 mg, 0.15 mmol) in DMF (0.5 mL). Stirring on ice continued for 1 h. LCMS confirmed the reaction was complete, and the reaction solution was directly purified by reverse phase column chromatography to afford A76 (20 mg, 32.3% yield) as a white solid. MS (ESI) m / z: calcd 413.11 (M+H), found 413.10; 1 H NMR (400 MHz, DMSO- d6 )δ12.64(s,1H),8.97(d,J=6.9Hz,1H),8.30(s,1H),8.19(s,1H),7.91(d,J=8.2Hz,1H),7.67(d,J=8.2H z,1H),7.45(s,1H),6.70(s,1H),4.53(m,4H),4.26-4.22(m,1H),2.78–2.64(m,2H),2.35-2.30(m,2H).

[0293] Effect Example 1: Biological Testing Method

[0294] JAK kinase activity is measured using homogeneous time-resolved fluorescence technology. The reaction is performed in a 384-well plate with a total reaction volume of 10 μL. A mixture of kinase protein, compound, ATP, and substrate is prepared in a reaction buffer containing 50 mM Hepes (pH 7.0), 0.02% NaN3, 0.01% BSA, 0.1 mM orthocanadate, 5 mM MgCl2, and 1 mM DTT. After a one-hour reaction, an antibody that recognizes phosphorylated substrates, the dye XL-615, and an EDTA-containing detection buffer (Cisbio) are added. The kinase reaction signal is detected using a PE multiwell plate reader. The parameters are set to excitation at 320 nm and emission at 615 and 665 nm. The ratio of the signals at 665 and 615 nm indirectly reflects JAK activity. Background wells without enzyme and wells containing compound-free, holoenzyme activity are included in the reaction.

[0295] Compounds inhibit protein IC 50 The value of is obtained by the formula: Y=100 / (1+10^((LogIC50-X)*HillSlope)).

[0296] In the JAK1 reaction system, the ATP concentration was 2 μM and the JAK1 protein concentration was 0.2 ng / μL.

[0297] In the JAK2 reaction system, the ATP concentration was 2 μM and the JAK1 protein concentration was 0.01 ng / μL.

[0298] In the JAK3 reaction system, the ATP concentration was 2 μM and the JAK1 protein concentration was 0.04 ng / μL.

[0299] In the TYK2 reaction system, the ATP concentration was 2 μM and the JAK1 protein concentration was 0.2 ng / μL.

[0300] Test data is divided into the following categories: A:IC 50 <10nM; B:IC 50 11-100nM; C:IC 50 101-1000nM; D:IC 50 1001-10000nM; E:IC 50 >10000nM.

[0301] The test results are shown in Table 2.

[0302] Table 2

[0303]

[0304]

[0305]

[0306] The above experimental results suggest that:

[0307] (1) The compounds of Formula I of the present invention exhibit excellent JAK inhibitory activity, particularly JAK1 activity. IC50 values ​​of the compounds of the present invention can be as low as 10 nM or lower. Thus, for subjects weighing approximately 70 kg (e.g., patients, particularly those with rheumatoid arthritis or psoriasis), a daily dose of 10 mg to 30 mg is typically sufficient to effectively inhibit JAKs, particularly JAK1.

[0308] (2) The compounds of formula I of the present invention exhibit very excellent JAK selectivity, i.e., the IC50 ratios of JAK3 / JAK1, JAK2 / JAK1, and TYK2 / JAK1 are increased by about 10 times (mostly about 20-100 times), which is far superior to currently marketed drugs.

[0309] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound represented by formula I or a pharmaceutically acceptable salt thereof, Where, R1, R2 and R3 are each independently selected from the following substituted or unsubstituted groups: H, halogen, amino, nitro, hydroxyl, cyano, carboxyl, C1-C6 alkyl, C1-C6 alkoxy; wherein, The substitution is by one or more R a replace; B is independently selected from the following group: -NH-C(=O)-; optionally, each hydrogen in the above group is replaced by a C1-C6 alkyl group; C is selected from the following groups: substituted or unsubstituted: C3-C8 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl; wherein, the substitution refers to the substitution of one or more R a replace; Selected from: and The H is optionally replaced by one or more R a Substituted; wherein q is 0, 1, 2 or 3; Among them, each R a Independently selected from the following groups: halogen, amino, nitro, hydroxyl, mercapto, cyano, carboxyl, methyl formate, formyl, formamide, C1-C6 alkyl, halogenated C1-C6 alkyl, (CH2) t G, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl and C6-C12 aryl, wherein t is 1, 2 or 3; G is selected from: 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl and C6-C12 aryl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein It has the structure shown in Formula II: Where q is 0, 1, 2 or 3; R1, R2, R3, R a , B and C are as defined in claim 1.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The compound satisfies one or more of the following conditions, (1) Selected from: Where q is 0, 1, 2 or 3; R a The definition of is as in claim 1; (2) C is selected from the group consisting of phenyl, thiazolyl, pyridyl, cyclopropyl, pyrazinyl, cyclohexyl, benzothiophenyl, benzofuranyl, pyrimidinyl, naphthyl, cyclobutyl, cyclopentyl, and cycloheptyl; wherein, optionally, C is substituted by a substituent selected from the group consisting of fluorine, chlorine, bromine, nitro, cyano, hydroxy, ethynyl, methyl, methoxy, methyl formate, and trifluoromethyl; (3) R1 is hydrogen; (4) R2 is hydrogen; (5) R3 is hydrogen.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein C is selected from: phenyl, Cyclopropyl, Cyclohexyl, naphthyl, cyclobutyl, cyclopentyl, cycloheptyl; wherein, optionally, C is substituted by a substituent selected from the group consisting of fluorine, chlorine, bromine, nitro, cyano, hydroxy, ethynyl, methyl, methoxy, methylformyl, trifluoromethyl.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein C is selected from: Phenyl, 6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Selected from 7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein In the compound, each substituent satisfies one or more of the following conditions: Each C1-C6 alkyl group is independently selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl; Each C1-C6 alkoxy group is independently selected from the group consisting of methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, and tert-butoxy; Each C2-C6 alkenyl group is independently selected from the group consisting of vinyl, propenyl, and allyl; Each C2-C6 alkynyl group is independently selected from: ethynyl, propynyl; Each 3-10 membered heterocycloalkyl group is independently selected from the group consisting of tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophene, tetrahydropyranyl, piperazinyl, piperidinyl, and morpholinyl; Each C3-C10 cycloalkyl group is independently selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl; Each 5-12 membered heteroaryl is independently selected from the group consisting of pyrrolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, indolyl, benzothienyl, and benzofuranyl; Each C6-C12 aryl group is independently selected from: phenyl, naphthyl.

8. A compound or a pharmaceutically acceptable salt thereof, characterized in that The compound is selected from the group consisting of:

9. A pharmaceutical composition, characterized in that The invention comprises the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

10. Use of the pharmaceutical composition according to claim 9 in preparing a drug, characterized in that: The medicine is used for treating or preventing diseases related to the activity or expression level of JAK kinase.

11. Use of the pharmaceutical composition according to claim 9 in preparing a drug, characterized in that: The drug acts as a JAK kinase inhibitor.

12. The use according to claim 11, characterized in that The drug acts as a JAK1 kinase inhibitor.

13. Use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof in the preparation of a medicament, characterized in that: The medicine is used for treating or preventing diseases related to the activity or expression level of JAK kinase.

14. The use according to claim 13, characterized in that The disease is selected from the group consisting of cancer, inflammation, immune disease, organ transplantation, viral disease, cardiovascular disease or metabolic disease, and skin disorders.

15. The use according to claim 13, characterized in that The disease is selected from myeloproliferative diseases.

16. The use according to claim 13, characterized in that The disease is an autoimmune disease in humans or animals.

17. The use according to claim 13, wherein The disease is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, myasthenia gravis, and psoriasis.

18. The use according to claim 13, wherein The disease is selected from the group consisting of prostate cancer, kidney cancer, liver cancer, breast cancer, lung cancer, thyroid cancer, Kaposi's sarcoma, giant lymphoproliferation, pancreatic cancer, leukemia, lymphoma, and multiple myeloma.

19. The use according to claim 13, wherein The disease associated with the activity or expression level of JAK kinase is a JAK1-related disorder.

20. The use according to claim 19, characterized in that The JAK kinase is JAK1 kinase, and the JAK1-related disorder is selected from the group consisting of type I diabetes, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease, and alopecia areata.

21. Use of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting JAK kinase activity.

22. The use according to claim 21, characterized in that The JAK kinase is JAK1 kinase.

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