CN111961037A - Pharmaceutical compound as JAK kinase inhibitor - Google Patents
Pharmaceutical compound as JAK kinase inhibitor Download PDFInfo
- Publication number
- CN111961037A CN111961037A CN202010976485.3A CN202010976485A CN111961037A CN 111961037 A CN111961037 A CN 111961037A CN 202010976485 A CN202010976485 A CN 202010976485A CN 111961037 A CN111961037 A CN 111961037A
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- Prior art keywords
- compound
- pharmaceutical compound
- pharmaceutical
- jak
- tyk2
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- General Health & Medical Sciences (AREA)
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- Heart & Thoracic Surgery (AREA)
- Emergency Medicine (AREA)
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- Obesity (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention provides a pharmaceutical compound, which is a compound shown by the following structural formula or a stereoisomer and a geometric isomer thereofA tautomer, a racemate, a hydrate, a solvate, a metabolite and a pharmaceutically acceptable salt or prodrug, wherein R represents 1 to 3 substituents on a benzene ring, and each of the 1 to 3 substituents is independently selected from halogen or cyano. The pharmaceutical compounds of the invention are capable of inhibiting JAK kinases, more particularly as dual inhibitors of JAK1/Tyk2 and Tyk2 specific inhibitors. More specifically, the pharmaceutical compound of the present invention can be used for preventing or treating autoimmune diseases such as rheumatoid arthritis, ankylosing spondylitis, ulcerative colitis, systemic lupus erythematosus, type I diabetes, sjogren's syndrome, vasculitis, alopecia areata, psoriasis, vitiligo, etc., or other inflammatory skin diseases such as atopic dermatitis, eczema, acne, hidradenitis suppurativa, etc.
Description
Technical Field
The invention belongs to the field of pharmaceutical compounds, and particularly relates to a pharmaceutical compound which can be used for preventing or treating autoimmune diseases such as rheumatoid arthritis, ankylosing spondylitis, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, dermatomyositis, multiple sclerosis, type I diabetes, psoriasis, vitiligo, Sjogren's syndrome and the like, or other inflammatory skin diseases such as atopic dermatitis, eczema, lichen planus, lichen glossus, lichen atrophicus sclerosis, panniculitis, acne, hidradenitis suppurativa and the like, and particularly relates to a compound serving as a JAK kinase inhibitor.
Background
Protein kinases catalyze the phosphorylation of amino acids at specific sites in proteins, and are classified into tyrosine, serine, and arginine kinases according to the phosphorylation of amino acids. JAKs are a family of intracellular non-receptor Tyrosine protein kinases (Tyrosine Kinase) including four members of JAK1, JAK2, JAK3 and Tyk 2. JAKs are expressed primarily in hematopoietic cells, leukocytes and intestinal epithelial cells and are responsible for mediating the signaling of various cytokines involved in inflammatory responses. When cytokines are combined with cell surface receptors, JAK is activated through phosphorylation, activated JAK is activated through phosphorylation of intracellular parts of the receptors and recruits STAT protein family members, and then STAT is activated through phosphorylation by JAK to form dimers, is separated from the receptors to enter cell nucleus and performs gene transcription regulation, so that the biological functions of cells are influenced. The JAK (Janus Kinase) -STAT (Signal Transducer and Activator of Transcription proteins) signaling pathway is the main pathway for intracellular signaling triggered after the binding of inflammatory cytokines and receptors. There is a great deal of evidence that the JAK-STAT signaling pathway is important in connection with many diseases, particularly autoimmune diseases such as rheumatoid arthritis, intestinal diseases, allergic diseases, and the like. Therefore, the protein kinase becomes the most important drug development target point for intervening diseases. At present, a plurality of pharmaceutical companies develop new drugs aiming at JAK family members, but mostly concentrate on inhibiting JAK1, JAK2 and JAK3, and inhibitors aiming at Tyk2 are rarely reported.
The JAK-STAT pathway can be activated by more than 50 different cytokines. Proinflammatory cytokines (IL6, TNF- α, IL12, IL23), anti-inflammatory cytokines (IL4, IL10), hematopoietic cell growth factors (g-CSF, EPO, TPO), and metabolic cytokines (leptin, GH), among others, activate this signaling pathway, thereby regulating cell proliferation, differentiation and activation, as well as multiple gene transcriptional regulation of human metabolic homeostasis. The Jak/STAT cascade is a junction of many extracellular regulatory signals within the cell and is therefore the central communication node of the cell. Studies have shown that cytokine-mediated signaling systems phosphorylate cytokine receptors, recruiting STATs, and ultimately lead to gene expression in cells through activation of JAK family members JAK1, JAK2, JAK3, and TYK2 tyrosine kinases. Pairing between JAK members is directly related to upstream cytokines. Depending on different cytokine stimuli, differences in upstream cytokine signals may occur in JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, JAK2/TYK2, JAK2/JAK2 pairing combinations, with JAK1 pairing being the most common. TYK2 is extremely important for the signal transduction of type I interferons (IFN-. alpha., IFN-. beta.), IL-6 and IL-23. Immune cell differentiation and function associated with inflammatory and autoimmune diseases are both important in connection with TYK 2. Typically TYK2 and its family members may be in the form of TYK2/JAK1, TYK2/JAK2, TYK2/JAK1/JAK2 pairings when activated by the signalling system. Tyk2 plays an extremely important role in mediating the signal transmission paths of IL12, IL17 and IL 23. The biological antibody drug aiming at IL17 and IL23 has good treatment effect on diseases such as psoriasis and the like, and can be expected to inhibit JAK kinase activity, particularly TYK2 kinase activity by utilizing efficient small molecules, so that a signal path mediated by inflammatory factors can be blocked, inflammation is controlled, autoimmune diseases and/or inflammatory skin diseases are effectively treated, and side effects are reduced.
The applicant has made a great deal of research in this field in recent years and found that a great number of JAK kinase inhibitors with good effects, for example, the applicant's prior application CN110627775A (title of the invention: a pharmaceutical compound) discloses a specific inhibitor, wherein a great number of active compounds are disclosed, and the compound TDM-180820 has the following structure:
the activity of the compound is against IC of TYK2, JAK1, JAK2 and JAK350The value was less than 0.1. mu.M. In addition, other prior art CN103298794A (published as 09/11/2013) also tested the activity of TYK2 with JAK2 of several compounds, among which compound 213:
the compounds are also active against JAK kinases, the IC thereof50Is 0.1-1 μ M or 1-10 μ M. However, the applicant expects to search for more targeted and active compounds based on such prior art.
Disclosure of Invention
The present invention aims at developing JAK kinase inhibitors, in particular Tyk2 inhibitors, and/or JAK1 inhibitors, and/or JAK1/Tyk2 or Tyk2/JAK1 and/or Tyk2/JAK2 dual inhibitors, suitable for the treatment of autoimmune diseases such as rheumatoid arthritis, ulcerative colitis, and inflammatory skin diseases such as eczema, psoriasis as indications, which are highly effective and specific.
In one aspect, the present invention provides a pharmaceutical compound, which is a compound represented by the following structural formula or a stereoisomer, a geometric isomer, a tautomer, a racemate, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug thereof:
wherein, the R represents 1 to 3 substituents on the benzene ring, and the 1 to 3 substituents are respectively and independently selected from halogen or cyano.
In one embodiment, the halogen is F, Cl or Br.
In another embodiment, the R is ortho-substituted F.
In another embodiment, the R is meta substituted F.
In another embodiment, R is para-substituted F.
In another embodiment, the R is a meta substituted cyano.
In another aspect, the invention also provides the use of the above pharmaceutical compounds in the inhibition of JAK kinases.
In another aspect, the invention also provides the use of a pharmaceutical compound as described above in the manufacture of a medicament for the prevention or treatment of autoimmune diseases, and immune-related inflammatory skin diseases, preferably where the pathogenesis of these diseases is associated with a dysregulation of JAK signaling.
In one embodiment, the autoimmune disease is selected from at least one of rheumatoid arthritis, ankylosing spondylitis, ulcerative colitis, crohn's disease, systemic lupus erythematosus, dermatomyositis, multiple sclerosis, type I diabetes, sjogren's syndrome, vasculitis, alopecia areata, psoriasis, and vitiligo.
In another embodiment, the immune-related inflammatory skin disease is selected from at least one of atopic dermatitis, eczema, lichen planus, lichen glossus, lichen sclerosus, panniculitis, acne, and hidradenitis suppurativa.
The invention has the following functions and effects:
the invention carries out purposeful reasonable design of a pharmaceutical compound according to the protein structure of JAK kinase, particularly the protein structure of Tyk2, the synthesized compound firstly carries out the biochemical activity detection of JAK kinase according to IC50Building SAR (structure-activity relationship) for IC50Potent inhibitors below 200nM were then tested in cytology and the selectivity of the compounds determined. Referring to specific activity experimental data, the compound related to the invention has good JAK kinase activity and inhibition capacity of cell biological activity. More particularly, the pharmaceutical compounds of the present invention can exert better therapeutic effects than when no substituent or a substituent other than halogen or cyano is substituted on the rightmost benzene ring.
Detailed Description
The following describes in detail specific embodiments of the present invention. It should be understood that the detailed description and specific examples, while indicating the present invention, are given by way of illustration and explanation only, not limitation.
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.
Before describing the present invention in detail, it is to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. For a more complete understanding of the invention described herein, the following terms are used, and their definitions are set forth below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
In one aspect, the present invention provides a pharmaceutical compound, which is a compound represented by the following structural formula or a stereoisomer, a geometric isomer, a tautomer, a racemate, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug thereof:
wherein, the R represents 1 to 3 substituents on the benzene ring, and the 1 to 3 substituents are respectively and independently selected from halogen or cyano. In other words, the pharmaceutical compound of the present invention comprises at least one substituent selected from halogen or cyano on the rightmost benzene ring. Further, when the pharmaceutical compound of the present invention contains at least two substituents on the rightmost benzene ring, the substituents may each independently be present at any position of the benzene ring.
According to the present invention, when the at least one substituent is halogen, the halogen species may each be independently selected from all halogen elements commonly found in the art, such as F, Cl, Br or I. In a preferred embodiment, the halogen may be F, Cl or Br. In a more preferred embodiment, the halogen may be F or Cl. In a most preferred embodiment, the halogen may be F.
In a particular embodiment, the R may be ortho-substituted F. In this case, the pharmaceutical compounds of the present invention have the following structural formula:
in a specific embodiment, R may beIs meta-substituted F. In this case, the pharmaceutical compounds of the present invention have the following structural formula:
in a particular embodiment, the R may be para-substituted F. In this case, the pharmaceutical compounds of the present invention have the following structural formula:
in a specific embodiment, the R may be a meta substituted cyano. In this case, the pharmaceutical compounds of the present invention have the following structural formula:
as used herein, the term "pharmaceutically acceptable" refers to a substance that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological response or interacting in an adverse manner with any of the components included in the composition. In the present invention, the "pharmaceutically acceptable salt" may include inorganic salts and organic salts, wherein the organic salts may include, but are not limited to, ammonium, lithium, sodium, potassium, cesium, calcium, magnesium, copper, aluminum, zinc, barium, or quaternary ammonium salts, and the inorganic salts may include, but are not limited to, arginine, tert-butylamine, dimethylamine, diethanolamine, ethanolamine, ethylenediamine, imidazole, lysine, methylamine, pyridine, picolinate, piperazine, triethylamine, triethanolamine, trimethylamine, or urea salts.
In another aspect, the invention provides the use of the above pharmaceutical compounds in the inhibition of JAK kinases, in particular as dual inhibitors of JAK1/Tyk2 and Tyk2 specific inhibitors.
In another aspect, the invention also provides the use of a pharmaceutical compound as described above in the manufacture of a medicament for the prevention or treatment of autoimmune diseases, and immune-related inflammatory skin diseases, preferably where the pathogenesis of these diseases is associated with a dysregulation of JAK signaling.
As used herein, the term "treatment" refers to any administration of a therapeutic agent according to a therapeutic regimen that achieves a desired effect, i.e., partially or completely reduces, ameliorates, alleviates, inhibits, delays onset, reduces severity, and/or reduces the incidence of one or more symptoms or features of a particular disease, disorder, and/or condition; in some embodiments, administration of a therapeutic agent according to a therapeutic regimen is correlated with achievement of a desired effect. Such treatment may be for subjects who do not exhibit the associated disease, disorder, and/or condition and/or for subjects who exhibit only early signs of the disease, disorder, and/or condition. Alternatively or additionally, such treatment may be directed to a subject exhibiting one or more determined signs of the associated disease, disorder, and/or condition. In some embodiments, the treatment may be directed to a subject who has been diagnosed with the relevant disease, disorder, and/or condition. In some embodiments, treatment may be directed to a subject known to have one or more susceptibility factors statistically associated with an increased risk of development of the associated disease, disorder, and/or condition.
According to the present invention, the medicament prepared in the above-mentioned use may comprise an effective amount of the pharmaceutical compound of the present invention, together with a pharmaceutically acceptable excipient, carrier or diluent.
As used herein, the term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" refers to the amount of a therapeutic agent that confers a therapeutic effect on a treated subject at a reasonable benefit/risk ratio applicable to any drug treatment. Such therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject gives an indication or feels the effect). In some embodiments, a "therapeutically effective amount" refers to an amount of a therapeutic agent or composition that is effective to treat, ameliorate or prevent (e.g., delay onset of) an associated disease or disorder and/or exhibit a detectable therapeutic or prophylactic effect, such as by ameliorating symptoms associated with the disease, preventing or delaying the onset of the disease, and/or also lessening the severity or frequency of symptoms of the disease.
One skilled in the art will recognize that the therapeutically effective amount of the pharmaceutical compound to be administered will vary according to: the nature and severity of the subject and disease, the physical condition of the subject, the treatment regimen (e.g., whether a second therapeutic agent is used), and the chosen route of administration; suitable dosages can be readily determined by those skilled in the art. In addition, the optimal number and spacing of individual doses of the drug will be determined by the nature and extent of the condition being treated, the form, route and location of administration, and the age and condition of the particular subject being treated, and the physician will ultimately determine the appropriate dose to be administered. This dose can be repeated as many times as necessary. If side effects occur, the amount and/or frequency of dosage may be varied or reduced according to normal clinical practice.
In the present invention, the "pharmaceutically acceptable excipient, carrier or diluent" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier, etc., which is approved by the relevant governmental regulatory agency as being acceptable for human or livestock use.
According to the present invention, the drug prepared by the above-mentioned use may further contain, as another active ingredient, other agents useful for preventing or treating autoimmune diseases and immune-related inflammatory skin diseases, in addition to the drug compound of the present invention as an active ingredient. Examples of such agents include, but are not limited to, vitamin D derivatives, vitamin a derivatives, glucocorticoids, calcineurin inhibitors, non-steroidal anti-inflammatory drugs, and the like. When the medicament comprises a plurality of active ingredients, the active ingredients may be administered simultaneously, sequentially or separately at the discretion of the physician.
In addition, the pharmaceutical compounds of the present invention can be administered to a patient by a variety of routes such as oral, transdermal, subcutaneous, intranasal, intravenous, intramuscular, intrathecal, regional or topical (e.g., mucosal). The most suitable route of administration in any given case will depend on the subject and the nature and severity of the disease, as well as the physical condition of the subject, etc. In one embodiment, the pharmaceutical compounds of the present invention may be administered intravenously. In another embodiment, the pharmaceutical compounds of the present invention may be administered orally. Accordingly, the pharmaceutical of the present invention can be prepared in various dosage forms according to various administration modes. For example, in one embodiment, the medicament may be prepared as a tablet, capsule, pill, granule, aerosol, spray or injection.
The inventor researches and discovers that the pharmaceutical compound of the invention or the prepared medicine thereof can play excellent effects in preventing or treating autoimmune diseases and inflammatory skin diseases related to immunity. In particular, the autoimmune disease may include, but is not limited to, rheumatoid arthritis, ankylosing spondylitis, ulcerative colitis, crohn's disease, systemic lupus erythematosus, dermatomyositis, multiple sclerosis, type I diabetes, sjogren's syndrome, vasculitis, alopecia areata, psoriasis, or vitiligo; and the immune-related inflammatory skin disease may include, but is not limited to, atopic dermatitis, eczema, lichen planus, lichen glossus, lichen sclerosus, panniculitis, acne, or hidradenitis suppurativa. More particularly, the pharmaceutical compounds of the present invention can exert better therapeutic effects than when no substituent or a substituent other than halogen or cyano is substituted on the rightmost benzene ring.
Hereinafter, the effects of the specific pharmaceutical compounds of the present invention will be described in detail by way of examples.
Examples
EXAMPLE 1 general procedure for the Synthesis of Compound 1(TDM-180944)
Step 1: preparation of Compound 1(TDM-180944)
To a solution of compound 1a (60mg, 0.225mmol) in pyridine (5mL) was added compound 1b (65.8mg, 0.315mmol) at room temperature, and the mixture was heated to 70 ℃ and stirred for 6 h. The mixture was then concentrated under reduced pressure and the residue was purified by silica gel chromatography (dichloromethane: 10% methanol in dichloromethane ═ 70: 30) and formic acid to afford compound 1, TDM-180944, i.e. 1- (2-fluorophenyl) -N- (4- (2- (((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) methanesulfonamide (34.5mg, 34.97% yield) as a yellow solid.
1H NMR(400MHz,DMSO-d6)10.34(s,1H),9.45(s,1H),8.45(d,J＝5.2Hz,1H),8.10(d,J＝8.6Hz,2H),7.93(s,1H),7.55(s,1H),7.45–7.30(m,4H),7.25–7.17(m,3H),4.60(s,2H),3.84(s,3H)。LCMS[M+1]+＝439.2。
Example 2 general procedure for the Synthesis of Compound 2 (TDM-180945)
Compound 2 was prepared in a similar manner to example 1:
TDM-180945, 1- (3-fluorophenyl) -N- (4- (2- (((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) methanesulfonamide (26.1mg, 19.8% yield).
1H NMR(400MHz,DMSO-d6)10.25(s,1H),9.45(s,1H),8.45(d,J＝5.2Hz,1H),8.12(d,J＝8.6Hz,2H),7.93(s,1H),7.56(s,1H),7.40(dd,J＝14.3,7.6Hz,1H),7.32(d,J＝8.6Hz,2H),7.26–7.15(m,2H),7.11(d,J＝7.3Hz,2H),4.63(s,2H),3.84(s,3H)。LCMS[M+1]+＝439.2。
Example 3 general procedure for the Synthesis of Compound 3(TDM-180958)
Step 1: preparation of Compound 3c (3-cyanobenzylaminothiocarbamate)
To a solution of compound 3a (1.78g, 9.08mmol) in ethanol (13mL) was added compound 3b (690mg, 9.08mmol), the reaction was warmed to 80 ℃ and stirred for 1 hour, LCMS [ M + H ]]+The detection reaction was complete 192. And (3) post-treatment: the reaction solution is concentrated to be dryTo give the title compound (Compound 3c,1.7g, 97.7% yield) as a white solid, LCMS [ M +1 ]]+＝192。
Step 2: preparation of Compound 3d ((3-cyanophenyl) methanesulfonyl chloride)
To a solution of N-chlorosuccinimide (4.85g,36.32mmol) in acetonitrile (20mL) was added 2N hydrochloric acid solution (2.5mL) and compound 3c (1.74g, 9.08mmol), and the reaction solution was stirred at room temperature for 30 minutes. And (3) post-treatment: after completion of the reaction, acetonitrile was concentrated and removed, water (15mL) was added, a white solid precipitated, filtered, and the solid was oil-pumped to dryness to give the desired compound (compound 3d, 1.776g, yield 90.7%) as a white solid.
And step 3: preparation of Compound 3(TDM-180958)
To a solution of compound 3e (500mg, 1.878mmol) in anhydrous pyridine (20mL) was added compound 3d (1g, 4.64mmol), the reaction mixture was warmed to 80 ℃ and reacted for 30 minutes, LCMS [ M + H ]]+At 446, the detection reaction was complete. And (3) post-treatment: concentrating the reaction solution to dryness, and passing the crude product through a column (eluent (D: M: 10: 1)/DCM: 0-50%]The crude product was slurried with DCM/MeOH ═ 30/1 to give a yellow solid which was purified by preparative HPLC to give the yellow title compound, 1- (3-cyanophenyl) -N- (4- (2- (((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) methanesulfonamide (compound 3, 155.4mg, 18.6% yield).
1H NMR(400MHz,DMSO)10.27(s,1H),9.46(s,1H),8.46(d,J＝5.2Hz,1H),8.12(d,J＝8.7Hz,2H),7.93(s,1H),7.84(dt,J＝7.2,1.6Hz,1H),7.71(s,1H),7.61(ddd,J＝17.3,10.8,4.8Hz,3H),7.32(d,J＝8.6Hz,2H),7.24(d,J＝5.2Hz,1H),4.71(s,2H),3.85(s,3H)。LCMS[M+H]+＝446。
Example 4 general procedure for the Synthesis of Compound 4(TDM-180963)
Step 1: preparation of Compound 4c
To a solution of compound 4a (7.2g, 50mmol) in ethanol (50mL) was added compound 4b (3.805g, 50mmol) at room temperature. Heating the mixture to 80 deg.CStirred for 0.5h, concentrated under reduced pressure and the residue was used directly in the next reaction. LCMS (liquid Crystal Module) (M + 1)]+＝185.1。
Step 2: preparation of Compound 4d
N-chlorosuccinimide (26.71g, 200mmol) was dissolved in a mixed solution of 2N hydrochloric acid (13.6mL) and acetonitrile (80mL) at room temperature, then Compound 4c was added and the mixture was stirred for 1 hour. The mixture was concentrated under reduced pressure, the residue was taken up in water and cooled, the solid was collected by filtration, the filter cake was taken up in water and sonicated, and filtration was carried out once more to give the desired compound 367d (7g, 67% yield) as a white solid, i.e. (4-fluorophenyl) methanesulfonyl chloride.
And step 3: preparation of Compound 4(TDM-180963)
To a solution of compound 4e (600mg, 2.25mmol) in pyridine (20mL) was added compound 4d (940mg, 4.5mmol) at room temperature. The mixture was heated to 80 ℃ and stirred for 1.5 hours, then concentrated under reduced pressure, methanol was added to the residue, and the solid was collected by filtration and purified by silica gel chromatography (dichloromethane: 10% methanol in dichloromethane ═ 30: 70) to give a yellow solid. The solid was slurried with dichloromethane and methanol, the filter cake was added to dimethyl sulfoxide, concentrated under reduced pressure, then water was added, ultrasonic filtration was repeated (3 times), and finally lyophilization was carried out to give the desired compound 4, TDM-180963 (compound 363, 381.8mg, yield 38.7%) as a yellow solid, i.e., 1- (4-fluorophenyl) -N- (4- (2- (((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) methanesulfonamide.
1H NMR(400MHz,DMSO-d6)10.18(s,1H),9.45(s,1H),8.45(d,J＝5.1Hz,1H),8.11(d,J＝8.5Hz,2H),7.93(s,1H),7.56(s,1H),7.37–7.27(m,4H),7.26–7.14(m,3H),4.59(s,2H),3.84(s,3H)。LCMS[M+1]+＝439.1。
Test example 1 detection of enzyme Activity inhibition by Small molecule inhibitors of JAK kinase
Experimental protocol
1. Reagent preparation
Kinase reaction buffer: preparing a kinase reaction buffer solution, which comprises the following components: 50mM HEPES, pH 7.5, 1mM EGTA, 10mM MgCl22mM DTT, 0.01% Tween 20. 1 × detection buffer: preparing detection buffer solution and deionized water9:1 dilution 10 Xdetection buffer to 1X. 4X kinase solution: the kinase reaction buffer diluted the JAK kinase to a final concentration of 4X (JAK 1: 80nM, JAK2/JAK3/Tyk 2: 4 nM). 4X substrate solution: dilution of ULight with kinase reaction bufferTMJAK (Tyr1023) substrate to 200nM (final concentration: 50 nM). 4XATP solution: the kinase reaction buffer diluted ATP to a final concentration of 4X (JAK 1: 160. mu.M, JAK2/JAK3/Tyk 2: 40. mu.M). 4X test compound solution: DMSO dissolves test compounds into 10mM stock solutions, 3-fold gradient dilutions are configured to the desired concentration, 10 concentration points are set for each compound, and the final concentration range of test compounds is: 10 μ M-0.5 nM. 4 Xenzyme reaction stop solution: the 1 Xdetection buffer dissolved EDTA to 40mM (final EDTA concentration: 10 mM). 4X detection antibody solution: the Eu-labeled detection antibody (anti-phosphotyrosine (PT66)) was diluted to 8nM (final antibody concentration: 2nM) in 1X detection buffer.
2. Procedure of experiment
To 384 plates were added 2.5. mu.L of 4X kinase solution and 2.5. mu.L of 4X test compound solution diluted to different concentrations in sequence, 2 duplicate wells per concentration, and enzyme solution blank and negative controls (DMSO). Shake 384 multi-well plates, mix enzyme and compound well, 1000 rpm, centrifuge for 1 min, incubate at room temperature for 60 min. Add 2.5. mu.L of 4 Xsubstrate solution to 384 multi-well plates and centrifuge for 1 min at 1000 rpm. The enzyme reaction was initiated by adding 2.5. mu.L of a 4XATP solution to 384 multi-well plates and centrifuging at 1000 rpm for 1 minute. JAK1 was reacted at room temperature for 2 hours, and JAK2/JAK3/Tyk2 was reacted at room temperature for 1 hour. The final concentrations of each component of the JAK1 reaction were: JAK 1: 20nM, substrate: 50nM, ATP: 40uM, final concentration range of test compound: 10 μ M-0.5 nM. The final concentrations of each component of the JAK2/JAK3/Tyk2 reaction are respectively: JAK 2: 1nM, substrate: 50nM, ATP: 10 μ M, final concentration range of test compound: 10 μ M-0.5 nM. After completion of the enzyme reaction, 5. mu.L of a 4 Xenzyme reaction-terminated solution was added to each well of a 384-well plate, and the mixture was centrifuged at 1000 rpm for 1 minute and incubated at room temperature for 5 minutes. mu.L of a 4 Xdetection antibody solution (final concentration of detection antibody: 2nM) was added to each well of 384-well plates at 1000 rpm, centrifuged for 1 minute, and incubated at room temperature for 1 hour. After the antibody incubation was completed, the signal value of each well was measured on an Envision plate reader
3. Data analysis
The percent inhibition rate corresponding to each concentration of the test compound was calculated with the enzyme solution blank control group as 100% inhibition rate and the negative control group (DMSO group) as 0% inhibition rate. Nonlinear regression analysis of the log concentration values and corresponding percent inhibition of the test compounds in GraphPad Prism software to obtain the median Inhibitory Concentration (IC) of the test compounds50) The experimental results obtained are shown in table 1 below. Among them, compounds TDM-180958, TDM-180944, TDM-180945 and TDM-180963 were used as experimental groups in this patent, and TDM-180820 in the applicant's prior application CN110627775A and compound 213 in prior art CN103298794A (data of this compound are directly from the source patent) were used as positive control groups.
TABLE 1
From the results of Table 1 above, it can be seen that the enzyme activity data of the compounds TDM-180958, TDM-180944, TDM-180945 and TDM-180963 of the present application are significantly better than the enzyme activity data of the compounds TDM-180820 and 213, more particularly the compound TDM-180958, which is even more superior by an order of magnitude to the half inhibitory concentration of Tyk2 and JAK1 than the compound TDM-180820 as a positive control. Therefore, the experiments prove that the compound of the application is a compound with stronger targeting and better enzyme activity aiming at JAK family.
Test example 2 detection of cellular Activity inhibition by Small molecule inhibitors of JAK kinase
We evaluated the inhibition of cytokine signaling in cells by small molecule inhibitors of JAK kinases using two cytological test systems: the expression level of pSTAT6 in THP-1 cells induced by IL-4 and the expression level of pSTAT1 in U2OS cells induced by IFN-alpha-B2 are respectively used for reflecting the cytological activity of JAK1 and Tyk 2.
1. Cell culture, cytokine stimulation and pSTAT assay
The THP-1 or U2OS cells were collected and resuspended in 1 × HBSS. Cells were plated in 384-well plates at 37 deg.C&CO2Incubating in an incubator. mu.L of compound diluted in DMSO at a final concentration of 0.1% was added to each well, and 37 ℃ was continued&CO2Incubating in an incubator. Add 5. mu.L of IL4 or IFN-. alpha. -B2 to each well, continue at 37 deg.C&CO2Incubating in an incubator. Discard the cell culture supernatant, add cell lysate, incubate at room temperature. The cell lysis suspension was tested for pSTAT6 using the alpha LISA SureFire Ultra p-STAT6 HV kit, or for pSTAT1 using the alpha LISA SureFire Ultra p-STAT1 HV kit. The reaction plate was incubated at room temperature for 2 hours. The signal for each culture void was read on an Envision plate reader.
2. Data analysis
From the nonlinear regression equation: y ═ Bottom + (Top-Bottom)/(1+10^ ((LogIC)50-X) HillSlope)) to compound IC50Wherein X represents the compound concentration; y represents inhibition%; top and Bottom are the same as Y units; logIC50Log units the same as X; HillSlope stands for slope coefficient or peak slope.
According to the above data analysis method, the cell activity inhibition data of the compounds TDM-180958 and TDM-180963, half Inhibitory Concentration (IC) thereof was obtained50) The results of the experiments are listed in table 2 below.
TABLE 2
| Numbering | JAK1 cells/nM | Tyk2 cells/nM |
| TDM-180958 | 3.01 | 4.17 |
| TDM-180963 | 3.04 | 4.57 |
Test example 3 hepatic microsomal stability and Caco-2 cell model assay of Small molecule inhibitors of JAK kinase
Liver microsome stability test: the method is characterized in that microsomes separated and extracted from the liver of an experimental animal of a specific species are used for testing a compound in vitro, and the liver microsome metabolic stability degree of the compound is determined by detecting the concentrations of a prototype compound and a degradation product thereof after the compound and liver microsomes containing liver cell I-phase metabolic enzyme (mainly P450) are incubated for different time periods, so that the pharmacokinetic trend of the compound in the animal of the species is preliminarily determined. The medium concentrations of liver microsomes, a compound to be tested and a cofactor NADPH in a tested reaction system are respectively 0.75mg/mL, 1 mu M and 2mM, and a positive control compound adopts Ketanserin (Ketanserin), a certain volume of reaction system solution is taken at different incubation time points (0, 15, 30 and 60 minutes), the reaction is stopped by using a pre-cooled precipitation solution, and after centrifugation, a supernatant is taken for LC-MS/MS analysis to obtain parameters such as drug solubility and the like.
The experimental steps are as follows: 1) 10 μ L of 10mM compound stock solution in DMSO and 190 μ L of methanol (MeOH) were mixed well to prepare 500 μ M of compound working solution; 2) mu.L of 500. mu.M compound working solution was taken and mixed with 18.75. mu.L of liver microsome (20mg/mL) and 479.75. mu.L of PBS to obtain 1.5. mu.M compound working solution (containing 0.75mg/mL of liver microsome); 3) preheating the reaction plate in an incubator at 37 ℃ for 5 minutes; 4) preparation of 0 time point assay samples (double wells for each time point): to a reaction plate pre-cooled on ice, 30. mu.L of 1.5. mu.M compound working solution (containing liver microsomes 0.75mg/mL), 400. mu.L of the precipitation solution, 15. mu.L of 6mM NADPH (prepared in PBS), shaking (600rpm, 10 min) after mixing, and centrifugation (4 ℃, 3000rpm, 10 min); 5) preparation of test samples at other time points: mu.L of 1.5. mu.M working solution of the compound (containing 0.75mg/mL of liver microsomes) and 90. mu.L of 6mM NADPH were mixed and incubated at 37 ℃ and at different time points 45. mu.L of the reaction solution and 400. mu.L of the pre-cooled precipitation solution were mixed, shaken and centrifuged; 6) 200 μ L of the supernatant was centrifuged for 10 minutes (13000g) and the sample was then subjected to LC-MS/MS quantitative analysis.
And (3) data analysis: percent (%) of proto-drug remaining in the sample at a single time point, (%) proto-drug concentration in the sample at that time point/concentration of proto-drug in the sample at 0 min x 100; wherein the plurality of time points are formulated as follows: ke ═ 2.303 Slope, T1/20.693/Ke, intrinsic clearance CLint(mL/min/kg)＝(0.693/T1/2) x (1/final concentration of liver microsomal protein in reaction system (0.5mg/mL) × conversion factor, CLint(μL·min-1·mg-1Protein) ((0.693 × 1000/T)1/2) Final concentration of liver microsomal protein (0.5mg/mL), results are shown in table 3 below.
TABLE 3
aConversion factor ═ microsomal protein per gram of liver x (weight of liver per kilogram)
Caco-2 cell permeability assay: caco-2 is a human colon cancer cell line, and a Caco-2 cell culture model established by using a Millipore cross-pore chamber (Transwell II) 24-well plate is widely used for testing the permeability (absorption and discharge of a drug) of the drug, and can reflect the absorption characteristics of the drug in the intestinal tract to a certain extent. In this cell test model, a monolayer of Caco-2 cells was seeded on the bottom of a semi-permeable membrane-coated inner chamber (a) that simulates the lumen of the intestine and an outer chamber (B) that houses the inner chamber that simulates the intestinal submucosal capillaries, both with culture fluid added to the inner chamber and the fluid level maintained in the inner and outer chambers. The cells will completely cover the bottom surface of the inner chamber after 21-24 days of culture, and the integrity can be detected by adding Lucifer Yellow (LY) or detecting trans-epidermal resistance (TEER) to A or B, wherein the TEER value of Caco-2 cells reaches 250 omega cm after 21 days of culture2The above. In testing, drug may be added to the inner chamber medium to detect transport of drug A → B (absorption), or to the outer chamber medium to detect transport of B → A (efflux), the solution containing the drug being referred to as the feed solution, and the test solution on the other side, which does not contain the drug, being referred to as the recipient solution.
The experimental steps are as follows: 1) before cell testing, the integrity of a cell layer needs to be detected, and then Hanks buffer solution is used for cleaning; 2) absorption test (A → B), adding the drug-containing solution to the inner chamber, incubating for 90 minutes, leaving 0 point and 90 minutes for the feeding and receiving solutions for analysis of drug concentration (D0, R0, D90, R90); 3) efflux test (B → A), adding a solution containing the drug to the external chamber, the rest as above; 4) the samples were subjected to LC-MS/MS analysis to detect drug concentration.
Drug permeability calculation Papp ═ (VA/(area × time)) × ((receiver-side end-point drug concentration/donor-side initial drug concentration) × dilution parameter)
The present application provides liver microsome stability data and Caco-2 cell model data for compound TDM-180958 of the present application as well as compound TDM-180820 as a positive control, with specific results see table 4 below.
TABLE 4
As can be seen from the results of table 4, the compound TDM-180958 of the present application has a significantly higher Papp value (nearly 6 times) in Caco-2 cell model than the compound TDM-180820 as a positive control, that is, the compound TDM-180958 of the present application has better drug absorbability than the compound TDM-180820, presumably because the number of electrons of the halogen or cyano group at the 1-3 position of the benzene ring on the right side is increased compared to the simple benzene ring, the reactivity and lipophilicity of the molecule are improved, and the molecule is favorable to enter into the cell through the cell membrane lipid bilayer. Although a high Papp value does not necessarily represent a longer plasma half-life or bioavailability, efficient absorption of the drug by cells is of great importance for topical routes of administration such as topical application to the skin, ocular administration, administration to the ear canal, etc.
The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.
It should be noted that the various technical features described in the above embodiments can be combined in any suitable manner without contradiction, and the invention is not described in any way for the possible combinations in order to avoid unnecessary repetition.
In addition, any combination of the various embodiments of the present invention is also possible, and the same should be considered as the disclosure of the present invention as long as it does not depart from the spirit of the present invention.
Claims (10)
1. A pharmaceutical compound, which is a compound represented by the following structural formula or a stereoisomer, a geometric isomer, a tautomer, a racemate, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug thereof:
wherein, the R represents 1 to 3 substituents on the benzene ring, and the 1 to 3 substituents are respectively and independently selected from halogen or cyano.
2. The pharmaceutical compound of claim 1, wherein the halogen is F, Cl or Br.
3. The pharmaceutical compound of claim 1, wherein R is ortho-substituted F.
4. The pharmaceutical compound of claim 1, wherein R is meta-substituted F.
5. The pharmaceutical compound of claim 1, wherein R is para-substituted F.
6. The pharmaceutical compound of claim 1, wherein R is a meta-substituted cyano group.
7. Use of a pharmaceutical compound according to any one of claims 1-6 for inhibiting a JAK kinase.
8. Use of a pharmaceutical compound according to any one of claims 1-6 in the manufacture of a medicament for the prevention or treatment of autoimmune diseases, and immune-related inflammatory skin diseases, the pathogenesis of which is associated with dysregulation of JAK signaling.
9. The use according to claim 8, wherein the autoimmune disease is selected from at least one of rheumatoid arthritis, ankylosing spondylitis, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, dermatomyositis, multiple sclerosis, type I diabetes, Sjogren's syndrome, vasculitis, alopecia areata, psoriasis and vitiligo.
10. The use according to claim 8, wherein the inflammatory skin disease associated with immunity is selected from at least one of atopic dermatitis, eczema, lichen planus, lichen glossus, lichen sclerosus, panniculitis, acne and hidradenitis suppurativa.
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| CN202010976485.3A CN111961037B (en) | 2020-09-17 | 2020-09-17 | Pharmaceutical compound as JAK kinase inhibitor |
| PCT/CN2021/118025 WO2022057770A1 (en) | 2020-09-17 | 2021-09-13 | Pharmaceutical compound used as jak kinase inhibitor |
| TW110134651A TWI779840B (en) | 2020-09-17 | 2021-09-16 | Medical compound acting as jak inhibitor |
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| CN202010976485.3A CN111961037B (en) | 2020-09-17 | 2020-09-17 | Pharmaceutical compound as JAK kinase inhibitor |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2022057770A1 (en) * | 2020-09-17 | 2022-03-24 | 嘉兴特科罗生物科技有限公司 | Pharmaceutical compound used as jak kinase inhibitor |
| CN114681461A (en) * | 2020-12-28 | 2022-07-01 | 杭州邦顺制药有限公司 | Compounds used in lupus erythematosus treatment |
| WO2023011301A1 (en) * | 2021-08-06 | 2023-02-09 | 嘉兴特科罗生物科技有限公司 | Jak inhibitor with high oral bioavailability |
| WO2023076161A1 (en) | 2021-10-25 | 2023-05-04 | Kymera Therapeutics, Inc. | Tyk2 degraders and uses thereof |
| CN117136059A (en) * | 2021-04-22 | 2023-11-28 | 深圳微芯生物科技股份有限公司 | Pharmaceutical compositions containing JAK3/JAK1/TBK1 selective inhibitors and their medicinal uses |
| CN117586285A (en) * | 2024-01-19 | 2024-02-23 | 英矽智能科技(上海)有限公司 | Tri-fused ring compounds |
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| WO2017050938A1 (en) * | 2015-09-25 | 2017-03-30 | Astrazeneca Ab | Compounds and methods for inhibiting jak |
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| CN110627775A (en) * | 2019-10-24 | 2019-12-31 | 嘉兴特科罗生物科技有限公司 | Small molecule compound |
| CN110862376A (en) * | 2019-10-24 | 2020-03-06 | 嘉兴特科罗生物科技有限公司 | Small molecule compound |
| CN111961037B (en) * | 2020-09-17 | 2021-09-21 | 嘉兴特科罗生物科技有限公司 | Pharmaceutical compound as JAK kinase inhibitor |
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- 2020-09-17 CN CN202010976485.3A patent/CN111961037B/en active Active
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- 2021-09-13 WO PCT/CN2021/118025 patent/WO2022057770A1/en active Application Filing
- 2021-09-16 TW TW110134651A patent/TWI779840B/en active
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| WO2012062704A1 (en) * | 2010-11-09 | 2012-05-18 | Cellzome Limited | Pyridine compounds and aza analogues thereof as tyk2 inhibitors |
| WO2017050938A1 (en) * | 2015-09-25 | 2017-03-30 | Astrazeneca Ab | Compounds and methods for inhibiting jak |
| CN110617775A (en) * | 2019-09-26 | 2019-12-27 | 杭州鲁尔物联科技有限公司 | Method, device and system for monitoring bridge deflection based on visual perception |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2022057770A1 (en) * | 2020-09-17 | 2022-03-24 | 嘉兴特科罗生物科技有限公司 | Pharmaceutical compound used as jak kinase inhibitor |
| CN114681461A (en) * | 2020-12-28 | 2022-07-01 | 杭州邦顺制药有限公司 | Compounds used in lupus erythematosus treatment |
| CN117136059A (en) * | 2021-04-22 | 2023-11-28 | 深圳微芯生物科技股份有限公司 | Pharmaceutical compositions containing JAK3/JAK1/TBK1 selective inhibitors and their medicinal uses |
| WO2023011301A1 (en) * | 2021-08-06 | 2023-02-09 | 嘉兴特科罗生物科技有限公司 | Jak inhibitor with high oral bioavailability |
| WO2023076161A1 (en) | 2021-10-25 | 2023-05-04 | Kymera Therapeutics, Inc. | Tyk2 degraders and uses thereof |
| CN117586285A (en) * | 2024-01-19 | 2024-02-23 | 英矽智能科技(上海)有限公司 | Tri-fused ring compounds |
| CN117586285B (en) * | 2024-01-19 | 2024-04-05 | 英矽智能科技(上海)有限公司 | Tri-fused ring compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111961037B (en) | 2021-09-21 |
| WO2022057770A1 (en) | 2022-03-24 |
| TW202212332A (en) | 2022-04-01 |
| TWI779840B (en) | 2022-10-01 |
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