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WO2017133423A1 - Fig. 1 : s102 % % % diviser m ports dmrs en k groupes de ports dmrs, k et m étant des entiers positifs et k étant inférieur ou égal à m s104 % % % utilisent un précodage indépendante sur chaque groupe de ports dmrs pour transmettre dmrs - Google Patents

Fig. 1 : s102 % % % diviser m ports dmrs en k groupes de ports dmrs, k et m étant des entiers positifs et k étant inférieur ou égal à m s104 % % % utilisent un précodage indépendante sur chaque groupe de ports dmrs pour transmettre dmrs Download PDF

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Publication number
WO2017133423A1
WO2017133423A1 PCT/CN2017/071128 CN2017071128W WO2017133423A1 WO 2017133423 A1 WO2017133423 A1 WO 2017133423A1 CN 2017071128 W CN2017071128 W CN 2017071128W WO 2017133423 A1 WO2017133423 A1 WO 2017133423A1
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WIPO (PCT)
Prior art keywords
compound
disease
compounds
mmol
acid
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PCT/CN2017/071128
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English (en)
Chinese (zh)
Inventor
王义汉
任兴业
Original Assignee
深圳市塔吉瑞生物医药有限公司
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Application filed by 深圳市塔吉瑞生物医药有限公司 filed Critical 深圳市塔吉瑞生物医药有限公司
Priority to CN202110328812.9A priority Critical patent/CN112851682B/zh
Priority to CN201780003907.5A priority patent/CN108349974B/zh
Publication of WO2017133423A1 publication Critical patent/WO2017133423A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of medicine.
  • the present invention relates to a deuterated pyridine amide compound and use thereof, and more particularly to a pyridine amide compound and its use as a JAK inhibitor, or for the treatment and prevention of a disease associated with a JAK enzyme.
  • Janus kinase is a cytoplasmic tyrosine kinase that transduces cytokine signaling from membrane receptors to STAT transcription factors.
  • JAK family members have been described in the prior art: JAK1, JAK2, JAK3, and TYK2. When a cytokine binds to its receptor, members of the JAK family autophosphorylate and/or transphosphorylate to each other, followed by phosphorylation of STATs and then migration into the nucleus to regulate transcription.
  • JAK-STAT intracellular signal transduction is applicable to interferons, most interleukins, and a variety of cytokines and endocrine factors such as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF, and PRL.
  • Cartilage degeneration is a hallmark of many diseases, of which rheumatoid arthritis and osteoarthritis are the most important.
  • Rheumatoid arthritis is a chronic joint degenerative disease characterized by inflammation and destruction of joint structures. When the disease is not inhibited, substantial disability and pain, even premature death, are caused by loss of joint function. Therefore, the purpose of RA treatment is not only to delay the disease, but also to achieve relief, thereby terminating joint destruction.
  • RA a highly prevalent RA ( ⁇ 0.8% of adults worldwide) is a high socioeconomic shock.
  • Osteoarthritis is the most common form of arthritis characterized by loss of articular cartilage, usually accompanied by bone hypertrophy and pain.
  • Osteoarthritis is difficult to treat. At present, it is still incurable, and treatment focuses on relieving pain and preventing deformation of diseased joints. Commonly used treatments include the use of non-steroidal anti-inflammatory drugs. Although therapeutic nutritional supplements such as chondroitin and glucosamine sulfate have been identified as safe and effective options for osteoarthritis, recent clinical trials have shown that these two treatments do not reduce the pain associated with osteoarthritis.
  • Filgotinib is a highly selective JAK1 inhibitor under development, discovered and developed by Galapagos. Based on clinical data obtained, Filgotinib treats rheumatoid arthritis (RA) and Crohn's disease (CD). It has rapid onset, high efficacy, and good safety and tolerability.
  • the compounds of the invention are useful in the treatment of degenerative joint diseases such as osteoarthritis, rheumatoid arthritis and osteoporosis, particularly osteoarthritis. Additionally, the invention provides a compound, a process for its preparation, and a pharmaceutical composition comprising a compound of the invention and a suitable pharmaceutical carrier. The invention also provides the use of a compound of the invention in the manufacture of a medicament for the treatment of a degenerative joint disease.
  • the present invention provides a deuterated picolinamide compound of the formula (I), and physiologically acceptable salts, solvates, hydrates, prodrugs, tautomers and stereoisomers thereof, including These compounds are mixtures formed in all ratios.
  • Each R is independently selected from the group consisting of "hydrogen (H), hydrazine (D)";
  • the strontium isotope content of the cerium in the deuterated position is at least greater than the natural strontium isotope content (0.015%), preferably greater than 30%, more preferably greater than 50%, and even more preferably greater than 75%, more Preferably, the ground is greater than 95%, more preferably greater than 99%.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 each of the deuterated positions has a strontium isotope content of at least 5%, preferably greater than 10%, more preferably greater than 15%, and more preferably greater than 20%, more preferably more than 25%, more preferably more than 30%, more preferably more than 35%, more preferably more than 40%, more preferably more than 45%, more preferably more than 50%, more preferably more than 55 More preferably, more than 60%, more preferably more than 65%, more preferably more than 70%, more preferably more than 75%, more preferably more than 80%, more preferably more than 85%, more preferably more than 90% More preferably, it is greater than 95%, more preferably greater than 99%
  • R contains ⁇ , more preferably four R contains ⁇ , more preferably five R contains ⁇ , more preferably six R contains ⁇ , more preferably seven R contains ⁇ , more preferably eight R contains ⁇ , More preferably, nine R ⁇ , more preferably ten R ⁇ , more preferably eleven R ⁇ , more preferably twelve R ⁇ , more preferably thirteen R ⁇ , better
  • the fourteen Rs contain ⁇ , more preferably fifteen R ⁇ , more preferably sixteen R ⁇ , more preferably seventeen R ⁇ , more preferably eight
  • R 1 , R 2 , R 3 , R 4 , R 5 are each independently hydrazine or hydrogen.
  • R 1 , R 2 , R 3 , R 4 and R 5 are deuterium.
  • R 6 , R 7 , R 8 are each independently hydrazine or hydrogen
  • R 6 is deuterium
  • R 7 is deuterium
  • R 8 is deuterium
  • R 9 , R 10 , R 11 , R 12 are each independently hydrazine or hydrogen.
  • R 9 is deuterium.
  • R 11 is hydrazine
  • R 13 and R 14 are each independently hydrazine or hydrogen.
  • R 13 and R 14 are deuterium.
  • R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 are each independently hydrazine or hydrogen.
  • R 15 and R 16 are deuterium.
  • R 17 and R 18 are deuterium.
  • R 19 and R 20 are deuterium.
  • R 21 and R 22 are deuterium.
  • R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 are ⁇ .
  • the compound is selected from the group consisting of a compound or a pharmaceutically acceptable salt thereof, but is not limited to the following compounds:
  • the compounds of the invention do not include non-deuterated compounds.
  • the compounds of the present invention are novel JAK inhibitors which exhibit significantly improved potency in vivo as compared to structurally similar compounds.
  • the compounds of the invention are JAK1 and JAK2 inhibitors.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention and a pharmaceutical carrier, excipient or diluent.
  • the compounds of the invention used in the pharmaceutical compositions and methods of treatment disclosed herein are pharmaceutically acceptable in the preparation and use.
  • the pharmaceutical composition may also contain other active ingredients suitable for use in combination with the compounds of the invention.
  • the invention provides methods of treating a mammal susceptible to or infecting those conditions listed herein, particularly conditions associated with aberrant JAK activity, such as inflammation, autoimmune diseases, proliferative diseases, Transplant rejection, diseases involving impaired cartilage turnover, congenital cartilage malformations, and/or diseases associated with excessive secretion of IL6, the method comprising administering a therapeutically effective amount of a pharmaceutical composition or compound of the invention as described herein.
  • the condition is associated with abnormal JAK1 and JAK2 activity.
  • the invention provides a compound of the invention for use in the treatment or prevention of a condition selected from those listed herein, particularly those conditions which may be associated with abnormal JAK activity, such as inflammation, autoimmune diseases Proliferative diseases, transplant rejection, diseases involving impaired cartilage renewal, congenital cartilage malformations, and/or diseases associated with excessive secretion of IL6.
  • a condition selected from those listed herein particularly those conditions which may be associated with abnormal JAK activity, such as inflammation, autoimmune diseases Proliferative diseases, transplant rejection, diseases involving impaired cartilage renewal, congenital cartilage malformations, and/or diseases associated with excessive secretion of IL6.
  • the invention provides a method of treating a mammal susceptible to or susceptible to a disorder associated with aberrant JAK activity, the method comprising administering an amount effective to treat or prevent a disorder, described herein A pharmaceutical composition or compound of the invention.
  • the condition is associated with abnormal JAK1 and JAK2 activity in the etiology.
  • the invention provides a compound of the invention for use in the treatment or prevention of a disorder associated with aberrant JAK activity.
  • the invention provides methods of synthesizing a compound of the invention using representative synthetic schemes and routes disclosed hereinafter.
  • the compounds of the invention modulate the activity of JAK1 and JAK2.
  • Another object of the present invention is to provide a compound which can treat or alleviate the symptoms of a disease or disease such as inflammation, autoimmune disease, proliferative disease, transplant rejection, disease involving impaired cartilage turnover, congenital cartilage malformation And diseases associated with excessive secretion of IL6, which may be associated with JAK, particularly JAK1 and JAK2 activity.
  • a disease or disease such as inflammation, autoimmune disease, proliferative disease, transplant rejection, disease involving impaired cartilage turnover, congenital cartilage malformation And diseases associated with excessive secretion of IL6, which may be associated with JAK, particularly JAK1 and JAK2 activity.
  • Another object of the present invention is to provide a pharmaceutical composition useful for treating or preventing a plurality of disease states, including diseases associated with JAK activity, such as inflammation, autoimmune diseases, proliferative diseases, transplant rejection, involving A disease in which cartilage renewal is impaired, congenital cartilage malformation, and a disease associated with excessive secretion of IL6.
  • diseases associated with JAK activity such as inflammation, autoimmune diseases, proliferative diseases, transplant rejection, involving A disease in which cartilage renewal is impaired, congenital cartilage malformation, and a disease associated with excessive secretion of IL6.
  • the disease is particularly associated with JAK1 and JAK2 activity.
  • JAK as used herein relates to the Janus kinase (JAKs) family, which is a cytoplasmic tyrosine kinase that transduces cytokine signaling from membrane receptors to STAT transcription factors.
  • JAKs Janus kinase family
  • JAK1, JAK2, JAK3, and TYK2 JAK1, JAK2, JAK3, and TYK2
  • JAK can refer to all JAK family members or one or more JAK family members as indicated by the context.
  • pharmaceutically acceptable means approved or approved by a regulatory agency of the federal or continental government or a corresponding agency in a country other than the United States, or for use in animals listed in the United States Pharmacopoeia or other generally recognized pharmacopoeia and More especially for people.
  • pharmaceutically acceptable salt means a salt of a compound of the invention which is pharmaceutically acceptable and which possesses the desired pharmacological activity of the parent compound.
  • such salts are non-toxic and may be inorganic or organic acid addition salts and base addition salts.
  • such salts include: (1) acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acid addition salts with organic acids
  • the organic acid such as acetic acid, propionic acid, caproic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, lemon Acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonate Acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid,
  • the salt further includes a salt such as sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium or the like; and when the compound contains a basic functional group, a salt of a non-toxic organic or inorganic acid such as a hydrochloride or a hydrobromide salt is formed. , tartrate, methanesulfonate, acetate, maleate, oxalate, and the like.
  • a salt such as sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium or the like
  • a salt of a non-toxic organic or inorganic acid such as a hydrochloride or a hydrobromide salt
  • pharmaceutically acceptable cation means an acceptable cationic counterion of an acidic functional group. Such cations are, for example, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations and the like.
  • “Pharmaceutically acceptable medium” means a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
  • Solvate means a form of a compound that is typically associated with a solvent by a solvolysis reaction. This physical association includes hydrogen bonding.
  • Conventional solvents include water, ethanol, acetic acid, and the like.
  • the compounds of the invention may be prepared, for example, in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and also include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate can be separated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid.
  • “Solvate” includes solution phases and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.
  • “Therapeutically effective amount” means that the amount of the compound when administered to an individual for the treatment of a disease is sufficient to effect treatment of the disease.
  • a “therapeutically effective amount” can vary depending on the compound, the disease and its severity, the age, weight, etc. of the individual being treated.
  • Preventing or “preventing” means reducing the risk of acquiring or developing a disease or condition, even if the clinical symptoms of at least one disease are not developed in the individual, the individual may be exposed to the agent or predisposed to the disease prior to the onset of the disease disease.
  • prevention relates to "prevention” and refers to a measure or method whose purpose is to prevent, rather than treat or cure, a disease.
  • the invention also includes isotopically-labeled compounds, examples of which may be listed as isotopes of the compounds of the invention, including hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, such as 2 H, 3 H, 13 C, 14 C, respectively. , 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F and 36 Cl. a compound, or an enantiomer, a diastereomer, an isomer, or a pharmaceutically acceptable salt or solvate of the present invention, wherein an isotope or other isotopic atom containing the above compound is within the scope of the present invention .
  • isotopically-labeled compounds of the present invention such as the radioisotopes of 3 H and 14 C, are also among them, useful in tissue distribution experiments of drugs and substrates. ⁇ , ie 3 H and carbon-14, ie 14 C, are easier to prepare and detect and are preferred in isotopes.
  • Isotopically labeled compounds can be prepared in a conventional manner by substituting a readily available isotopically labeled reagent with a non-isotopic reagent using the protocol of the examples.
  • Non-limiting examples of preventive measures include administration of a vaccine; administration of low molecular weight heparin to a hospital patient at risk of thrombosis, for example, due to inactivity; and administration of an anti-malarial drug prior to travel to a geographic area where the risk of malaria or malaria is high, such as Chloroquine.
  • treating of any disease or condition means ameliorating the disease or condition (ie, preventing the disease or reducing the appearance, extent or severity of at least one of its clinical symptoms). In another embodiment, “treating” means ameliorating at least one physical indicator that may not be detectable by the individual. In another embodiment, “treating” means modulating a disease or disorder, either physically (eg, stabilizing a detectable symptom), physiologically (eg, stabilizing a body indicator), or both.
  • treating means slowing the progression of the disease.
  • inflammation refers to a group of conditions including rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, allergic airway diseases (eg asthma, rhinitis), inflammatory bowel disease (eg, Crohn's disease, colitis), endotoxin-driven disease states (eg, complications following bypass surgery or chronic endotoxin status due to, for example, chronic heart failure) and related diseases involving cartilage, such as joint diseases.
  • the term specifically refers to rheumatoid arthritis, osteoarthritis, allergic airway diseases such as asthma, and inflammatory bowel disease.
  • autoimmune disease refers to a group of diseases, including obstructive airway diseases, including Including conditions such as COPD, asthma (eg endogenous asthma, exogenous asthma, dust asthma, infant asthma), especially chronic or long-term asthma (eg advanced asthma and airway hyperresponsiveness), bronchitis (including bronchi) Asthma), systemic lupus erythematosus (SLE), multiple sclerosis, type I diabetes and its associated complications, atopic eczema (atopic dermatitis), contact dermatitis, including eczema dermatitis, inflammatory bowel disease (eg, Crohn's disease and ulcerative colitis), atherosclerosis, and amyotrophic lateral sclerosis.
  • COPD chronic or long-term asthma
  • bronchitis including bronchi
  • Asthma systemic lupus erythematosus
  • SLE systemic lupus erythematosus
  • multiple sclerosis type I diabetes
  • proliferative disease refers to a condition, such as a cancer (eg, uterine leiomyosarcoma or prostate cancer), a myeloproliferative disorder (eg, polycythemia vera, primary thrombocytosis, and myelofibrosis), leukemia (eg, Acute myeloid leukemia and acute lymphocytic leukemia), multiple myeloma, psoriasis, restenosis, sclerosing dermatitis or fibrosis.
  • a cancer eg, uterine leiomyosarcoma or prostate cancer
  • a myeloproliferative disorder eg, polycythemia vera, primary thrombocytosis, and myelofibrosis
  • leukemia eg, Acute myeloid leukemia and acute lymphocytic leukemia
  • multiple myeloma psoriasis
  • restenosis sclerosing derma
  • cancer refers to the malignant or benign growth of cells in the skin or body organs such as, but not limited to, the breast, prostate, lung, kidney, pancreas, stomach or intestine. Cancer is prone to invade adjacent tissues and spread (metastasize) to distant organs such as bone, liver, lungs or brain.
  • cancer as used herein includes metastatic tumor cell types such as, but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma, as well as tissue cancer types such as, but not limited to, colorectal cancer, prostate cancer, Small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, kidney cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, prostate cancer, and uterine leiomyosarcoma.
  • metastatic tumor cell types such as, but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma
  • tissue cancer types such as, but not limited to, colorectal cancer, prostate cancer, Small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, kidney cancer, gastric cancer, glio
  • leukemia refers to a neoplastic disease of blood and hematopoietic organs. Such diseases can cause bone marrow and immune system dysfunction, which makes the host highly susceptible to infection and bleeding.
  • leukemia specifically refers to acute myeloid leukemia and acute lymphocytic leukemia.
  • graft rejection refers to cells, tissues or cells such as islets, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal tissue, heart, lung, cardiopulmonary, kidney, liver, intestine, pancreas, trachea or esophagus or Acute or chronic rejection of allografts or xenografts of solid organs, or graft versus host disease.
  • disease involving impaired cartilage renewal includes disorders such as osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive joints. Inflammation, reflex sympathetic dystrophy, painful malnutrition, tidy syndrome or costal cartilage, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic arthritis such as place Deformative osteoarthritis, Mseleni disease and Handigodu disease, degeneration caused by fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis.
  • congenital cartilage malformation includes disorders such as hereditary chondrolysis, dyschondroplasia, and pseudochondral dysplasia, particularly but not limited to microtia, malformation, metaphyseal dysplasia, and related disorders.
  • disease associated with excessive secretion of IL6 includes disorders such as Castleman's disease, multiple myeloma, psoriasis, Kaposi's sarcoma and/or mesangial proliferative glomerulonephritis.
  • Compound of the invention and equivalent expression are meant to include compounds of the formulae described herein, including pharmaceutically acceptable salts and solvates, such as hydrates, and solvates of pharmaceutically acceptable salts, as the context permits. Similarly, reference to intermediates (whether or not they are claimed) Their salts and solvates are included as long as they are permitted in the context.
  • Both acid and acid-derived forms of other derivatives of the compounds of the invention are active, but acid-sensitive forms generally provide more favorable solubility, histocompatibility or delayed release in mammalian organisms (Bundgard, H. Design of Prodrugs) (Design of prodrugs), pp. 7-9, 21-24, Elsevier, Amsterdam 1985).
  • the compounds of the invention are novel JAK inhibitors.
  • the compound is a potent JAK1 and JAK2 inhibitor.
  • the compounds of the invention When used as a pharmaceutical, the compounds of the invention are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the art of pharmacy and comprise at least one active compound. Generally, the compounds of the invention are administered in a pharmaceutically effective amount. The amount of compound actually administered is generally determined by the physician, depending on the condition being treated, the route of administration selected, the actual compound administered, the age, weight and response of the individual patient, the patient The severity of the symptoms, etc.
  • compositions of this invention may be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intraarticular, intravenous, intramuscular, and intranasal.
  • the compounds of the invention are preferably formulated as injectable compositions or oral compositions or all ointments, lotions or patches for transdermal administration, depending on the intended route of administration.
  • compositions for oral administration can take the form of large amounts of liquid solutions or suspensions or bulks. More often, however, the compositions are presented in unit dosage form for ease of administration.
  • unit dosage form means a physically discrete unit suitable for administration as a unit of human individual and other mammals, each unit containing a predetermined amount of active substance (calculated to produce the desired therapeutic effect) and a suitable pharmaceutical ingredient Forming agent, medium or carrier.
  • Typical unit dosage forms include ampoules or syringes of pre-filled, pre-determined liquid compositions, or in the case of solid compositions, pills, tablets, capsules and the like.
  • the compounds of the invention are generally minor components (from about 0.1% to about 50% by weight, preferably from about 1% to about 40% by weight), with the balance being a plurality of media or carriers and processing. Auxiliaries are used to help form the desired form of administration.
  • Liquid forms suitable for oral administration can include suitable aqueous or nonaqueous vehicles containing buffers, suspending and dispersing agents, coloring agents, flavoring agents and the like.
  • the solid form may include, for example, any of the following ingredients or compounds of similar nature: a binder such as microcrystalline cellulose, tragacanth or gelatin; an excipient such as starch or lactose; a disintegrant such as alginic acid, Primogel or corn starch.
  • Lubricants such as magnesium stearate; glidants such as colloidal silica; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate or citrus flavoring agents.
  • Injectable compositions are generally based on injectable sterile saline or phosphate buffered saline or other injectable carriers known in the art.
  • the active compound in the composition will generally be a minor component, typically from about 0.05% to about 10% by weight, with the balance being injectable carriers and the like.
  • the transdermal compositions are usually formulated as a topical ointment or cream containing the active ingredient in an amount generally ranging from about 0.01% to about 20% by weight, preferably from about 0.1% to about 20% by weight, preferably from about 0.1% to about 10% by weight and more preferably from about 0.5 to about 15% by weight.
  • the active ingredient is usually mixed with a paraffin or water-miscible ointment base.
  • the active ingredient in the cream may be formulated with, for example, an oil-in-water cream base.
  • Such transdermal formulations are well known in the art and generally comprise other Divided to enhance the penetration stability of the active ingredient or formulation. All such known transdermal formulations and ingredients are included within the scope of the invention.
  • transdermal administration can be accomplished using a patch of a reservoir or a porous membrane type or a solid matrix variant.
  • the compounds of the invention may also be administered in sustained release form or from sustained release drug delivery systems.
  • sustained release material see Remington's Pharmaceutical Sciences.
  • formulation examples illustrate representative pharmaceutical compositions that can be prepared in accordance with the present invention.
  • the invention is not limited to the following pharmaceutical compositions.
  • the compound of the present invention can be mixed as a dry powder and a dry gelatin binder in a weight ratio of about 1:2. A small amount of magnesium stearate was added as a lubricant. The mixture was made into a 240-270 mg tablet (each tablet containing 80-90 mg of active amide compound) in a tablet press.
  • the compound of the present invention can be mixed as a dry powder with a starch diluent in a weight ratio of about 1:1.
  • the mixture was filled into 250 mg capsules (each capsule containing 125 mg of active amide compound).
  • the compound of the present invention (125 mg) can be mixed with sucrose (1.75 g) and xanthan gum (4 mg), and the resulting mixture can be mixed, passed through a No. 10 mesh US sieve, and then with previously prepared microcrystalline cellulose and An aqueous solution of sodium carboxymethylcellulose (11:89, 50 mg) was mixed.
  • Sodium benzoate (10 mg) flavor and color are diluted with water and added with stirring. A sufficient amount of water can then be added with agitation. Sufficient water was then added to make a total volume of 5 mL.
  • the compound of the present invention can be mixed as a dry powder and a dry gelatin binder in a weight ratio of about 1:2. A small amount of magnesium stearate was added as a lubricant. The mixture was made into a 450-900 mg tablet (150-300 mg of active amide compound) in a tablet press.
  • the compounds of the invention may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of about 5 mg/mL.
  • Stearyl alcohol (250 g) and white petrolatum (250 g) were melted at about 75 ° C, then added to the compound of the invention (50 g) dissolved in water (about 370 g), methyl p-hydroxybenzoate (0.25 g), A mixture of propyl paraben (0.25 g), sodium lauryl sulfate (10 g) and propylene glycol (120 g) was added and the resulting mixture was stirred until coagulation.
  • the compounds of the invention may be used as therapeutic agents for the treatment of aberrant activity associated with JAK in a mammal Or a condition caused by abnormal activity of JAK.
  • such conditions are associated with JAK1 and/or JAK2 abnormal activity.
  • the compounds of the present invention and the pharmaceutical compositions of the present invention have been found to be useful as therapeutic agents for the prevention and/or treatment of inflammation in mammals including humans, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving impaired cartilage renewal, congenital Cartilage malformations and diseases associated with excessive secretion of IL6.
  • the invention provides methods of treating a mammal susceptible to or susceptible to inflammation.
  • the method comprises administering one or more of the pharmaceutical compositions or compounds of the invention described herein in an amount effective to treat or prevent the condition.
  • the inflammation is selected from the group consisting of rheumatoid arthritis, osteoarthritis, allergic airway diseases (such as asthma), and inflammatory bowel disease.
  • the invention provides a compound of the invention for use in the treatment, prevention or prevention of inflammation.
  • the inflammation is selected from the group consisting of rheumatoid arthritis, osteoarthritis, allergic airway diseases (such as asthma), and inflammatory bowel disease.
  • the invention provides methods of treating a mammal susceptible to or susceptible to an autoimmune disease.
  • the method comprises administering one or more of the pharmaceutical compositions or compounds of the invention described herein in an amount effective to treat or prevent the condition.
  • the autoimmune disease is selected from the group consisting of COPD, asthma, systemic lupus erythematosus, type I diabetes, and inflammatory bowel disease.
  • the invention provides a compound of the invention for use in the treatment, prevention or prevention of an autoimmune disease.
  • the autoimmune disease is selected from the group consisting of COPD, asthma, systemic lupus erythematosus, type I diabetes, and inflammatory bowel disease.
  • the invention provides for the treatment of a susceptible or infectious proliferative disorder, in particular a cancer (eg a solid tumor such as uterine leiomyosarcoma or prostate cancer), a leukemia (eg AML or ALL), multiple myeloma and/or A method of psoriasis in mammals.
  • a cancer eg a solid tumor such as uterine leiomyosarcoma or prostate cancer
  • a leukemia eg AML or ALL
  • multiple myeloma eg A method of psoriasis in mammals.
  • the invention provides a compound of the invention for use in the treatment, prevention or prevention of a proliferative disorder, in particular a cancer (such as a solid tumor such as uterine leiomyosarcoma or prostate cancer), a leukemia (such as AML or ALL), multiple bone marrow Tumor and / or psoriasis.
  • a cancer such as a solid tumor such as uterine leiomyosarcoma or prostate cancer
  • a leukemia such as AML or ALL
  • the present invention provides methods of treating a mammal susceptible to or susceptible to transplant rejection.
  • the invention provides a method of treating organ transplant rejection.
  • the invention provides a compound of the invention for use in treating, preventing or preventing transplant rejection.
  • the invention provides a method of treating organ transplant rejection.
  • the present invention provides a method of treating, preventing or preventing a mammal susceptible to or susceptible to a disease involving impaired cartilage turnover, the method comprising administering a therapeutically effective amount of a compound of the invention or a compound described herein.
  • a mammal susceptible to or susceptible to a disease involving impaired cartilage turnover comprising administering a therapeutically effective amount of a compound of the invention or a compound described herein.
  • the invention provides a compound of the invention for use in the treatment, prevention or prevention of a disease involving impaired cartilage turnover.
  • the invention also provides a method of treating a congenital cartilage malformation comprising administering an effective amount of one or more of the pharmaceutical compositions or compounds of the invention described herein.
  • the invention provides a compound of the invention for use in the treatment, prevention or prevention of congenital cartilage malformations.
  • the invention provides a compound of the invention for use as a medicament, in particular for the treatment or prevention of the above mentioned conditions and diseases. Also provided herein are compounds of the invention in the preparation for treatment or pre-treatment Use in a medicament against one of the above mentioned conditions and diseases.
  • a particular embodiment of the method comprises administering to an individual suffering from inflammation an effective amount of a compound of the invention for a period of time sufficient to reduce the level of inflammation in the patient, and preferably to terminate the progression of the inflammation.
  • a particular embodiment of the method comprises administering to an individual patient suffering from or susceptible to rheumatoid arthritis an effective amount of a compound of the invention for a period of time sufficient to reduce or prevent joint inflammation, respectively, and preferably to terminate The progression of the inflammation.
  • Another particular aspect of the method comprises administering to an individual having a condition characterized by cartilage or joint degeneration (such as rheumatoid arthritis and/or osteoarthritis) an effective amount of a compound of the invention for a period of time sufficient
  • the degraded self-developing process is reduced and preferably terminated.
  • a particular embodiment of the method comprises administering to an individual patient suffering from or susceptible to developing osteoarthritis an effective amount of a compound of the invention for a period of time sufficient to reduce or prevent cartilage degradation of the joint of the patient, respectively, and preferably to terminate
  • the degraded self is evolving in progress.
  • the compound will exhibit cartilage anabolic and/or anti-catabolic properties.
  • the injection dosage level ranges from about 0.1 mg/kg/hr to at least 10 mg/kg/hr for a total period of from about 1 to about 120 hours, particularly from 24 to 96 hours. It is also possible to apply from about 0.1 mg/kg to about 10 mg/kg or more of pre-filled bolus to achieve a sufficient steady state level.
  • the maximum total dose is expected to be no more than about 2 g/day for a 40 to 80 kg human patient.
  • each dose provides from about 0.01 to about 20 mg/kg of a compound of the invention, for a particular dose, each providing from about 0.1 to about 10 mg/kg, especially from about 1 to about 5 mg/kg.
  • Transdermal administration is generally selected to provide a similar or lower blood level than that obtained by administration by injection.
  • the compounds of the invention are typically administered to a patient at risk of developing the condition at the above dosage levels, as directed and supervised by a physician.
  • Patients at risk of developing a particular condition typically include those with a family history of the condition, or those identified as being particularly susceptible to developing the condition by genetic testing or screening.
  • the compounds of the invention may be administered as separate active agents, or they may be administered in combination with other active agents, including other compounds which have the same or similar therapeutic activity and which are determined to be safe and effective for such combination administration.
  • the co-administration of the two (or more) active agents allows for a significant reduction in the dosage of each active agent used, thereby reducing the side effects seen.
  • a compound of the invention is co-administered with an additional therapeutic agent for the treatment and/or prevention of an inflammatory disease, particularly active agents including, but not limited to, immunomodulators such as azathioprine, corticosteroids (eg, prednisone) Dragon or dexamethasone), cyclophosphamide, cyclosporine A, tacrolimus, mycophenolate mofetil, morozumab-CD3 (OKT3, for example), ATG, aspirin, acetaminophen, Ibuprofen, naproxen and piroxicam.
  • immunomodulators such as azathioprine, corticosteroids (eg, prednisone) Dragon or dexamethasone), cyclophosphamide, cyclosporine A, tacrolimus, mycophenolate mofetil, morozumab-CD3 (OKT3, for example), ATG, aspirin, acetaminophen, Ibuprofen
  • a compound of the invention is co-administered with other therapeutic agents for the treatment and/or prevention of arthritis (eg, rheumatoid arthritis), particularly active agents including, but not limited to, analgesics, non-steroidal anti-inflammatory Pharmacy (NSAIDS), steroids, synthetic DMARDS (such as, but not limited to, methotrexate, fluoride) Mitt, sulfasalazine, auranofin, disodium thiocyanate, penicillamine, chloroquine, hydroxychloroquine, azathioprine and cyclosporine) and biological products such as, but not limited to, infliximab, ina Cipu, adalimumab, rituximab and abatacil.
  • active agents including, but not limited to, analgesics, non-steroidal anti-inflammatory Pharmacy (NSAIDS), steroids, synthetic DMARDS (such as, but not limited to, methotrexate, fluoride) Mitt
  • a compound of the invention is co-administered with other therapeutic agents for the treatment and/or prophylaxis of proliferative disorders, specific but not limited to: methotrexate, folinic acid, doxorubicin, prednisone , bleomycin, cyclophosphamide, 5-fluorouracil, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, doxorubicin, tamoxifen, toremifene, acetate progesterone, anastrozole, goserelin, anti -HER2 monoclonal antibody (e.g.
  • the compounds of the invention may be administered in combination with other therapies, including but not limited to radiation therapy or surgery.
  • the proliferative disorder is selected from the group consisting of cancer, myeloproliferative disease, or leukemia.
  • a compound of the invention is co-administered with other therapeutic agents for the treatment and/or prevention of autoimmune diseases, particularly active agents including, but not limited to, glucocorticoids, cell proliferation inhibitors (eg, purine analogs), Alkylating agents (eg, nitrogen mustard (cyclophosphamide), nitrosourea, platinum compounds, etc., antimetabolites (eg methotrexate, azathioprine and guanidine), cytotoxic antibiotics (eg, dactinomycin ring) , mitomycin C, bleomycin and pucamycin), antibodies (eg anti-CD20, anti-CD25 or anti-CD3 (OTK3) monoclonal antibodies, cyclosporine, tacrolimus, rapa Taxomycin, interferon, TNF-binding protein, etanercept or adalimumab, mycophenolate mofetil, fingolimod and myriocin.
  • active agents including, but not limited
  • a compound of the invention is co-administered with other therapeutic agents for the treatment and/or prevention of transplant rejection, particularly active agents including, but not limited to, calcineurin inhibitors (eg, cyclosporine or tacrolimus, mTOR inhibitors (eg sirolimus, everolimus), antiproliferative drugs (eg azathioprine, mycophenolic acid), corticosteroids (eg prednisolone, hydrocortisone), antibodies (eg single Cloning anti-IL-2R ⁇ receptor antibody, basiliximab, daclizumab), polyclonal anti-T-cell antibody (eg, anti-thymocyte globulin (ATG), anti-lymphocyte globulin.
  • active agents including, but not limited to, calcineurin inhibitors (eg, cyclosporine or tacrolimus, mTOR inhibitors (eg sirolimus, everolimus), antiproliferative drugs (eg azathioprine,
  • a compound of the invention is co-administered with other therapeutic agents for the treatment and/or prevention of asthma and/or rhinitis and/or COPD, particularly active agents including, but not limited to, ⁇ 2 -adrenergic receptor agonists (eg, salbutamol, L-salbutamol, terbutaline and Bitoterol), adrenaline (eg inhalation or tablets), anticholinergics (eg ipratropium bromide), glucocorticoids (eg oral or inhalation) a combination of long-acting ⁇ 2 -agonists (such as salmeterol, formoterol, bambuterol, and sustained-release oral salbutamol), inhaled steroids, and long-acting bronchodilators (eg, fluticasone/salmeterol, Budesonide/formoterol), leukotriene antagonists and synthetic inhibitors (eg, montelukast, zafirluka
  • the compounds of the invention may be administered in combination with emergency treatment for asthma and/or COPD, such treatments including oxygen or a mixture of aerobics, spraying salbutamol or terbutaline (optionally in combination with an anticholinergic), Synthetic steroids (oral or intravenous, such as prednisone, prednisolone, methylprednisolone, dexamethasone or hydrocortisone), intravenous salbutamol, non-specific beta-agonists, injection or inhalation (eg Such as adrenaline, iso-lin, isoproterenol, oxacillin), anticholinergic drugs (such as glycopyrrolate, atropine, ipratropium), methylxanthine (theophylline, aminophylline, Benzylamine theophylline), inhalation anesthetics (isoflurane, halothane, enflurane), ketamine and intravenous magnesium sulfate.
  • Synthetic steroids oral or
  • a compound of the invention is co-administered with other therapeutic agents for the treatment and/or prevention of inflammatory bowel disease (IBD), particularly active agents including, but not limited to, glucocorticoids (eg, prednisone, budesonide) German, synthetic immune-modifying agents (such as methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6-mercaptopurine and cyclosporine) and biological products to alleviate diseases Immunomodulators (eg, infliximab, adalimumab, rituximab, and abatacil).
  • IBD inflammatory bowel disease
  • a compound of the invention is co-administered with other therapeutic agents for the treatment and/or prevention of systemic lupus erythematosus, particularly active agents including, but not limited to, disease-modifying antirheumatic drugs such as anti-malarial drugs (eg, hydroxychloroquine) , hydroxychloroquine), immunosuppressive agents (such as methotrexate and azathioprine), cyclophosphamide and mycophenolic acid; immunosuppressive drugs and analgesics, such as non-steroidal anti-inflammatory drugs, anesthetics (such as right C Oxygen and compound codeine paracetamol), opioids (such as hydrocodone, oxycodone, mesaconidine or methadone) and fentanyl transdermal patch.
  • disease-modifying antirheumatic drugs such as anti-malarial drugs (eg, hydroxychloroquine) , hydroxychloroquine), immunosuppressive agents (
  • a compound of the invention is co-administered with other therapeutic agents for the treatment and/or prevention of psoriasis, particularly active agents including, but not limited to, topical therapies such as bathing solutions, wetting agents, medicated milk Ointments and ointments containing coal tar, indole phenol, corticosteroids such as deoxymetazone, fluocinolone acetonide, vitamin D analogues (such as calcipotriol), Arganoiland retinoids (arc A, Avi A, Tazarotene), systemic therapies such as methotrexate, cyclosporine, retinoids, thioguanine, hydroxyurea, sulfasalazine, mycophenolate mofetil, azathioprine, tacrolimus , fumarate or biological products such as afaxet, etanercept, adalimumab, infliximab, ruthenium
  • Co-administration includes any means of delivering two or more therapeutic agents to a patient as part of the same treatment regimen, as will be apparent to the skilled artisan. Although two or more active agents can be administered simultaneously in a single formulation, this is not required. The active agents can be administered in different formulations and at different times.
  • the compounds of the invention are prepared from readily available starting materials using the following general methods and procedures. It should be understood that when typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can be applied unless otherwise stated. Optimum reaction conditions may vary depending on the particular reactants or solvents used, but these conditions can be determined by one skilled in the art by routine optimization procedures.
  • protecting groups may be required to prevent certain functional groups from undergoing undesired reactions.
  • suitable protecting groups for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art.
  • T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991 and the literature cited therein describe a number of protecting groups and their introduction and removal.
  • the following methods describe in detail the preparation of the compounds of the invention listed above and the compounds of the comparative examples.
  • the compounds of the present invention and the compounds of the comparative examples can be prepared by those skilled in the art of organic synthesis using known or commercially available starting materials and reagents.
  • the compounds of the present invention have a number of advantages over non-deuterated compounds known in the art.
  • the main advantages of the present invention include: (1) the compound of the present invention has excellent inhibitory effect on JAK kinase; (2) the chemical conversion of the compound in the organism by the technique of deuteration, so that the compound has better pharmacokinetics.
  • the dosage can be changed and a long-acting preparation can be formed to improve the applicability; (3) the substitution of a hydrogen atom in the compound with hydrazine can increase the drug concentration of the compound in the animal due to its strontium isotope effect, In order to improve the efficacy of the drug; replacing the hydrogen atom in the compound with hydrazine may increase the safety of the compound due to inhibition of certain metabolites.
  • Step 1 Synthesis of (6-bromopyridin-2-yl)-3-ethoxycarbonyl-thiourea (Compound 3).
  • Step 2 Synthesis of 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Compound 4).
  • Step 3 Synthesis of N-(5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropylcarboxamide (Compound 6).
  • Step 4 Synthesis of 4-(4-bromobenzyl) 1,1-dioxo-thiomorpholine (Compound 9).
  • Triethylamine (2.18 mL, 15.7 mmol) was added dropwise to 1 D of bromobenzyl bromide (1.28 g, 5.10 mmol) and thiomorpholine 1,1-dioxide hydrochloride (944 mg, 5.50 mmol). In a mixture of 15 mL), the reaction solution was stirred at room temperature for a reaction overnight. The reaction was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. Used directly in the next step.
  • Step 5 4-(4-(4,4,5,5-tetramethyl-dioxaborolan-2-yl)benzyl)thiomorpholine 1,1-dioxide (compound 10) synthesis.
  • Step 6 N-[5-[4-[(1,1-dioxo-thiomorpholinyl)methyl]phenyl]-[1,2,4]triazolo[1,5-a Synthesis of pyridin-2-yl]cyclopropanecarboxamide (Compound 11).
  • Step 7 4-(4-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)phenyl)thiomorpholine-1,1-di Synthesis of oxo-2,2,6,6-d4 (compound 12).
  • Step 8 N-(5-(4-((1,1-dioxo-thiothiomorpholine-2,2,6,6-d 4 )methyl)phenyl)-[1,2 , 4] Synthesis of triazolo[1,5-a]pyridin-2-yl)cyclopropylformyl (Compound 13).
  • Triethylamine 32 mg, 0.31 mmol
  • cyclopropanoyl chloride 35 mg, 0.31 mmol
  • 4-(4-(2-amino-[1,2,4]3, respectively, at 5 °C Zoxao[1,5-a]pyridin-5-yl)phenyl)thiomorpholine-1,1-dioxo-2,2,6,6-d 4 28 mg, 0.08 mmol
  • the reaction was warmed to room temperature until the reaction was completed (16h).
  • Step 1 N-(5-(4-Formylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropylcarboxamide (Compound 15) synthesis.
  • Step 2 N-(5-(4-(Hydroxymethyl-d)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropylcarboxamide Synthesis of (Compound 16).
  • Step 3 (4-(2-(cyclopropylformamide)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)phenyl)methyl-d-methyl Synthesis of sulfonic acid (Compound 17).
  • Step 4 N-(5-(4-((1,1-dioxo-4-thiomorpholinyl)methyl-d)phenyl-[1,2,4]triazolo[1, Synthesis of 5-a]pyridin-2-yl)cyclopropylformamide (Compound 18).
  • Step 1 Synthesis of 4-carboxylic acid methyl ester phenylboronic acid (Compound 20).
  • Step 2 Synthesis of methyl 4-(2-(cyclopropylformamide)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)benzoate (Compound 21).
  • Step 3 N-(5-(4-(hydroxymethyl-d 2 )phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropyl Synthesis of amide (Compound 22).
  • Tetrakiladene lithium (27 mg, 0.63 mmol) was added portionwise to 4-(2-(cyclopropylformamide)-[1,2,4]triazolo[1,5-a]pyridine under ice bath.
  • a solution of methyl 5-benzoate 200 mg, 0.60 mmol) in anhydrous tetrahydrofurane (10 mL).
  • Step 4 (4-(2-(cyclopropylformamide)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)phenyl)methyl-d 2 -A Synthesis of a base sulfonic acid (Compound 23).
  • Step 5 N-(5-(4-((1,1-dioxo-thiothiomorpholine)methyl-d 2 )phenyl)-[1,2,4]triazolo[1 Synthesis of 5-a]pyridin-2-yl)cyclopropylformamide (Compound 24).
  • Step 1 4-((4-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)phenyl)methyl-d 2 )thio? Synthesis of porphyrin 1,1-dioxide-2,2,6,6-d 4 (compound 25).
  • Step 2 N-(5-(4-((1,1-dioxo-thiothiomorpholine-2,2,6,6-d 4 )methyl-d 2 )phenyl)-[ Synthesis of 1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropylformamide (Compound 26).
  • Triethylamine (80 mg, 0.76 mmol) and cyclopropanoyl chloride (80 mg, 0.76 mmol) were slowly added dropwise to 4-((4-(2-amino-[1,2,4]) at 5 °C.
  • Triazolo[1,5-a]pyridin-5-yl)phenyl)methyl-d 2 )thiomorpholine 1,1-dioxide-2,2,6,6-d 4 70 mg, 0.19 mmol
  • the reaction mixture was warmed to room temperature until the reaction was completed (16h).
  • reaction solvent was removed under reduced pressure, and the residue was added to a methanol solution of ammonia (7M, 5mL), and the bis acylation product (6h) was stirred at room temperature to obtain a monoacylated target.
  • the reaction was quenched with EtOAc (EtOAc) (EtOAc) Obtained 50 m g of a beige solid, yield: 61.0%.
  • Step 2 Synthesis of 2,6-d 2 -4-bromotoluene (Compound 29).
  • the HBr (40wt% aqueous solution, 22mL) was slowly added dropwise 4-methyl-aniline -2,6-d 2 (3.60g, 33.0mmol ) aqueous solution (16mL). After stirring in the greenhouse for 15 min, the ice salt bath was cooled to -5 °C. Sodium nitrite (2.67 g, 38.6 mmol) in water (10 mL) was then slowly added dropwise, the reaction temperature was kept at 0 ° C and stirred for 30 min.
  • reaction liquid was slowly dropwise added to a suspension of cuprous bromide (6.86 g, 47.8 mmol) in HBr (40 wt% aqueous solution, 30 mL), and the mixture was applied, and the reaction was carried out at 50 ° C for 2 h.
  • Step 3 Synthesis of 1-bromo-4-(bromomethyl)benzene-2,6-d 2 (Compound 30).
  • Step 4 Synthesis of 4-(4-bromobenzyl-3,5-d 2 ) 1,1-dioxo-thiomorpholine (Compound 31).
  • Triethylamine (850 mg, 8.34 mmol) was added dropwise to 1-bromo-4-(bromomethyl)benzene-2,6-d 2 (700 mg, 2.78 mmol) and thiomorpholine 1,1-dioxide
  • the reaction was diluted with ethyl acetate (50 mL), washed with water (20 mL ⁇ 3) and brine (20mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 5 Compound 4-(3,5-d 2 -4-(4,4,5,5-tetramethyl-dioxaborolan-2-yl)benzyl)thiomorpholine 1,1- Synthesis of Dioxide (Compound 32)
  • Step 6 N-(5-(4-((1,1-dioxo-thiomorpholinyl)methyl]phenyl-2,6-d 2 )-[1,2,4]triazole Synthesis of [1,5-a]pyridin-2-yl]cyclopropanecarboxamide (Compound 33).
  • Test compounds were dissolved in DMSO to make a 20 mM stock solution. Compounds were diluted to 0.1 mM in DMSO (100 times the final concentration of the dilution) before use and diluted in 3 folds at 11 concentrations. Dilute to 4 times the final concentration of the dilution solution with the buffer.
  • kinase inhibition IC 50 ( ⁇ M) in the examples is summarized in Table 1 below.
  • the compound of the present invention has an excellent selective inhibitory effect on JAK enzyme, and has an inhibitory effect on JAK1 (Examples 1, 2, and 3 are equivalent to Filgotinib activity, and the activities of Examples 4 and 5 are even Better than Filgotinib) is superior to JAK2 and better than JAK3. Therefore, the compounds of the present invention are useful for treating disorders associated with abnormal JAK activity while effectively reducing their toxic side effects.
  • Microsomal experiments human liver microsomes: 0.5 mg/mL, Xenotech; rat liver microsomes: 0.5 mg/mL, Xenotech; coenzyme (NADPH/NADH): 1 mM, Sigma Life Science; magnesium chloride: 5 mM, 100 mM phosphate buffer Agent (pH 7.4).
  • phosphate buffer 100 mM, pH 7.4.
  • the pH was adjusted to 7.4, diluted 5 times with ultrapure water before use, and magnesium chloride was added to obtain a phosphate buffer (100 mM) containing 100 mM potassium phosphate, 3.3 mM magnesium chloride, and a pH of 7.4.
  • NADPH regeneration system containing 6.5 mM NADP, 16.5 mM G-6-P, 3 U/mL G-6-P D, 3.3 mM magnesium chloride was prepared and placed on wet ice before use.
  • Formulation stop solution acetonitrile solution containing 50 ng/mL propranolol hydrochloride and 200 ng/mL tolbutamide (internal standard). Take 25057.5 ⁇ L of phosphate buffer (pH 7.4) into a 50 mL centrifuge tube, add 812.5 ⁇ L of human liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg/mL. 25057.5 ⁇ L of phosphate buffer (pH 7.4) was taken into a 50 mL centrifuge tube, and 812.5 ⁇ L of SD rat liver microsomes were added and mixed to obtain a liver microsome dilution having a protein concentration of 0.625 mg/mL.
  • the corresponding compound had a reaction concentration of 1 ⁇ M and a protein concentration of 0.5 mg/mL.
  • 100 ⁇ L of the reaction solution was taken at 10, 30, and 90 min, respectively, and added to the stopper, and the reaction was terminated by vortexing for 3 min.
  • the plate was centrifuged at 5000 x g for 10 min at 4 °C.
  • 100 ⁇ L of the supernatant was taken into a 96-well plate to which 100 ⁇ L of distilled water was previously added, mixed, and sample analysis was performed by LC-MS/MS.
  • control group N-(5-(4) -((1,1-dioxo-4-thiomorpholinyl)methyl)phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropane Base carboxamide;
  • Test group Examples 1-5, comparing their pharmacokinetic differences.
  • Rats were fed a standard diet and given water. Fasting began 16 hours before the test.
  • the drug was dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the eyelids at a time point of 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration.
  • Rats were briefly anesthetized after inhalation of ether, and 300 ⁇ L of blood samples were collected from the eyelids in test tubes. There was 30 ⁇ L of 1% heparin salt solution in the test tube. The tubes were dried overnight at 60 ° C before use. After the blood sample collection was completed at a later time point, the rats were anesthetized with ether and sacrificed.
  • Plasma samples were centrifuged at 5000 rpm for 5 minutes at 4 ° C to separate plasma from red blood cells. Pipette 100 ⁇ L of plasma into a clean plastic centrifuge tube to indicate the name and time point of the compound. Plasma was stored at -80 °C prior to analysis. The concentration of the compound of the invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points.
  • the experimental results show that the compound of the present invention has better pharmacokinetics in animals relative to the control compound, and thus has better pharmacodynamics and therapeutic effects.

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Abstract

COMPOSÉ PICOLINAMIDE SUBSTITUÉ ET SON UTILISATION La présente invention décrit en particulier, un composé picolinamide substitué par du deutérium représenté par la formule (I) et une composition pharmaceutique comprenant le composé ou une forme cristalline, un sel, un promédicament, un stéréoisomère, un hydrate ou un solvate pharmaceutiquement acceptables de ce dernier. Le composé peut être utilisé comme inhibiteur des JAK et peut à son tour être utile dans la préparation de médicaments destinés au traitement des maladies liées aux JAK (par exemple les maladies auto-immunes et similaires).
PCT/CN2017/071128 2016-02-02 2017-01-13 Fig. 1 : s102 % % % diviser m ports dmrs en k groupes de ports dmrs, k et m étant des entiers positifs et k étant inférieur ou égal à m s104 % % % utilisent un précodage indépendante sur chaque groupe de ports dmrs pour transmettre dmrs WO2017133423A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2018024236A1 (fr) * 2016-08-03 2018-02-08 苏州科睿思制药有限公司 Nouvelle forme cristalline d'inhibiteur sélectif de jak1, son procédé de fabrication et son application
CN110204542A (zh) * 2019-05-23 2019-09-06 四川伊诺达博医药科技有限公司 一种JAK1抑制剂Filgotinib的合成方法
CN110878097A (zh) * 2019-11-29 2020-03-13 杭州科巢生物科技有限公司 菲格替尼的制备方法
WO2021023207A1 (fr) * 2019-08-06 2021-02-11 江苏柯菲平医药股份有限公司 Inhibiteur de janus kinases jak et son utilisation
CN114075188A (zh) * 2020-08-11 2022-02-22 南京柯菲平盛辉制药有限公司 芳香杂环酰胺类化合物及其制备方法和医药用途
WO2023082839A1 (fr) * 2021-11-10 2023-05-19 奥锐特药业(天津)有限公司 Procédé de préparation de filgotinib

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