WO2022032484A1 - Composé de pyridazine-3-formamide, son procédé de préparation et son utilisation médicale - Google Patents

Composé de pyridazine-3-formamide, son procédé de préparation et son utilisation médicale Download PDF

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WO2022032484A1
WO2022032484A1 PCT/CN2020/108468 CN2020108468W WO2022032484A1 WO 2022032484 A1 WO2022032484 A1 WO 2022032484A1 CN 2020108468 W CN2020108468 W CN 2020108468W WO 2022032484 A1 WO2022032484 A1 WO 2022032484A1
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amino
mmol
pyridazine
alkyl
difluorophenyl
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陈向阳
庞育成
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北京诺诚健华医药科技有限公司
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Priority to PCT/CN2020/108468 priority Critical patent/WO2022032484A1/fr
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Definitions

  • the present invention relates to a novel pyridazine-3-carboxamide compound or a pharmaceutically acceptable salt thereof that regulates or inhibits the activity of Janus kinase (JAK), especially tyrosine kinase 2 (TYK2), and contains the compound Pharmaceutical composition or pharmaceutically acceptable salt thereof, preparation method of said compound or pharmaceutically acceptable salt thereof, and said compound or pharmaceutically acceptable salt thereof or medicament containing said compound or pharmaceutically acceptable salt thereof Use of the composition in the manufacture of a medicament for the treatment and/or prevention of related disorders mediated by the kinase, particularly autoimmune diseases, inflammatory diseases and cancer, and methods of use thereof.
  • JAK Janus kinase
  • TYK2 tyrosine kinase 2
  • Janus kinase is a non-receptor tyrosine protein kinase consisting of four family members, namely, JAK1, JAK2, JAK3 and TYK2.
  • JAK has 7 homology domains (JAK Homology Domain, JH) in structure, of which JH1 domain is a kinase domain, JH2 domain is a pseudokinase domain (regulating the activity of JH1), JH6 and JH7 are receptors binding area.
  • Cytokine Receptor When the cell surface region of the Cytokine Receptor binds to the cytokine (Cytokine), causing the JAK bound to the intracellular region to be phosphorylated, creating a dock for the Signal Transducer and Activator of Transcription (STAT) protein site.
  • the STAT protein is further phosphorylated by the activated JAK to form a dimer, enter the nucleus, regulate the expression and transcription of related genes, and realize the transduction of signals from the cell membrane to the nucleus (Liffd et.al, Ann.Rev.Immunol.1998,16,293 -322).
  • JAK transduces cytokine-mediated signals through the JAK-STAT pathway, and plays an important role in many cellular functions such as cytokine-dependent regulation of cell proliferation, differentiation, apoptosis, and immune response.
  • One of the popular targets in immune diseases and cancer (Alicea-Velazquez et.al, Curr. Drug Targets 2011, 12, 546-55).
  • Pfizer's pan-JAK inhibitor Tofacitinib was approved for the treatment of rheumatoid arthritis in 2012; the JAK1/JAK2 inhibitor Ruxolitinib developed by Incyte in the United States was approved in 2011. Approved for the treatment of myelofibrosis.
  • JAKs and STATs play a highly specific role in the control of different immune responses.
  • One JAK kinase can participate in the signal transduction process of multiple cytokines, and the signaling pathway of one cytokine can also activate multiple JAK kinases, but cytokines have certain selectivity for activated STAT proteins, such as interleukin (IL)-4 activates STAT6, while IL-12 specifically activates STAT4.
  • IL interleukin
  • JAK1, JAK2, and TYK2 widely exist in various tissues and cells.
  • JAK1 is closely related to the activation of inflammatory factors such as IL-6 and interferon (IFN), so JAK1 selective inhibitors are considered to be effective in the treatment of rheumatoid arthritis (RA), psoriasis and other autoimmune diseases have potential therapeutic effects; JAK2 can mediate cytokines such as erythropoietin (EPO) and thrombopoietin (TPO) alone (Won et.al, BMC Bioinformatics 2009,10, S53), closely related to the proliferation and differentiation of blood cells.
  • cytokines such as erythropoietin (EPO) and thrombopoietin (TPO) alone (Won et.al, BMC Bioinformatics 2009,10, S53), closely related to the proliferation and differentiation of blood cells.
  • JAK3 exists only in the bone marrow and lymphatic system, mediates the signaling of IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21, these cytokines are important for inducing the proliferation, differentiation and activation of T cells
  • Antibody production by B cells, activation of macrophages, enhancement of natural killer cell (NK cell) activity, and induction of other cytokines such as IFN play important roles. Therefore, JAK3 selective inhibitors are expected to play an important role in the treatment of organ transplantation, autoimmune diseases, and inflammatory pneumonia.
  • the JAK/STAT pathway can be hyperactivated by autocrine and paracrine cytokines, as well as some mutations, and is associated with a variety of malignancies, such as breast, liver, prostate, colon, lung, pancreatic, bladder, and diffuse Large B-cell lymphoma et al (Tan et.al, Curr. Drug Targets 2014, 15, 1341-53; Lam et.al, Blood 2008, 111, 3701-13).
  • JAK2 mutant JAK2/V617F
  • JAK2/V617F occurs in the pseudokinase domain of JH2, causing a conformational change in JAK2, resulting in persistent activation of the kinase domain of JH1 independent of extracellular cytokine signaling, which in turn causes cell proliferation and hematological cancer, and is associated with true erythrocytes
  • PV Polycythaemia Vera
  • Essential Thrombocythemia Essential Thrombocythemia
  • MF Myelofibrosis
  • the JAK2 inhibitor Ruxolitinib can be used for the treatment of such blood diseases, but the efficacy is not related to the presence or absence of JAK2/V617F mutation, indicating that the antitumor activity is not only based on the inhibition of JAK2/V617F-involved signaling, but also Probably from the regulation of JAK1-STAT.
  • TYK2 is involved in the signal transduction of inflammatory cytokines such as interferons (IFNs), IL-12 and IL-23, and plays a key role in innate and adaptive immunity.
  • TYK2 knockout mice had normal red blood cell counts and were able to survive.
  • JAK3-deficient mice have severe immunodeficiency, and JAK1 or JAK2 knockout mice will be embryonic lethal, but no disease related to JAK1/2 loss of function has been found in humans, which may indirectly indicate the importance of JAK1/2 physiological functions. .
  • TYK2 One patient with a null mutation in TYK2 had hyperimmunoglobulin E syndrome, but the other seven patients with null mutations in TYK2 homotypic binding did not have hyperimmunoglobulin E syndrome, but were Attenuated responses to / ⁇ increase susceptibility to mycobacterial or viral infection. Therefore, inhibition of TYK2 did not cause acute toxicity. The lack of TYK2 expression is reflected in attenuated signaling of various proinflammatory cytokines and a severe imbalance in T helper cell differentiation. Furthermore, evidence from genetic association studies supports TYK2 as a shared autoimmune disease susceptibility gene.
  • TYK2-regulated channels have also been further demonstrated in disease treatment by antibody therapy, such as ustekinumab targeting IL-12/IL-23 for psoriasis and systemic lupus erythematosus in clinical trials.
  • TYK2 inhibitors for the treatment of psoriasis, systemic lupus erythematosus (SLE) and inflammatory bowel disease (IBD).
  • TYK2 is also associated with some cancers, such as the abnormal survival of acute lymphoblastic leukemia (T-ALL) cells associated with the activation of TYK2.
  • T-ALL acute lymphoblastic leukemia
  • Gene knockout experiments showed that 88% of T-ALL cell lines and 63% of T-ALL cells from patients were TYK2-dependent, thus, TYK2 is an oncogene in T-ALL (Sanda et.al, Cancer Disc.2013, 3,564-77).
  • TYK2 selective inhibitor NDI-031301 can induce apoptosis to inhibit the growth of human T-ALL cell lines, and also has good safety and efficacy in a mouse model with KOPT-K1 T-ALL tumor cells (Akahane et.al, British J. Haematol. 2017, 177, 271-82), showing the promise of TYK2 selective inhibitors in the treatment of T-ALL.
  • JAK1/2/3 inhibitor drugs such as Tofacitinib, Baricitinib and Ruxolitinib, and many more are in clinical Tested drugs such as Upadacitinib, Filgotinib, Peficitinib, etc., but only one TYK2-specific inhibitor, BMS-986165, has been reported to enter clinical trials.
  • BMS-986165 TYK2-specific inhibitor
  • Ruxolitinib is used for the treatment of myelofibrosis with good safety and no toxic and side effects on non-target organs.
  • tofacitinib has certain toxic and side effects due to its inhibition of JAK2 activity, which affects the production of blood cells and lymphocytes, which limits the clinical dosage of this drug in RA. Therefore, more selective TYK2-specific inhibitors than JAK2 were developed to avoid the side effects of anemia due to inhibition of JAK2 activity (Vincenti et.al, Am.J.Transplant.2012, 12, 2446-56; Ghoreschi et. al, Nature Immunol. 2009, 4, 356-360) has attracted great attention from pharmaceutical companies. However, due to the high sequence similarity of the active sites of the JAK kinase family, it is quite difficult to develop a highly selective TYK2 inhibitor.
  • TYK2 selective inhibitors include WO2010142752, WO2012062704, WO2013180265, WO2015032423, WO2015131080 and WO2017040757, etc., based on TYK2 specific inhibitors in the treatment of inflammatory diseases, autoimmune diseases and cancer, etc.
  • the demonstrated prospects still need to develop new compounds with better druggability, stronger efficacy and higher TYK2 kinase selectivity.
  • the present invention devised a compound having the structure represented by the general formula (I), and found that the compound having such a structure exhibited excellent effects and functions.
  • the present invention provides a compound of general formula (I), its prodrugs, stable isotope derivatives, pharmaceutically acceptable salts, isomers and mixtures thereof as Janus kinase, especially TYK2 inhibitors:
  • Z is N or CR 1 ;
  • Ring A is an optionally substituted C 6-10 aromatic ring or a 5-10 membered heteroaromatic ring
  • L is a bond or an optionally substituted C 1-6 alkylene group, wherein one or more -CH 2 - in the alkylene group is optionally selected from -N(R 2 )-, -N(R 2 )C(O)-, -C(O)N(R 2 )-, -N(R 2 )S(O) 2 -, -S(O) 2 N(R 2 )-, -O-, - C(O)-, -OC(O)-, -C(O)O-, -S- and -S(O) m - groups are replaced;
  • R is selected from H, halogen, cyano, -SF5 , -OR3 , -SR3 , -NR3R4 , -S(O ) mR3 , -S(O ) 2NR3R4 , -C (O)R 3 , -C(O)OR 3 , -C(O)NR 3 R 4 , -C(O)N(R 3 )OR 4 , -OC(O)R 3 , -OC(O) NR 3 R 4 , -N(R 3 )C(O)OR 4 , -N(R 3 )C(O)OR 4 , -N(R 3 )C(O)R 4 , -N(R 2 )C(O)NR 3 R 4 , -C(O )N(R 3 )S(O) 2 R 4 , -N(R 3 )S(O) 2 R 4 , or optionally substituted C 1-6 alkyl
  • Ra , Rb , Rc , Rd and Re are each independently selected from H, halogen, cyano, -SF5 , -OR3 , -S(O) mR3 , -S(O ) 2NR 3 R 4 , -C(O)NR 3 R 4 , or optionally substituted C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heterocyclyl Aryl;
  • R 1 is selected from H, halogen, cyano or optionally substituted C 1-6 alkyl
  • R 2 , R 3 and R 4 are each independently selected from H or optionally substituted C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heterocyclyl Aryl; alternatively, R3 and R4 on the same nitrogen atom are optionally taken together with the nitrogen atom to which they are attached to form a 4-7 membered heterocycle optionally containing additional heteroatoms; the heterocycle is optionally replace;
  • the present invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by general formula (I) or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer and mixture thereof, and a pharmaceutically acceptable salt thereof.
  • acceptable carriers and excipients comprising a compound represented by general formula (I) or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer and mixture thereof, and a pharmaceutically acceptable salt thereof.
  • Another aspect of the present invention relates to a compound represented by general formula (I) or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer and mixture thereof, or the use of the pharmaceutical composition in the preparation of a medicament Use, wherein the medicament is used to treat or prevent TYK2-mediated diseases, including but not limited to autoimmune diseases, inflammatory diseases including intestinal inflammation, cancer, skin diseases, diabetes, eye diseases, neurodegeneration Sexual diseases, allergic reactions, asthma and other obstructive airway diseases, transplant rejection, etc.
  • TYK2-mediated diseases including but not limited to autoimmune diseases, inflammatory diseases including intestinal inflammation, cancer, skin diseases, diabetes, eye diseases, neurodegeneration Sexual diseases, allergic reactions, asthma and other obstructive airway diseases, transplant rejection, etc.
  • Yet another aspect of the present invention provides a method for treating or preventing TYK2-mediated diseases, the method comprising administering to a patient in need thereof a therapeutically effective amount of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, Prodrugs, stable isotope derivatives, isomers and mixtures thereof, or pharmaceutical compositions comprising said compounds, including but not limited to autoimmune diseases, inflammatory diseases including intestinal inflammation, cancer, skin Diseases, diabetes, eye diseases, neurodegenerative diseases, allergic reactions, asthma and other obstructive airway diseases, transplant rejection, etc.
  • autoimmune diseases including intestinal inflammation, cancer, skin Diseases, diabetes, eye diseases, neurodegenerative diseases, allergic reactions, asthma and other obstructive airway diseases, transplant rejection, etc.
  • Another aspect of the present invention relates to the compound represented by the general formula (I) or its pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers and mixtures thereof, which are used for the treatment or prevention of TYK2-mediated diseases , including but not limited to autoimmune diseases, inflammatory diseases including intestinal inflammation, tumors, skin diseases, diabetes, eye diseases, neurodegenerative diseases, allergic reactions, asthma and other obstructive airway diseases, transplantation exclusion, etc.
  • TYK2-mediated diseases including but not limited to autoimmune diseases, inflammatory diseases including intestinal inflammation, tumors, skin diseases, diabetes, eye diseases, neurodegenerative diseases, allergic reactions, asthma and other obstructive airway diseases, transplantation exclusion, etc.
  • C xy refers to a range of carbon atoms, where x and y are integers, eg C 3-8 cycloalkyl refers to a cycloalkyl group having 3-8 carbon atoms, ie having 3 , 4, 5, 6, 7 or 8 carbon atoms cycloalkyl. It should also be understood that “ C3-8 " also includes any subrange therein, eg, C3-7 , C3-6 , C4-7 , C4-6 , C5-6 , and the like.
  • Alkyl refers to a saturated straight or branched chain hydrocarbyl group containing 1 to 20 carbon atoms, eg, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl -2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, etc
  • Alkylene refers to a divalent group of a straight or branched chain saturated hydrocarbon containing 1 to 20 carbon atoms, eg, 1 to 6 carbon atoms or 1 to 4 carbon atoms.
  • alkylene groups include -CH2- , -CH( CH3 )-, -CH2CH2- , -CH2CH2CH2- , - ( CH3 ) C( CH3 ) -, -CH2CH2CH2CH2- , -CH2CH ( CH3 ) CH2- , etc.
  • the alkylene group may be optionally substituted.
  • Cycloalkyl refers to a saturated cyclic hydrocarbyl substituent containing 3 to 14 carbon ring atoms. Cycloalkyl groups may be monocarbocyclic rings, typically containing 3 to 8, 3 to 7 or 3 to 6 carbon ring atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Cycloalkyl may alternatively be bi- or tricyclic fused together, such as decalinyl. The cycloalkyl group may be optionally substituted.
  • Heterocyclyl or heterocycle refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic group comprising 3 to 20 ring atoms, such as may be 3 to 14, 3 to 12, 3 to 10 , 3 to 8, 3 to 6, or 5 to 6 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) m (wherein m is an integer from 0 to 2), but not including The ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • It preferably includes 3 to 12 ring atoms, more preferably 3 to 10 ring atoms, more preferably 4 to 7 ring atoms, more preferably 4 to 6 ring atoms, most preferably 5 or 6 ring atoms, of which 1 to 4 is a heteroatom, more preferably 1 to 3 are heteroatoms, and most preferably 1 to 2 are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, oxetanyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpho Linoyl, homopiperazinyl, azetidinyl, etc.
  • Polycyclic heterocyclic groups include fused, bridged or spiro polycyclic heterocyclic groups such as octahydrocyclopentadieno[c]pyrrole, octahydropyrrolo[1,2-a]pyrazine, 3,8-di Azabicyclo[3.2.1]octane, 5-azaspiro[2.4]heptane, 2-oxa-7-azaspiro[3.5]nonane, etc.
  • the heterocyclyl or heterocycle may be optionally substituted.
  • Aryl or aromatic ring refers to an aromatic monocyclic or fused polycyclic group containing 6 to 14 carbon atoms, preferably 6 to 10 membered, such as phenyl and naphthyl, most preferably phenyl.
  • the aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples include:
  • the aryl group or aromatic ring may be optionally substituted.
  • Heteroaryl or heteroaromatic ring refers to a heteroaromatic system comprising 5 to 14 ring atoms, wherein 1 to 4 ring atoms are selected from heteroatoms including oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10-membered, more preferably heteroaryl is 5- or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, tetra oxazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl and the like.
  • the heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is a heteroaryl
  • heteroaryl or heteroaryl ring may be optionally substituted.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • Cyano refers to -CN.
  • heterocyclic group optionally substituted with alkyl means that an alkyl group may, but need not, be present, and the expression includes both instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group .
  • Optionally substituted means that one or more hydrogen atoms, preferably 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • the substituents include but are not limited to halogen, cyano, nitro, oxo, -SF 5 , C 1-4 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5 -6-membered heteroaryl, -OR', -NR'R", -C(O)R', -C(O)OR', -C(O)NR'R", -C(O)N( R')OR", -OC(O)R', -OC(O)NR'R", -N(R')C(O)OR", -N(R')C(O)R", -N(R')C(O)OR", -N(R')C(O)R", -N(R'")C(O)NR'R", -N(R')S(O) 2 R", -S(O) m R'(m is 1 or 2), -S(O ) 2 NR
  • “Isomers” refer to compounds that have the same molecular formula but differ in the nature or order in which their atoms are bonded or in the spatial arrangement of their atoms. Isomers that differ in the arrangement of atoms in space are called “stereoisomers”. Stereoisomers include optical isomers, geometric isomers and conformational isomers.
  • optical isomers may exist in the form of optical isomers. These optical isomers are of the "R” or “S” configuration, depending on the configuration of the substituents around the chiral carbon atom. Optical isomers include enantiomers and diastereomers. Methods for the preparation and separation of optical isomers are known in the art.
  • the compounds of the present invention may also exist as geometric isomers.
  • the present invention contemplates various geometric isomers and mixtures thereof resulting from the distribution of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl or heterocyclic groups. Substituents around carbon-carbon double bonds or carbon-nitrogen bonds are assigned the Z or E configuration, and substituents around cycloalkyl or heterocycles are assigned the cis or trans configuration.
  • the compounds of the present invention may also exhibit tautomerism, such as keto-enol tautomerism.
  • the present invention includes any tautomeric or stereoisomeric forms and mixtures thereof, and is not limited to any one tautomeric or stereoisomeric form used in the naming of the compounds or chemical structural formulae.
  • isotopes include all isotopes of atoms occurring in the compounds of the present invention. Isotopes include those atoms with the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation into the compounds of the present invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, 2H(D), 3H , 13C , 14C , 15N , 18 , respectively . O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the accompanying Examples, using the appropriate isotopically labeled reagents in place of non-isotopically labeled reagents.
  • Such compounds have various potential uses, such as as standards and reagents in the determination of biological activity. In the case of stable isotopes, such compounds have the potential to advantageously alter biological, pharmacological or pharmacokinetic properties.
  • prodrugs refers to a derivative that is converted to a biologically active compound of the present invention under physiological conditions in vivo, eg, by oxidation, reduction, hydrolysis, etc., each with or without enzymes.
  • prodrugs are compounds wherein the amino group in the compounds of the invention is acylated, alkylated or phosphorylated, such as eicosanoylamino, alanylamino, pivaloyloxymethylamino, or Where the hydroxyl group is acylated, alkylated, phosphorylated or converted to a borate, e.g.
  • “Pharmaceutically acceptable salts” or “pharmaceutically acceptable salts” refer to salts prepared from pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids. Where the compounds of the present invention contain one or more acidic or basic groups, the present invention also includes their corresponding pharmaceutically acceptable salts. Thus, the compounds of the invention which contain acidic groups can exist in salt form and can be used according to the invention, for example as alkali metal salts, alkaline earth metal salts or as ammonium salts. More precise examples of such salts include sodium, potassium, calcium, magnesium or salts with ammonia or organic amines such as ethylamine, ethanolamine, triethanolamine or amino acids.
  • the compounds according to the invention which contain basic groups can exist in salt form and can be used according to the invention in the form of their addition salts with inorganic or organic acids.
  • suitable acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propylene acid, pivalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, Adipic acid and other acids known to those skilled in the art.
  • the present invention includes, in addition to the salt forms mentioned, inner or betaine salts.
  • the respective salts can be obtained by conventional methods known to those skilled in the art, for example by contacting these with organic or inorganic acids or bases in solvents or dispersants or by anion exchange or cation exchange with other salts.
  • “Pharmaceutical composition” means a compound containing one or more of the compounds described herein, or pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers, and mixtures thereof, together with other components such as a pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • autoimmune disease or inflammatory disease includes, but is not limited to, arthritis, Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune cerebrospinal Inflammation, autoimmune orchitis, Goodpasture disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves disease, primary biliary cirrhosis, hepatitis, primary sclerosis Cholangitis, chronic invasive hepatitis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, ulcerative colitis, membranous glomerulopathy, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis , Sjögren's syndrome, Reiter's syndrome, polymyositis, dermatomyositis, type I interferon disease including Aicardi-Goutines
  • intestinal inflammation includes, but is not limited to, Crohn's disease, ulcerative colitis, inflammatory bowel disease, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis.
  • cancer/tumor includes, but is not limited to, digestive/gastrointestinal cancer, colon cancer, liver cancer, skin cancer (including mast cell tumor and squamous cell carcinoma), breast cancer, ovarian cancer, prostate cancer, Lymphoma, leukemia (including acute myeloid leukemia and chronic myeloid leukemia), kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer, brain cancer, melanoma (including oral and metastatic melanoma), cardia Posey's sarcoma (myeloma including multiple myeloma), myeloproliferative disorders, proliferative diabetic retinopathy, vascular proliferation-related disorders/tumors.
  • leukemia including acute myeloid leukemia and chronic myeloid leukemia
  • kidney cancer including acute myeloid leukemia and chronic myeloid leukemia
  • kidney cancer including acute myeloid leukemia and chronic myeloid leukemia
  • kidney cancer including acute myeloid leukemia and chronic myeloid leukemia
  • skin disease includes, but is not limited to, atopic dermatitis, eczema, psoriasis, scleroderma, pruritus or other symptoms of itching, vitiligo, alopecia.
  • diabetes includes, but is not limited to, Type I diabetes and diabetic complications.
  • eye disease includes, but is not limited to, keratoconjunctivitis, uveitis (including uveitis associated with Behçet's disease and lens-induced uveitis), keratitis, herpetic keratitis, keratoconus , Corneal Epithelial Dystrophy, Leukopenia, Epiphthalmitis, Mooren's Ulcer, Scleritis, Graves' Eye Disease, Vogt-Koyanagi-Harada Syndrome, Keratoconjunctivitis Sicca (dry eye), Small Blisters, Iridilis body inflammation, sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmia, allergic conjunctivitis, ocular neovascularization.
  • neurodegenerative disease includes, but is not limited to, motor neuron disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia; Neurodegenerative diseases caused by glutamate neurotoxicity or hypoxia; ischemia in stroke, myocardial ischemia, renal ischemia, heart attack, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ hypoxia, or platelet aggregation /Reperfusion injury.
  • allergic reaction includes, but is not limited to, mammalian allergic dermatitis (including equine allergic diseases such as bite allergy), summer eczema, horseshoe itch, cramping, inflammatory airway disease, recurrent airway obstruction, Airway hyperresponsiveness, chronic obstructive pulmonary disease.
  • asthma and other obstructive airway diseases includes, but is not limited to, chronic or excessive asthma, late-onset asthma, bronchitis, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust Sexual asthma.
  • transplant rejection includes, but is not limited to, islet transplant rejection, bone marrow transplant rejection, graft-versus-host disease, organ and cell transplant rejection (eg, bone marrow, cartilage, cornea, heart, intervertebral disc, islet, kidney, limb, liver, lung, muscle, myoblast, nerve, pancreas, skin, small intestine or trachea), xenograft.
  • organ and cell transplant rejection eg, bone marrow, cartilage, cornea, heart, intervertebral disc, islet, kidney, limb, liver, lung, muscle, myoblast, nerve, pancreas, skin, small intestine or trachea
  • terapéuticaally effective amount is meant to include an amount of a compound of the present invention effective to inhibit the function of TYK2 and/or treat or prevent the disease.
  • patient refers to mammals, especially humans.
  • One aspect of the present invention is a compound of formula (I), its prodrugs, stable isotope derivatives, pharmaceutically acceptable salts, isomers and mixtures thereof:
  • Z is N or CR 1 ;
  • Ring A is an optionally substituted C 6-10 aromatic ring or a 5-10 membered heteroaromatic ring
  • L is a bond or an optionally substituted C 1-6 alkylene group, wherein one or more -CH 2 - in the alkylene group is optionally selected from -N(R 2 )-, -N(R 2 )C(O)-, -C(O)N(R 2 )-, -N(R 2 )S(O) 2 -, -S(O) 2 N(R 2 )-, -O-, - C(O)-, -OC(O)-, -C(O)O-, -S- and -S(O) m - groups are replaced;
  • R is selected from H, halogen, cyano, -SF5 , -OR3 , -SR3 , -NR3R4 , -S(O ) mR3 , -S(O ) 2NR3R4 , -C (O)R 3 , -C(O)OR 3 , -C(O)NR 3 R 4 , -C(O)N(R 3 )OR 4 , -OC(O)R 3 , -OC(O) NR 3 R 4 , -N(R 3 )C(O)OR 4 , -N(R 3 )C(O)OR 4 , -N(R 3 )C(O)R 4 , -N(R 2 )C(O)NR 3 R 4 , -C(O )N(R 3 )S(O) 2 R 4 , -N(R 3 )S(O) 2 R 4 , or optionally substituted C 1-6 alkyl
  • Ra , Rb , Rc , Rd and Re are each independently selected from H, halogen, cyano, -SF5 , -OR3 , -S(O) mR3 , -S(O ) 2NR 3 R 4 , -C(O)NR 3 R 4 , or optionally substituted C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heterocyclyl Aryl;
  • R 1 is selected from H, halogen, cyano or optionally substituted C 1-6 alkyl
  • R 2 , R 3 and R 4 are each independently selected from H or optionally substituted C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heterocyclyl Aryl; alternatively, R3 and R4 on the same nitrogen atom are optionally taken together with the nitrogen atom to which they are attached to form a 4-7 membered heterocycle optionally containing additional heteroatoms, optionally by replace;
  • Z is CH.
  • the compound of general formula (I) has the following general formula (II):
  • Ring A is optionally surrounded by one or more groups selected from halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, oxo, -C(O)OR 3 , -OC 1-4 alkyl, -OC 1-4 haloalkyl and -SO 2 C 1-4 alkyl substituents substituted C 6-10 aromatic ring or 5-10 membered heteroaromatic ring;
  • L is a bond or an optionally substituted C 1-6 alkylene group wherein one or more -CH 2 - in the alkylene group is optionally selected from -N(R 2 )-, -O- and - C(O)- group is replaced;
  • R is selected from H, halogen, cyano, -SF5 , -OR3 , -NR3R4 , -S(O ) 2R3 , -S(O) R3 , -S(O ) 2NR3R 4 , -C(O)OR 3 , -C(O)R 3 , -C(O)NR 3 R 4 , -N(R 3 )C(O)OR 4 , -N(R 3 )C(O ) R 4 , -C(O)N(R 3 )S(O) 2 R 4 , or optionally substituted C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocyclyl, Phenyl or 5-6 membered heteroaryl;
  • Ra and Re are each independently selected from halogen
  • R 2 is selected from H or C 1-6 alkyl
  • R3 and R4 are each independently selected from H or optionally substituted C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; Alternatively, R3 and R4 on the same nitrogen atom are optionally taken together with the nitrogen atom to which they are attached to form a 4-7 membered heterocycle optionally containing additional heteroatoms, the heterocycle being optionally substituted.
  • the compound is in the form of a compound of formula (II) above, or a prodrug, stable isotope derivative, pharmaceutically acceptable salt, isomer, and mixtures thereof, wherein:
  • Ring A is optionally surrounded by one or two selected from halogen, cyano, C 1-4 alkyl, oxo, -C(O)OH, -OC 1-4 alkyl and -SO 2 C 1-4 alkyl C 6-10 aromatic ring or 5-10 membered heteroaromatic ring substituted by the substituent of the base;
  • L is a bond or a C 1-6 alkylene group or -OC 1-4 alkylene group optionally substituted by a C 1-6 alkyl group;
  • R is selected from H, cyano, -SF5 , -OR3 , -S(O) 2R3 , -S(O) R3 , -S (O ) 2NR3R4 , -C (O)OR 3 , -C(O)R 3 , -C(O)NR 3 R 4 , -C(O)N(R 3 )S(O) 2 R 4 , C 1-6 alkyl, or optionally selected C 3-7 cycloalkyl substituted from substituents of -OH, C 1-4 alkyl, oxo, -OC 1-4 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocyclyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
  • Ra and Re are each independently selected from halogen
  • R 3 and R 4 are each independently selected from H or C 1-6 alkyl, C 3-7 cycloalkyl optionally substituted with substituents selected from halogen, -OH, oxo and C 1-4 alkyl , 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; alternatively, R3 and R4 on the same nitrogen atom are optionally taken together with the nitrogen atom to which they are attached to form an optionally containing additional 4-7 membered heterocycle of heteroatoms optionally selected from -OH, C 1-4 alkyl, -OC 1-4 alkyl, oxo, C 3-6 cycloalkyl or 4- Substituent substitution of 6-membered heterocyclic group.
  • the compound is in the form of a compound of formula (II) above, or a prodrug, stable isotope derivative, pharmaceutically acceptable salt, isomer, and mixtures thereof, wherein:
  • Ring A is C optionally substituted with one or two substituents selected from halogen, C 1-4 alkyl, oxo, -COOH, -OC 1-4 alkyl and -SO 2 C 1-4 alkyl 6-10 aromatic ring or 5-6 membered heteroaromatic ring;
  • L is a bond or a C 1-6 alkylene group or -OC 1-4 alkylene group optionally substituted by a C 1-4 alkyl group;
  • R is independently selected from H, cyano, -SF5 , -OR3 , -S(O) 2C1-6alkyl , -S(O) C1-6alkyl , -S(O ) 2NR 3 R 4 , -C(O)OH, -C(O)NR 3 R 4 , -C(O)NHS(O) 2 C 1-6 alkyl, C 1-6 alkyl , optionally selected from -OH, C 1-4 alkyl, oxo, -OC 1-4 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocyclyl substituted 4-7 membered heterocyclyl, or 5-6 membered heteroaryl optionally substituted by C 1-4 alkyl;
  • Ra and Re are each independently selected from halogen
  • R and R are each independently selected from H, C 1-6 alkyl optionally substituted with halogen or -OH, C 3-7 cycloalkyl optionally substituted with -OH, or optionally oxo or C 1-4 alkyl substituted 4-7-membered heterocyclic group; or, R and R on the same nitrogen atom are optionally together with the nitrogen atom to which they are attached to form a group optionally containing another group selected from N, 4-7 membered heterocycle of heteroatoms of O and S optionally selected from -OH, C1-4alkyl , -OC1-4alkyl , oxo, C3-6cycloalkane substituted by substituents of 4-6 membered heterocyclyl.
  • Ring A is optionally halogen, cyano, C1-4alkyl , oxo, -C (O)OH, -OC1-4alkyl , or -SO2C1-4alkane
  • Ring A is an unsubstituted benzene ring; in other embodiments, Ring A is a ring consisting of one or two selected from the group consisting of halogen, -C(O)OH, -OC 1-4 alkyl and - A benzene ring substituted with a substituent of SO2Ci - 4 alkyl; in still other embodiments, Ring A is a benzene ring substituted with one halogen, such as fluorine.
  • Ring A is an unsubstituted pyridine ring; in other embodiments, Ring A is a pyridine ring substituted with one or two substituents selected from halogen, C1-4 alkyl, and oxo .
  • the pyridine ring is attached to the parent nucleus, eg, through the 2-position. In some embodiments, the pyridine ring is attached to the parent nucleus, eg, through the 3-position.
  • Ring A is a substituted or unsubstituted pyrimidine ring.
  • the pyrimidine ring is attached to the parent nucleus through the 2-position.
  • Ring A is an unsubstituted pyrazole ring or a methyl-substituted pyrazole ring.
  • the pyrazole ring is attached to the parent nucleus, eg, through the 4-position. In some embodiments, the pyrazole ring is attached to the parent nucleus, eg, through the 3-position.
  • the "L-R” moiety is attached to Ring A in the para position to the -NH- group. In other embodiments, the "L-R” moiety is attached to Ring A in the meta position of the -NH- group.
  • Another aspect of the present invention is the compound represented by the above-mentioned general formula (I) or (II) or its prodrugs, stable isotope derivatives, pharmaceutically acceptable salts, isomers and mixtures thereof, said compounds having the general formula Formula (IIIa) or (IIIb):
  • X 1 , X 2 and X 3 are each independently selected from N or CG 1 ;
  • G 1 is selected from H, halogen, C 1-4 alkyl, oxo, -COOH, -OC 1-4 alkyl or -SO 2 C 1-4 alkyl ;
  • L, R, Ra and Re are as previously described.
  • X 1 , X 2 and X 3 are all CH.
  • no more than two of X 1 , X 2 and X 3 are N.
  • X 1 is N and X 2 and X 3 are CH.
  • X 2 is N and X 1 and X 3 are CH.
  • X 3 is N and X 1 and X 2 are CH.
  • X 1 and X 3 are N and X 2 is CH.
  • X 1 and X 2 are N and X 3 is CH.
  • X 2 and X 3 are N and X 1 is CH.
  • L is a bond.
  • L is C 1-6 alkylene optionally substituted with C 1-4 alkyl, eg -CH 2 - or -( CH 3 )C(CH 3 )-.
  • L is -OC1-4alkylene , eg, -O - CH2-.
  • L is a bond and R is -OC 1-6 alkyl or -OC 1-6 haloalkyl, eg -OCH 3 , -OC 2 H 5 , -OCHF 2 .
  • L is a bond and R is -S(O) 2C1-6alkyl or -S (O) C1-6alkane groups such as -S(O) 2CH3 or -S(O ) CH3 .
  • L is a bond and R is a cyano group.
  • R is a 5-6 membered heteroaryl group, eg, furyl, thienyl, thiazolyl, imidazolyl, oxazolyl, oxadi azolyl, thiadiazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyranyl, pyrazolyl, pyridyl, pyrimidinyl.
  • R is C1-6 alkyl, eg, methyl, ethyl.
  • R is optionally selected from -OH, C 1-4 alkyl, oxo, -OC 1-4 alkyl, C 4-7 membered heterocyclyl substituted by substituents of 3-6 cycloalkyl and 4-6 membered heterocyclyl, such as optionally -OH, methyl, oxo, methoxy, isopropoxy, ring propyl or oxetanyl substituted morpholinyl, thiomorpholinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, azetidinyl, pyrrolidinyl, oxetanyl, imidazolyl or piperidinyl.
  • R is selected from oxabutanyl, 3-hydroxyoxabutanyl, morpholino, 4-methylpiperazinyl, tetra Hydropyranyl, 3-methoxyoxetanyl, 4-methyl-2-oxopiperazinyl, 3-oxomorpholino, 1-methylpiperidinyl, 3-methylmorpholine , 2-methylmorpholino, 4-cyclopropyl-2-oxopiperazinyl, 4-(oxetan-3-yl)-2-oxopiperazinyl, 1-methylimidazolyl and 3-isopropoxyoxetanyl.
  • L is a bond
  • R is -OR and R is 4- optionally substituted with oxo and C 1-4 alkyl 7-membered heterocyclyl.
  • R3 is tetrahydrothiopyranyl, oxotetrahydrothiopyranyl, piperidinyl or 1-methylpiperidinyl.
  • R is -S(O) 2NR3R4 or -C (O ) NR3R4 , wherein R3 and R4
  • the heterocycle is optionally selected from -OH, C 1-4 alkyl, -OC 1-4 alkyl, oxo, C 3-6 cycloalkyl and 4 Substituent substitution of -6-membered heterocyclyl, for example, the heterocycle is morpholino, 4-methylpiperazinyl, 4-cyclopropylpiperazinyl, 4-(oxetan-3-yl)piperyl oxazinyl, ox
  • R is -C(O ) NR3R4 , wherein one of R3 and R4 is H and the other is optional C 1-6 alkyl substituted with -OH.
  • R is -C(O ) NR3R4 , wherein one of R3 and R4 is H and the other is optional C3-6 cycloalkyl substituted with -OH, eg cyclohexyl.
  • R is -C(O) NR3R4 , wherein one of R3 and R4 is H and the other is 4- 7-membered heterocyclyl, such as oxetanyl, piperidinyl or tetrahydropyranyl.
  • Some embodiments of the present invention are compounds of general formula (IIIa), wherein:
  • X 1 , X 2 and X 3 are all CH, or X 1 and X 2 are CH and X 3 is N;
  • G 1 is H or halogen
  • L is a bond, C 1-6 alkylene or -OC 1-4 alkylene optionally substituted by C 1-4 alkyl;
  • R is independently selected from cyano, -SF5 , -OR3 , -S(O) 2C1-6alkyl , -S(O) C1-6alkyl , -S(O ) 2NR3R 4 , -C(O)OH, -C(O)NR 3 R 4 , -C(O)NHS(O) 2 C 1-6 alkyl, optionally selected from -OH, C 1-4 alkyl , oxo, -OC 1-4 alkyl, C 3-6 cycloalkyl and 4-7 membered heterocyclyl substituted with substituents of 4-6 membered heterocyclyl, or optionally by C 1-4 alkyl Substituted 5-6 membered heteroaryl;
  • Ra and Re are each independently selected from halogen
  • R and R are each independently selected from H, C 1-6 alkyl optionally substituted with halogen or -OH, C 3-7 cycloalkyl optionally substituted with -OH, or optionally oxo or C 1-4 alkyl substituted 4-7-membered heterocyclic group; or, R and R on the same nitrogen atom are optionally together with the nitrogen atom to which they are attached to form a group optionally containing another group selected from N, 4-7 membered heterocycle of heteroatoms of O and S optionally selected from -OH, C1-4alkyl , -OC1-4alkyl , oxo, C3-6cycloalkane Substituents of 4-6 membered heterocyclyl groups.
  • Some embodiments of the present invention are compounds of general formula (IIIa), wherein:
  • X 1 , X 2 and X 3 are all CH;
  • G 1 is H or halogen
  • L is a bond or a C 1-6 alkylene group or -OC 1-4 alkylene group optionally substituted by a C 1-4 alkyl group;
  • R is independently selected from cyano, -SF5 , -OR3 , -S(O) 2C1-6alkyl , -S(O) C1-6alkyl , -S(O ) 2NR3R 4 , -C(O)OH, -C(O)NR 3 R 4 , -C(O)NHS(O) 2 C 1-6 alkyl, optionally selected from -OH, C 1-4 alkyl , oxo, -OC 1-4 alkyl, C 3-6 cycloalkyl and 4-7 membered heterocyclyl substituted with substituents of 4-6 membered heterocyclyl, or optionally by C 1-4 alkyl Substituted 5-6 membered heteroaryl;
  • Ra and Re are each independently selected from halogen
  • R and R are each independently selected from H, C 1-6 alkyl optionally substituted with halogen or -OH, C 3-7 cycloalkyl optionally substituted with -OH, or optionally oxo or C 1-4 alkyl substituted 4-7-membered heterocyclic group; or, R and R on the same nitrogen atom are optionally together with the nitrogen atom to which they are attached to form a group optionally containing another group selected from N, 4-7 membered heterocycle of heteroatoms of O and S optionally selected from -OH, C1-4alkyl , -OC1-4alkyl , oxo, cyclopropyl and oxetine Substituents of cyclyl groups are substituted.
  • Some embodiments of the present invention are compounds of general formula (IIIa), wherein:
  • X 1 and X 2 are CH and X 3 is N;
  • G 1 is H or halogen
  • L is a bond, C 1-6 alkylene or -OC 1-4 alkylene optionally substituted by C 1-4 alkyl;
  • R is independently selected from cyano, -SF5 , -OR3 , -S(O) 2C1-6alkyl , -S(O) C1-6alkyl , -S(O ) 2NR3R 4 , -C(O)OH, -C(O)NR 3 R 4 , -C(O)NHS(O) 2 C 1-6 alkyl, optionally selected from -OH, C 1-4 alkyl , oxo, -OC 1-4 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclyl substituted by substituents of 4-6 membered heterocyclyl, or optionally by C 1-4 alkyl Substituted 5-6 membered heteroaryl;
  • Ra and Re are each independently selected from halogen
  • R and R are each independently selected from H, C 1-6 alkyl optionally substituted with halogen or -OH, C 3-7 cycloalkyl optionally substituted with -OH, or optionally oxo or C 1-4 alkyl substituted 4-7-membered heterocyclic group; or, R and R on the same nitrogen atom are optionally together with the nitrogen atom to which they are attached to form a group optionally containing another group selected from N, 4-7 membered heterocycle of heteroatoms of O and S optionally selected from -OH, C1-4alkyl , -OC1-4alkyl , oxo, cyclopropyl and oxetine Substituents of cyclic groups are substituted.
  • X 1 and X 2 are CH and X 3 is N;
  • G 1 is H
  • L is a bond or a C 1-6 alkylene group optionally substituted with a C 1-4 alkyl group;
  • R is independently selected from -OR 3 , -S(O) 2 C 1-6 alkyl, -C(O)OH, -C(O)NR 3 R 4 or is optionally selected from C 1-4 alkyl Or a 4-7 membered heterocyclic group substituted by an oxo substituent;
  • Ra and Re are each independently selected from halogen
  • R 3 and R 4 are each independently selected from H; alternatively, R 3 and R 4 on the same nitrogen atom optionally together with the nitrogen atom to which they are attached form a compound optionally containing another selected from N, O and S 4-7 membered heterocycle of heteroatoms.
  • the present invention further relates to the compound represented by the above-mentioned general formula (I), wherein the compound is selected from:
  • the compounds of the present invention have a significant inhibitory effect on the activity of Janus kinases, especially TYK2.
  • the compounds of the present invention can effectively inhibit the activity of TYK2, preferably with an IC 50 of 10 to 100 nM, more preferably with an IC 50 of less than 10 nM, and most preferably with an IC 50 of less than 1 nM.
  • the compounds of the present invention have a significant inhibitory effect on the physiological function of TYK2 in NK92 cells.
  • the drug can be in any pharmaceutical dosage form, including but not limited to tablets, capsules, solutions, freeze-dried preparations, and injections.
  • the pharmaceutical formulations of the present invention may be administered in dosage unit form containing a predetermined amount of active ingredient per dosage unit.
  • a unit may contain, for example, from 0.5 mg to 1 gram, preferably from 1 mg to 700 mg, particularly preferably from 5 mg to 300 mg, of a compound of the invention, depending on the condition to be treated, the method of administration and the age, weight and condition of the patient.
  • Preferred dosage unit formulations are those containing a daily dose or sub-dose, as indicated above, or a corresponding fraction thereof, of an active ingredient.
  • pharmaceutical formulations of this type can be prepared using methods well known in the pharmaceutical art.
  • the pharmaceutical formulations of the present invention may be suitable for administration by any desired suitable method, such as oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods of administration.
  • suitable method such as oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods of administration.
  • Such formulations can be prepared, for example, by combining the active ingredient with one or more excipients or one or more adjuvants, using all methods known in the art of pharmacy.
  • the present invention also provides methods for preparing the compounds.
  • the preparation of compounds of formula (I) of the present invention can be accomplished by the following illustrative methods and examples, which should not be construed in any way as limiting the scope of the invention.
  • the compounds of the present invention can also be synthesized by synthetic techniques known to those skilled in the art, or a combination of methods known in the art and methods of the present invention are used.
  • the products obtained in each step of the reaction are obtained by separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatographic separation, and the like.
  • the starting materials and chemical reagents required for the synthesis can be routinely synthesized or purchased according to literature (available from SciFinder).
  • the pyridazine compounds of the general formula (I) of the present invention can be synthesized according to the route described in Method A: 1) A2 is obtained by substitution reaction of the starting material A1 with a (hetero)aromatic amine containing a functional group; 2) A2 is reacted with phenylboronic acid or The boronate ester generates A3 through Suzuki coupling reaction; 3) The ester group of A3 is hydrolyzed to acid, then amidated (first converted to acid chloride and then coupled with ammonia or directly coupled with ammonia through a condensing agent) to obtain A4, or directly transaminated A4 is obtained; 4) The functional group of A4 can be further derivatized according to synthetic methods known in the art to obtain some target compounds.
  • Intermediate A3 can also be synthesized according to the route described in method B: A1 is firstly reacted with phenylboronic acid or boronic acid ester through Suzuki coupling reaction to form B2, and then Buchwald coupling reaction is carried out with (hetero)aromatic amine containing functional groups to form A3.
  • Intermediate A3 can also be synthesized according to the route described in method C: 1) the starting material A1 is first substituted with benzylamine to obtain C2; 2) C2 and phenylboronic acid or boronic acid ester are subjected to Suzuki coupling reaction to generate C3; 3) C3 Debenzylation in acid gives C4; 4) C4 undergoes substitution reaction or Buchwald coupling reaction to give A3.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the MS was measured using an Agilent SQD (ESI) mass spectrometer (manufacturer: Agilent, model: 6120).
  • ESI Agilent SQD
  • the thin layer chromatography silica gel plate uses Qingdao Ocean GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15 ⁇ 0.2mm, and the size of the thin layer chromatography separation and purification products is 0.4 ⁇ 0.5mm silica gel plate .
  • the known starting materials of the present invention can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Beijing Coupling Chemicals, etc.
  • the reactions were carried out in an argon atmosphere or a nitrogen atmosphere.
  • Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • the microwave reaction used a CEM Discover-SP type microwave reactor.
  • reaction temperature is room temperature, and the temperature range is 20°C-30°C.
  • the reaction progress in the examples was monitored using an Agilent LC/MS instrument (1260/6120).
  • the monitoring of the reaction progress can also be performed by thin-layer chromatography (TLC).
  • the systems used as developing solvents include A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system.
  • the volume ratio of the solvent is based on the polarity of the compound. adjust differently.
  • the eluent system for column chromatography and the developing solvent system for thin layer chromatography used to purify the compound include A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system, and the volume ratio of the solvent is based on the compound It can be adjusted according to different polarities. It can also be adjusted by adding a small amount of triethylamine and acidic or basic reagents, or by using other solvent systems.
  • Compounds were also purified using Waters' mass spectrometry-guided automated preparation system (mass detector: SQD2) with appropriate acetonitrile/water (containing 0.1% trifluoroacetic acid or formic acid) or acetonitrile/water (containing 0.05% ammonia water) according to the polarity of the compound
  • a reverse phase high pressure column (XBridge-C18, 19 x 150 mm, 5 ⁇ m) was eluted with a gradient at a flow rate of 20 mL/min.
  • Example 2 Example 3, Example 4, Example 5, Example 6, Example 7
  • Example 2 Example 3
  • Example 4 Example 5
  • Example 6 Example 7
  • different amines are used instead of 4 -Ethoxyaniline, as follows:
  • the target product was synthesized by referring to the steps in the second to fourth steps in Example 1, but using 6-chloro-4-((4-(methylsulfonyl)phenyl)amino)pyridazine-3 in the second step - Methyl carboxylate 8a in place of methyl 6-chloro-4-((4-ethoxyphenyl)amino)pyridazine-3-carboxylate 1b.
  • Example 9 was synthesized following the synthesis procedure of Example 8, but using 4-cyanoaniline instead of 4-methanesulfonylaniline in the first step.
  • the target product was synthesized by referring to the steps in the second to fourth steps in Example 1, but using 4-((4-(tert-butoxycarbonyl)phenyl)amino)-6-chloropyridine in the second step Methyl oxazine-3-carboxylate 10a replaces methyl 6-chloro-4-((4-ethoxyphenyl)amino)pyridazine-3-carboxylate 1b.
  • Example 21 Example 21, Example 23, Example 24, Example 25, Example 27, Example 28, Example 29, Example 30
  • Example 21 Example 21, Example 23, Example 24, Example 25, Example 27, Example 28, Example 29, Example 30
  • tetrahydro-2H-pyran-4-amine 22a was replaced with a different amine, as shown in the following table:
  • Example 37 Example 40, Example 47, Example 48, Example 66, Example 76, Example 80, Example 81, Example 82, Example 83, Example 84, Example 88, Example 90, Example 94
  • Example 37 Example 40, Example 47, Example 48, Example 66, Example 76, Example 80, Example 81, Example 82, Example 83, Example 84, Example 88, Example 90, Example 94
  • Example 37 Example 40, Example 47, Example 48, Example 66, Example 76, Example 80, Example 81, Example 82, Example 83, Example 84, Example 88, Example 90, Example 94
  • Example 39 Example 39, Example 43, Example 44, Example 71, Example 78
  • Example 78 Example 71, Example 78
  • different halides were used to replace 4-(6 -chloropyridin-3-yl)morpholine, as follows:
  • Example 50 Example 50
  • Example 51 Example 51
  • Characterization data are shown in the following table:
  • Example 53 Example 53
  • Example 54 Example 54
  • Characterization data are shown in the following table:
  • Example 57 Example 58, Example 59, Example 60
  • Example 57 Example 58, Example 59, Example 60
  • Example 57 Example 57, Example 58, Example 59, Example 60
  • Characterization data are shown in the following table:
  • Example 63 Example 63, Example 64, Example 65
  • Example 63 Example 63, Example 64, Example 65
  • Example 63 Example 63, Example 64, Example 65
  • Example 63, Example 64, Example 65 different fatty amines are used instead of 1-methylpiperazine. Characterization data are shown in the following table:
  • N,N-diphenylmethyl-4-bromoaniline 69b (3g, 8.5mmol) was dissolved in anhydrous tetrahydrofuran (3g, 8.5mmol), cooled to -78°C after deoxygenation, and added with n-butyllithium in hexane. alkane solution (2.4M, 4.6 mL, 11 mmol). After stirring at this temperature for 1 hour, oxetan-3-one (795 mg, 11 mmol) was added.
  • the compound 4-(6-(3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)aminopyridin-3-yl)-3-oxopiperazine-1- The tert-butyl carboxylate 70d (350 mg, 0.66 mmol) was mixed with a solution of hydrogen chloride in 1,4-dioxane (2M, 10 mL), stirred for 1 hour, and then the solvent was removed under reduced pressure to give the target product 6-(2,6 -Difluorophenyl)-4-((5-(2-oxopiperazin-1-yl)pyridin-2-yl)amino)pyridazine-3-carboxamide 70e (250 mg, yellow solid), yield : 89%.

Abstract

La présente invention concerne un composé de pyridazine-3-formamide approprié pour inhiber ou réguler la Janus kinase (JAK), en particulier la tyrosine kinase 2 (TYK2), son procédé de préparation et son utilisation médicale. En particulier, la présente invention concerne un composé tel que représenté par la formule générale (I) et un sel pharmaceutiquement acceptable de celui-ci ; une composition pharmaceutique contenant le composé ou un sel pharmaceutiquement acceptable de celui-ci ; une méthode de traitement et/ou de prévention de maladies associées à médiation par la Janus kinase, en particulier des maladies auto-immunes, des maladies inflammatoires et des cancers, à l'aide du composé ou d'un sel pharmaceutiquement acceptable de celui-ci et un procédé de préparation du composé ou du sel pharmaceutiquement acceptable de celui-ci. Chaque substituant dans la formule générale (I) a la même définition que celle donnée dans la description.
PCT/CN2020/108468 2020-08-11 2020-08-11 Composé de pyridazine-3-formamide, son procédé de préparation et son utilisation médicale WO2022032484A1 (fr)

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