WO2022032484A1 - Pyridazine-3-formamide compound, and preparation method therefor and medical use thereof - Google Patents

Pyridazine-3-formamide compound, and preparation method therefor and medical use thereof 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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PCT/CN2020/108468
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Chinese (zh)
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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/en
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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%.

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Abstract

Disclosed in the present invention are a pyridazine-3-formamide compound suitable for inhibiting or regulating the Janus kinase (JAK), in particular tyrosine kinase 2 (TYK2), and a preparation method therefor and the medical use thereof. In particular, disclosed in the present invention are a compound as represented by general formula (I) and a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound or the pharmaceutically acceptable salt thereof, a method for treating and/or preventing Janus kinase-mediated related diseases, in particular autoimmune diseases, inflammatory diseases and cancers, by means of using the compound or the pharmaceutically acceptable salt thereof, and a method for preparing the compound or the pharmaceutically acceptable salt thereof. Each substituent of general formula (I) has the same definition as that in the description.

Description

哒嗪-3-甲酰胺类化合物、其制备方法及其在医药学上的应用Pyridazine-3-carboxamide compound, its preparation method and its application in medicine 技术领域technical field
本发明涉及一种新的调控或抑制Janus激酶(JAK)、尤其是酪氨酸激酶2(TYK2)的活性的哒嗪-3-甲酰胺类化合物或其可药用的盐、含有所述化合物或其可药用的盐的药物组合物、所述化合物或其可药用的盐的制备方法以及所述化合物或其可药用的盐或含有所述化合物或其可药用的盐的药物组合物在制备用于治疗和/或预防由该激酶介导的相关性病症、特别是自身免疫性疾病、炎性疾病和癌症的药物中的用途和其使用方法。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.
背景技术Background technique
Janus激酶(JAK)是一种非受体酪氨酸蛋白激酶，由四个家族成员，即，JAK1、JAK2、JAK3和TYK2所组成。JAK在结构上有7个同源结构域(JAK Homology Domain,JH)，其中JH1结构域为激酶区，JH2结构域为伪激酶区(对JH1的活性起调节作用)，JH6和JH7是受体结合区域。当细胞因子受体(Cytokine Receptor)的细胞表面区域与细胞因子(Cytokine)结合，引起与之细胞内区域相结合的JAK被磷酸化，从而为信号转导和转录激活因子(STAT)蛋白创建停泊位点。STAT蛋白进一步被激活的JAK磷酸化，形成二聚体，进入细胞核，调控相关基因的表达和转录，实现信号从细胞膜至细胞核的转导(Lionard et.al,Ann.Rev.Immunol.1998,16,293-322)。因此，JAK通过JAK-STAT通路转导细胞因子介导的信号，在细胞因子依赖性调节的细胞增殖、分化、凋亡以及免疫反应等许多细胞功能中起重要作用，是治疗炎性疾病、自身免疫性疾病和癌症的热门靶点之一(Alicea-Velazquez et.al,Curr.Drug Targets 2011,12,546-55)。辉瑞公司的pan-JAK抑制剂托法替尼(Tofacitinib)于2012年被批准用于治疗类风湿性关节炎；美国Incyte公司开发的JAK1/JAK2抑制剂鲁索替尼(Ruxolitinib)于2011年被批准用于治疗骨髓纤维化。Janus kinase (JAK) 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. 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 (Lionard et.al, Ann.Rev.Immunol.1998,16,293 -322). Therefore, 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.
基因敲除研究显示JAKs和STATs对不同免疫应答的控制起高度的特异作用。一种JAK激酶可以参与多种细胞因子的信号转导过程，一种细胞因子的信号通路也可以激活多个JAK激酶，但细胞因子对激活的STAT蛋白却具有一定的选择性，例如白细胞介素(IL)-4激活STAT6、IL-12却特异性激活STAT4。JAK1、JAK2、TYK2广泛存在于各种组织和细胞中，JAK1与IL-6、干扰素(IFN)等炎症因子的激活密切相关，因此JAK1选择性抑制剂被认为对治疗类风湿性关节炎(RA)、银屑病等自身免疫性疾病具有潜在的治疗效果；JAK2可单独介导红细胞生成 素(EPO)和血小板生成素(TPO)等细胞因子(Won et.al,BMC Bioinformatics 2009,10,S53)，与血液细胞的增殖分化密切相关。JAK3仅存在于骨髓和淋巴系统，介导IL-2、IL-4、IL-7、IL-9、IL-15和IL-21的信号传导，这些细胞因子对诱导T细胞的增殖分化、激活B细胞产生抗体、活化巨噬细胞、增强自然杀伤细胞(NK细胞)的活性和IFN等其他细胞因子的诱导具有重要作用。因此，JAK3选择性抑制剂有望对器官移植、自身免疫性疾病、炎性肺炎等治疗具有重要作用。Gene knockout studies have shown that 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. 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. 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.
JAK/STAT通路可被自分泌和旁分泌细胞因子，以及一些突变过度激活，而与多种恶性肿瘤相关，例如乳腺癌、肝癌、前列腺癌、结肠癌、肺癌、胰腺癌、膀胱癌和弥漫性大B细胞淋巴瘤等(Tan et.al,Curr.Drug Targets 2014,15,1341-53；Lam et.al,Blood 2008,111,3701-13)。JAK2的突变体JAK2/V617F发生在假性的JH2伪激酶区域，引起JAK2构象改变，造成了不依赖胞外细胞因子信号的JH1激酶区域的持续激活，进而引起细胞增生和血液癌症，与真性红血球增多症(Polycythaemia Vera,PV)、原发性血小板增多症(Essential Thrombocythemia)和骨髓纤维化(Myelofibrosis,MF)密切相关(O’Shea et.al,Ann.Rev.Med.2015,66,311-28)。JAK2抑制剂鲁索利替尼(Ruxolitinib)可以用于这类血液疾病的治疗，但疗效与是否存在JAK2/V617F突变无关，表明抗肿瘤活性并不单是基于抑制JAK2/V617F参与的信号传递，还可能来自对JAK1-STAT的调控。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). The JAK2 mutant, 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 Polycythaemia Vera (PV), Essential Thrombocythemia (Essential Thrombocythemia) and Myelofibrosis (MF) are closely related (O'Shea et.al, Ann.Rev.Med.2015,66,311-28) . 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涉及炎症细胞因子如干扰素(IFNs)、IL-12和IL-23等的信号转导，在先天免疫和适应性免疫中发挥着关键作用。TYK2剔除小鼠的红细胞数正常，能够存活。但JAK3缺陷的小鼠有严重的免疫缺陷，JAK1或JAK2剔除的小鼠会胚胎致死，但在人体中尚未发现JAK1/2功能缺失相关的疾病，也许间接表明了JAK1/2生理功能的重要性。1例具有TYK2基因无效突变的病人患有高免疫球蛋白E综合征，但是其他七例TYK2同型结合的无效突变并没有高免疫球蛋白E综合征，而是由于对IL-12和INF-α/β的反应减弱增加了对分枝细菌或病毒感染的敏感度。所以，抑制TYK2并不会引起急性毒性。TYK2表达的缺乏体现在多种促炎细胞因子的减弱的信号传递和T辅助细胞分化的严重的不平衡。此外，来自遗传相关研究的证据支持了TYK2是一种共有的自身免疫性疾病易感基因。TYK2调控的通道在疾病治疗上也被抗体疗法进一步证实，例如用于治疗牛皮癣的靶向IL-12/IL-23的优特克单抗(ustekinumab)和针对系统性红斑狼疮在临床试验中有明显疗效的靶向于I型干扰素受体的Anifrolumab。因此TYK2作为自身免疫性疾病的靶点也得到了极大的关注，比如TYK2抑制剂用于治疗牛皮癣、系统性红斑狼疮(SLE)和炎性肠疾病(IBD)等。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. However, 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. . 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 /β 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. Anifrolumab targeting the type I interferon receptor with significant efficacy. Therefore, TYK2 has also received great attention as a target for autoimmune diseases, such as TYK2 inhibitors for the treatment of psoriasis, systemic lupus erythematosus (SLE) and inflammatory bowel disease (IBD).
TYK2还与一些癌症相关，比如急性淋巴细胞性白血病(T-ALL)细胞的异常生存与TYK2的激活相关。基因敲除实验显示出88％T-ALL 细胞系和63％来自病人的T-ALL细胞对TYK2有依赖性，因此，TYK2是T-ALL的致癌基因(Sanda et.al,Cancer Disc.2013,3,564-77)。TYK2选择性抑制剂NDI-031301能够诱导细胞凋亡来抑制人类T-ALL细胞系的生长，在带有KOPT-K1 T-ALL肿瘤细胞的小鼠模型上也有很好的安全性和疗效(Akahane et.al,British J.Haematol.2017,177,271-82)，显示出TYK2选择性抑制剂在治疗T-ALL方面的前景。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. 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.
目前市场上已有几个针对JAK1/2/3的抑制剂药物例如托法替尼(Tofacitinib)、巴瑞克替尼(Baricitinib)和鲁索利替尼(Ruxolitinib)，还有众多在临床上试验的药物例如乌帕替尼(Upadacitinib)、Filgotinib、Peficitinib等，但目前只有一个TYK2特异性抑制剂BMS-986165报道进入临床试验。由于JAK在JAK-STAT中调控不同的免疫应答，不同JAK激酶选择性的抑制剂具有不同的潜在用途和毒副作用。鲁索利替尼(Ruxolitinib)用于治疗骨髓纤维化，具有良好的安全性，对非靶器官无毒副作用。然而托法替尼(Tofacitinib)由于其抑制JAK2的活性，影响血细胞和淋巴细胞的生成，具有一定的毒副作用，限制了该药在RA临床上的用量。因此开发比JAK2更好选择性的TYK2特异性抑制剂，从而避免由于抑制JAK2的活性而引起的贫血副作用(Vincenti et.al,Am.J.Transplant.2012,12,2446-56；Ghoreschi et.al,Nature Immunol.2009,4,356-360)吸引了制药公司的极大关注。可是由于JAK激酶家族的活性部位的高度序列相似性，研发一个高选择性的TYK2抑制剂是相当困难的。尽管目前已公开了一些TYK2选择性抑制剂的专利申请，其中包括WO2010142752、WO2012062704、WO2013180265、WO2015032423、WO2015131080和WO2017040757等等，基于TYK2特异性抑制剂在治疗炎性疾病、自身免疫性疾病和癌症等所展示的前景，仍需开发新的化合物，其具有更好成药性，更强的药效及更高的TYK2激酶选择性。经过不断努力，本发明设计具有通式(I)所示的结构的化合物，并发现具有此类结构的化合物表现出优异的效果和作用。At present, there are several JAK1/2/3 inhibitor drugs on the market 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. Since JAKs regulate different immune responses in JAK-STAT, different JAK kinase-selective inhibitors have different potential uses and toxic side effects. Ruxolitinib is used for the treatment of myelofibrosis with good safety and no toxic and side effects on non-target organs. However, 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. Although some patent applications for TYK2 selective inhibitors have been published, including 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. Through continuous efforts, 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.
发明内容SUMMARY OF THE INVENTION
本发明提供作为Janus激酶、尤其是TYK2抑制剂的一种通式(I)所示的化合物、其前药、稳定同位素衍生物、可药用的盐、异构体及其混合物形式：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:
Figure PCTCN2020108468-appb-000001
Figure PCTCN2020108468-appb-000001
其中：in:
Z为N或CR 1； Z is N or CR 1 ;
环A为任选取代的C 6-10芳环或5-10元杂芳环； Ring A is an optionally substituted C 6-10 aromatic ring or a 5-10 membered heteroaromatic ring;
L为键或任选取代的C 1-6亚烷基，其中所述亚烷基中的一个或多个-CH 2-任选被选自-N(R 2)-、-N(R 2)C(O)-、-C(O)N(R 2)-、-N(R 2)S(O) 2-、-S(O) 2N(R 2)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-和-S(O) m-的基团所代替； 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选自H、卤素、氰基、-SF 5、-OR 3、-SR 3、-NR 3R 4、-S(O) mR 3、-S(O) 2NR 3R 4、-C(O)R 3、-C(O)OR 3、-C(O)NR 3R 4、-C(O)N(R 3)OR 4、-OC(O)R 3、-OC(O)NR 3R 4、-N(R 3)C(O)OR 4、-N(R 3)C(O)R 4、-N(R 2)C(O)NR 3R 4、-C(O)N(R 3)S(O) 2R 4、-N(R 3)S(O) 2R 4，或任选取代的C 1- 6烷基、C 3-7环烷基、4-7元杂环基、苯基或5-6元杂芳基； 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)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, C 3-7 cycloalkyl , 4- 7-membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
R a、R b、R c、R d和R e各自独立地选自H、卤素、氰基、-SF 5、-OR 3、-S(O) mR 3、-S(O) 2NR 3R 4、-C(O)NR 3R 4，或任选取代的C 1-6烷基、C 3-7环烷基、4-7元杂环基、苯基或5-6元杂芳基； 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选自H、卤素、氰基或任选取代的C 1-6烷基； R 1 is selected from H, halogen, cyano or optionally substituted C 1-6 alkyl;
R 2、R 3和R 4各自独立地选自H或任选取代的C 1-6烷基、C 3-7环烷基、4-7元杂环基、苯基或5-6元杂芳基；或者，在同一个氮原子上的R 3和R 4任选与它们连接的氮原子共同形成一任选含有另外的杂原子的4-7元杂环；所述杂环任选被取代； 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;
且m为1或2。and m is 1 or 2.
本发明进一步涉及一种药物组合物，所述药物组合物包含通式(I)所示的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物和药学上可接受的载体和赋形剂。The present invention further relates to 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.
本发明的另一方面涉及通式(I)所示的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物、或所述药物组合物在制备药物中的用途，其中所述药物用于治疗或者预防TYK2介导的疾病，所述疾病包括但不限于自身免疫性疾病、包括肠炎症在内的炎性疾病、癌症、皮肤疾病、糖尿病、眼病、神经退行性疾病、过敏反应、哮喘和其他阻塞性气道疾病、移植排斥等。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.
本发明的再一方面提供一种治疗或者预防TYK2介导的疾病的方法，所述方法包括给予有需要的患者治疗有效量的通式(I)所示的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物、或包含所述化合物的药物组合物，所述疾病包括但不限于自身免疫性疾病、包括肠炎症在内的炎性疾病、癌症、皮肤疾病、糖尿病、眼病、神经退行性疾病、过敏反应、哮喘和其他阻塞性气道疾病、移植排斥等。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.
本发明的再一方面涉及通式(I)所示的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物，其用于治疗或者预防TYK2介导的疾病，所述疾病包括但不限于自身免疫性疾病、包括肠炎症在内 的炎性疾病、肿瘤、皮肤疾病、糖尿病、眼病、神经退行性疾病、过敏反应、哮喘和其他阻塞性气道疾病、移植排斥等。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.
具体实施方式detailed description
定义definition
除非另有相反陈述，否则下列用在说明书和权利要求书中的术语具有下述含义。Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.
在本文中使用的表示方式“C x-y”表示碳原子数的范围，其中x和y均为整数，例如C 3-8环烷基表示具有3-8个碳原子的环烷基，即具有3、4、5、6、7或8个碳原子的环烷基。还应理解，“C 3-8”还包含其中的任意亚范围，例如C 3-7、C 3-6、C 4-7、C 4-6、C 5-6等。 The notation "C xy " as used herein 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.
“烷基”指含有1至20个碳原子，例如1至8个碳原子、1至6个碳原子或1至4个碳原子的饱和的直链或支链的烃基基团。烷基的非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基等。所述烷基可以是任选取代的。"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. Non-limiting examples of 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. The alkyl group may be optionally substituted.
“亚烷基”指含有1至20个碳原子，例如1至6个碳原子或1至4个碳原子的直链或支链的饱和烃的二价基团。亚烷基的非限制性实例包括-CH 2-、-CH(CH 3)-、-CH 2CH 2-、-CH 2CH 2CH 2-、-(CH 3)C(CH 3)-、-CH 2CH 2CH 2CH 2-、-CH 2CH(CH 3)CH 2-等。所述亚烷基可以是任选取代的。 "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. Non-limiting examples of alkylene groups include -CH2- , -CH( CH3 )-, -CH2CH2- , -CH2CH2CH2- , - ( CH3 ) C( CH3 ) -, -CH2CH2CH2CH2- , -CH2CH ( CH3 ) CH2- , etc. The alkylene group may be optionally substituted.
“环烷基”指含有3至14个碳环原子的饱和环状烃基取代基。环烷基可以是单碳环，通常含有3至8个、3至7个或3至6个碳环原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环己基、环庚基等。环烷基可选择地可以是稠合到一起的双或三环，如十氢萘基。所述环烷基可以是任选取代的。"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.
“杂环基或杂环”指饱和或部分不饱和的单环或多环环状基团，其包括3至20个环原子，例如可以是3至14个、3至12个、3至10个、3至8个、3至6个或5至6个环原子，其中一个或多个环原子选自氮、氧或S(O) m(其中m是整数0至2)，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包括3至12个环原子，更优选3至10个环原子，更优选4至7个环原子，更优选4至6个环原子，最优选5或6个环原子，其中1～4个是杂原子，更优选1～3个是杂原子，最优选1～2个是杂原子。单环杂环基的非限制性实例包含吡咯烷基、噁丁环基、哌啶基、哌嗪基、四氢呋喃基、四氢吡喃基、四氢噻喃基、吗啉基、硫代吗啉基、高哌嗪基、吖丁啶基等。多环杂环基包括稠合、桥接或螺多环杂环基，如八氢环戊二烯并[c]吡咯、八氢吡咯并[1,2-a]吡嗪、3,8-二氮杂二环[3.2.1]辛烷、5-氮杂螺[2.4]庚烷、2-氧杂-7-氮杂螺[3.5]壬烷等。 所述杂环基或杂环可以是任选取代的。 "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.
“芳基或芳环”指含有6至14个碳原子的芳香族单环或稠合多环基团，优选为6至10元，例如苯基和萘基，最优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，非限制性实例包括："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:
Figure PCTCN2020108468-appb-000002
Figure PCTCN2020108468-appb-000003
等。
Figure PCTCN2020108468-appb-000002
Figure PCTCN2020108468-appb-000003
Wait.
所述芳基或芳环可以是任选取代的。The aryl group or aromatic ring may be optionally substituted.
“杂芳基或杂芳环”指包含5至14个环原子的杂芳族体系，其中1至4个环原子选自包括氧、硫和氮的杂原子。杂芳基优选为5至10元，更优选杂芳基是5元或6元，例如呋喃基、噻吩基、吡啶基、吡咯基、嘧啶基、吡嗪基、吡唑基、咪唑基、四唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、喹啉基、异喹啉基、吲哚基、异吲哚基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，非限制性实例包括："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 ring, non-limiting examples include:
Figure PCTCN2020108468-appb-000004
Figure PCTCN2020108468-appb-000005
等。
Figure PCTCN2020108468-appb-000004
Figure PCTCN2020108468-appb-000005
Wait.
所述杂芳基或杂芳环可以是任选取代的。The heteroaryl or heteroaryl ring may be optionally substituted.
“卤素”指氟、氯、溴或碘。"Halogen" refers to fluorine, chlorine, bromine or iodine.
“氰基”指-CN。"Cyano" refers to -CN.
“氧代”指＝O。"Oxo" refers to =O.
“羰基”指-C(＝O)-基团。"Carbonyl" refers to a -C(=O)- group.
“磺酰基”指-S(O) 2-基团。 "Sulfonyl" refers to the -S(O) 2- group.
“亚硫酰基”指-S(O)-基团。"Sulfinyl" refers to the -S(O)- group.
“任选”意味着随后所描述的事件或环境可以但不必发生，该表述包括该事件或环境发生或不发生的情形。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该表述包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"Optional" means that the subsequently described event or circumstance can, but need not, occur, and that the expression includes instances where the event or circumstance does or does not occur. For example, "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 .
“任选取代”指基团中的一个或多个氢原子，优选为5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。所述取代基包括但不限于卤素、氰基、硝基、氧代、- SF 5、C 1-4烷基、C 3-7环烷基、4-7元杂环基、苯基、5-6元杂芳基、-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)NR′R″、-N(R′)S(O) 2R″、-S(O) mR′(m为1或2)、-S(O) 2NR′R″等，其中所述烷基、环烷基、杂环基、苯基或杂芳基任选被一个或多个选自卤素、氰基、C 1- 4烷基、C 3-7环烷基、4-7元杂环基、苯基、5-6元杂芳基、-OR′、-NR′R″、-C(O)R′、-C(O)OR′、-C(O)NR′R″、-OC(O)NR′R″、-N(R′)C(O)OR″、-N(R′)C(O)R″、-N(R′″)C(O)NR′R″、-N(R′)S(O) 2R″、-S(O) 2R′、-S(O) 2NR′R″的取代基所取代；R′、R″和R′″各自独立地选自H、任选含有选自N、O和S的杂原子的C 1-4烷基、C 3-7环烷基、4-7元杂环基、苯基或5-6元杂芳基，其中所述烷基、环烷基、杂环基、苯基或杂芳基任选被一个或多个选自卤素、氰基、C 1-4烷基、卤代C 1-4烷基、-O-C 1-4烷基的取代基所取代；在同一个氮原子上的R′和R″任选与它们连接的氮原子共同形成一任选含有另外的选自O、S和N的杂原子的4-7元杂环。 "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)NR'R", -N(R')S(O) 2 R", -S(O) m R'(m is 1 or 2), -S(O ) 2 NR'R", etc., wherein the alkyl, cycloalkyl, heterocyclyl, phenyl or heteroaryl is optionally selected from one or more halogens, cyano, 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", -OC(O)NR'R", -N(R')C(O)OR", -N(R')C(O)R", -N Substituents of (R'")C(O)NR'R", -N(R')S(O) 2 R", -S(O) 2 R', -S(O) 2 NR'R"substituted;R',R" and R'" are each independently selected from H, C 1-4 alkyl optionally containing heteroatoms selected from N, O and S, C 3-7 cycloalkyl, 4- 7-membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, phenyl or heteroaryl is optionally selected from one or more of halogen, cyano , C 1-4 alkyl, halogenated C 1-4 alkyl, -OC 1-4 alkyl substituents; R' and R" on the same nitrogen atom are optionally connected to the nitrogen atom to which they are attached Together they form a 4-7 membered heterocycle optionally containing additional heteroatoms selected from O, S and N.
“异构体”指具有相同分子式但其原子结合的性质或顺序或其原子的空间排列不同的化合物。原子空间排列不同的异构体称为“立体异构体”。立体异构体包括光学异构体、几何异构体和构象异构体。"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.
本发明的化合物可以以光学异构体形式存在。根据手性碳原子周围取代基的构型，这些光学异构体是“R”或“S”构型。光学异构体包括对映异构体和非对映异构体。制备和分离光学异构体的方法是本领域中已知的。The compounds of the present invention 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.
本发明的化合物也可以存在几何异构体。本发明考虑由碳-碳双键、碳-氮双键、环烷基或杂环基团周围的取代基的分布所产生的各种几何异构体和其混合物。碳-碳双键或碳-氮键周围的取代基指定为Z或E构型，环烷基或杂环周围的取代基指定为顺式或反式构型。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.
本发明的化合物还可能显示互变异构现象，例如酮-烯醇互变异构。The compounds of the present invention may also exhibit tautomerism, such as keto-enol tautomerism.
应该理解，本发明包括任何互变异构或立体异构形式和其混合物，并且不仅仅限于化合物的命名或化学结构式中所使用的任何一个互变异构或立体异构形式。It should be understood that 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.
“同位素”包括在本发明化合物中出现的原子的所有同位素。同位素包括具有相同原子序数但不同质量数的那些原子。适合并入本发明化合物中的同位素的实例是氢、碳、氮、氧、磷、氟和氯，分别例如但不限于 2H(D)、 3H、 13C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。本发明的同位素标记化合物通常可通过本领域技术人员已知的传统技术或通过与所附实施例中描述的那些类似的方法使用适当的同位素标记的试剂代替非同位素标记的试剂来制备。这样的化合物具有各种潜在用途，例如作为测定生物活性中的标样和试剂。在稳定同位素的情况下，这样的化合物具有有利地改变生物、药理学或药代动力学性质的潜力。 "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.
本发明的化合物可以以前药的形式给予。“前药”是指在活体内的生理条件下例如通过氧化、还原、水解等(它们各自利用酶或在没有酶参与下进行)转化成本发明的生物活性化合物的衍生物。前药的实例是下述化合物：其中本发明的化合物中的氨基被酰化、烷基化或磷酸化，例如二十烷酰基氨基、丙氨酰氨基、新戊酰氧基甲基氨基，或其中羟基被酰化、烷基化、磷酸化或转化成硼酸盐，例如乙酰氧基、棕榈酰氧基、新戊酰氧基、琥珀酰氧基、富马酰氧基、丙氨酰氧基，或其中羧基被酯化或酰胺化，或其中巯基与选择性地向靶和/或向细胞的胞质溶胶递送药物的载体分子，例如肽形成二硫桥键。这些化合物可以由本发明的化合物根据公知方法制备。The compounds of the present invention can be administered in the form of prodrugs. "Prodrug" 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. Examples of 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. acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy group, or in which the carboxyl group is esterified or amidated, or in which the sulfhydryl group forms a disulfide bridge with a carrier molecule, such as a peptide, that selectively delivers the drug to the target and/or to the cytosol of the cell. These compounds can be prepared from the compounds of the present invention according to known methods.
“可药用的盐”或者“药学上可接受的盐”是指由可药用的碱或酸，包括无机碱或酸和有机碱或酸制成的盐。在本发明的化合物含有一个或多个酸性或碱性基团的情况下，本发明还包含它们相应的可药用盐。因此，含有酸性基团的本发明的化合物可以以盐形式存在并可根据本发明使用，例如作为碱金属盐、碱土金属盐或作为铵盐。这样的盐的更确切实例包括钠盐、钾盐、钙盐、镁盐或与氨或有机胺，例如乙胺、乙醇胺、三乙醇胺或氨基酸的盐。含有碱性基团的本发明的化合物可以以盐形式存在并可根据本发明以它们与无机或有机酸的加成盐的形式使用。合适的酸的实例包括盐酸、氢溴酸、磷酸、硫酸、硝酸、甲磺酸、对甲苯磺酸、萘二磺酸、草酸、乙酸、酒石酸、乳酸、水杨酸、苯甲酸、甲酸、丙酸、特戊酸、丙二酸、琥珀酸、庚二酸、富马酸、马来酸、苹果酸、氨基磺酸、苯基丙酸、葡糖酸、抗坏血酸、异烟酸、柠檬酸、己二酸和本领域技术人员已知的其它酸。如果本发明的化合物在分子中同时含有酸性和碱性基团，本发明除所提到的盐形式外还包括内盐或内铵盐。各盐可通过本领域技术人员已知的常规方法获得，例如通过在溶剂或分散剂中使这些与有机或无机酸或碱接触或通过与其它盐阴离子交换或阳离子交换。"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. Examples of 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. If the compounds of the present invention contain both acidic and basic groups in the molecule, 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.
“药物组合物”指含有一种或多种本文所述的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式以及其他组分例如可药用的载体和赋形剂的组合物。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。"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.
因此，在本申请中当提及“化合物”、“本发明化合物”或“本发明所述化合物”时，包括所有所述化合物形式，例如其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物。Thus, when referring to a "compound", "a compound of the present invention" or "a compound of the present invention" in this application, all such compound forms, such as pharmaceutically acceptable salts, prodrugs, stable isotope derivatives thereof, are included , isomers and mixtures thereof.
在本文中，术语“自身免疫性疾病或炎性疾病”包括但不限于关节炎、桥本氏甲状腺炎、自身免疫性溶血性贫血、恶性贫血的自身免疫性萎缩性胃炎、自身免疫性脑脊髓炎、自身免疫性睾丸炎、古德帕斯丘病、自身免疫性血小板减少症、交感性眼炎、重症肌无力、格雷夫斯病、原发性胆汁性肝硬化、肝炎、原发性硬化性胆管炎、慢性侵袭性肝炎、非 酒精性脂肪性肝病、非酒精性脂肪性肝炎、溃疡性结肠炎、膜性肾小球病、系统性红斑狼疮、类风湿性关节炎、牛皮癣性关节炎、干燥综合征、赖特综合征、多肌炎、皮肌炎、I-型干扰素病包括Aicardi-Goutières综合征和其他过度表达I-型干扰素的系统性硬化症、孟德尔疾病、结节性多动脉炎、多发性硬化症、复发缓解型多发性硬化症、原发性进行性多发性硬化症、继发性进展性多发性硬化症、大疱性类天疱疮；另外基于O-细胞(体液)或T-细胞的自身免疫性疾病，包括科根综合征、强直性脊柱炎、韦格纳肉芽肿病、自身免疫性脱发、I-型或青少年型糖尿病、甲状腺炎。As used herein, the term "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-Goutières syndrome and other systemic sclerosis that overexpress type I interferon, Mendelian disease, Polyarteritis nodosa, multiple sclerosis, relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis, secondary progressive multiple sclerosis, bullous pemphigoid; additionally based on O - Cell (humoral) or T-cell autoimmune diseases, including Kogan's syndrome, ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, type I or juvenile diabetes, thyroiditis.
在本文中，术语“肠炎症”包括但不限于克罗恩氏病、溃疡性结肠炎、炎性肠病、乳糜泻、直肠炎、嗜酸性粒细胞胃肠炎、肥大细胞增多症。As used herein, the term "intestinal inflammation" includes, but is not limited to, Crohn's disease, ulcerative colitis, inflammatory bowel disease, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis.
在本文中，术语“癌症/肿瘤”包括但不限于消化道/胃肠道癌、结肠癌、肝癌、皮肤癌(包括肥大细胞瘤和鳞状细胞癌)、乳腺癌、卵巢癌、前列腺癌、淋巴瘤、白血病(包括急性骨髓性白血病和慢性髓细胞性白血病)、肾癌、肺癌、肌肉癌、骨癌、膀胱癌、脑癌、黑素瘤(包括口腔和转移性黑素瘤)、卡波西肉瘤(包括多发性骨髓瘤的骨髓瘤)、骨髓增殖性疾病、增殖性糖尿病视网膜病变、血管增生相关病症/肿瘤。As used herein, the term "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.
在本文中，术语“皮肤疾病”包括但不限于特应性皮炎、湿疹、牛皮癣、硬皮病、瘙痒症或其他瘙痒症状、白癜风、脱发。As used herein, the term "skin disease" includes, but is not limited to, atopic dermatitis, eczema, psoriasis, scleroderma, pruritus or other symptoms of itching, vitiligo, alopecia.
在本文中，术语“糖尿病”包括但不限于I-型糖尿病和糖尿病并发症。As used herein, the term "diabetes" includes, but is not limited to, Type I diabetes and diabetic complications.
在本文中，术语“眼病”包括但不限于角膜结膜炎、葡萄膜炎(包括与白塞病有关的葡萄膜炎和晶状体引起的葡萄膜炎)、角膜炎、疱疹性角膜炎、圆锥角膜炎、角膜上皮营养不良、角膜白细胞减少症、眼球前膜炎、Mooren's溃疡、巩膜炎、格雷夫斯眼病、Vogt-Koyanagi-Harada综合征、干燥性角膜结膜炎(干眼)、小水疱、虹膜睫状体炎、结节病、内分泌性眼病、交感性眼炎、过敏性结膜炎、眼部新生血管。As used herein, the term "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.
在本文中，术语“神经退行性疾病”包括但不限于运动神经元病、阿尔茨海默病、帕金森病、肌萎缩性侧索硬化症、亨廷顿病、脑缺血；由创伤、损伤、谷氨酸神经毒性或缺氧引起的神经变性疾病；在中风、心肌缺血、肾缺血、心脏病发作、心脏肥大、动脉粥样硬化和动脉硬化、器官缺氧或血小板聚集中的缺血/再灌注损伤。As used herein, the term "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.
在本文中，术语“过敏反应”包括但不限于哺乳动物过敏性皮炎(包括马过敏性疾病，如咬过敏症)、夏季湿疹、马蹄痒、痉挛、炎性气道疾病、气道反复阻塞、气道高反应性、慢性阻塞性肺病。As used herein, the term "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.
在本文中，术语“哮喘和其他阻塞性气道疾病”包括但不限于慢性或过度哮喘、迟发性哮喘、支气管炎、支气管哮喘、过敏性哮喘、内源性哮喘、外源性哮喘、尘埃性哮喘。As used herein, the term "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.
在本文中，术语“移植排斥”包括但不限于胰岛移植排斥、骨髓移植排斥、移植物抗宿主病、器官和细胞移植排斥(如骨髓、软骨、角膜、心脏、椎间盘、胰岛、肾、肢体、肝、肺、肌肉、成肌细胞、神经、胰腺、皮肤、小肠或气管)、异种移植。As used herein, the term "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.
在本文中，术语“治疗有效量”是指包括可有效抑制TYK2的功能和/或治疗或防止所述疾病的本发明化合物的量。As used herein, the term "therapeutically 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.
在本文中，术语“患者”是指哺乳动物，尤其是人类。As used herein, the term "patient" refers to mammals, especially humans.
化合物compound
本发明的一个方面是通式(I)所示的化合物、其前药、稳定同位素衍生物、可药用的盐、异构体及其混合物形式：One aspect of the present invention is a compound of formula (I), its prodrugs, stable isotope derivatives, pharmaceutically acceptable salts, isomers and mixtures thereof:
Figure PCTCN2020108468-appb-000006
Figure PCTCN2020108468-appb-000006
其中：in:
Z为N或CR 1； Z is N or CR 1 ;
环A为任选取代的C 6-10芳环或5-10元杂芳环； Ring A is an optionally substituted C 6-10 aromatic ring or a 5-10 membered heteroaromatic ring;
L为键或任选取代的C 1-6亚烷基，其中所述亚烷基中的一个或多个-CH 2-任选被选自-N(R 2)-、-N(R 2)C(O)-、-C(O)N(R 2)-、-N(R 2)S(O) 2-、-S(O) 2N(R 2)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-和-S(O) m-的基团所代替； 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选自H、卤素、氰基、-SF 5、-OR 3、-SR 3、-NR 3R 4、-S(O) mR 3、-S(O) 2NR 3R 4、-C(O)R 3、-C(O)OR 3、-C(O)NR 3R 4、-C(O)N(R 3)OR 4、-OC(O)R 3、-OC(O)NR 3R 4、-N(R 3)C(O)OR 4、-N(R 3)C(O)R 4、-N(R 2)C(O)NR 3R 4、-C(O)N(R 3)S(O) 2R 4、-N(R 3)S(O) 2R 4，或任选取代的C 1- 6烷基、C 3-7环烷基、4-7元杂环基、苯基或5-6元杂芳基； 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)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, C 3-7 cycloalkyl , 4- 7-membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
R a、R b、R c、R d和R e各自独立地选自H、卤素、氰基、-SF 5、-OR 3、-S(O) mR 3、-S(O) 2NR 3R 4、-C(O)NR 3R 4，或任选取代的C 1-6烷基、C 3-7环烷基、4-7元杂环基、苯基或5-6元杂芳基； 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选自H、卤素、氰基或任选取代的C 1-6烷基； R 1 is selected from H, halogen, cyano or optionally substituted C 1-6 alkyl;
R 2、R 3和R 4各自独立地选自H或任选取代的C 1-6烷基、C 3-7环烷基、4-7元杂环基、苯基或5-6元杂芳基；或者，在同一个氮原子上的R 3和R 4任选与它们连接的氮原子共同形成一任选含有另外的杂原子的4-7元杂环，所述杂环任选被取代； 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;
且m为1或2。and m is 1 or 2.
在一些实施方案中，Z为CH。In some embodiments, Z is CH.
在一些实施方案中，所述通式(I)化合物具有以下通式(II)：In some embodiments, the compound of general formula (I) has the following general formula (II):
Figure PCTCN2020108468-appb-000007
Figure PCTCN2020108468-appb-000007
其中：in:
环A为任选被一个或多个选自卤素、氰基、C 1-4烷基、C 1-4卤代烷基、氧代、-C(O)OR 3、-OC 1-4烷基、-OC 1-4卤代烷基和-SO 2C 1-4烷基的取代基取代的C 6-10芳环或5-10元杂芳环； 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为键或任选取代的C 1-6亚烷基，其中所述亚烷基中的一个或多个-CH 2-任选被选自-N(R 2)-、-O-和-C(O)-的基团所代替； 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选自H、卤素、氰基、-SF 5、-OR 3、-NR 3R 4、-S(O) 2R 3、-S(O)R 3、-S(O) 2NR 3R 4、-C(O)OR 3、-C(O)R 3、-C(O)NR 3R 4、-N(R 3)C(O)OR 4、-N(R 3)C(O)R 4、-C(O)N(R 3)S(O) 2R 4，或任选取代的C 1-6烷基、C 3-7环烷基、4-7元杂环基、苯基或5-6元杂芳基； 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;
R a和R e各自独立地选自卤素； Ra and Re are each independently selected from halogen;
R 2选自H或C 1-6烷基； R 2 is selected from H or C 1-6 alkyl;
R 3和R 4各自独立地选自H或任选取代的C 1-6烷基、C 3-7环烷基、4-7元杂环基、苯基或5-6元杂芳基；或者，在同一个氮原子上的R 3和R 4任选与它们连接的氮原子共同形成一任选含有另外的杂原子的4-7元杂环，所述杂环任选被取代。 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.
在另一些实施方案中，所述化合物为上述通式(II)的化合物、或其前药、稳定同位素衍生物、可药用的盐、异构体及其混合物形式，其中：In other embodiments, 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:
环A为任选被一个或两个选自卤素、氰基、C 1-4烷基、氧代、-C(O)OH、-OC 1-4烷基和-SO 2C 1-4烷基的取代基取代的C 6-10芳环或5-10元杂芳环； 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为键或任选被C 1-6烷基取代的C 1-6亚烷基或-O-C 1-4亚烷基； 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选自H、氰基、-SF 5、-OR 3、-S(O) 2R 3、-S(O)R 3、-S(O) 2NR 3R 4、-C(O)OR 3、-C(O)R 3、-C(O)NR 3R 4、-C(O)N(R 3)S(O) 2R 4、C 1-6烷基，或任选被选自-OH、C 1-4烷基、氧代、-O-C 1-4烷基、C 3-6环烷基和4-6元杂环基的取代基取代的C 3-7环烷基、4-7元杂环基、苯基或5-6元杂芳基； 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;
R a和R e各自独立地选自卤素； Ra and Re are each independently selected from halogen;
R 3和R 4各自独立地选自H或任选被选自卤素、-OH、氧代和C 1-4烷基的取代基取代的C 1-6烷基、C 3-7环烷基、4-7元杂环基、苯基或5-6元杂芳基；或者，在同一个氮原子上的R 3和R 4任选与它们连接的氮原子共同形成一任选含有另外的杂原子的4-7元杂环，所述杂环任选被选自-OH、C 1-4烷基、-O-C 1-4烷基、氧代、C 3-6环烷基或4-6元杂环基的取代基取代。 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.
在再一些实施方案中，所述化合物为上述通式(II)的化合物、或其前药、稳定同位素衍生物、可药用的盐、异构体及其混合物形式，其中：In still other embodiments, 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:
环A为任选被一个或两个选自卤素、C 1-4烷基、氧代、-COOH、-OC 1- 4烷基和-SO 2C 1-4烷基的取代基取代的C 6-10芳环或5-6元杂芳环； 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为键或任选被C 1-4烷基取代的C 1-6亚烷基或-O-C 1-4亚烷基； 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独立地选自H、氰基、-SF 5、-OR 3、-S(O) 2C 1-6烷基、-S(O)C 1-6烷基、-S(O) 2NR 3R 4、-C(O)OH、-C(O)NR 3R 4、-C(O)NHS(O) 2C 1-6烷基、C 1- 6烷基，任选被选自-OH、C 1-4烷基、氧代、-O-C 1-4烷基、C 3-6环烷基和4-6元杂环基的取代基取代的4-7元杂环基，或任选被C 1-4烷基取代的5-6元杂芳基； 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;
R a和R e各自独立地选自卤素； Ra and Re are each independently selected from halogen;
R 3和R 4各自独立地选自H，任选被卤素或-OH取代的C 1-6烷基，任选被-OH取代的C 3-7环烷基，或任选被氧代或C 1-4烷基取代的4-7元杂环基；或者，在同一个氮原子上的R 3和R 4任选与它们连接的氮原子共同形成一任选含有另外的选自N、O和S的杂原子的4-7元杂环，所述杂环任选被选自-OH、C 1-4烷基、-O-C 1-4烷基、氧代、C 3-6环烷基和4-6元杂环基的取代基取代。 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.
在一些实施方案中，环A为任选被卤素、氰基、C 1-4烷基、氧代、-C(O)OH、-OC 1-4烷基或-SO 2C 1-4烷基取代的苯环、吡啶环、嘧啶环、二氢吲哚环、异二氢吲哚环或吡唑环，优选为苯环和吡啶环。 In some embodiments, Ring A is optionally halogen, cyano, C1-4alkyl , oxo, -C (O)OH, -OC1-4alkyl , or -SO2C1-4alkane A benzene ring, a pyridine ring, a pyrimidine ring, an indoline ring, an isoindoline ring, or a pyrazole ring substituted with a phenyl group, preferably a benzene ring and a pyridine ring.
在一些实施方案中，环A为未取代的苯环；在另一些实施方案中，环A为被一或两个选自卤素、-C(O)OH、-OC 1-4烷基和-SO 2C 1-4烷基的取代基取代的苯环；在再一些实施方案中，环A为被一个卤素例如氟取代的苯环。 In some embodiments, 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.
在一些实施方案中，环A为未取代的吡啶环；在另一些实施方案中，环A为被一或两个选自卤素、C 1-4烷基和氧代的取代基取代的吡啶环。在一些实施方案中，所述吡啶环例如通过2-位连接到母核上。在一些实施方案中，所述吡啶环例如通过3-位连接到母核上。 In some embodiments, 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 . In some embodiments, 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.
在一些实施方案中，环A为取代或未取代的嘧啶环。在优选的实施方案中，所述嘧啶环通过2-位连接到母核上。In some embodiments, Ring A is a substituted or unsubstituted pyrimidine ring. In a preferred embodiment, the pyrimidine ring is attached to the parent nucleus through the 2-position.
在一些实施方案中，环A为未取代的吡唑环或被甲基取代的吡唑环。在一些实施方案中，所述吡唑环例如通过4-位连接到母核上。在一些实施方案中，所述吡唑环例如通过3-位连接到母核上。In some embodiments, Ring A is an unsubstituted pyrazole ring or a methyl-substituted pyrazole ring. In some embodiments, 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.
在一些实施方案中，“L-R”部分连接在环A上-NH-基团的对位。在另一些实施方案中，“L-R”部分连接在环A上-NH-基团的间位。In some embodiments, 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.
本发明的再一方面是上述通式(I)或(II)所示的化合物或其前药、稳定同位素衍生物、可药用的盐、异构体及其混合物形式，所述化合物具有通式(IIIa)或(IIIb)：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):
Figure PCTCN2020108468-appb-000008
Figure PCTCN2020108468-appb-000008
其中：in:
X 1、X 2和X 3各自独立地选自N或CG 1； X 1 , X 2 and X 3 are each independently selected from N or CG 1 ;
G 1选自H、卤素、C 1-4烷基、氧代、-COOH、-OC 1-4烷基或-SO 2C 1- 4烷基； 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、R a和R e的定义如前所述。 The definitions of L, R, Ra and Re are as previously described.
在通式(IIIa)化合物的一些实施方案中，X 1、X 2和X 3都为CH。 In some embodiments of compounds of general formula (IIIa), X 1 , X 2 and X 3 are all CH.
在通式(IIIa)化合物的一些实施方案中，X 1、X 2和X 3中的不超过两个为N。 In some embodiments of compounds of general formula (IIIa), no more than two of X 1 , X 2 and X 3 are N.
在通式(IIIa)化合物的一些实施方案中，X 1为N且X 2和X 3为CH。 In some embodiments of compounds of general formula (IIIa), X 1 is N and X 2 and X 3 are CH.
在通式(IIIa)化合物的一些实施方案中，X 2为N且X 1和X 3为CH。 In some embodiments of compounds of general formula (IIIa), X 2 is N and X 1 and X 3 are CH.
在通式(IIIa)化合物的一些实施方案中，X 3为N且X 1和X 2为CH。 In some embodiments of compounds of general formula (IIIa), X 3 is N and X 1 and X 2 are CH.
在通式(IIIa)化合物的一些实施方案中，X 1和X 3为N且X 2为CH。 In some embodiments of compounds of general formula (IIIa), X 1 and X 3 are N and X 2 is CH.
在通式(IIIa)化合物的一些实施方案中，X 1和X 2为N且X 3为CH。 In some embodiments of compounds of general formula (IIIa), X 1 and X 2 are N and X 3 is CH.
在通式(IIIa)化合物的一些实施方案中，X 2和X 3为N且X 1为CH。 In some embodiments of compounds of general formula (IIIa), X 2 and X 3 are N and X 1 is CH.
在通式(I)、(II)和(IIIa)化合物的一些实施方案中，L为键。In some embodiments of compounds of general formula (I), (II) and (IIIa), L is a bond.
在通式(I)、(II)和(IIIa)化合物的一些实施方案中，L为任选被C 1-4烷基取代的C 1-6亚烷基，例如-CH 2-或-(CH 3)C(CH 3)-。 In some embodiments of compounds of general formula (I), (II) and (IIIa), L is C 1-6 alkylene optionally substituted with C 1-4 alkyl, eg -CH 2 - or -( CH 3 )C(CH 3 )-.
在通式(I)、(II)和(IIIa)化合物的一些实施方案中，L为-O-C 1- 4亚烷基，例如-O-CH 2-。 In some embodiments of compounds of general formula (I), (II) and (IIIa), L is -OC1-4alkylene , eg, -O - CH2-.
在通式(I)、(II)和(IIIa)化合物的一些实施方案中，L为键，R为-OC 1-6烷基或-OC 1-6卤代烷基，例如-OCH 3、-OC 2H 5、-OCHF 2。 In some embodiments of compounds of general formula (I), (II) and (IIIa), 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 .
在通式(I)、(II)和(IIIa)化合物的一些实施方案中，L为键，R为-S(O) 2C 1-6烷基或-S(O)C 1-6烷基，例如-S(O) 2CH 3或-S(O)CH 3。 In some embodiments of compounds of general formula (I), (II) and (IIIa), 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 .
在通式(I)、(II)和(IIIa)化合物的一些实施方案中，L为键，R为氰基。In some embodiments of compounds of general formula (I), (II) and (Ilia), L is a bond and R is a cyano group.
在通式(I)、(II)和(IIIa)化合物的一些实施方案中，R为5-6元杂芳基，例如呋喃基、噻吩基、噻唑基、咪唑基、噁唑基、噁二唑基、噻二唑基、三唑基、四唑基、异噁唑基、异噻唑基、吡咯基、吡喃基、吡唑基、吡啶基、嘧啶基。In some embodiments of compounds of general formula (I), (II) and (IIIa), 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.
在通式(I)、(II)和(IIIa)化合物的一些实施方案中，R为C 1-6烷基，例如甲基、乙基。 In some embodiments of compounds of general formula (I), (II) and (IIIa), R is C1-6 alkyl, eg, methyl, ethyl.
在通式(I)、(II)和(IIIa)化合物的一些实施方案中，R为任选被选自-OH、C 1-4烷基、氧代、-O-C 1-4烷基、C 3-6环烷基和4-6元杂环基的取代基取代的4-7元杂环基，例如任选被-OH、甲基、氧代、甲氧基、异丙氧基、环丙基或噁丁环基取代的吗啉基、硫代吗啉基、哌嗪基、四氢吡喃基、四氢噻喃基、吖丁啶基、吡咯烷基、噁丁环基、咪唑基或哌啶基。 In some embodiments of compounds of general formula (I), (II) and (IIIa), 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.
在通式(I)、(II)和(IIIa)化合物的一些实施方案中，R选自噁丁环基、3-羟基噁丁环基、吗啉代、4-甲基哌嗪基、四氢吡喃基、3-甲氧基噁丁环基、4-甲基-2-氧代哌嗪基、3-氧代吗啉代、1-甲基哌啶基、3-甲基吗啉代、2-甲基吗啉代、4-环丙基-2-氧代哌嗪基、4-(噁丁环-3-基)-2-氧代哌嗪基、1-甲基咪唑基和3-异丙氧基噁丁环基。In some embodiments of compounds of general formula (I), (II) and (IIIa), 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.
在通式(I)、(II)和(IIIa)化合物的一些实施方案中，L为键，R为-OR 3且R 3为任选被氧代和C 1-4烷基取代的4-7元杂环基。在进一步的实施方案中，R 3为四氢噻喃基、氧代四氢噻喃基、哌啶基或1-甲基哌啶基。 In some embodiments of compounds of general formula (I), (II) and (IIIa), L is a bond, R is -OR and R is 4- optionally substituted with oxo and C 1-4 alkyl 7-membered heterocyclyl. In a further embodiment, R3 is tetrahydrothiopyranyl, oxotetrahydrothiopyranyl, piperidinyl or 1-methylpiperidinyl.
在通式(I)、(II)和(IIIa)化合物的一些实施方案中，R为-S(O) 2NR 3R 4或-C(O)NR 3R 4，其中R 3和R 4与它们连接的氮原子共同形成一任选含有另外的选自N、O和S的杂原子的4-7元杂环，例如吗啉环、哌嗪环、哌啶环、硫代吗啉环、吖丁啶环或吡咯烷环；进一步地，所述杂环任选被选自-OH、C 1-4烷基、-O-C 1-4烷基、氧代、C 3-6环烷基和4-6元杂环基的取代基取代，例如所述杂环为吗啉代、4-甲基哌嗪基、4-环丙基哌嗪基、4-(噁丁环-3-基)哌嗪基、氧代硫代吗啉代、3-羟基吖丁啶基、3-甲氧基吡咯烷基、吖丁啶基或甲基吗啉代。 In some embodiments of compounds of general formula (I), (II) and (IIIa), R is -S(O) 2NR3R4 or -C (O ) NR3R4 , wherein R3 and R4 The nitrogen atoms to which they are attached together form a 4-7 membered heterocyclic ring optionally containing additional heteroatoms selected from N, O and S, such as morpholine, piperazine, piperidine, thiomorpholine , azetidine ring or pyrrolidine ring; further, 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, oxothiomorpholino, 3-hydroxyazetidinyl, 3-methoxypyrrolidinyl, azetidinyl or methylmorpholino.
在通式(I)、(II)和(IIIa)化合物的一些实施方案中，R为-C(O)NR 3R 4，其中R 3和R 4中的一个为H且另一个为任选被-OH取代的C 1-6烷基。 In some embodiments of compounds of general formula (I), (II) and (IIIa), 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.
在通式(I)、(II)和(IIIa)化合物的一些实施方案中，R为-C(O)NR 3R 4，其中R 3和R 4中的一个为H且另一个为任选被-OH取代的C 3-6环烷基，例如环己基。 In some embodiments of compounds of general formula (I), (II) and (IIIa), 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.
在通式(I)、(II)和(IIIa)化合物的一些实施方案中，R为-C(O)NR 3R 4，其中R 3和R 4中的一个为H且另一个为4-7元杂环基，例如噁丁环基，哌啶基或四氢吡喃基。 In some embodiments of compounds of general formula (I), (II) and (IIIa), 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.
应当理解，本发明中对于通式化合物各基团/取代基的定义可以相互组合，这样的组合所产生的化合物也在本发明的范围内。It should be understood that the definitions of each group/substituent of the compound of the general formula in the present invention can be combined with each other, and the compounds produced by such a combination are also within the scope of the present invention.
本发明的一些实施方案是通式(IIIa)的化合物，其中：Some embodiments of the present invention are compounds of general formula (IIIa), wherein:
X 1、X 2和X 3都为CH，或X 1和X 2为CH且X 3为N； 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为H或卤素； G 1 is H or halogen;
L为键、任选被C 1-4烷基取代的C 1-6亚烷基或-O-C 1-4亚烷基； L is a bond, C 1-6 alkylene or -OC 1-4 alkylene optionally substituted by C 1-4 alkyl;
R独立地选自氰基、-SF 5、-OR 3、-S(O) 2C 1-6烷基、-S(O)C 1-6烷基、-S(O) 2NR 3R 4、-C(O)OH、-C(O)NR 3R 4、-C(O)NHS(O) 2C 1-6烷基，任选被 选自-OH、C 1-4烷基、氧代、-O-C 1-4烷基、C 3-6环烷基和4-6元杂环基的取代基取代的4-7元杂环基，或任选被C 1-4烷基取代的5-6元杂芳基； 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;
R a和R e各自独立地选自卤素； Ra and Re are each independently selected from halogen;
R 3和R 4各自独立地选自H，任选被卤素或-OH取代的C 1-6烷基，任选被-OH取代的C 3-7环烷基，或任选被氧代或C 1-4烷基取代的4-7元杂环基；或者，在同一个氮原子上的R 3和R 4任选与它们连接的氮原子共同形成一任选含有另外的选自N、O和S的杂原子的4-7元杂环，所述杂环任选被选自-OH、C 1-4烷基、-O-C 1-4烷基、氧代、C 3-6环烷基和4-6元杂环基基的取代基取代。 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.
本发明的一些实施方案是通式(IIIa)的化合物，其中：Some embodiments of the present invention are compounds of general formula (IIIa), wherein:
X 1、X 2和X 3都为CH； X 1 , X 2 and X 3 are all CH;
G 1为H或卤素； G 1 is H or halogen;
L为键或任选被C 1-4烷基取代的C 1-6亚烷基或-O-C 1-4亚烷基； 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独立地选自氰基、-SF 5、-OR 3、-S(O) 2C 1-6烷基、-S(O)C 1-6烷基、-S(O) 2NR 3R 4、-C(O)OH、-C(O)NR 3R 4、-C(O)NHS(O) 2C 1-6烷基，任选被选自-OH、C 1-4烷基、氧代、-O-C 1-4烷基、C 3-6环烷基和4-6元杂环基的取代基取代的4-7元杂环基，或任选被C 1-4烷基取代的5-6元杂芳基； 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;
R a和R e各自独立地选自卤素； Ra and Re are each independently selected from halogen;
R 3和R 4各自独立地选自H，任选被卤素或-OH取代的C 1-6烷基，任选被-OH取代的C 3-7环烷基，或任选被氧代或C 1-4烷基取代的4-7元杂环基；或者，在同一个氮原子上的R 3和R 4任选与它们连接的氮原子共同形成一任选含有另外的选自N、O和S的杂原子的4-7元杂环，所述杂环任选被选自-OH、C 1-4烷基、-O-C 1-4烷基、氧代、环丙基和噁丁环基基的取代基取代。 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.
本发明的一些实施方案是通式(IIIa)的化合物，其中：Some embodiments of the present invention are compounds of general formula (IIIa), wherein:
X 1和X 2为CH且X 3为N； X 1 and X 2 are CH and X 3 is N;
G 1为H或卤素； G 1 is H or halogen;
L为键、任选被C 1-4烷基取代的C 1-6亚烷基或-O-C 1-4亚烷基； L is a bond, C 1-6 alkylene or -OC 1-4 alkylene optionally substituted by C 1-4 alkyl;
R独立地选自氰基、-SF 5、-OR 3、-S(O) 2C 1-6烷基、-S(O)C 1-6烷基、-S(O) 2NR 3R 4、-C(O)OH、-C(O)NR 3R 4、-C(O)NHS(O) 2C 1-6烷基，任选被选自-OH、C 1-4烷基、氧代、-O-C 1-4烷基、C 3-6环烷基或4-6元杂环基的取代基取代的4-7元杂环基，或任选被C 1-4烷基取代的5-6元杂芳基； 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;
R a和R e各自独立地选自卤素； Ra and Re are each independently selected from halogen;
R 3和R 4各自独立地选自H，任选被卤素或-OH取代的C 1-6烷基，任选被-OH取代的C 3-7环烷基，或任选被氧代或C 1-4烷基取代的4-7元杂环基；或者，在同一个氮原子上的R 3和R 4任选与它们连接的氮原子共同形成一任选含有另外的选自N、O和S的杂原子的4-7元杂环，所述杂环任选被选自-OH、C 1-4烷基、-O-C 1-4烷基、氧代、环丙基和噁丁环基的取代基取代。 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.
本发明的另一些实施方案是通式(IIIa)的化合物，其中：Other embodiments of the present invention are compounds of general formula (IIIa), wherein:
X 1和X 2为CH且X 3为N； X 1 and X 2 are CH and X 3 is N;
G 1为H； G 1 is H;
L为键或任选被C 1-4烷基取代的C 1-6亚烷基； L is a bond or a C 1-6 alkylene group optionally substituted with a C 1-4 alkyl group;
R独立地选自-OR 3、-S(O) 2C 1-6烷基、-C(O)OH、-C(O)NR 3R 4或任选被选自C 1-4烷基或氧代的取代基取代的4-7元杂环基； 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;
R a和R e各自独立地选自卤素； Ra and Re are each independently selected from halogen;
R 3和R 4各自独立地选自H；或者，在同一个氮原子上的R 3和R 4任选与它们连接的氮原子共同形成一任选含有另外的选自N、O和S的杂原子的4-7元杂环。 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.
本发明进一步涉及上述通式(I)所示的化合物，其中所述化合物选自：The present invention further relates to the compound represented by the above-mentioned general formula (I), wherein the compound is selected from:
Figure PCTCN2020108468-appb-000009
Figure PCTCN2020108468-appb-000009
Figure PCTCN2020108468-appb-000010
Figure PCTCN2020108468-appb-000010
Figure PCTCN2020108468-appb-000011
Figure PCTCN2020108468-appb-000011
Figure PCTCN2020108468-appb-000012
Figure PCTCN2020108468-appb-000012
Figure PCTCN2020108468-appb-000013
Figure PCTCN2020108468-appb-000013
Figure PCTCN2020108468-appb-000014
Figure PCTCN2020108468-appb-000014
Figure PCTCN2020108468-appb-000015
Figure PCTCN2020108468-appb-000015
Figure PCTCN2020108468-appb-000016
Figure PCTCN2020108468-appb-000016
Figure PCTCN2020108468-appb-000017
Figure PCTCN2020108468-appb-000017
Figure PCTCN2020108468-appb-000018
Figure PCTCN2020108468-appb-000018
Figure PCTCN2020108468-appb-000019
Figure PCTCN2020108468-appb-000019
Figure PCTCN2020108468-appb-000020
Figure PCTCN2020108468-appb-000020
Figure PCTCN2020108468-appb-000021
Figure PCTCN2020108468-appb-000021
Figure PCTCN2020108468-appb-000022
Figure PCTCN2020108468-appb-000022
Figure PCTCN2020108468-appb-000023
Figure PCTCN2020108468-appb-000023
Figure PCTCN2020108468-appb-000024
Figure PCTCN2020108468-appb-000024
Figure PCTCN2020108468-appb-000025
Figure PCTCN2020108468-appb-000025
Figure PCTCN2020108468-appb-000026
Figure PCTCN2020108468-appb-000026
Figure PCTCN2020108468-appb-000027
Figure PCTCN2020108468-appb-000027
Figure PCTCN2020108468-appb-000028
Figure PCTCN2020108468-appb-000028
Figure PCTCN2020108468-appb-000029
Figure PCTCN2020108468-appb-000029
Figure PCTCN2020108468-appb-000030
Figure PCTCN2020108468-appb-000030
Figure PCTCN2020108468-appb-000031
Figure PCTCN2020108468-appb-000031
或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式。or its pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers and mixtures thereof.
本发明化合物对Janus激酶、尤其是TYK2的活性具有显著抑制效应。本发明化合物能够有效抑制TYK2的活性，优选其IC 50为10至100nM，更优选IC 50小于10nM，最优选其IC 50小于1nM。本发明化合物对NK92细胞中TYK2生理功能具有显著抑制效应。 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.
根据本发明，所述药物可以是任何药物剂型，包括但不限于片剂、胶囊剂、溶液剂、冻干制剂、注射剂。According to the present invention, the drug can be in any pharmaceutical dosage form, including but not limited to tablets, capsules, solutions, freeze-dried preparations, and injections.
本发明的药物制剂可以以每剂量单位包含预定量的活性成分的剂量单位形式给药。这种单位可根据治疗的病症、给药方法和患者的年龄、体重和状况包含例如0.5毫克至1克，优选1毫克至700毫克，特别优选5毫克至300毫克的本发明的化合物。优选剂量单位制剂是包含如上指示的日剂量或分剂量或其相应分数的活性成分的那些。此外，可以使用制药领域中公知的方法制备这种类型的药物制剂。The pharmaceutical formulations of the present invention may be administered in dosage unit form containing a predetermined amount of active ingredient per dosage unit. Such 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. Furthermore, pharmaceutical formulations of this type can be prepared using methods well known in the pharmaceutical art.
本发明药物制剂可适于通过任何所需的合适方法给药，例如通过经口(包括口腔或舌下)、直肠、经鼻、局部(包括口腔、舌下或经皮)、阴道或肠道外(包括皮下、肌内、静脉内或皮内)方法给药。可以使用制药领域中已知的所有方法通过例如将活性成分与一种或多种赋形剂或一种或多种辅助剂合并来制备这样的制剂。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. 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.
合成方法resolve resolution
本发明还提供制备所述化合物的方法。本发明通式(I)所述化合物的制备可通过以下示例性方法和实施例完成，但这些方法和实施例不应以任何方式被认为是对本发明范围的限制。也可通过本领域技术人 员所知的合成技术合成本发明所述的化合物，或者综合使用本领域已知方法和本发明所述方法。每步反应所得的产物用本领域已知的分离技术得到，包括但不限于萃取、过滤、蒸馏、结晶、色谱分离等。合成所需的起始原料和化学试剂可以根据文献(可从SciFinder上查询)常规合成或购买。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).
本发明通式(I)所述哒嗪类化合物可按照方法A所述路线合成：1)起始物A1与含有官能团的(杂)芳香胺发生取代反应得到A2；2)A2与苯硼酸或硼酸酯通过Suzuki偶联反应生成A3；3)A3的酯基水解成酸、再酰胺化(先转化为酰氯再与氨耦合或直接通过缩合剂与氨耦合)得到A4，也可直接转氨得到A4；4)A4的功能团可根据本领域已知的合成方法进一步衍生化得到一些目标化合物。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.
方法A：Method A:
Figure PCTCN2020108468-appb-000032
Figure PCTCN2020108468-appb-000032
中间体A3也可按照方法B所述路线合成：A1先与苯硼酸或硼酸酯通过Suzuki偶联反应生成B2，再和含有官能团的(杂)芳香胺进行Buchwald偶联反应生成A3。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.
方法B：Method B:
Figure PCTCN2020108468-appb-000033
Figure PCTCN2020108468-appb-000033
中间体A3还可按照方法C所述路线合成：1)起始物A1先与苄胺发生取代反应得到C2；2)C2与苯硼酸或硼酸酯通过Suzuki偶联反应生成C3；3)C3在酸中脱苄得到C4；4)C4经过取代反应或Buchwald偶联反应得到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.
方法C：Method C:
Figure PCTCN2020108468-appb-000034
Figure PCTCN2020108468-appb-000034
实施例Example
化合物的结构是通过核磁共振(NMR)或质谱(MS)来确定的。NMR的测定是用Bruker ASCEND-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDC1 3)、氘代甲醇(CD 3OD)，内标为四甲基甲硅烷(TMS)，化学位移是以10 -6(ppm)作为单位给出。 The structures of compounds were determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR was measured by Bruker ASCEND-400 nuclear magnetic instrument, the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDC1 3 ), deuterated methanol (CD 3 OD), and the internal standard was four Methylsilane (TMS), chemical shifts are given in units of 10-6 (ppm).
MS的测定使用Agilent SQD(ESI)质谱仪(生产商：安捷伦，型号：6120)。The MS was measured using an Agilent SQD (ESI) mass spectrometer (manufacturer: Agilent, model: 6120).
HPLC的测定使用安捷伦1260 DAD高压液相色谱仪(Poroshell120 EC-C18，50×3.0mm，2.7μm色谱柱)或Waters Arc高压液相色谱仪(Sunfirc C18，150×4.6mm，5μm色谱柱)。The determination of HPLC was performed using an Agilent 1260 DAD high pressure liquid chromatograph (Poroshell120 EC-C18, 50×3.0mm, 2.7μm column) or a Waters Arc high pressure liquid chromatograph (Sunfirc C18, 150×4.6mm, 5μm column).
薄层层析硅胶板使用青岛海洋GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15～0.2mm，薄层层析分离纯化产品采用的规格是0.4～0.5mm硅胶板。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 .
柱层析一般使用青岛海洋200～300目硅胶为载体。Column chromatography generally uses Qingdao Ocean 200-300 mesh silica gel as the carrier.
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG、Acros Organics、Aldrich Chemical Company、韶远化学科技(Accela ChemBio Inc.)、北京偶合化学品等公司。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.
实施例中如无特殊说明，反应均在氩气气氛或氮气气氛下进行。Unless otherwise specified in the examples, the reactions were carried out in an argon atmosphere or a nitrogen atmosphere.
氩气气氛或氮气气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
氢气气氛是指反应瓶连接一个约1L容积的氢气气球。Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.
氢化反应通常抽真空，充入氢气，反复操作3次。The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
微波反应使用CEM Discover-SP型微波反应器。The microwave reaction used a CEM Discover-SP type microwave reactor.
实施例中如无特殊说明，反应的温度为室温，温度范围是20℃-30℃。Unless otherwise specified in the examples, the reaction temperature is room temperature, and the temperature range is 20°C-30°C.
实施例中的反应进程的监测使用安捷伦的液质联用仪(1260/6120)。反应进程的监测也可采用薄层色谱法(TLC)，展开剂所使用的体系有A：二氯甲烷和甲醇体系；B：石油醚和乙酸乙酯体系，溶剂的体积比 根据化合物的极性不同而进行调节。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.
纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂的体系包括A：二氯甲烷和甲醇体系；B：石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和酸性或碱性试剂等进行调节，或者采用其它的溶剂体系。纯化化合物还采用Waters的质谱导向自动制备系统(质谱检测器：SQD2)，根据化合物的极性用适当的乙腈/水(含0.1％三氟乙酸或甲酸)或乙腈/水(含0.05％氨水)梯度于20mL/min的流速洗脱反相高压柱(XBridge-C18，19×150mm，5μm)。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 μm) was eluted with a gradient at a flow rate of 20 mL/min.
实施例1Example 1
6-(2,6-二氟苯基)-4-((4-乙氧苯基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((4-ethoxyphenyl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000035
Figure PCTCN2020108468-appb-000035
第一步first step
6-氯-4-((4-乙氧苯基)氨基)哒嗪-3-羧酸甲酯Methyl 6-chloro-4-((4-ethoxyphenyl)amino)pyridazine-3-carboxylate
将化合物4,6-二氯哒嗪-3-羧酸甲酯1a(206mg，1.00mmol)、4-乙氧基苯胺(205mg，1.50mmol)和二异丙基乙基胺(387mg，3.00mmol)溶于乙腈(3mL)，然后在微波反应器中加热到85℃并搅拌2小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝50/1至10/1)纯化，得到目标产物6-氯-4-((4-乙氧苯基)氨基)哒嗪-3-羧酸甲酯1b(240mg，黄色油状物)，产率：78％。Compound 4,6-dichloropyridazine-3-carboxylate methyl ester 1a (206 mg, 1.00 mmol), 4-ethoxyaniline (205 mg, 1.50 mmol) and diisopropylethylamine (387 mg, 3.00 mmol) ) was dissolved in acetonitrile (3 mL), then heated to 85°C in a microwave reactor and stirred for 2 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/1 to 10/1) to obtain the target product 6-chloro-4-((4-ethoxy) Phenyl)amino)pyridazine-3-carboxylate methyl ester 1b (240 mg, yellow oil), yield: 78%.
MS m/z(ESI):308[M+1]MS m/z(ESI): 308[M+1]
第二步second step
6-(2,6-二氟苯基)-4-((4-乙氧苯基)氨基)哒嗪-3-羧酸甲酯Methyl 6-(2,6-difluorophenyl)-4-((4-ethoxyphenyl)amino)pyridazine-3-carboxylate
将化合物6-氯-4-((4-乙氧苯基)氨基)哒嗪-3-羧酸甲酯1b(240mg，0.78mmol)、2,6-二氟苯硼酸(369mg，2.34mmol)、二异丙基乙基胺 (403mg，3.12mmol)和四(三苯基膦)钯(90mg，0.078mmol)溶于1,4-二氧六环(9mL)，除氧后在氮气气氛下用微波反应器加热到110℃并搅拌1小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝50/1至5/1)纯化，得到目标产物6-(2,6-二氟苯基)-4-((4-乙氧苯基)氨基)哒嗪-3-羧酸甲酯1c(270mg，黄色油状物)，产率：89％。Compound 6-chloro-4-((4-ethoxyphenyl)amino)pyridazine-3-carboxylate methyl ester 1b (240 mg, 0.78 mmol), 2,6-difluorophenylboronic acid (369 mg, 2.34 mmol) , diisopropylethylamine (403 mg, 3.12 mmol) and tetrakis(triphenylphosphine)palladium (90 mg, 0.078 mmol) were dissolved in 1,4-dioxane (9 mL), deoxygenated under nitrogen atmosphere Heat to 110°C with a microwave reactor and stir for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/1 to 5/1) to obtain the target product 6-(2,6-difluorophenyl) -4-((4-Ethoxyphenyl)amino)pyridazine-3-carboxylate methyl ester 1c (270 mg, yellow oil), yield: 89%.
MS m/z(ESI):386[M+1]MS m/z(ESI): 386[M+1]
第三步third step
6-(2,6-二氟苯基)-4-((4-乙氧苯基)氨基)哒嗪-3-羧酸6-(2,6-Difluorophenyl)-4-((4-ethoxyphenyl)amino)pyridazine-3-carboxylic acid
将化合物6-(2,6-二氟苯基)-4-((4-乙氧苯基)氨基)哒嗪-3-羧酸甲酯1c(270mg，0.7mmol)溶于四氢呋喃(10mL)，然后加入氢氧化锂水溶液(1M，3mL)并搅拌1小时。反应完成后，用稀盐酸(1N)调节至pH＝6-7，然后用乙酸乙酯萃取(50mL×3)。有机相合并后，用饱和食盐水(20mL)洗涤后用无水硫酸钠干燥，过滤后滤液在减压条件下干燥，得到目标产物6-(2,6-二氟苯基)-4-((4-乙氧苯基)氨基)哒嗪-3-羧酸1d(240mg，黄色油状物)，产率：92％。Compound 6-(2,6-difluorophenyl)-4-((4-ethoxyphenyl)amino)pyridazine-3-carboxylate methyl ester 1c (270 mg, 0.7 mmol) was dissolved in tetrahydrofuran (10 mL) , then an aqueous lithium hydroxide solution (1 M, 3 mL) was added and stirred for 1 hour. After the reaction was completed, it was adjusted to pH=6-7 with dilute hydrochloric acid (1N), and then extracted with ethyl acetate (50 mL×3). After the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under reduced pressure to obtain the target product 6-(2,6-difluorophenyl)-4-( (4-Ethoxyphenyl)amino)pyridazine-3-carboxylic acid 1d (240 mg, yellow oil), yield: 92%.
MS m/z(ESI):372[M+1]MS m/z(ESI): 372[M+1]
第四步the fourth step
6-(2,6-二氟苯基)-4-((4-乙氧苯基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((4-ethoxyphenyl)amino)pyridazine-3-carboxamide
将化合物6-(2,6-二氟苯基)-4-((4-乙氧苯基)氨基)哒嗪-3-羧酸1d(240mg，0.64mmol)溶于氯化亚砜(10mL)，然后加热到40℃并搅拌1小时。冷却到室温后，减压除去溶剂，残余物溶于无水四氢呋喃(15mL)，然后加入氨水(2mL)并搅拌1小时。反应完成后，减压除去溶剂，残余物用反相高效制备液相色谱纯化，得到目标产物6-(2,6-二氟苯基)-4-((4-乙氧苯基)氨基)哒嗪-3-甲酰胺1(66mg，黄色固体)，产率：27％。Compound 6-(2,6-difluorophenyl)-4-((4-ethoxyphenyl)amino)pyridazine-3-carboxylic acid 1d (240 mg, 0.64 mmol) was dissolved in thionyl chloride (10 mL ), then heated to 40°C and stirred for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, the residue was dissolved in anhydrous tetrahydrofuran (15 mL), then ammonia water (2 mL) was added and stirred for 1 hour. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase high performance liquid chromatography to obtain the target product 6-(2,6-difluorophenyl)-4-((4-ethoxyphenyl)amino) Pyridazine-3-carboxamide 1 (66 mg, yellow solid), yield: 27%.
MS m/z(ESI):371[M+1]MS m/z(ESI): 371[M+1]
1H NMR(400MHz,CD 3OD)δ7.53(t,J＝7.3Hz,1H),7.21(d,J＝8.7Hz,2H),7.12(t,J＝8.1Hz,2H),7.05(s,1H),6.98(d,J＝8.7Hz,2H),4.04(q,J＝6.9Hz,2H),1.39(t,J＝6.9Hz,3H)。 1 H NMR (400 MHz, CD 3 OD) δ 7.53 (t, J=7.3 Hz, 1H), 7.21 (d, J=8.7 Hz, 2H), 7.12 (t, J=8.1 Hz, 2H), 7.05 ( s, 1H), 6.98 (d, J=8.7Hz, 2H), 4.04 (q, J=6.9Hz, 2H), 1.39 (t, J=6.9Hz, 3H).
以下实施例(实施例2、实施例3、实施例4、实施例5、实施例6、实施例7)均参照实施例1的操作方法合成，但在第一步中用不同的胺代替4-乙氧基苯胺，如下所示：The following examples (Example 2, Example 3, Example 4, Example 5, Example 6, Example 7) are all synthesized with reference to the operation method of Example 1, but in the first step, different amines are used instead of 4 -Ethoxyaniline, as follows:
Figure PCTCN2020108468-appb-000036
Figure PCTCN2020108468-appb-000036
Figure PCTCN2020108468-appb-000037
Figure PCTCN2020108468-appb-000037
实施例8Example 8
6-(2,6-二氟苯基)-4-((4-(甲磺酰)苯基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((4-(methylsulfonyl)phenyl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000038
Figure PCTCN2020108468-appb-000038
Figure PCTCN2020108468-appb-000039
Figure PCTCN2020108468-appb-000039
第一步first step
6-氯-4-((4-(甲磺酰)苯基)氨基)哒嗪-3-羧酸甲酯Methyl 6-chloro-4-((4-(methylsulfonyl)phenyl)amino)pyridazine-3-carboxylate
将化合物4,6-二氯哒嗪-3-羧酸甲酯1a(206mg，1.00mmol)和4-甲磺酰基苯胺(342mg，2.00mmol)溶于乙醇(3mL)，然后在微波反应器中加热到80℃并搅拌1小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝50/1至1/1)纯化，得到目标产物6-氯-4-((4-(甲磺酰)苯基)氨基)哒嗪-3-羧酸甲酯8a(220mg，黄色固体)，产率：64％。Compounds 4,6-dichloropyridazine-3-carboxylate methyl ester 1a (206 mg, 1.00 mmol) and 4-methanesulfonylaniline (342 mg, 2.00 mmol) were dissolved in ethanol (3 mL) and then in a microwave reactor Heat to 80°C and stir for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/1 to 1/1) to obtain the target product 6-chloro-4-((4-(methyl) Sulfonyl)phenyl)amino)pyridazine-3-carboxylate methyl ester 8a (220 mg, yellow solid), yield: 64%.
MS m/z(ESI):342[M+1]MS m/z(ESI): 342[M+1]
第二步至第四步Steps 2 to 4
6-(2,6-二氟苯基)-4-((4-(甲磺酰)苯基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((4-(methylsulfonyl)phenyl)amino)pyridazine-3-carboxamide
参照实施例1中第二步至第四步中的步骤合成目标产物，但在第二步中用6-氯-4-((4-(甲磺酰)苯基)氨基)哒嗪-3-羧酸甲酯8a代替6-氯-4-((4-乙氧苯基)氨基)哒嗪-3-羧酸甲酯1b。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.
MS m/z(ESI):405[M+1]MS m/z(ESI): 405[M+1]
1H NMR(400MHz,CD 3OD)δ8.01(d,J＝8.6Hz,2H),7.72–7.48(m,4H),7.18(t,J＝8.2Hz,2H),3.14(s,3H)。 1 H NMR (400 MHz, CD 3 OD) δ 8.01 (d, J=8.6 Hz, 2H), 7.72-7.48 (m, 4H), 7.18 (t, J=8.2 Hz, 2H), 3.14 (s, 3H) ).
实施例9Example 9
4-((4-氰基苯基)氨基)-6-(2,6-二氟苯基)哒嗪-3-甲酰胺4-((4-cyanophenyl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000040
Figure PCTCN2020108468-appb-000040
参照实施例8的合成步骤合成实施例9，但在第一步用4-氰基苯胺代替4-甲磺酰基苯胺。Example 9 was synthesized following the synthesis procedure of Example 8, but using 4-cyanoaniline instead of 4-methanesulfonylaniline in the first step.
MS m/z(ESI):352[M+1]MS m/z(ESI): 352[M+1]
1H NMR(400MHz,DMSO-d 6)δ11.24(s,1H),8.87(s,1H),8.15(s,1H),7.84(d,J＝7.8Hz,2H),7.67–7.42(m,4H),7.30(d,J＝7.6Hz,2H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 11.24(s, 1H), 8.87(s, 1H), 8.15(s, 1H), 7.84(d, J=7.8Hz, 2H), 7.67-7.42( m, 4H), 7.30 (d, J=7.6Hz, 2H).
实施例10Example 10
6-(2,6-二氟苯基)-4-((4-(2-羟基丙烷-2-基)苯基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((4-(2-hydroxypropan-2-yl)phenyl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000041
Figure PCTCN2020108468-appb-000041
第一步first step
4-((4-(叔-丁氧基羰基)苯基)氨基)-6-氯哒嗪-3-羧酸甲酯Methyl 4-((4-(tert-butoxycarbonyl)phenyl)amino)-6-chloropyridazine-3-carboxylate
将化合物4,6-二氯哒嗪-3-羧酸甲酯1a(1.03g，5.00mmol)和4-氨基苯甲酸叔丁酯(1.93g，10.0mmol)溶于乙醇(30mL)，加热回流3小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝50/1至2/1)纯化，得到目标产物4-((4-(叔-丁氧基羰基)苯基)氨基)-6-氯哒嗪-3-羧酸甲酯10a(750mg，淡黄色油状物)，产率：41％。Compound 4,6-dichloropyridazine-3-carboxylate methyl ester 1a (1.03 g, 5.00 mmol) and tert-butyl 4-aminobenzoate (1.93 g, 10.0 mmol) were dissolved in ethanol (30 mL), heated to reflux 3 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/1 to 2/1) to obtain the target product 4-((4-(tert-butoxy) Carbonyl)phenyl)amino)-6-chloropyridazine-3-carboxylic acid methyl ester 10a (750 mg, pale yellow oil), yield: 41%.
MS m/z(ESI):364[M+1]MS m/z(ESI): 364[M+1]
第二步至第四步Steps 2 to 4
4-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)苯甲酸叔丁酯tert-Butyl 4-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)benzoate
参照实施例1中第二步至第四步中的步骤合成目标产物，但在第二步中用4-((4-(叔-丁氧基羰基)苯基)氨基)-6-氯哒嗪-3-羧酸甲酯10a代替6-氯-4-((4-乙氧苯基)氨基)哒嗪-3-羧酸甲酯1b。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.
MS m/z(ESI):427[M+1]MS m/z(ESI): 427[M+1]
第五步the fifth step
6-(2,6-二氟苯基)-4-((4-(2-羟基丙烷-2-基)苯基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((4-(2-hydroxypropan-2-yl)phenyl)amino)pyridazine-3-carboxamide
将化合物4-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)苯甲酸叔丁酯10d(40mg，0.094mmol)溶于无水四氢呋喃(10mL)，冷却到0℃后加入甲基锂的四氢呋喃溶液(2M，0.47mL，0.94mmol)。搅拌1小时后，用水淬灭，然后减压除去溶剂，残余物用反相高效制备液相 色谱纯化，得到目标产物6-(2,6-二氟苯基)-4-((4-(2-羟基丙烷-2-基)苯基)氨基)哒嗪-3-甲酰胺10(16mg，白色固体)，产率：44％。Compound 4-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)benzoic acid tert-butyl ester 10d (40 mg, 0.094 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), cooled to 0°C and added methyllithium in tetrahydrofuran (2M, 0.47 mL, 0.94 mmol). After stirring for 1 hour, it was quenched with water, then the solvent was removed under reduced pressure, and the residue was purified by reverse-phase high-performance preparative liquid chromatography to give the target product 6-(2,6-difluorophenyl)-4-((4-( 2-Hydroxypropan-2-yl)phenyl)amino)pyridazine-3-carboxamide 10 (16 mg, white solid), yield: 44%.
MS m/z(ESI):385[M+1]MS m/z(ESI): 385[M+1]
1H NMR(400MHz,DMSO-d 6)δ10.82(s,1H),8.76(s,1H),8.03(s,1H),7.59(ddd,J＝15.0,8.4,6.6Hz,1H),7.51(d,J＝8.5Hz,2H),7.26(dd,J＝9.0,7.4Hz,5H),5.02(s,1H),1.42(s,6H)。 1 H NMR (400MHz, DMSO-d 6 )δ10.82(s,1H),8.76(s,1H),8.03(s,1H),7.59(ddd,J=15.0,8.4,6.6Hz,1H), 7.51 (d, J=8.5 Hz, 2H), 7.26 (dd, J=9.0, 7.4 Hz, 5H), 5.02 (s, 1H), 1.42 (s, 6H).
实施例11Example 11
6-(2,6-二氟苯基)-4-((4-(3-羟基噁丁环-3-基)苯基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((4-(3-hydroxyoxetan-3-yl)phenyl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000042
Figure PCTCN2020108468-appb-000042
第一步first step
6-氯-4-((4-(3-羟基噁丁环-3-基)苯基)氨基)哒嗪-3-羧酸甲酯Methyl 6-chloro-4-((4-(3-hydroxyoxetan-3-yl)phenyl)amino)pyridazine-3-carboxylate
将化合物4,6-二氯哒嗪-3-羧酸甲酯1a(206mg，1.00mmol)、3-(4-氨基苯基)噁丁环-3-醇(205mg，1.50mmol)和二异丙基乙基胺(387mg，3.00mmol)溶于乙腈(3mL)，然后在微波反应器中加热到90℃并搅拌2小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝50/1至1/1)纯化，得到目标产物6-氯-4-((4-(3-羟基噁丁环-3-基)苯基)氨基)哒嗪-3-羧酸甲酯11a(260mg，淡黄色油状物)，产率：77％。Compound 4,6-dichloropyridazine-3-carboxylate methyl ester 1a (206 mg, 1.00 mmol), 3-(4-aminophenyl)oxetan-3-ol (205 mg, 1.50 mmol) and diiso Propylethylamine (387 mg, 3.00 mmol) was dissolved in acetonitrile (3 mL), then heated to 90°C in a microwave reactor and stirred for 2 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/1 to 1/1) to obtain the target product 6-chloro-4-((4-(3 -Hydroxyoxetan-3-yl)phenyl)amino)pyridazine-3-carboxylate methyl ester 11a (260 mg, pale yellow oil), yield: 77%.
MS m/z(ESI):308[M+1]MS m/z(ESI): 308[M+1]
第二步second step
6-(2,6-二氟苯基)-4-((4-(3-羟基噁丁环-3-基)苯基)氨基)哒嗪-3-羧酸甲酯Methyl 6-(2,6-difluorophenyl)-4-((4-(3-hydroxyoxetan-3-yl)phenyl)amino)pyridazine-3-carboxylate
将化合物6-氯-4-((4-(3-羟基噁丁环-3-基)苯基)氨基)哒嗪-3-羧酸甲酯11a(260mg，0.8mmol)、2,6-二氟苯硼酸(380mg，2.4mmol)、二异丙基乙基胺(309mg，2.4mmol)和四(三苯基膦)钯(92mg，0.080mmol)溶于1,4-二氧六环(9mL)，除氧后在氮气气氛下用微波反应器 加热到110℃并搅拌1小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝20/1至1/2)纯化，得到目标产物6-(2,6-二氟苯基)-4-((4-(3-羟基噁丁环-3-基)苯基)氨基)哒嗪-3-羧酸甲酯11b(140mg，黄色油状物)，产率：42％。Compound 6-chloro-4-((4-(3-hydroxyoxetan-3-yl)phenyl)amino)pyridazine-3-carboxylic acid methyl ester 11a (260 mg, 0.8 mmol), 2,6- Difluorophenylboronic acid (380 mg, 2.4 mmol), diisopropylethylamine (309 mg, 2.4 mmol) and tetrakis(triphenylphosphine)palladium (92 mg, 0.080 mmol) were dissolved in 1,4-dioxane ( 9 mL), deoxygenated and heated to 110°C in a microwave reactor under nitrogen atmosphere and stirred for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=20/1 to 1/2) to obtain the target product 6-(2,6-difluorophenyl) -4-((4-(3-Hydroxyoxetan-3-yl)phenyl)amino)pyridazine-3-carboxylate methyl ester 11b (140 mg, yellow oil), yield: 42%.
MS m/z(ESI):414[M+1]MS m/z(ESI): 414[M+1]
第三步third step
6-(2,6-二氟苯基)-4-((4-(3-羟基噁丁环-3-基)苯基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((4-(3-hydroxyoxetan-3-yl)phenyl)amino)pyridazine-3-carboxamide
将化合物6-(2,6-二氟苯基)-4-((4-(3-羟基噁丁环-3-基)苯基)氨基)哒嗪-3-羧酸甲酯11b(140mg，0.34mmol)溶于四氢呋喃(5mL)，然后加入氨水(3mL)。室温下搅拌15小时后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2,6-二氟苯基)-4-((4-(3-羟基噁丁环-3-基)苯基)氨基)哒嗪-3-甲酰胺11(75mg，白色固体)，产率56％。Compound 6-(2,6-difluorophenyl)-4-((4-(3-hydroxyoxetan-3-yl)phenyl)amino)pyridazine-3-carboxylate methyl ester 11b (140 mg , 0.34 mmol) was dissolved in tetrahydrofuran (5 mL), then ammonia (3 mL) was added. After stirring at room temperature for 15 hours, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to obtain the target product 6-(2,6-difluorophenyl)-4-((4-(3-hydroxyl). Oxetan-3-yl)phenyl)amino)pyridazine-3-carboxamide 11 (75 mg, white solid) in 56% yield.
MS m/z(ESI):398[M+1]MS m/z(ESI): 398[M+1]
1H NMR(400MHz,CD 3OD)δ7.75(d,J＝8.5Hz,2H),7.60–7.51(m,1H),7.40(d,J＝8.5Hz,2H),7.31(s,1H),7.19–7.11(m,2H),4.93–4.86(m,4H)。 1 H NMR (400MHz, CD 3 OD) δ 7.75 (d, J=8.5Hz, 2H), 7.60-7.51 (m, 1H), 7.40 (d, J=8.5Hz, 2H), 7.31 (s, 1H) ), 7.19–7.11 (m, 2H), 4.93–4.86 (m, 4H).
实施例12Example 12
6-(2,6-二氟苯基)-4-((4-(甲基亚硫酰基)苯基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((4-(methylsulfinyl)phenyl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000043
Figure PCTCN2020108468-appb-000043
第一步first step
6-氯-4-((4-(甲硫基)苯基)氨基)哒嗪-3-羧酸甲酯Methyl 6-chloro-4-((4-(methylthio)phenyl)amino)pyridazine-3-carboxylate
将化合物4,6-二氯哒嗪-3-羧酸甲酯1a(414mg，2.00mmol)和4-甲硫基苯胺(417mg，3mmol)溶于乙醇(6mL)，用微波反应器加热至90℃并搅拌3小时。冷却到室温后，减压除去溶剂，残余物用硅胶 柱层析(石油醚/乙酸乙酯＝50/1至1/1)纯化，得到目标产物6-氯-4-((4-(甲硫基)苯基)氨基)哒嗪-3-羧酸甲酯12a(540mg，黄色固体)，产率：87％。Compound 4,6-dichloropyridazine-3-carboxylic acid methyl ester 1a (414 mg, 2.00 mmol) and 4-methylthioaniline (417 mg, 3 mmol) were dissolved in ethanol (6 mL) and heated to 90 in a microwave reactor °C and stirring for 3 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/1 to 1/1) to obtain the target product 6-chloro-4-((4-(methyl) Thio)phenyl)amino)pyridazine-3-carboxylate methyl ester 12a (540 mg, yellow solid), yield: 87%.
MS m/z(ESI):310[M+1]MS m/z(ESI): 310[M+1]
第二步second step
6-(2,6-二氟苯基)-4-((4-(甲硫基)苯基)氨基)哒嗪-3-羧酸甲酯Methyl 6-(2,6-difluorophenyl)-4-((4-(methylthio)phenyl)amino)pyridazine-3-carboxylate
将化合物6-氯-4-((4-(甲硫基)苯基)氨基)哒嗪-3-羧酸甲酯12a(155mg，0.5mmol)、2,6-二氟苯硼酸(237mg，1.5mmol)、二异丙基乙基胺(194mg，1.5mmol)和四(三苯基膦)钯(58mg，0.05mmol)溶于1,4-二氧六环(6mL)，除氧后在氮气气氛下用微波反应器加热到110℃并搅拌1小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝50/1至3/1)纯化，得到目标产物6-(2,6-二氟苯基)-4-((4-(甲硫基)苯基)氨基)哒嗪-3-羧酸甲酯12b(100mg，黄色固体)，产率：52％。Compound 6-chloro-4-((4-(methylthio)phenyl)amino)pyridazine-3-carboxylate methyl ester 12a (155 mg, 0.5 mmol), 2,6-difluorophenylboronic acid (237 mg, 1.5 mmol), diisopropylethylamine (194 mg, 1.5 mmol) and tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) were dissolved in 1,4-dioxane (6 mL), deoxygenated in The microwave reactor was heated to 110°C under nitrogen atmosphere and stirred for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/1 to 3/1) to obtain the target product 6-(2,6-difluorophenyl) -4-((4-(methylthio)phenyl)amino)pyridazine-3-carboxylate methyl ester 12b (100 mg, yellow solid), yield: 52%.
MS m/z(ESI):388[M+1]MS m/z(ESI): 388[M+1]
第三步third step
6-(2,6-二氟苯基)-4-((4-(甲基亚硫酰基)苯基)氨基)哒嗪-3-羧酸甲酯Methyl 6-(2,6-difluorophenyl)-4-((4-(methylsulfinyl)phenyl)amino)pyridazine-3-carboxylate
将化合物6-(2,6-二氟苯基)-4-((4-(甲硫基)苯基)氨基)哒嗪-3-羧酸甲酯12b(100mg，0.26mmol)溶于二氯甲烷(20mL)后，加入间氯过氧苯甲酸(60％，58mg，0.22mmol)。室温下搅拌2小时后，用二氯甲烷(30mL)稀释，依次用饱和碳酸氢钠(10mL)和水(10mL)洗涤，然后用无水硫酸钠干燥。过滤后滤液在减压条件下除去溶剂得到目标产物6-(2,6-二氟苯基)-4-((4-(甲基亚硫酰基)苯基)氨基)哒嗪-3-羧酸甲酯12c(130mg，粗品，淡黄色固体)。该产品未经进一步纯化，直接用于下一步反应。Compound 6-(2,6-difluorophenyl)-4-((4-(methylthio)phenyl)amino)pyridazine-3-carboxylate methyl ester 12b (100 mg, 0.26 mmol) was dissolved in two After methyl chloride (20 mL), m-chloroperoxybenzoic acid (60%, 58 mg, 0.22 mmol) was added. After stirring at room temperature for 2 hours, it was diluted with dichloromethane (30 mL), washed successively with saturated sodium bicarbonate (10 mL) and water (10 mL), and then dried over anhydrous sodium sulfate. After filtration, the solvent was removed from the filtrate under reduced pressure to obtain the target product 6-(2,6-difluorophenyl)-4-((4-(methylsulfinyl)phenyl)amino)pyridazine-3-carboxylate Methyl acid 12c (130 mg, crude, pale yellow solid). This product was used directly in the next reaction without further purification.
MS m/z(ESI):404[M+1]MS m/z(ESI): 404[M+1]
第四步the fourth step
6-(2,6-二氟苯基)-4-((4-(甲基亚硫酰基)苯基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((4-(methylsulfinyl)phenyl)amino)pyridazine-3-carboxamide
将化合物6-(2,6-二氟苯基)-4-((4-(甲基亚硫酰基)苯基)氨基)哒嗪-3-羧酸甲酯12c(130mg，粗品)溶于四氢呋喃(10mL)，然后加入氨水(3mL)。室温下搅拌15小时后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2,6-二氟苯基)-4-((4-(甲基亚硫酰基)苯基)氨基)哒嗪-3-甲酰胺12(62.5mg，白色固体)，产率：两步54％。Compound 6-(2,6-difluorophenyl)-4-((4-(methylsulfinyl)phenyl)amino)pyridazine-3-carboxylate methyl ester 12c (130 mg, crude) was dissolved in Tetrahydrofuran (10 mL), then ammonia (3 mL) was added. After stirring at room temperature for 15 hours, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high performance liquid chromatography to obtain the target product 6-(2,6-difluorophenyl)-4-((4-(methylidene) Sulfuryl)phenyl)amino)pyridazine-3-carboxamide 12 (62.5 mg, white solid), yield: 54% for two steps.
MS m/z(ESI):389[M+1]MS m/z(ESI): 389[M+1]
1H NMR(400MHz,CD 3OD)δ7.85–7.75(m,2H),7.63–7.53(m,3H),7.51(s,1H),7.22–7.12(m,2H),2.83(s,3H)。 1 H NMR (400MHz, CD 3 OD) δ 7.85-7.75(m, 2H), 7.63-7.53(m, 3H), 7.51(s, 1H), 7.22-7.12(m, 2H), 2.83(s, 3H).
实施例13Example 13
6-(2,6-二氟苯基)-4-((6-(甲磺酰)吡啶-3-基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((6-(methylsulfonyl)pyridin-3-yl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000044
Figure PCTCN2020108468-appb-000044
第一步first step
6-氯-4-((6-(甲硫基)吡啶-3-基)氨基)哒嗪-3-羧酸甲酯Methyl 6-chloro-4-((6-(methylthio)pyridin-3-yl)amino)pyridazine-3-carboxylate
将化合物4,6-二氯哒嗪-3-羧酸甲酯1a(100mg，0.483mmol)和6-(甲硫基)吡啶-3-胺(101mg，0.724mmol)溶于乙醇(2mL)，用微波反应器加热至110℃并搅拌1小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝2/1至1/1)纯化，得到目标产物6-氯-4-((6-(甲硫基)吡啶-3-基)氨基)哒嗪-3-羧酸甲酯13a(100mg，黄色固体)，产率：66％。Compound 4,6-dichloropyridazine-3-carboxylate methyl ester 1a (100 mg, 0.483 mmol) and 6-(methylthio)pyridin-3-amine (101 mg, 0.724 mmol) were dissolved in ethanol (2 mL), Heat to 110°C with a microwave reactor and stir for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1 to 1/1) to obtain the target product 6-chloro-4-((6-(methyl) Thio)pyridin-3-yl)amino)pyridazine-3-carboxylate methyl ester 13a (100 mg, yellow solid), yield: 66%.
MS m/z(ESI):311[M+1]MS m/z(ESI): 311[M+1]
第二步second step
6-(2,6-二氟苯基)-4-((6-(甲硫基)吡啶-3-基)氨基)哒嗪-3-羧酸甲酯Methyl 6-(2,6-difluorophenyl)-4-((6-(methylthio)pyridin-3-yl)amino)pyridazine-3-carboxylate
将化合物6-氯-4-((6-(甲硫基)吡啶-3-基)氨基)哒嗪-3-羧酸甲酯13a(100mg，0.321mmol)、2,6-二氟苯硼酸(101mg，0.642mmol)、二异丙基乙基胺(124mg，0.963mmol)和四(三苯基膦)钯(37mg，0.0321mmol)溶于1,4-二氧六环(5mL)，除氧后在氮气气氛下加热回流18小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化，得到目标产物6-(2,6-二氟苯基)-4-((6-(甲硫基)吡啶-3-基)氨基)哒嗪-3-羧酸甲酯13b(75mg，棕色固体)，产率：60％。Compound 6-chloro-4-((6-(methylthio)pyridin-3-yl)amino)pyridazine-3-carboxylate methyl ester 13a (100 mg, 0.321 mmol), 2,6-difluorophenylboronic acid (101 mg, 0.642 mmol), diisopropylethylamine (124 mg, 0.963 mmol) and tetrakis(triphenylphosphine)palladium (37 mg, 0.0321 mmol) were dissolved in 1,4-dioxane (5 mL), except After oxygen, it was heated to reflux under nitrogen atmosphere for 18 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain the target product 6-(2,6-difluorophenyl)-4-( Methyl (6-(methylthio)pyridin-3-yl)amino)pyridazine-3-carboxylate 13b (75 mg, brown solid), yield: 60%.
MS m/z(ESI):389[M+1]MS m/z(ESI): 389[M+1]
第三步third step
6-(2,6-二氟苯基)-4-((6-(甲硫基)吡啶-3-基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((6-(methylthio)pyridin-3-yl)amino)pyridazine-3-carboxamide
将化合物6-(2,6-二氟苯基)-4-((6-(甲硫基)吡啶-3-基)氨基)哒嗪-3-羧酸甲酯13b(75mg，0.192mmol)溶于四氢呋喃(3mL)，然后加入氨水(1mL)。室温下搅拌2小时后，减压除去溶剂，得到目标产物6-(2,6-二氟苯基)-4-((6-(甲硫基)吡啶-3-基)氨基)哒嗪-3-甲酰胺13c(60mg，粗 品)。该产品未经进一步纯化，直接用于下一步反应。Compound 6-(2,6-difluorophenyl)-4-((6-(methylthio)pyridin-3-yl)amino)pyridazine-3-carboxylate methyl ester 13b (75 mg, 0.192 mmol) Dissolve in tetrahydrofuran (3 mL), then add ammonia (1 mL). After stirring at room temperature for 2 hours, the solvent was removed under reduced pressure to give the desired product 6-(2,6-difluorophenyl)-4-((6-(methylthio)pyridin-3-yl)amino)pyridazine- 3-Carboxamide 13c (60 mg, crude). This product was used directly in the next reaction without further purification.
MS m/z(ESI):374[M+1]MS m/z(ESI): 374[M+1]
第四步the fourth step
6-(2,6-二氟苯基)-4-((6-(甲磺酰)吡啶-3-基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((6-(methylsulfonyl)pyridin-3-yl)amino)pyridazine-3-carboxamide
将化合物6-(2,6-二氟苯基)-4-((6-(甲硫基)吡啶-3-基)氨基)哒嗪-3-甲酰胺13c(60mg，粗品)溶于二氯甲烷(2mL)后，加入间氯过氧苯甲酸(60％，125mg，0.48mmol)。室温下搅拌2小时后，用饱和碳酸氢钠(4mL)淬灭反应，然后用二氯甲烷(10mL×2)萃取。有机相合并后，在减压条件下除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2,6-二氟苯基)-4-((6-(甲磺酰)吡啶-3-基)氨基)哒嗪-3-甲酰胺13(4.5mg，白色固体)，产率：两步6％。Compound 6-(2,6-difluorophenyl)-4-((6-(methylthio)pyridin-3-yl)amino)pyridazine-3-carboxamide 13c (60 mg, crude) was dissolved in dichloromethane After methyl chloride (2 mL), m-chloroperoxybenzoic acid (60%, 125 mg, 0.48 mmol) was added. After stirring at room temperature for 2 hours, the reaction was quenched with saturated sodium bicarbonate (4 mL), then extracted with dichloromethane (10 mL x 2). After the organic phases were combined, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to obtain the target product 6-(2,6-difluorophenyl)-4-((6-(methanesulfonic acid) Acyl)pyridin-3-yl)amino)pyridazine-3-carboxamide 13 (4.5 mg, white solid), yield: 6% for two steps.
MS m/z(ESI):406[M+1]MS m/z(ESI): 406[M+1]
1H NMR(400MHz,CDCl 3)δ11.16(s,1H),8.71(d,J＝2.3Hz,1H),8.32(s,1H),8.14(d,J＝8.4Hz,1H),7.84(dd,J＝8.5,2.5Hz,1H),7.58–7.40(m,2H),7.08(t,J＝8.2Hz,2H),5.81(s,1H),3.24(s,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 11.16 (s, 1H), 8.71 (d, J=2.3 Hz, 1H), 8.32 (s, 1H), 8.14 (d, J=8.4 Hz, 1H), 7.84 (dd, J=8.5, 2.5 Hz, 1H), 7.58–7.40 (m, 2H), 7.08 (t, J=8.2 Hz, 2H), 5.81 (s, 1H), 3.24 (s, 3H).
实施例14Example 14
6-(2,6-二氟苯基)-4-((5-(甲磺酰)吡啶-2-基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((5-(methylsulfonyl)pyridin-2-yl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000045
Figure PCTCN2020108468-appb-000045
第一步first step
6-氯-4-((5-(甲硫基)吡啶-2-基)氨基)哒嗪-3-羧酸甲酯Methyl 6-chloro-4-((5-(methylthio)pyridin-2-yl)amino)pyridazine-3-carboxylate
将化合物4,6-二氯哒嗪-3-羧酸甲酯1a(414mg，2.00mmol)和5-(甲硫基)吡啶-2-胺(280mg，2mmol)溶于乙醇(3mL)，用微波反应器加热120℃并搅拌3小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝50/1至1/1)纯化，得到目标产物6-氯-4-((5-(甲硫基)吡啶-2-基)氨基)哒嗪-3-羧酸甲酯14a(120mg，黄色油状物)，产率：19％。Compound 4,6-dichloropyridazine-3-carboxylate methyl ester 1a (414 mg, 2.00 mmol) and 5-(methylthio)pyridin-2-amine (280 mg, 2 mmol) were dissolved in ethanol (3 mL), The microwave reactor was heated to 120°C and stirred for 3 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/1 to 1/1) to obtain the target product 6-chloro-4-(((5-(methyl) Thio)pyridin-2-yl)amino)pyridazine-3-carboxylate methyl ester 14a (120 mg, yellow oil), yield: 19%.
MS m/z(ESI):311[M+1]MS m/z(ESI): 311[M+1]
第二步second step
6-(2,6-二氟苯基)-4-((5-(甲硫基)吡啶-2-基)氨基)哒嗪-3-羧酸甲酯Methyl 6-(2,6-difluorophenyl)-4-((5-(methylthio)pyridin-2-yl)amino)pyridazine-3-carboxylate
将化合物6-氯-4-((5-(甲硫基)吡啶-2-基)氨基)哒嗪-3-羧酸甲酯14a(120mg，0.38mmol)、2,6-二氟苯硼酸(182mg，1.14mmol)、二异丙基乙基胺(147mg，1.14mmol)和四(三苯基膦)钯(44mg，0.038mmol)溶于1,4-二氧六环(6mL)，除氧后在氮气气氛下用微波反应器加热到110℃并搅拌1小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝50/1至3/1)纯化，得到目标产物6-(2,6-二氟苯基)-4-((5-(甲硫基)吡啶-2-基)氨基)哒嗪-3-羧酸甲酯14b(110mg，黄色油状物)，产率：75％。Compound 6-chloro-4-((5-(methylthio)pyridin-2-yl)amino)pyridazine-3-carboxylate methyl ester 14a (120 mg, 0.38 mmol), 2,6-difluorophenylboronic acid (182 mg, 1.14 mmol), diisopropylethylamine (147 mg, 1.14 mmol) and tetrakis(triphenylphosphine)palladium (44 mg, 0.038 mmol) were dissolved in 1,4-dioxane (6 mL), except Oxygen was then heated to 110°C in a microwave reactor under nitrogen atmosphere and stirred for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/1 to 3/1) to obtain the target product 6-(2,6-difluorophenyl) - Methyl 4-((5-(methylthio)pyridin-2-yl)amino)pyridazine-3-carboxylate 14b (110 mg, yellow oil), yield: 75%.
MS m/z(ESI):389[M+1]MS m/z(ESI): 389[M+1]
第三步third step
6-(2,6-二氟苯基)-4-((5-(甲磺酰)吡啶-2-基)氨基)哒嗪-3-羧酸甲酯Methyl 6-(2,6-difluorophenyl)-4-((5-(methylsulfonyl)pyridin-2-yl)amino)pyridazine-3-carboxylate
将化合物6-(2,6-二氟苯基)-4-((5-(甲硫基)吡啶-2-基)氨基)哒嗪-3-羧酸甲酯14b(110mg，0.28mmol)溶于二氯甲烷(10mL)后，加入间氯过氧苯甲酸(60％，177mg，0.68mmol)。室温下搅拌2小时后，用二氯甲烷(50mL)稀释，依次用饱和碳酸氢钠(10mL)和水(10mL)洗涤，然后用无水硫酸钠干燥。过滤后滤液在减压条件下除去溶剂得到目标产物6-(2,6-二氟苯基)-4-((5-(甲磺酰)吡啶-2-基)氨基)哒嗪-3-羧酸甲酯14c(110mg，粗品，淡黄色油状物)。该产品未经进一步纯化，直接用于下一步反应。Compound 6-(2,6-difluorophenyl)-4-((5-(methylthio)pyridin-2-yl)amino)pyridazine-3-carboxylate methyl ester 14b (110 mg, 0.28 mmol) After dissolving in dichloromethane (10 mL), m-chloroperoxybenzoic acid (60%, 177 mg, 0.68 mmol) was added. After stirring at room temperature for 2 hours, it was diluted with dichloromethane (50 mL), washed successively with saturated sodium bicarbonate (10 mL) and water (10 mL), and then dried over anhydrous sodium sulfate. After filtration, the solvent was removed from the filtrate under reduced pressure to obtain the target product 6-(2,6-difluorophenyl)-4-((5-(methylsulfonyl)pyridin-2-yl)amino)pyridazine-3- Methyl carboxylate 14c (110 mg, crude, pale yellow oil). This product was used directly in the next reaction without further purification.
MS m/z(ESI):421[M+1]MS m/z(ESI): 421[M+1]
第四步the fourth step
6-(2,6-二氟苯基)-4-((5-(甲磺酰)吡啶-2-基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((5-(methylsulfonyl)pyridin-2-yl)amino)pyridazine-3-carboxamide
将化合物6-(2,6-二氟苯基)-4-((5-(甲磺酰)吡啶-2-基)氨基)哒嗪-3-羧酸甲酯14c(110mg，粗品)溶于四氢呋喃(10mL)，然后加入氨水(3mL)。室温下搅拌15小时后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2,6-二氟苯基)-4-((5-(甲磺酰)吡啶-2-基)氨基)哒嗪-3-甲酰胺14(7.4mg，近白色固体)，产率：两步7％。Compound 6-(2,6-difluorophenyl)-4-((5-(methylsulfonyl)pyridin-2-yl)amino)pyridazine-3-carboxylate methyl ester 14c (110 mg, crude) was dissolved in was dissolved in tetrahydrofuran (10 mL), followed by ammonia (3 mL). After stirring at room temperature for 15 hours, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to obtain the target product 6-(2,6-difluorophenyl)-4-((5-(methanesulfonyl) )pyridin-2-yl)amino)pyridazine-3-carboxamide 14 (7.4 mg, off-white solid), yield: 7% for two steps.
MS m/z(ESI):406[M+1]MS m/z(ESI): 406[M+1]
1H NMR(400MHz,DMSO-d 6)δ12.40(s,1H),9.16(s,1H),9.04(s,1H),8.79(s,1H),8.29(s,1H),8.19(s,1H),7.67(dt,J＝14.8,7.5Hz,1H),7.38-7.31(m,3H),3.26(s,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ12.40(s,1H), 9.16(s,1H), 9.04(s,1H), 8.79(s,1H), 8.29(s,1H), 8.19( s, 1H), 7.67 (dt, J=14.8, 7.5 Hz, 1H), 7.38-7.31 (m, 3H), 3.26 (s, 3H).
实施例15Example 15
6-(2-氯-6-氟苯基)-4-((4-(甲磺酰)苯基)氨基)哒嗪-3-甲酰胺6-(2-Chloro-6-fluorophenyl)-4-((4-(methylsulfonyl)phenyl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000046
Figure PCTCN2020108468-appb-000046
第一步first step
6-(2-氯-6-氟苯基)-4-((4-(甲硫基)苯基)氨基)哒嗪-3-羧酸甲酯Methyl 6-(2-chloro-6-fluorophenyl)-4-((4-(methylthio)phenyl)amino)pyridazine-3-carboxylate
将化合物6-氯-4-((4-(甲硫基)苯基)氨基)哒嗪-3-羧酸甲酯12a(155mg，0.5mmol)、2-氯-6-氟苯硼酸(262mg，1.5mmol)、二异丙基乙基胺(194mg，1.5mmol)和四(三苯基膦)钯(57mg，0.05mmol)溶于1,4-二氧六环(3mL)，除氧后在氮气气氛下用微波反应器加热到100℃并搅拌1小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝50/1至1/1)纯化，得到目标产物6-(2-氯-6-氟苯基)-4-((4-(甲硫基)苯基)氨基)哒嗪-3-羧酸甲酯15a(80mg，黄色油状物)，产率：39％。Compound 6-chloro-4-((4-(methylthio)phenyl)amino)pyridazine-3-carboxylate methyl ester 12a (155mg, 0.5mmol), 2-chloro-6-fluorophenylboronic acid (262mg , 1.5 mmol), diisopropylethylamine (194 mg, 1.5 mmol) and tetrakis(triphenylphosphine)palladium (57 mg, 0.05 mmol) were dissolved in 1,4-dioxane (3 mL), and after deoxygenation The microwave reactor was heated to 100°C under nitrogen atmosphere and stirred for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/1 to 1/1) to obtain the target product 6-(2-chloro-6-fluorophenyl) )-4-((4-(methylthio)phenyl)amino)pyridazine-3-carboxylate methyl ester 15a (80 mg, yellow oil), yield: 39%.
MS m/z(ESI):404[M+1]MS m/z(ESI): 404[M+1]
第二步second step
6-(2-氯-6-氟苯基)-4-((4-(甲磺酰)苯基)氨基)哒嗪-3-羧酸甲酯Methyl 6-(2-chloro-6-fluorophenyl)-4-((4-(methylsulfonyl)phenyl)amino)pyridazine-3-carboxylate
将化合物6-(2-氯-6-氟苯基)-4-((4-(甲硫基)苯基)氨基)哒嗪-3-羧酸甲酯15a(80mg，0.2mmol)溶于二氯甲烷(10mL)后，加入间氯过氧苯甲酸(60％，125mg，0.48mmol)。室温下搅拌2小时后，用二氯甲烷(40mL)稀释，依次用饱和碳酸氢钠(10mL)和水(10mL)洗涤，然后用无水硫酸钠干燥。过滤后滤液在减压条件下除去溶剂得到目标产物6-(2-氯-6-氟苯基)-4-((4-(甲磺酰)苯基)氨基)哒嗪-3-羧酸甲酯15b(75mg，淡黄色固体)，产率：86％。Compound 6-(2-chloro-6-fluorophenyl)-4-((4-(methylthio)phenyl)amino)pyridazine-3-carboxylate methyl ester 15a (80 mg, 0.2 mmol) was dissolved in After dichloromethane (10 mL), m-chloroperoxybenzoic acid (60%, 125 mg, 0.48 mmol) was added. After stirring at room temperature for 2 hours, it was diluted with dichloromethane (40 mL), washed successively with saturated sodium bicarbonate (10 mL) and water (10 mL), and then dried over anhydrous sodium sulfate. After filtration, the solvent was removed from the filtrate under reduced pressure to obtain the target product 6-(2-chloro-6-fluorophenyl)-4-((4-(methylsulfonyl)phenyl)amino)pyridazine-3-carboxylic acid Methyl ester 15b (75 mg, pale yellow solid), yield: 86%.
MS m/z(ESI):436[M+1]MS m/z(ESI): 436[M+1]
第三步third step
6-(2-氯-6-氟苯基)-4-((4-(甲磺酰)苯基)氨基)哒嗪-3-甲酰胺6-(2-Chloro-6-fluorophenyl)-4-((4-(methylsulfonyl)phenyl)amino)pyridazine-3-carboxamide
将化合物6-(2-氯-6-氟苯基)-4-((4-(甲磺酰)苯基)氨基)哒嗪-3-羧酸甲酯15b(75mg，0.17mmol)溶于四氢呋喃(10mL)，然后加入氨水(3 mL)。室温下搅拌15小时后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2-氯-6-氟苯基)-4-((4-(甲磺酰)苯基)氨基)哒嗪-3-甲酰胺15(5mg，白色固体)，产率：两步7％。Compound 6-(2-chloro-6-fluorophenyl)-4-((4-(methylsulfonyl)phenyl)amino)pyridazine-3-carboxylate methyl ester 15b (75 mg, 0.17 mmol) was dissolved in Tetrahydrofuran (10 mL), then ammonia (3 mL) was added. After stirring at room temperature for 15 hours, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to obtain the target product 6-(2-chloro-6-fluorophenyl)-4-((4-(methanesulfonic acid) Acyl)phenyl)amino)pyridazine-3-carboxamide 15 (5 mg, white solid), yield: 7% for two steps.
MS m/z(ESI):406[M+1]MS m/z(ESI): 406[M+1]
1H NMR(400MHz,CD 3OD)δ8.01(d,J＝8.7Hz,2H),7.64–7.50(m,4H),7.46(d,J＝8.2Hz,1H),7.30(t,J＝8.7Hz,1H),3.14(s,3H)。 1 H NMR (400 MHz, CD 3 OD) δ 8.01 (d, J=8.7 Hz, 2H), 7.64-7.50 (m, 4H), 7.46 (d, J=8.2 Hz, 1H), 7.30 (t, J = 8.7 Hz, 1H), 3.14 (s, 3H).
实施例16Example 16
6-(2,6-二氟苯基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)哒嗪-3-甲酰胺 6-(2,6-Difluorophenyl)-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000047
Figure PCTCN2020108468-appb-000047
第一步first step
6-氯-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)哒嗪-3-羧酸甲酯 Methyl 6-chloro-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)pyridazine-3-carboxylate
将化合物4,6-二氯哒嗪-3-羧酸甲酯1a(519mg，2.51mmol)和4-(五氟硫烷基)苯胺(500mg，2.28mmol)溶于乙醇(5mL)，加热至70℃并搅拌24小时。冷却到室温后，减压除去溶剂，得到目标产物6-氯-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)哒嗪-3-羧酸甲酯16a(1.37g，粗品)。该产品未经进一步纯化，直接用于下一步反应。 Compound 4,6-dichloropyridazine-3-carboxylate methyl ester 1a (519 mg, 2.51 mmol) and 4-(pentafluorosulfanyl)aniline (500 mg, 2.28 mmol) were dissolved in ethanol (5 mL) and heated to 70°C and stirring for 24 hours. After cooling to room temperature, the solvent was removed under reduced pressure to obtain the target product, methyl 6-chloro-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)pyridazine-3-carboxylate 16a ( 1.37g, crude). This product was used directly in the next reaction without further purification.
MS m/z(ESI):390[M+1]MS m/z(ESI): 390[M+1]
第二步second step
6-(2,6-二氟苯基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)哒嗪-3-羧酸甲酯 Methyl 6-(2,6-difluorophenyl)-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)pyridazine-3-carboxylate
将化合物6-氯-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)哒嗪-3-羧酸甲酯16a(1.37g，粗品)、2,6-二氟苯硼酸(1.4g，6.85mmol)、二异丙基乙基胺(2.36g，18.26mmol)和二(三苯基膦)二氯化钯(80mg，0.11mmol)溶于1,4-二氧六环(10mL)，除氧后在氮气气氛下加热回流18小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝100/0至3/2)纯化，得到目标产物6-(2,6-二氟苯基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)哒嗪-3-羧酸甲酯16b(53mg，黄色固体)，产率：两 步5％。 The compound 6-chloro-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)pyridazine-3-carboxylate methyl ester 16a (1.37g, crude), 2,6-di Fluorophenylboronic acid (1.4 g, 6.85 mmol), diisopropylethylamine (2.36 g, 18.26 mmol) and bis(triphenylphosphine)palladium dichloride (80 mg, 0.11 mmol) were dissolved in 1,4-bis Oxane (10 mL), deoxygenated and heated to reflux under nitrogen atmosphere for 18 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100/0 to 3/2) to obtain the target product 6-(2,6-difluorophenyl) - Methyl 4-((4-(pentafluoro-λ6 - sulfanyl)phenyl)amino)pyridazine-3-carboxylate 16b (53 mg, yellow solid), yield: 5% for two steps.
MS m/z(ESI):468[M+1]MS m/z(ESI): 468[M+1]
第三步third step
6-(2,6-二氟苯基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)哒嗪-3-甲酰胺 6-(2,6-Difluorophenyl)-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)pyridazine-3-carboxamide
将化合物6-(2,6-二氟苯基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)哒嗪-3-羧酸甲酯16b(53mg，0.11mmol)溶于四氢呋喃(3mL)，然后加入氨水(2mL)。室温下搅拌2小时后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2,6-二氟苯基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)哒嗪-3-甲酰胺16(4.4mg，白色固体)，产率：8％。 Compound 6-(2,6-difluorophenyl)-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)pyridazine-3-carboxylate methyl ester 16b (53 mg, 0.11 mmol) was dissolved in tetrahydrofuran (3 mL), then ammonia (2 mL) was added. After stirring at room temperature for 2 hours, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to obtain the target product 6-(2,6-difluorophenyl)-4-((4-(pentafluoro- λ 6 -Sulfanyl)phenyl)amino)pyridazine-3-carboxamide 16 (4.4 mg, white solid), yield: 8%.
MS m/z(ESI):406[M+1]MS m/z(ESI): 406[M+1]
1H NMR(400MHz,CD 3OD)δ7.97–8.00(m,2H),7.74–7.75(m,1H),7.70–7.72(m,1H),7.63(d,J＝8Hz,2H),7.26(t,J＝8Hz,2H)。 1 H NMR (400MHz, CD 3 OD) δ 7.97-8.00 (m, 2H), 7.74-7.75 (m, 1H), 7.70-7.72 (m, 1H), 7.63 (d, J=8Hz, 2H), 7.26 (t, J=8Hz, 2H).
实施例17Example 17
4-((4-(1H-四唑-5-基)苯基)氨基)-6-(2,6-二氟苯基)哒嗪-3-甲酰胺4-((4-(1H-Tetrazol-5-yl)phenyl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000048
Figure PCTCN2020108468-appb-000048
将化合物4-((4-氰基苯基)氨基)-6-(2,6-二氟苯基)哒嗪-3-甲酰胺9(100mg，0.285mmol)溶于N,N-二甲基甲酰胺(10mL)，然后加入叠氮钠(185mg，2.85mmol)和氯化铵(302mg，5.7mmol)，加热到140℃并搅拌1小时。冷却到室温后，用水(30mL)淬灭，然后用二氯甲烷(20mL×3)萃取。有机相合并后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物4-((4-(1H-四唑-5-基)苯基)氨基)-6-(2,6-二氟苯基)哒嗪-3-甲酰胺17(16mg，白色固体)，产率：14％。Compound 4-((4-cyanophenyl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxamide 9 (100 mg, 0.285 mmol) was dissolved in N,N-dimethyl formamide (10 mL), then sodium azide (185 mg, 2.85 mmol) and ammonium chloride (302 mg, 5.7 mmol) were added, heated to 140° C. and stirred for 1 hour. After cooling to room temperature, it was quenched with water (30 mL), then extracted with dichloromethane (20 mL x 3). After the organic phases were combined, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to obtain the target product 4-((4-(1H-tetrazol-5-yl)phenyl)amino)-6-( 2,6-Difluorophenyl)pyridazine-3-carboxamide 17 (16 mg, white solid), yield: 14%.
MS m/z(ESI):406[M+1]MS m/z(ESI): 406[M+1]
1H NMR(400MHz,DMSO-d 6)δ11.02(s,1H),8.81(s,1H),8.09(s,1H),8.06–7.99(m,2H),7.65–7.55(m,1H),7.51–7.40(m,3H),7.27(t,J＝8.2Hz,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ11.02(s,1H), 8.81(s,1H), 8.09(s,1H), 8.06-7.99(m,2H), 7.65-7.55(m,1H) ), 7.51–7.40 (m, 3H), 7.27 (t, J=8.2Hz, 2H).
实施例18Example 18
3-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)苯甲酸3-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)benzoic acid
Figure PCTCN2020108468-appb-000049
Figure PCTCN2020108468-appb-000049
第一步first step
4-((3-(叔-丁氧基羰基)苯基)氨基)-6-氯哒嗪-3-羧酸甲酯Methyl 4-((3-(tert-butoxycarbonyl)phenyl)amino)-6-chloropyridazine-3-carboxylate
将化合物4,6-二氯哒嗪-3-羧酸甲酯1a(353mg，1.71mmol)和3-氨基苯甲酸叔丁酯(300mg，1.55mmol)溶于乙醇(6mL)，加热至65℃并搅拌过夜。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝100/0至14/1)纯化，得到目标产物4-((3-(叔-丁氧基羰基)苯基)氨基)-6-氯哒嗪-3-羧酸甲酯18a(153mg，无色油状物)，产率：27％。Compound 4,6-dichloropyridazine-3-carboxylate methyl ester 1a (353 mg, 1.71 mmol) and tert-butyl 3-aminobenzoate (300 mg, 1.55 mmol) were dissolved in ethanol (6 mL) and heated to 65°C and stirred overnight. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100/0 to 14/1) to obtain the target product 4-((3-(tert-butoxy) Carbonyl)phenyl)amino)-6-chloropyridazine-3-carboxylic acid methyl ester 18a (153 mg, colorless oil), yield: 27%.
MS m/z(ESI):364[M+1]MS m/z(ESI): 364[M+1]
第二步second step
4-((3-(叔-丁氧基羰基)苯基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯Methyl 4-((3-(tert-butoxycarbonyl)phenyl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxylate
将化合物4-((3-(叔-丁氧基羰基)苯基)氨基)-6-氯哒嗪-3-羧酸甲酯18a(100mg，0.27mmol)、2,6-二氟苯硼酸(130mg，0.82mmol)、二异丙基乙基胺(249mg，1.92mmol)和二(三苯基膦)二氯化钯(4mg，0.005mmol)溶于1,4-二氧六环(4mL)，除氧后在氮气气氛下用微波反应器加热到110℃并搅拌1小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝100/0至24/1)纯化，得到目标产物4-((3-(叔-丁氧基羰基)苯基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯18b(49mg，黄色油状物)，产率：40％。Compound 4-((3-(tert-butoxycarbonyl)phenyl)amino)-6-chloropyridazine-3-carboxylate methyl ester 18a (100 mg, 0.27 mmol), 2,6-difluorophenylboronic acid (130 mg, 0.82 mmol), diisopropylethylamine (249 mg, 1.92 mmol) and bis(triphenylphosphine)palladium dichloride (4 mg, 0.005 mmol) were dissolved in 1,4-dioxane (4 mL) ), deoxygenated and heated to 110°C with a microwave reactor under nitrogen atmosphere and stirred for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100/0 to 24/1) to obtain the target product 4-((3-(tert-butoxy) Carbonyl)phenyl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxylic acid methyl ester 18b (49 mg, yellow oil), yield: 40%.
MS m/z(ESI):442[M+1]MS m/z(ESI): 442[M+1]
第三步third step
3-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)苯甲酸叔丁酯tert-Butyl 3-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)benzoate
将化合物4-((3-(叔-丁氧基羰基)苯基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯18b(76mg，0.17mmol)溶于四氢呋喃(8mL)，然后加入氨水(2.5mL)。室温下搅拌15小时后，减压除去溶剂，得到目标产物3-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)苯甲酸叔丁酯18c(59 mg，粗品)。该产品未经进一步纯化，直接用于下一步反应。Compound 4-((3-(tert-butoxycarbonyl)phenyl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxylate methyl ester 18b (76 mg, 0.17 mmol) Dissolve in tetrahydrofuran (8 mL), then add ammonia (2.5 mL). After stirring at room temperature for 15 hours, the solvent was removed under reduced pressure to give the target product tert-butyl 3-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)benzoate Ester 18c (59 mg, crude). This product was used directly in the next reaction without further purification.
MS m/z(ESI):427[M+1]MS m/z(ESI): 427[M+1]
第四步the fourth step
3-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)苯甲酸3-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)benzoic acid
将化合物3-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)苯甲酸叔丁酯18c(59mg，粗品)溶于三氟乙酸(3mL)并搅拌1小时。减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物3-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)苯甲酸18(23mg，黄色固体)，产率：两步36％。Compound 3-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)benzoic acid tert-butyl ester 18c (59 mg, crude) was dissolved in trifluoroacetic acid ( 3 mL) and stirred for 1 hour. The solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to give the target product 3-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino ) benzoic acid 18 (23 mg, yellow solid), yield: 36% for two steps.
MS m/z(ESI):371[M+1]MS m/z(ESI): 371[M+1]
1H NMR(400MHz,DMSO-d 6)δ11.20(s,1H),8.78(s,1H),8.17(s,2H),7.84–7.28(m,8H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.20 (s, 1H), 8.78 (s, 1H), 8.17 (s, 2H), 7.84-7.28 (m, 8H).
实施例19Example 19
4-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)苯甲酸4-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)benzoic acid
Figure PCTCN2020108468-appb-000050
Figure PCTCN2020108468-appb-000050
将化合物4-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)苯甲酸叔丁酯10d(205mg，0.48mmol)溶于三氟乙酸(5mL)并搅拌1小时。减压除去溶剂，得到一粗品(180mg，黄色固体)。从该粗品中取出60mg粗品用反相制备高效液相色谱纯化，得到目标产物4-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)苯甲酸19(20mg，白色固体)。Compound 4-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)benzoic acid tert-butyl ester 10d (205 mg, 0.48 mmol) was dissolved in trifluoroacetic acid (5 mL) and stirred for 1 hour. The solvent was removed under reduced pressure to give a crude product (180 mg, yellow solid). 60 mg of the crude product was taken out of the crude product and purified by reverse-phase preparative high performance liquid chromatography to obtain the target product 4-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino ) benzoic acid 19 (20 mg, white solid).
MS m/z(ESI):371[M+1]MS m/z(ESI): 371[M+1]
1H NMR(400MHz,DMSO-d 6)δ12.88(s,1H),11.19(s,1H),8.85(s,1H),8.13(s,1H),7.96(d,J＝8.5Hz,2H),7.67–7.55(m,2H),7.44(d,J＝8.6Hz,2H),7.27(dd,J＝14.0,5.8Hz,2H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 12.88(s, 1H), 11.19(s, 1H), 8.85(s, 1H), 8.13(s, 1H), 7.96(d, J=8.5Hz, 2H), 7.67–7.55 (m, 2H), 7.44 (d, J=8.6 Hz, 2H), 7.27 (dd, J=14.0, 5.8 Hz, 2H).
实施例20Example 20
6-(2,6-二氟苯基)-4-((4-(甲基氨基甲酰)苯基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((4-(methylcarbamoyl)phenyl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000051
Figure PCTCN2020108468-appb-000051
将化合物4-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)苯甲酸19(60mg，0.16mmol)与二氯亚砜(5mL)混合，然后加热至40℃并搅拌1小时。冷却到室温后，减压除去溶剂。残余物溶于无水四氢呋喃(5mL)中，然后加入甲胺的四氢呋喃溶液(1M，2mL，2mmol)并搅拌1小时。在减压条件下除去溶剂后，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2,6-二氟苯基)-4-((4-(甲基氨基甲酰)苯基)氨基)哒嗪-3-甲酰胺20(25.3mg，白色固体)，产率：41％。Compound 4-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)benzoic acid 19 (60 mg, 0.16 mmol) was combined with thionyl chloride (5 mL) Mix, then heat to 40°C and stir for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was dissolved in dry tetrahydrofuran (5 mL), then methylamine in tetrahydrofuran (1 M, 2 mL, 2 mmol) was added and stirred for 1 hour. After removing the solvent under reduced pressure, the residue was purified by reverse-phase preparative high-performance liquid chromatography to give the target product 6-(2,6-difluorophenyl)-4-((4-(methylcarbamoyl) Phenyl)amino)pyridazine-3-carboxamide 20 (25.3 mg, white solid), yield: 41%.
MS m/z(ESI):384[M+1]MS m/z(ESI): 384[M+1]
1H NMR(400MHz,CD 3OD)δ7.94–7.87(m,2H),7.58(ddd,J＝14.9,8.5,6.4Hz,1H),7.49(s,1H),7.47–7.41(m,2H),7.17(t,J＝8.2Hz,2H),2.93(s,3H)。 1 H NMR (400MHz, CD 3 OD) δ 7.94-7.87 (m, 2H), 7.58 (ddd, J=14.9, 8.5, 6.4Hz, 1H), 7.49 (s, 1H), 7.47-7.41 (m, 2H), 7.17(t, J=8.2Hz, 2H), 2.93(s, 3H).
实施例22Example 22
6-(2,6-二氟苯基)-4-((4-((四氢-2H-吡喃-4-基)氨基甲酰)苯基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((4-((tetrahydro-2H-pyran-4-yl)carbamoyl)phenyl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000052
Figure PCTCN2020108468-appb-000052
将化合物4-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)苯甲酸19(60mg，0.16mmol)、四氢-2H-吡喃-4-胺22a(32mg，0.32mmol)、二异丙基乙基胺(42mg，0.32mmol)和N,N-二甲基甲酰胺(3mL)混合，然后加入O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓六氟磷酸盐(121mg，0.32mmol)。室温下搅拌1小时后，用水淬灭，然后在 减压条件下除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2,6-二氟苯基)-4-((4-((四氢-2H-吡喃-4-基)氨基甲酰)苯基)氨基)哒嗪-3-甲酰胺22(27.9mg，白色固体)，产率：38％。Compound 4-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)benzoic acid 19 (60 mg, 0.16 mmol), tetrahydro-2H-pyran -4-amine 22a (32 mg, 0.32 mmol), diisopropylethylamine (42 mg, 0.32 mmol) and N,N-dimethylformamide (3 mL) were mixed, followed by O-(7-azabenzene) Triazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (121 mg, 0.32 mmol). After stirring at room temperature for 1 hour, quenched with water, then the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to give the desired product 6-(2,6-difluorophenyl)-4- ((4-((Tetrahydro-2H-pyran-4-yl)carbamoyl)phenyl)amino)pyridazine-3-carboxamide 22 (27.9 mg, white solid), yield: 38%.
MS m/z(ESI):454[M+1]MS m/z(ESI): 454[M+1]
1H NMR(400MHz,CD 3OD)δ7.92(d,J＝8.6Hz,2H),7.58(ddd,J＝14.9,8.4,6.4Hz,1H),7.49(s,1H),7.44(d,J＝8.6Hz,2H),7.25–7.08(m,2H),4.19–4.06(m,1H),4.00(dd,J＝11.9,2.4Hz,2H),3.54(dd,J＝11.9,10.0Hz,2H),1.92(dd,J＝12.6,2.3Hz,2H),1.72-1.66(m,2H)。 1 H NMR (400MHz, CD 3 OD) δ 7.92(d, J=8.6Hz, 2H), 7.58(ddd, J=14.9, 8.4, 6.4Hz, 1H), 7.49(s, 1H), 7.44(d , J=8.6Hz, 2H), 7.25–7.08 (m, 2H), 4.19–4.06 (m, 1H), 4.00 (dd, J=11.9, 2.4Hz, 2H), 3.54 (dd, J=11.9, 10.0 Hz, 2H), 1.92 (dd, J=12.6, 2.3 Hz, 2H), 1.72-1.66 (m, 2H).
以下实施例(实施例21、实施例23、实施例24、实施例25、实施例27、实施例28、实施例29、实施例30)均参照实施例22的操作方法合成，但在第一步中用不同的胺代替四氢-2H-吡喃-4-胺22a，如下表所示：The following examples (Example 21, Example 23, Example 24, Example 25, Example 27, Example 28, Example 29, Example 30) are all synthesized with reference to the operation method of Example 22, but in the first example In this step, tetrahydro-2H-pyran-4-amine 22a was replaced with a different amine, as shown in the following table:
Figure PCTCN2020108468-appb-000053
Figure PCTCN2020108468-appb-000053
Figure PCTCN2020108468-appb-000054
Figure PCTCN2020108468-appb-000054
实施例26Example 26
6-(2,6-二氟苯基)-4-((4-(哌啶-4-基氨基甲酰基)苯基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((4-(piperidin-4-ylcarbamoyl)phenyl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000055
Figure PCTCN2020108468-appb-000055
第一步first step
4-(4-(3-氨基甲酰基-6-(2,6-二氟苯基)哒嗪-4-基)氨基)苯甲酰氨基哌啶-1-羧酸叔丁酯4-(4-(3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)benzoylaminopiperidine-1-carboxylate tert-butyl ester
将化合物4-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)苯甲酸19(60mg，0.16mmol)、4-氨基哌啶-1-甲酸叔丁酯(64mg，0.32mmol)、二异丙基乙基胺(62mg，0.48mmol)和N,N-二甲基甲酰胺(10mL)混合，然后加入O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓六氟磷酸盐(121mg，0.32mmol)。室温下搅拌1小时后，用水淬灭，然后在减压条件下除去溶剂，得到目标产物4-(4-(3-氨基甲酰基-6-(2,6-二氟苯基)哒嗪-4-基)氨基)苯甲酰氨基哌啶-1-羧酸叔丁酯26a(280mg，粗品)。该产品未经进一步纯化，直接用于下一步反应。Compound 4-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)benzoic acid 19 (60 mg, 0.16 mmol), 4-aminopiperidine-1 - tert-butyl formate (64 mg, 0.32 mmol), diisopropylethylamine (62 mg, 0.48 mmol) and N,N-dimethylformamide (10 mL) were mixed, then O-(7-azabenzene was added Triazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (121 mg, 0.32 mmol). After stirring at room temperature for 1 hour, quenched with water, then the solvent was removed under reduced pressure to give the desired product 4-(4-(3-carbamoyl-6-(2,6-difluorophenyl)pyridazine- 4-yl)amino)benzamidopiperidine-1-carboxylate tert-butyl ester 26a (280 mg, crude). This product was used directly in the next reaction without further purification.
MS m/z(ESI):553[M+1]MS m/z(ESI): 553[M+1]
第二步second step
6-(2,6-二氟苯基)-4-((4-(哌啶-4-基氨基甲酰基)苯基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((4-(piperidin-4-ylcarbamoyl)phenyl)amino)pyridazine-3-carboxamide
将化合物4-(4-(3-氨基甲酰基-6-(2,6-二氟苯基)哒嗪-4-基)氨基)苯甲酰氨基哌啶-1-羧酸叔丁酯26a(280mg，粗品)溶于二氯甲烷(10mL)，然后加入三氟乙酸(3mL)。室温下搅拌3小时后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2,6-二氟苯基)-4-((4-(哌啶-4-基氨基甲酰基)苯基)氨基)哒嗪-3-甲酰胺26(22.1mg，白色固体)，产率：两步30％。Compound 4-(4-(3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)benzamidopiperidine-1-carboxylate tert-butyl ester 26a (280 mg, crude) was dissolved in dichloromethane (10 mL), then trifluoroacetic acid (3 mL) was added. After stirring at room temperature for 3 hours, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to give the target product 6-(2,6-difluorophenyl)-4-((4-(piperidine- 4-ylcarbamoyl)phenyl)amino)pyridazine-3-carboxamide 26 (22.1 mg, white solid), yield: 30% for two steps.
MS m/z(ESI):453[M+1]MS m/z(ESI): 453[M+1]
1H NMR(400MHz,CD 3OD)δ7.79(d,J＝8.4Hz,2H),7.46(ddd,J＝14.8,8.4,6.5Hz,1H),7.37(s,1H),7.31(d,J＝8.6Hz,2H),7.05(t,J＝8.2Hz,2H),3.88(ddd,J＝15.2,11.2,3.9Hz,1H),3.01(d,J＝12.8Hz,2H),2.63(dd,J＝17.5,7.2Hz,2H),1.85(d,J＝13.3Hz,2H),1.46(qd,J＝12.3,3.9Hz,2H)。 1 H NMR (400MHz, CD 3 OD) δ 7.79(d, J=8.4Hz, 2H), 7.46(ddd, J=14.8, 8.4, 6.5Hz, 1H), 7.37(s, 1H), 7.31(d , J＝8.6Hz, 2H), 7.05(t, J＝8.2Hz, 2H), 3.88(ddd, J＝15.2, 11.2, 3.9Hz, 1H), 3.01(d, J＝12.8Hz, 2H), 2.63 (dd, J=17.5, 7.2 Hz, 2H), 1.85 (d, J=13.3 Hz, 2H), 1.46 (qd, J=12.3, 3.9 Hz, 2H).
实施例31Example 31
6-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)烟酸6-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)nicotinic acid
Figure PCTCN2020108468-appb-000056
Figure PCTCN2020108468-appb-000056
第一步first step
6-氯-4-((2,4-二甲氧苄基)氨基)哒嗪-3-羧酸甲酯Methyl 6-chloro-4-((2,4-dimethoxybenzyl)amino)pyridazine-3-carboxylate
将化合物4,6-二氯哒嗪-3-羧酸甲酯1a(20.7g，100mmol)、2,4-二甲氧基苄胺(17.5g，105mmol)和二异丙基乙基胺(25.84g，200mmol)溶于乙腈(800mL)。室温搅拌15小时后，减压除去溶剂，残余物分散至水(1L)中。搅拌30分钟后过滤，滤出的固体依次用水(300mL)和冷乙腈(300mL)洗涤，得到目标产物6-氯-4-((2,4-二甲氧苄基)氨基)哒嗪-3-羧酸甲酯31a(26g，白色固体)，产率：76％。Compound 4,6-dichloropyridazine-3-carboxylate methyl ester 1a (20.7 g, 100 mmol), 2,4-dimethoxybenzylamine (17.5 g, 105 mmol) and diisopropylethylamine ( 25.84 g, 200 mmol) was dissolved in acetonitrile (800 mL). After stirring at room temperature for 15 hours, the solvent was removed under reduced pressure and the residue was dispersed in water (1 L). After stirring for 30 minutes, it was filtered, and the filtered solid was washed with water (300 mL) and cold acetonitrile (300 mL) successively to obtain the target product 6-chloro-4-((2,4-dimethoxybenzyl)amino)pyridazine-3 - Methyl carboxylate 31a (26 g, white solid), yield: 76%.
MS m/z(ESI):338[M+1]MS m/z(ESI): 338[M+1]
第二步second step
6-(2,6-二氟苯基)-4-((2,4-二甲氧基苄基)氨基)哒嗪-3-羧酸甲酯Methyl 6-(2,6-difluorophenyl)-4-((2,4-dimethoxybenzyl)amino)pyridazine-3-carboxylate
将化合物6-氯-4-((2,4-二甲氧苄基)氨基)哒嗪-3-羧酸甲酯31a(2g，6mmol)、2,6-二氟苯硼酸(2.84g，18mmol)、二异丙基乙基胺(2.34g，18mmol)和四(三苯基膦)钯(346mg，0.3mmol)溶于1,4-二氧六环(15mL)，除氧后在氮气气氛下用微波反应器加热到110℃并搅拌30分钟。以上操作步骤重复10次，将10份反应液合并，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝50/1至1/1)纯化，得到目标产物6-(2,6-二氟苯基)-4-((2,4-二甲氧基苄基)氨基)哒嗪-3-羧酸甲酯31b(20g，淡黄色固体)，产率：80％。Compound 6-chloro-4-((2,4-dimethoxybenzyl)amino)pyridazine-3-carboxylate methyl ester 31a (2 g, 6 mmol), 2,6-difluorophenylboronic acid (2.84 g, 18 mmol), diisopropylethylamine (2.34 g, 18 mmol) and tetrakis(triphenylphosphine)palladium (346 mg, 0.3 mmol) were dissolved in 1,4-dioxane (15 mL), deoxygenated under nitrogen The atmosphere was heated to 110°C with a microwave reactor and stirred for 30 minutes. The above operation steps were repeated 10 times, 10 reaction solutions were combined, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/1 to 1/1) to obtain the target product 6-( Methyl 2,6-difluorophenyl)-4-((2,4-dimethoxybenzyl)amino)pyridazine-3-carboxylate 31b (20 g, pale yellow solid), yield: 80% .
MS m/z(ESI):416[M+1]MS m/z(ESI): 416[M+1]
第三步third step
4-氨基-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯Methyl 4-amino-6-(2,6-difluorophenyl)pyridazine-3-carboxylate
将化合物6-(2,6-二氟苯基)-4-((2,4-二甲氧基苄基)氨基)哒嗪-3-羧酸甲酯31b(20g，48.2mmol)溶于三氟乙酸(100mL)。室温下搅拌15小时后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物4-氨基-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯31c(7g，白色固体)，产率：70％。Compound 6-(2,6-difluorophenyl)-4-((2,4-dimethoxybenzyl)amino)pyridazine-3-carboxylate methyl ester 31b (20 g, 48.2 mmol) was dissolved in Trifluoroacetic acid (100 mL). After stirring at room temperature for 15 hours, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to obtain the target product 4-amino-6-(2,6-difluorophenyl)pyridazine-3-carboxylic acid Methyl ester 31c (7 g, white solid), yield: 70%.
MS m/z(ESI):266[M+1]MS m/z(ESI): 266[M+1]
第四步the fourth step
4-((5-(叔丁氧羰基)吡啶-2-基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸4-((5-(tert-butoxycarbonyl)pyridin-2-yl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxylic acid
将化合物4-氨基-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯31c(200mg，0.751mmol)、6-氯烟酸叔丁酯(160mg，0.751mmol)、三(二亚苄基丙酮)二钯(69mg，0.0752mmol)、2-二环己基磷-2,4,6-三异丙基联苯(62mg，0.15mmol)、碳酸铯(487mg，1.5mmol)和1,4-二氧六环(10mL)混合，除氧后在氮气气氛下用微波反应器加热到90℃并搅拌1小时。冷却到室温后过滤，滤液在减压条件下除去溶剂，残余物用硅胶柱层析(二氯甲烷/甲醇＝3/1)纯化，得到目标产物4-((5-(叔丁氧羰基)吡啶-2-基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸31d(100mg，黄色固体)，产率：31％。Compound 4-amino-6-(2,6-difluorophenyl)pyridazine-3-carboxylate methyl ester 31c (200 mg, 0.751 mmol), tert-butyl 6-chloronicotinate (160 mg, 0.751 mmol), Tris(dibenzylideneacetone)dipalladium (69mg, 0.0752mmol), 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl (62mg, 0.15mmol), cesium carbonate (487mg, 1.5mmol) ) and 1,4-dioxane (10 mL), deoxygenated, heated to 90° C. with a microwave reactor under nitrogen atmosphere and stirred for 1 hour. After cooling to room temperature, the filtrate was filtered, and the solvent was removed from the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=3/1) to obtain the target product 4-((5-(tert-butoxycarbonyl) Pyridin-2-yl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxylic acid 31d (100 mg, yellow solid), yield: 31%.
MS m/z(ESI):429[M+1]MS m/z(ESI): 429[M+1]
第五步the fifth step
6-((3-氨基甲酰基-6-(2,6-二氟苯基)哒嗪-4-基)氨基)烟酸叔丁酯tert-Butyl 6-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)nicotinate
将化合物4-((5-(叔丁氧羰基)吡啶-2-基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸31d(100mg，0.233mmol)和二氯亚砜(10mL)混合，室温下搅拌10分钟后在减压条件下除去溶剂。残余物溶于四氢呋喃(5mL)，然后加入氨水(1mL)。室温下搅拌1小时后，减压除去溶剂，得到目标产物6-((3-氨基甲酰基-6-(2,6-二氟苯基)哒嗪-4-基)氨基)烟酸叔丁酯31e(102mg，粗品)。该产品未经进一步纯化，直接用于下一步反应。Compound 4-((5-(tert-butoxycarbonyl)pyridin-2-yl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxylic acid 31d (100 mg, 0.233 mmol) and Mix with thionyl chloride (10 mL), stir at room temperature for 10 minutes and remove the solvent under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL), and ammonia (1 mL) was added. After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure to obtain the target product, tert-butyl 6-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)nicotinic acid. Ester 31e (102 mg, crude). This product was used directly in the next reaction without further purification.
MS m/z(ESI):428[M+1]MS m/z(ESI): 428[M+1]
第六步Step 6
6-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)烟酸6-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)nicotinic acid
将化合物6-((3-氨基甲酰基-6-(2,6-二氟苯基)哒嗪-4-基)氨基)烟酸叔丁酯31e(102mg，粗品)和三氟乙酸(10mL)混合，室温下搅拌10分钟，然后减压除去溶剂。残余物与氨水(5mL)混合，然后搅拌2小时。减压除去溶剂，残余物用反相制备液相色谱纯化，得到目标产物6-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)烟酸31(30mg，白色固体)，产率：两步34％。Compound 6-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)nicotinic acid tert-butyl ester 31e (102 mg, crude) and trifluoroacetic acid (10 mL) were combined ) and stirred at room temperature for 10 minutes, then the solvent was removed under reduced pressure. The residue was mixed with aqueous ammonia (5 mL) and stirred for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative liquid chromatography to give the desired product 6-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino) Niacin 31 (30 mg, white solid), yield: 34% for two steps.
MS m/z(ESI):372[M+1]MS m/z(ESI): 372[M+1]
1H NMR(400MHz,DMSO-d 6)δ12.27(s,1H),9.17(s,1H),8.99(s,1H),8.84(d,J＝2.1Hz,1H),8.27(s,1H),8.19(dd,J＝8.6,2.2Hz,1H),7.71–7.62(m,1H),7.35(t,J＝8.1Hz,2H),7.17(d,J＝8.6Hz,1H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 12.27(s, 1H), 9.17(s, 1H), 8.99(s, 1H), 8.84(d, J=2.1Hz, 1H), 8.27(s, 1H), 8.19 (dd, J=8.6, 2.2Hz, 1H), 7.71–7.62 (m, 1H), 7.35 (t, J=8.1Hz, 2H), 7.17 (d, J=8.6Hz, 1H).
实施例32和33Examples 32 and 33
4-((5-氨基甲酰吡啶-2-基)氨基)-6-(2,6-二氟苯基)哒嗪-3-甲酰胺32和6-(2,6-二氟苯基)-4-((5-(吗啉-4-羰基)吡啶-2-基)氨基)哒嗪-3-甲酰胺334-((5-carbamoylpyridin-2-yl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxamide 32 and 6-(2,6-difluorophenyl) )-4-((5-(morpholine-4-carbonyl)pyridin-2-yl)amino)pyridazine-3-carboxamide 33
Figure PCTCN2020108468-appb-000057
Figure PCTCN2020108468-appb-000057
将化合物6-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)烟酸31(100mg，0.27mmol)溶于二氯甲烷(10mL)中，然后依次加入O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓六氟磷酸盐(123mg，0.323mmol)、二异丙基乙基胺(70mg，0.54mmol)和吗啉(28mg，0.323mmol)。室温下搅拌1小时后，用水淬灭，然后在减压条件下除去溶剂，残余物用反相制备高效液相色谱(流动相：水(含0.5％氨水)和乙腈)纯化，得到目标产物4-((5-氨基甲酰吡啶-2-基)氨基)-6-(2,6-二氟苯基)哒嗪-3-甲酰胺32(15mg，白色固体，转氨反应副产物)，产率：15％；以及6-(2,6-二氟苯基)-4-((5-(吗啉-4-羰基)吡啶-2-基)氨基)哒嗪-3-甲酰胺33(20mg，白色固体)，产率：17％。Compound 6-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)nicotinic acid 31 (100 mg, 0.27 mmol) was dissolved in dichloromethane (10 mL) , and then added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (123 mg, 0.323 mmol), diiso Propylethylamine (70 mg, 0.54 mmol) and morpholine (28 mg, 0.323 mmol). After stirring at room temperature for 1 hour, quenched with water, then the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high performance liquid chromatography (mobile phase: water (containing 0.5% ammonia) and acetonitrile) to give the target product 4 -((5-carbamoylpyridin-2-yl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxamide 32 (15 mg, white solid, by-product of transamination), Yield: 15%; and 6-(2,6-difluorophenyl)-4-((5-(morpholin-4-carbonyl)pyridin-2-yl)amino)pyridazine-3-carboxamide 33 (20 mg, white solid), yield: 17%.
4-((5-氨基甲酰吡啶-2-基)氨基)-6-(2,6-二氟苯基)哒嗪-3-甲酰胺324-((5-carbamoylpyridin-2-yl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxamide 32
MS m/z(ESI):371[M+1]MS m/z(ESI): 371[M+1]
1H NMR(400MHz,DMSO-d 6)δ12.20(s,1H),9.18(s,1H),8.98(s,1H),8.84(d,J＝1.8Hz,1H),8.30–8.15(m,2H),7.98(s,1H),7.67(t,J＝7.4Hz,1H),7.37(dd,J＝24.6,16.5Hz,3H),7.19(d,J＝8.6Hz,1H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 12.20(s, 1H), 9.18(s, 1H), 8.98(s, 1H), 8.84(d, J=1.8Hz, 1H), 8.30-8.15( m, 2H), 7.98 (s, 1H), 7.67 (t, J=7.4Hz, 1H), 7.37 (dd, J=24.6, 16.5Hz, 3H), 7.19 (d, J=8.6Hz, 1H).
6-(2,6-二氟苯基)-4-((5-(吗啉-4-羰基)吡啶-2-基)氨基)哒嗪-3-甲酰胺336-(2,6-Difluorophenyl)-4-((5-(morpholine-4-carbonyl)pyridin-2-yl)amino)pyridazine-3-carboxamide 33
MS m/z(ESI):441[M+1]MS m/z(ESI): 441[M+1]
1H NMR(400MHz,CD 3OD)δ12.17(s,1H),9.13(s,1H),8.98(s,1H),8.43(s,1H),8.25(s,1H),7.85(d,J＝8.1Hz,1H),7.74–7.61(m,1H),7.34(t,J＝8.0Hz,2H),7.19(d,J＝8.4Hz,1H),3.60(brs,4H),3.51(brs,4H)。 1 H NMR (400MHz, CD 3 OD) δ 12.17(s, 1H), 9.13(s, 1H), 8.98(s, 1H), 8.43(s, 1H), 8.25(s, 1H), 7.85(d , J=8.1Hz, 1H), 7.74–7.61 (m, 1H), 7.34 (t, J=8.0Hz, 2H), 7.19 (d, J=8.4Hz, 1H), 3.60 (brs, 4H), 3.51 (brs, 4H).
实施例34Example 34
5-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)邻吡啶甲酸5-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)o-picolinic acid
Figure PCTCN2020108468-appb-000058
Figure PCTCN2020108468-appb-000058
第一步first step
4-((6-(叔-丁氧基羰基)吡啶-3-基)氨基)-6-氯哒嗪-3-羧酸甲酯Methyl 4-((6-(tert-butoxycarbonyl)pyridin-3-yl)amino)-6-chloropyridazine-3-carboxylate
将化合物5-氨基吡啶-2-甲酸叔丁酯(300mg，1.54mmol)溶于无水四氢呋喃(15mL)，然后依次加入氢化钠(60％，618mg，15.4mmol)和4,6-二氯哒嗪-3-羧酸甲酯1a(959mg，4.63mmol)。室温下搅拌3天后，用甲醇(5mL)淬灭反应，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝100/0至1/1)纯化，得到目标产物4-((6-(叔-丁氧基羰基)吡啶-3-基)氨基)-6-氯哒嗪-3-羧酸甲酯34a(75mg，黄色油状物)，产率：13％。The compound tert-butyl 5-aminopyridine-2-carboxylate (300 mg, 1.54 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL), then sodium hydride (60%, 618 mg, 15.4 mmol) and 4,6-dichloropyridine were sequentially added Methyl oxazine-3-carboxylate la (959 mg, 4.63 mmol). After stirring at room temperature for 3 days, the reaction was quenched with methanol (5 mL), the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100/0 to 1/1) to obtain the target product 4- ((6-(tert-Butoxycarbonyl)pyridin-3-yl)amino)-6-chloropyridazine-3-carboxylate methyl ester 34a (75 mg, yellow oil), yield: 13%.
MS m/z(ESI):365[M+1]MS m/z(ESI): 365[M+1]
第二步second step
4-((6-(叔-丁氧基羰基)吡啶-3-基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯Methyl 4-((6-(tert-butoxycarbonyl)pyridin-3-yl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxylate
将化合物4-((6-(叔-丁氧基羰基)吡啶-3-基)氨基)-6-氯哒嗪-3-羧酸甲酯34a(75mg，0.21mmol)、2,6-二氟苯硼酸(97mg，0.62mmol)、二异丙基乙基胺(186mg，1.44mmol)和二(三苯基膦)二氯化钯(3mg，0.004mmol)溶于1,4-二氧六环(6mL)，除氧后在氮气气氛下用微波反应器加热到110℃并搅拌1小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝100/0至1/1)纯化，得到目标产物4-((6-(叔-丁氧基羰基)吡啶-3-基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯34b(57mg，黄色油状物)，产率：63％。Compound 4-((6-(tert-butoxycarbonyl)pyridin-3-yl)amino)-6-chloropyridazine-3-carboxylate methyl ester 34a (75 mg, 0.21 mmol), 2,6-dicarboxylate Fluorophenylboronic acid (97 mg, 0.62 mmol), diisopropylethylamine (186 mg, 1.44 mmol) and bis(triphenylphosphine)palladium dichloride (3 mg, 0.004 mmol) were dissolved in 1,4-dioxane The ring (6 mL) was deoxygenated and heated to 110°C in a microwave reactor under nitrogen atmosphere and stirred for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100/0 to 1/1) to obtain the target product 4-((6-(tert-butoxy) Carbonyl)pyridin-3-yl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxylate methyl ester 34b (57 mg, yellow oil), yield: 63%.
MS m/z(ESI):443[M+1]MS m/z(ESI): 443[M+1]
第三步third step
5-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)吡啶-2-甲酸叔丁酯tert-Butyl 5-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)pyridine-2-carboxylate
将化合物4-((6-(叔-丁氧基羰基)吡啶-3-基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯34b(49mg，0.11mmol)溶于四氢呋喃(4mL)，加入 氨水(2.5mL)。然后加热到70℃并搅拌24小时。冷却到室温后，减压除去溶剂，得到目标产物5-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)吡啶-2-甲酸叔丁酯34c(42mg，粗品)。该产品未经进一步纯化，直接用于下一步反应。Compound 4-((6-(tert-butoxycarbonyl)pyridin-3-yl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxylate methyl ester 34b (49 mg, 0.11 mmol) was dissolved in tetrahydrofuran (4 mL), and aqueous ammonia (2.5 mL) was added. It was then heated to 70°C and stirred for 24 hours. After cooling to room temperature, the solvent was removed under reduced pressure to obtain the target product 5-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)pyridine-2-carboxylic acid tertiary Butyl ester 34c (42 mg, crude). This product was used directly in the next reaction without further purification.
MS m/z(ESI):428[M+1]MS m/z(ESI): 428[M+1]
第四步the fourth step
5-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)邻吡啶甲酸5-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)o-picolinic acid
将化合物5-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)吡啶-2-甲酸叔丁酯34c(42mg，粗品)溶于三氟乙酸(3mL)并搅拌1小时。减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物5-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)邻吡啶甲酸34(5.1mg，白色固体)，产率：两步11％。Compound 5-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)pyridine-2-carboxylate tert-butyl ester 34c (42 mg, crude) was dissolved in triplicate Fluoroacetic acid (3 mL) and stirred for 1 hour. The solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to give the target product 5-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino ) o-picolinic acid 34 (5.1 mg, white solid), yield: 11% for two steps.
MS m/z(ESI):372[M+1]MS m/z(ESI): 372[M+1]
1H NMR(400MHz,DMSO-d 6)δ11.43(s,1H),9.22(s,1H),8.47–8.50(m,1H),8.08(d,J＝8Hz,1H),7.71(s,1H),7.59–7.65(m,1H),7.29–7.33(m,2H),7.15(s,1H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 11.43 (s, 1H), 9.22 (s, 1H), 8.47-8.50 (m, 1H), 8.08 (d, J=8Hz, 1H), 7.71 (s , 1H), 7.59–7.65 (m, 1H), 7.29–7.33 (m, 2H), 7.15 (s, 1H).
实施例35Example 35
6-(2,6-二氟苯基)-4-(二氢吲哚-5-基氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-(indoline-5-ylamino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000059
Figure PCTCN2020108468-appb-000059
第一步first step
5-((6-氯-3-(甲氧羰基)哒嗪-4-基)氨基)二氢吲哚-1-羧酸叔丁酯5-((6-Chloro-3-(methoxycarbonyl)pyridazin-4-yl)amino)indoline-1-carboxylate tert-butyl ester
将化合物5-氨基二氢吲哚-1-羧酸叔丁酯(200mg，0.77mmol)和4,6-二氯哒嗪-3-羧酸甲酯1a(200mg，0.97mmol)溶于乙醇(10mL)，然后在密封管中加热到90℃并搅拌12小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化，得到目 标产物5-((6-氯-3-(甲氧羰基)哒嗪-4-基)氨基)二氢吲哚-1-羧酸叔丁酯35a(200mg，白色固体)，产率：58％。Compounds tert-butyl 5-aminoindoline-1-carboxylate (200 mg, 0.77 mmol) and methyl 4,6-dichloropyridazine-3-carboxylate 1a (200 mg, 0.97 mmol) were dissolved in ethanol ( 10 mL), then heated to 90°C in a sealed tube and stirred for 12 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain the target product 5-((6-chloro-3-(methoxycarbonyl)pyridine) Azin-4-yl)amino)indoline-1-carboxylate tert-butyl ester 35a (200 mg, white solid), yield: 58%.
MS m/z(ESI):405[M+1]MS m/z(ESI): 405[M+1]
第二步second step
5-((6-(2,6-二氟苯基)-3-(甲氧羰基)哒嗪-4-基)氨基)二氢吲哚-1-羧酸叔丁酯5-((6-(2,6-Difluorophenyl)-3-(methoxycarbonyl)pyridazin-4-yl)amino)indoline-1-carboxylate tert-butyl ester
将化合物5-((6-氯-3-(甲氧羰基)哒嗪-4-基)氨基)二氢吲哚-1-羧酸叔丁酯35a(100mg，0.247mmol)、2,6-二氟苯硼酸(47mg，0.30mmol)、二异丙基乙基胺(63mg，0.49mmol)和四(三苯基膦)钯(30mg，0.0247mmol)溶于1,4-二氧六环(6mL)，除氧后在氮气气氛下用微波反应器加热到110℃并搅拌1小时。冷却到室温后，过滤并在减压条件下除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝2/1至1/1)纯化，得到目标产物5-((6-(2,6-二氟苯基)-3-(甲氧羰基)哒嗪-4-基)氨基)二氢吲哚-1-羧酸叔丁酯35b(144mg，黄色固体)，产率：72％。Compound 5-((6-chloro-3-(methoxycarbonyl)pyridazin-4-yl)amino)indoline-1-carboxylate tert-butyl ester 35a (100 mg, 0.247 mmol), 2,6- Difluorophenylboronic acid (47 mg, 0.30 mmol), diisopropylethylamine (63 mg, 0.49 mmol) and tetrakis(triphenylphosphine)palladium (30 mg, 0.0247 mmol) were dissolved in 1,4-dioxane ( 6 mL), deoxygenated and heated to 110 °C in a microwave reactor under nitrogen atmosphere and stirred for 1 hour. After cooling to room temperature, filtering and removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1 to 1/1) to obtain the target product 5-((6-( 2,6-Difluorophenyl)-3-(methoxycarbonyl)pyridazin-4-yl)amino)indoline-1-carboxylate tert-butyl ester 35b (144 mg, yellow solid), yield: 72 %.
MS m/z(ESI):483[M+1]MS m/z(ESI): 483[M+1]
第三步third step
4-((1-(叔-丁氧基羰基)二氢吲哚-5-基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸4-((1-(tert-Butoxycarbonyl)indoline-5-yl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxylic acid
将化合物5-((6-(2,6-二氟苯基)-3-(甲氧羰基)哒嗪-4-基)氨基)二氢吲哚-1-羧酸叔丁酯35b(100mg，0.247mmol)溶于四氢呋喃(10mL)，然后加入氢氧化锂水溶液(15％，10mL)并搅拌过夜。反应完成后，用稀盐酸(1N)调节至pH＝6-7，然后用乙酸乙酯萃取(20mL×3)。有机相合并后，用饱和食盐水(20mL)洗涤并用无水硫酸钠干燥，过滤后滤液在减压条件下干燥，得到目标产物4-((1-(叔-丁氧基羰基)二氢吲哚-5-基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸35c(100mg，粗品)。该产品未经进一步纯化，直接用于下一步反应。Compound 5-((6-(2,6-difluorophenyl)-3-(methoxycarbonyl)pyridazin-4-yl)amino)indoline-1-carboxylate tert-butyl ester 35b (100 mg , 0.247 mmol) was dissolved in tetrahydrofuran (10 mL), then aqueous lithium hydroxide (15%, 10 mL) was added and stirred overnight. After the reaction was completed, it was adjusted to pH=6-7 with dilute hydrochloric acid (1N), and then extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was dried under reduced pressure to obtain the target product 4-((1-(tert-butoxycarbonyl)indoline) Indol-5-yl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxylic acid 35c (100 mg, crude). This product was used directly in the next reaction without further purification.
MS m/z(ESI):469[M+1]MS m/z(ESI): 469[M+1]
第四步the fourth step
5-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)二氢吲哚-1-羧酸叔丁酯5-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)indoline-1-carboxylate tert-butyl ester
将化合物4-((1-(叔-丁氧基羰基)二氢吲哚-5-基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸35c(100mg，粗品)溶于氯化亚砜(10mL)并搅拌10分钟，然后在减压条件下除去溶剂。残余物溶于四氢呋喃(10mL)，然后加入氨水(10mL)。室温下搅拌1小时后，减压除去溶剂，得到目标产物5-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)二氢吲哚-1-羧酸叔丁酯35d(100mg，粗品)。该产品未经进一步纯化，直接用于下一步反应。Compound 4-((1-(tert-butoxycarbonyl)indoline-5-yl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxylic acid 35c (100 mg , crude) was dissolved in thionyl chloride (10 mL) and stirred for 10 min, then the solvent was removed under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), and then aqueous ammonia (10 mL) was added. After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure to give the target product 5-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)indoline - 1-Carboxylic acid tert-butyl ester 35d (100 mg, crude). This product was used directly in the next reaction without further purification.
MS m/z(ESI):468[M+1]MS m/z(ESI): 468[M+1]
第五步the fifth step
6-(2,6-二氟苯基)-4-(二氢吲哚-5-基氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-(indoline-5-ylamino)pyridazine-3-carboxamide
将化合物5-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)二氢吲哚-1-羧酸叔丁酯35d(100mg，粗品)溶于三氟乙酸(10mL)并搅拌1小时。减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2,6-二氟苯基)-4-(二氢吲哚-5-基氨基)哒嗪-3-甲酰胺35(72mg，白色固体)，产率：三步92％。Compound 5-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)indoline-1-carboxylate tert-butyl ester 35d (100 mg, crude ) was dissolved in trifluoroacetic acid (10 mL) and stirred for 1 hour. The solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to give the target product 6-(2,6-difluorophenyl)-4-(indoline-5-ylamino)pyridazine-3 - Formamide 35 (72 mg, white solid), yield: 92% for three steps.
MS m/z(ESI):368[M+1]MS m/z(ESI): 368[M+1]
1H NMR(400MHz,DMSO-d 6)δ11.06(s,1H),8.80(s,1H),8.12(s,1H),7.68–7.57(m,1H),7.43(s,1H),7.37(d,J＝4.1Hz,2H),7.31(d,J＝3.2Hz,1H),7.28(s,1H),7.24(s,1H),7.11(s,1H),3.70(t,J＝7.9Hz,2H),3.18(t,J＝7.8Hz,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ11.06(s,1H), 8.80(s,1H), 8.12(s,1H), 7.68–7.57(m,1H), 7.43(s,1H), 7.37(d,J＝4.1Hz,2H),7.31(d,J＝3.2Hz,1H),7.28(s,1H),7.24(s,1H),7.11(s,1H),3.70(t,J = 7.9 Hz, 2H), 3.18 (t, J = 7.8 Hz, 2H).
实施例36Example 36
6-(2,6-二氟苯基)-4-((6-吗啉代吡啶-3-基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((6-morpholinopyridin-3-yl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000060
Figure PCTCN2020108468-appb-000060
第一步first step
6-氯-4-((6-吗啉代吡啶-3-基)氨基)哒嗪-3-羧酸甲酯Methyl 6-chloro-4-((6-morpholinopyridin-3-yl)amino)pyridazine-3-carboxylate
将化合物4,6-二氯哒嗪-3-羧酸甲酯1a(1g，4.83mmol)、6-吗啉代吡啶-3-胺(870mg，4.83mmol)、二异丙基乙基胺(1.24g，9.66mmol)和乙醇(20mL)混合，加热到80℃并搅拌18小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(二氯甲烷/甲醇＝19/1)纯化，得到目标产物6-氯-4-((6-吗啉代吡啶-3-基)氨基)哒嗪-3-羧酸甲酯36a(1.5g，黄色固体)，产率：89％。Compound 4,6-dichloropyridazine-3-carboxylate methyl ester 1a (1 g, 4.83 mmol), 6-morpholinopyridin-3-amine (870 mg, 4.83 mmol), diisopropylethylamine ( 1.24 g, 9.66 mmol) and ethanol (20 mL) were mixed, heated to 80°C and stirred for 18 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=19/1) to obtain the target product 6-chloro-4-((6-morpholinopyridine-3- (yl)amino)pyridazine-3-carboxylate methyl ester 36a (1.5 g, yellow solid), yield: 89%.
MS m/z(ESI):350[M+1]MS m/z(ESI): 350[M+1]
第二步second step
6-(2,6-二氟苯基)-4-((6-吗啉代吡啶-3-基)氨基)哒嗪-3-羧酸甲酯Methyl 6-(2,6-difluorophenyl)-4-((6-morpholinopyridin-3-yl)amino)pyridazine-3-carboxylate
将化合物6-氯-4-((6-吗啉代吡啶-3-基)氨基)哒嗪-3-羧酸甲酯36a (1.5g，4.29mmol)、2,6-二氟苯硼酸(2.03g，12.9mmol)、二异丙基乙基胺(1.66g，12.9mmol)和四(三苯基膦)钯(498mg，0.429mmol)溶于1,4-二氧六环(20mL)，除氧后在氮气气氛下用微波反应器加热到100℃并搅拌1小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(二氯甲烷/甲醇＝19/1)纯化，得到目标产物6-(2,6-二氟苯基)-4-((6-吗啉代吡啶-3-基)氨基)哒嗪-3-羧酸甲酯36b(1.2g，黄色固体)，产率：65％。The compound 6-chloro-4-((6-morpholinopyridin-3-yl)amino)pyridazine-3-carboxylate methyl ester 36a (1.5 g, 4.29 mmol), 2,6-difluorophenylboronic acid ( 2.03 g, 12.9 mmol), diisopropylethylamine (1.66 g, 12.9 mmol) and tetrakis(triphenylphosphine)palladium (498 mg, 0.429 mmol) were dissolved in 1,4-dioxane (20 mL), After deoxygenation, it was heated to 100°C with a microwave reactor under nitrogen atmosphere and stirred for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=19/1) to obtain the target product 6-(2,6-difluorophenyl)-4-(( 6-Morpholinopyridin-3-yl)amino)pyridazine-3-carboxylate methyl ester 36b (1.2 g, yellow solid), yield: 65%.
MS m/z(ESI):428[M+1]MS m/z(ESI): 428[M+1]
第三步third step
6-(2,6-二氟苯基)-4-((6-吗啉代吡啶-3-基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((6-morpholinopyridin-3-yl)amino)pyridazine-3-carboxamide
将化合物6-(2,6-二氟苯基)-4-((6-吗啉代吡啶-3-基)氨基)哒嗪-3-羧酸甲酯36b(1.2g，2.81mmol)溶于四氢呋喃(30mL)，加入氨水(5mL)。室温下搅拌3小时后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2,6-二氟苯基)-4-((6-吗啉代吡啶-3-基)氨基)哒嗪-3-甲酰胺36(495.7mg，黄色固体)，产率：43％。Compound 6-(2,6-difluorophenyl)-4-((6-morpholinopyridin-3-yl)amino)pyridazine-3-carboxylate methyl ester 36b (1.2 g, 2.81 mmol) was dissolved in In tetrahydrofuran (30 mL), ammonia water (5 mL) was added. After stirring at room temperature for 3 hours, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high performance liquid chromatography to obtain the target product 6-(2,6-difluorophenyl)-4-((6-morpholinopyridine) -3-yl)amino)pyridazine-3-carboxamide 36 (495.7 mg, yellow solid), yield: 43%.
MS m/z(ESI):413[M+1]MS m/z(ESI): 413[M+1]
1H NMR(400MHz,DMSO-d 6)δ8.13(d,J＝2.7Hz,1H),7.59–7.50(m,2H),7.14(t,J＝8.1Hz,2H),6.99(s,1H),6.91(d,J＝9.0Hz,1H),3.84–3.76(m,4H),3.55–3.48(m,4H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.13 (d, J=2.7 Hz, 1H), 7.59-7.50 (m, 2H), 7.14 (t, J=8.1 Hz, 2H), 6.99 (s, 1H), 6.91 (d, J=9.0Hz, 1H), 3.84–3.76 (m, 4H), 3.55–3.48 (m, 4H).
以下实施例(实施例37、实施例40、实施例47、实施例48、实施例66、实施例76、实施例80、实施例81、实施例82、实施例83、实施例84、实施例88、实施例90、实施例94)均参照实施例36的操作方法合成，但在第一步中用不同的胺代替6-吗啉代吡啶-3-胺，如下所示：The following examples (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) are all synthesized with reference to the operation method of Example 36, but in the first step, a different amine is used to replace 6-morpholinopyridine-3-amine, as shown below:
Figure PCTCN2020108468-appb-000061
Figure PCTCN2020108468-appb-000061
Figure PCTCN2020108468-appb-000062
Figure PCTCN2020108468-appb-000062
Figure PCTCN2020108468-appb-000063
Figure PCTCN2020108468-appb-000063
Figure PCTCN2020108468-appb-000064
Figure PCTCN2020108468-appb-000064
实施例38Example 38
6-(2,6-二氟苯基)-4-((5-吗啉代吡啶-2-基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((5-morpholinopyridin-2-yl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000065
Figure PCTCN2020108468-appb-000065
第一步first step
6-(2,6-二氟苯基)-4-((5-吗啉代吡啶-2-基)氨基)哒嗪-3-羧酸6-(2,6-Difluorophenyl)-4-((5-morpholinopyridin-2-yl)amino)pyridazine-3-carboxylic acid
将化合物4-氨基-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯31c(800mg，3.0mmol)、4-(6-氯吡啶-3-基)吗啉(700mg，3.5mmol)、碳酸铯(1.46g，4.5mmol)、三(二亚苄基丙酮)二钯(274mg，0.3mmol)、2-(二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯(160mg，0.3mmol)和1,4-二氧六环(15mL)混合，除氧后在氮气气氛下加热到90℃并搅拌15小时。冷却到室温后过滤，滤液在减压条件下除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2,6-二氟苯基)-4-((5-吗啉代吡啶-2-基)氨基)哒嗪-3-羧酸38a(700mg，黄色固体)，产率：56％。Compound 4-amino-6-(2,6-difluorophenyl)pyridazine-3-carboxylate methyl ester 31c (800 mg, 3.0 mmol), 4-(6-chloropyridin-3-yl)morpholine ( 700mg, 3.5mmol), cesium carbonate (1.46g, 4.5mmol), tris(dibenzylideneacetone)dipalladium (274mg, 0.3mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy -2',4',6'-Triisopropyl-1,1'-biphenyl (160 mg, 0.3 mmol) and 1,4-dioxane (15 mL) were mixed and heated under nitrogen atmosphere after deoxygenation to 90°C and stirred for 15 hours. After cooling to room temperature, the filtrate was filtered, and the solvent was removed from the filtrate under reduced pressure. The residue was purified by reverse-phase preparative high performance liquid chromatography to obtain the target product 6-(2,6-difluorophenyl)-4-((5-methylene chloride). Linopyridin-2-yl)amino)pyridazine-3-carboxylic acid 38a (700 mg, yellow solid), yield: 56%.
MS m/z(ESI):414[M+1]MS m/z(ESI): 414[M+1]
第二步second step
6-(2,6-二氟苯基)-4-((5-吗啉代吡啶-2-基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((5-morpholinopyridin-2-yl)amino)pyridazine-3-carboxamide
将化合物6-(2,6-二氟苯基)-4-((5-吗啉代吡啶-2-基)氨基)哒嗪-3-羧酸38a(700mg，1.69mmol)、二异丙基乙基胺(654mg，5.07mmol)、O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓六氟磷酸盐(963mg，2.53mmol)和N,N-二甲基甲酰胺(10mL)混合，室温下搅拌5分钟后加入氨水(5mL)，然后继续搅拌15小时。在减压条件下除去溶剂后，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2,6-二氟苯基)-4-((5-吗啉代吡啶-2-基)氨基)哒嗪-3-甲酰胺38(213mg，黄色固体)，产率：31％。Compound 6-(2,6-difluorophenyl)-4-((5-morpholinopyridin-2-yl)amino)pyridazine-3-carboxylic acid 38a (700 mg, 1.69 mmol), diisopropyl ethylamine (654 mg, 5.07 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (963 mg, 2.53 mmol) and N,N-dimethylformamide (10 mL) were mixed, stirred at room temperature for 5 minutes, then added with ammonia water (5 mL), and then continued to stir for 15 hours. After removing the solvent under reduced pressure, the residue was purified by reverse-phase preparative high-performance liquid chromatography to give the target product 6-(2,6-difluorophenyl)-4-((5-morpholinopyridine-2- (yl)amino)pyridazine-3-carboxamide 38 (213 mg, yellow solid), yield: 31%.
MS m/z(ESI):413[M+1]MS m/z(ESI): 413[M+1]
1H NMR(400MHz,DMSO-d 6)δ11.71(s,1H),8.88(d,J＝7.6Hz,2H),8.13(s,1H),8.04(d,J＝2.9Hz,1H),7.70–7.58(m,1H),7.48(dd,J＝9.0, 3.0Hz,1H),7.37–7.26(m,2H),7.07(d,J＝8.9Hz,1H),3.82–3.62(m,4H),3.18–3.04(m,4H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 11.71(s, 1H), 8.88(d, J=7.6Hz, 2H), 8.13(s, 1H), 8.04(d, J=2.9Hz, 1H) ,7.70–7.58(m,1H),7.48(dd,J=9.0,3.0Hz,1H),7.37–7.26(m,2H),7.07(d,J=8.9Hz,1H),3.82–3.62(m , 4H), 3.18–3.04 (m, 4H).
以下实施例(实施例39、实施例43、实施例44、实施例71、实施例78)均参照实施例38的操作方法合成，但在第一步中用不同的卤代物代替4-(6-氯吡啶-3-基)吗啉，如下所示：The following examples (Example 39, Example 43, Example 44, Example 71, Example 78) were all synthesized with reference to the operation method of Example 38, but in the first step, different halides were used to replace 4-(6 -chloropyridin-3-yl)morpholine, as follows:
Figure PCTCN2020108468-appb-000066
Figure PCTCN2020108468-appb-000066
Figure PCTCN2020108468-appb-000067
Figure PCTCN2020108468-appb-000067
实施例41Example 41
6-(2,6-二氟苯基)-4-((1-(2-甲氧基乙基)-1H-吡唑-4-基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000068
Figure PCTCN2020108468-appb-000068
第一步first step
4-((1H-吡唑-4-基)氨基)-6-氯哒嗪-3-羧酸甲酯Methyl 4-((1H-pyrazol-4-yl)amino)-6-chloropyridazine-3-carboxylate
将化合物4,6-二氯哒嗪-3-羧酸甲酯1a(206mg，1mmol)、1H-吡唑-4-胺(83mg，1mmol)、二异丙基乙基胺(258mg，2mmol)和乙醇(20mL)混合，加热到80℃并搅拌2小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(二氯甲烷/甲醇＝19/1)纯化，得到目标产物4-((1H-吡唑-4-基)氨基)-6-氯哒嗪-3-羧酸甲酯41a(150mg，黄色固体)，产率：59％。Compound 4,6-dichloropyridazine-3-carboxylate methyl ester 1a (206 mg, 1 mmol), 1H-pyrazol-4-amine (83 mg, 1 mmol), diisopropylethylamine (258 mg, 2 mmol) Mixed with ethanol (20 mL), heated to 80°C and stirred for 2 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=19/1) to obtain the target product 4-((1H-pyrazol-4-yl)amino)-6 -chloropyridazine-3-carboxylate methyl ester 41a (150 mg, yellow solid), yield: 59%.
MS m/z(ESI):254[M+1]MS m/z(ESI): 254[M+1]
第二步second step
4-((1H-吡唑-4-基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯Methyl 4-((1H-pyrazol-4-yl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxylate
将化合物4-((1H-吡唑-4-基)氨基)-6-氯哒嗪-3-羧酸甲酯41a(150mg，4.29mmol)、2,6-二氟苯硼酸(281mg，1.78mmol)、二异丙基乙基胺(229mg，1.78mmol)和四(三苯基膦)钯(68mg，0.059mmol)溶于1,4-二氧六环(20mL)，除氧后在氮气气氛下用微波反应器加热到100℃并搅拌1小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(二氯甲烷/甲醇＝19/1)纯化，得到目标产物4-((1H-吡唑-4-基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯41b(120mg，黄色固体)，产率：61％。Compound 4-((1H-pyrazol-4-yl)amino)-6-chloropyridazine-3-carboxylate methyl ester 41a (150 mg, 4.29 mmol), 2,6-difluorophenylboronic acid (281 mg, 1.78 mmol), diisopropylethylamine (229 mg, 1.78 mmol) and tetrakis(triphenylphosphine)palladium (68 mg, 0.059 mmol) were dissolved in 1,4-dioxane (20 mL), deoxygenated under nitrogen The atmosphere was heated to 100°C with a microwave reactor and stirred for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=19/1) to obtain the target product 4-((1H-pyrazol-4-yl)amino)-6 -(2,6-Difluorophenyl)pyridazine-3-carboxylate methyl ester 41b (120 mg, yellow solid), yield: 61%.
MS m/z(ESI):332[M+1]MS m/z(ESI): 332[M+1]
第三步third step
6-(2,6-二氟苯基)-4-((1-(2-甲氧基乙基)-1H-吡唑-4-基)氨基)哒嗪-3-羧酸甲酯Methyl 6-(2,6-difluorophenyl)-4-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyridazine-3-carboxylate
将化合物4-((1H-吡唑-4-基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯41b(120mg，0.36mmol)、1-氯-2-甲氧基乙烷(41mg，0.43mmol)、碳酸钾(74.5mg，0.54mmol)和N,N-二甲基甲酰胺(30mL)混合，加热到80℃并搅拌3小时。冷却到室温后过滤，滤液在减压条件下除去溶剂，残余物用硅胶柱层析(二氯甲烷/甲醇＝9/1)纯化，得到目标产物6-(2,6-二氟苯基)-4-((1-(2-甲氧基乙基)-1H-吡唑-4-基)氨基)哒嗪-3-羧酸甲酯41c(100mg，黄色固体)，产率：71％。Compound 4-((1H-pyrazol-4-yl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxylate methyl ester 41b (120 mg, 0.36 mmol), 1-chloro -2-Methoxyethane (41 mg, 0.43 mmol), potassium carbonate (74.5 mg, 0.54 mmol) and N,N-dimethylformamide (30 mL) were mixed, heated to 80°C and stirred for 3 hours. After cooling to room temperature, the filtrate was filtered, and the solvent was removed from the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=9/1) to obtain the target product 6-(2,6-difluorophenyl) - Methyl 4-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyridazine-3-carboxylate 41c (100 mg, yellow solid), yield: 71% .
MS m/z(ESI):390[M+1]MS m/z(ESI): 390[M+1]
第四步the fourth step
6-(2,6-二氟苯基)-4-((1-(2-甲氧基乙基)-1H-吡唑-4-基)氨基)哒嗪-3-羧酸6-(2,6-Difluorophenyl)-4-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyridazine-3-carboxylic acid
将化合物6-(2,6-二氟苯基)-4-((1-(2-甲氧基乙基)-1H-吡唑-4-基)氨基)哒嗪-3-羧酸甲酯41c(100mg，0.25mmol)溶于四氢呋喃(10mL)和甲醇(10mL)的混合溶剂，然后加入氢氧化锂一水合物(24mg，1mmol)并搅拌2小时。反应完成后过滤，滤液在减压条件下除去溶剂，得到目标产物6-(2,6-二氟苯基)-4-((1-(2-甲氧基乙基)-1H-吡唑-4-基)氨基)哒嗪-3-羧酸41d(80mg，黄色固体)，产率：85％。The compound 6-(2,6-difluorophenyl)-4-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyridazine-3-carboxylate methyl Ester 41c (100 mg, 0.25 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and methanol (10 mL), then lithium hydroxide monohydrate (24 mg, 1 mmol) was added and stirred for 2 hours. After the reaction is completed, filter the filtrate and remove the solvent under reduced pressure to obtain the target product 6-(2,6-difluorophenyl)-4-((1-(2-methoxyethyl)-1H-pyrazole -4-yl)amino)pyridazine-3-carboxylic acid 41d (80 mg, yellow solid), yield: 85%.
MS m/z(ESI):376[M+1]MS m/z(ESI): 376[M+1]
第五步the fifth step
6-(2,6-二氟苯基)-4-((1-(2-甲氧基乙基)-1H-吡唑-4-基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyridazine-3-carboxamide
将化合物6-(2,6-二氟苯基)-4-((1-(2-甲氧基乙基)-1H-吡唑-4-基)氨基)哒嗪-3-羧酸41d(80mg，0.21mmol)溶于二氯甲烷(20mL)，然后加入草酰氯(37mg，0.29mmol)。室温下搅拌30分钟后，减压除去溶剂，残余物溶于无水四氢呋喃(15mL)，然后加入氨水(1mL)并搅拌30分钟。反应完成后，减压除去溶剂，残余物用反相高效制备液相色谱纯化，得到目标产物6-(2,6-二氟苯基)-4-((1-(2-甲氧基乙基)-1H-吡唑-4-基)氨基)哒嗪-3-甲酰胺41(16mg，黄色固体)，产率：20％。The compound 6-(2,6-difluorophenyl)-4-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyridazine-3-carboxylic acid 41d (80 mg, 0.21 mmol) was dissolved in dichloromethane (20 mL), then oxalyl chloride (37 mg, 0.29 mmol) was added. After stirring at room temperature for 30 minutes, the solvent was removed under reduced pressure, the residue was dissolved in anhydrous tetrahydrofuran (15 mL), then aqueous ammonia (1 mL) was added and stirred for 30 minutes. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase high-performance preparative liquid chromatography to obtain the target product 6-(2,6-difluorophenyl)-4-((1-(2-methoxyethyl) yl)-1H-pyrazol-4-yl)amino)pyridazine-3-carboxamide 41 (16 mg, yellow solid), yield: 20%.
MS m/z(ESI):375[M+1]MS m/z(ESI): 375[M+1]
1H NMR(400MHz,CD 3OD)δ7.83(d,J＝0.7Hz,1H),7.61–7.51(m,2H),7.19–7.12(m,2H),7.11(t,J＝0.9Hz,1H),4.34–4.28(m,2H),3.77–3.71(m,2H),3.30(s,3H)。 1 H NMR (400MHz, CD 3 OD) δ 7.83 (d, J=0.7Hz, 1H), 7.61-7.51 (m, 2H), 7.19-7.12 (m, 2H), 7.11 (t, J=0.9Hz) , 1H), 4.34–4.28 (m, 2H), 3.77–3.71 (m, 2H), 3.30 (s, 3H).
实施例42Example 42
6-(2,6-二氟苯基)-4-((1-((1-甲基吖丁啶-3-基)甲基)-1H-吡唑-4-基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((1-((1-methylazetidin-3-yl)methyl)-1H-pyrazol-4-yl)amino)pyridazine -3-Carboxamide
Figure PCTCN2020108468-appb-000069
Figure PCTCN2020108468-appb-000069
第一步first step
4-((1-((1-(叔-丁氧基羰基)吖丁啶-3-基)甲基)-1H-吡唑-4-基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯4-((1-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-1H-pyrazol-4-yl)amino)-6-(2,6-di Fluorophenyl)pyridazine-3-carboxylate methyl ester
将化合物三苯基膦(288mg，1.1mmol)和偶氮二甲酸二异丙酯(222mg，1.1mmol)溶于四氢呋喃(10mL)，然后依次加入4-((1H-吡唑-4-基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯41b(331mg，1mmol)和3-(羟甲基)吖丁啶-1-羧酸叔丁酯(187mg，1mmol)。室温下搅拌3小时后，减压除去溶剂，残余物用硅胶柱层析(二氯甲烷/甲醇＝9/1)纯化，得到目标产物4-((1-((1-(叔-丁氧基羰基)吖丁啶-3-基)甲基)-1H-吡唑-4-基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯42a(300mg，黄色固体)，产率：60％。Compound triphenylphosphine (288 mg, 1.1 mmol) and diisopropyl azodicarboxylate (222 mg, 1.1 mmol) were dissolved in tetrahydrofuran (10 mL), and then 4-((1H-pyrazol-4-yl) was added sequentially Amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxylate methyl ester 41b (331 mg, 1 mmol) and tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate ( 187 mg, 1 mmol). After stirring at room temperature for 3 hours, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=9/1) to obtain the target product 4-((1-((1-(tert-butoxy (ylcarbonyl)azetidin-3-yl)methyl)-1H-pyrazol-4-yl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxylate methyl ester 42a ( 300 mg, yellow solid), yield: 60%.
MS m/z(ESI):501[M+1]MS m/z(ESI): 501[M+1]
第二步second step
3-((4-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)-1H-吡唑-1-基)甲基)吖丁啶-1-羧酸叔丁酯3-((4-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)-1H-pyrazol-1-yl)methyl)azetidine tert-Butyl pyridine-1-carboxylate
将化合物4-((1-((1-(叔-丁氧基羰基)吖丁啶-3-基)甲基)-1H-吡唑-4-基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯42a(300mg，0.6mmol)溶于四氢呋喃(10mL)，然后加入氨水(2mL)。室温下搅拌2小时后，减压除去溶剂，得到目标产物3-((4-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)-1H-吡唑-1-基)甲基)吖丁啶-1-羧酸叔丁酯42b(200mg，黄色固体)，产率：68％。Compound 4-((1-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-1H-pyrazol-4-yl)amino)-6-(2,6 Methyl difluorophenyl)pyridazine-3-carboxylate 42a (300 mg, 0.6 mmol) was dissolved in tetrahydrofuran (10 mL), followed by addition of ammonia (2 mL). After stirring at room temperature for 2 hours, the solvent was removed under reduced pressure to give the desired product 3-((4-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino) -1H-pyrazol-1-yl)methyl)azetidine-1-carboxylate tert-butyl ester 42b (200 mg, yellow solid), yield: 68%.
MS m/z(ESI):486[M+1]MS m/z(ESI): 486[M+1]
第三步third step
4-((1-(吖丁啶-3-基甲基)-1H-吡唑-4-基)氨基)-6-(2,6-二氟苯基)哒嗪-3-甲酰胺4-((1-(azetidin-3-ylmethyl)-1H-pyrazol-4-yl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxamide
将化合物3-((4-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)-1H-吡唑-1-基)甲基)吖丁啶-1-羧酸叔丁酯42b(200mg，0.41mmol)溶于乙醇(10mL)，然后加入氯化氢的乙醇溶液(33％，1mL)。室温下搅拌2小时后，减压除去溶剂，得到目标产物4-((1-(吖丁啶-3-基甲基)-1H-吡唑-4-基)氨基)-6-(2,6-二氟苯基)哒嗪-3-甲酰胺42c(150mg，黄色固体)，产率：95％。Compound 3-((4-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)-1H-pyrazol-1-yl)methyl) Azetidine-1-carboxylate tert-butyl ester 42b (200 mg, 0.41 mmol) was dissolved in ethanol (10 mL), followed by the addition of hydrogen chloride in ethanol (33%, 1 mL). After stirring at room temperature for 2 hours, the solvent was removed under reduced pressure to obtain the target product 4-((1-(azetidin-3-ylmethyl)-1H-pyrazol-4-yl)amino)-6-(2, 6-Difluorophenyl)pyridazine-3-carboxamide 42c (150 mg, yellow solid), yield: 95%.
MS m/z(ESI):386[M+1]MS m/z(ESI): 386[M+1]
第四步the fourth step
6-(2,6-二氟苯基)-4-((1-((1-甲基吖丁啶-3-基)甲基)-1H-吡唑-4-基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((1-((1-methylazetidin-3-yl)methyl)-1H-pyrazol-4-yl)amino)pyridazine -3-Carboxamide
将化合物4-((1-(吖丁啶-3-基甲基)-1H-吡唑-4-基)氨基)-6-(2,6-二氟苯基)哒嗪-3-甲酰胺42c(150mg，0.39mmol)、多聚甲醛(23mg，0.78mmol)和甲醇(10mL)混合，然后加入氰基硼氢化钠(54mg，0.86mmol)。室温下搅拌2小时后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2,6-二氟苯基)-4-((1-((1-甲基吖丁啶-3-基)甲基)-1H-吡唑-4-基)氨基)哒嗪-3-甲酰胺42(8mg，黄色固体)，产率：5％。Compound 4-((1-(azetidin-3-ylmethyl)-1H-pyrazol-4-yl)amino)-6-(2,6-difluorophenyl)pyridazine-3-methyl Amide 42c (150 mg, 0.39 mmol), paraformaldehyde (23 mg, 0.78 mmol) and methanol (10 mL) were combined, then sodium cyanoborohydride (54 mg, 0.86 mmol) was added. After stirring at room temperature for 2 hours, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to obtain the target product 6-(2,6-difluorophenyl)-4-((1-((1- Methylazetidin-3-yl)methyl)-1H-pyrazol-4-yl)amino)pyridazine-3-carboxamide 42 (8 mg, yellow solid), yield: 5%.
MS m/z(ESI):400[M+1]MS m/z(ESI): 400[M+1]
1H NMR(400MHz,CD 3OD)δ7.84(d,J＝0.5Hz,1H),7.61–7.52(m,2H),7.19–7.13(m,2H),7.09(s,1H),4.33(d,J＝7.1Hz,2H),3.51–3.44(m,2H),3.17–3.11(m,2H),3.04–2.96(m,1H),2.34(s,3H)。 1 H NMR (400MHz, CD 3 OD) δ 7.84 (d, J=0.5Hz, 1H), 7.61-7.52 (m, 2H), 7.19-7.13 (m, 2H), 7.09 (s, 1H), 4.33 (d, J=7.1 Hz, 2H), 3.51–3.44 (m, 2H), 3.17–3.11 (m, 2H), 3.04–2.96 (m, 1H), 2.34 (s, 3H).
实施例45和46Examples 45 and 46
6-(2,6-二氟苯基)-4-((4-((1-氧化四氢-2H-噻喃-4-基)氧基)苯基)氨基)哒嗪-3-甲酰胺(45)和6-(2,6-二氟苯基)-4-((4-((1,1-二氧化四氢-2H-噻喃-4-基)氧基)苯基)氨基)哒嗪-3-甲酰胺(46)6-(2,6-Difluorophenyl)-4-((4-((1-oxytetrahydro-2H-thiopyran-4-yl)oxy)phenyl)amino)pyridazine-3-methyl Amide (45) and 6-(2,6-difluorophenyl)-4-((4-((1,1-dioxytetrahydro-2H-thiopyran-4-yl)oxy)phenyl) Amino)pyridazine-3-carboxamide (46)
Figure PCTCN2020108468-appb-000070
Figure PCTCN2020108468-appb-000070
Figure PCTCN2020108468-appb-000071
Figure PCTCN2020108468-appb-000071
第一步first step
4-(4-硝基苯氧基)四氢-2H-噻喃4-(4-Nitrophenoxy)tetrahydro-2H-thiopyran
将化合物4-硝基苯酚45a(1g，7.19mmol)、四氢-2H-噻喃-4-醇(1g，8.63mmol)和三苯基膦(5.6g，21.6mmol)溶于四氢呋喃(20mL)，然后加入偶氮二甲酸二异丙酯(5g，24.7mmol)。室温下搅拌过夜后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝2/1至1/1)纯化，得到目标产物4-(4-硝基苯氧基)四氢-2H-噻喃45b(1g，黄色固体)，产率：58％。Compound 4-nitrophenol 45a (1 g, 7.19 mmol), tetrahydro-2H-thiopyran-4-ol (1 g, 8.63 mmol) and triphenylphosphine (5.6 g, 21.6 mmol) were dissolved in tetrahydrofuran (20 mL) , and then diisopropyl azodicarboxylate (5 g, 24.7 mmol) was added. After stirring at room temperature overnight, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1 to 1/1) to obtain the target product 4-(4-nitrophenoxy) Tetrahydro-2H-thiopyran 45b (1 g, yellow solid), yield: 58%.
MS m/z(ESI):240[M+1]MS m/z(ESI): 240[M+1]
第二步second step
4-((四氢-2H-噻喃-4-基)氧基)苯胺4-((Tetrahydro-2H-thiopyran-4-yl)oxy)aniline
将化合物4-(4-硝基苯氧基)四氢-2H-噻喃45b(1g，4.18mmol)溶于乙醇(10mL)，然后加入10％钯炭(200mg)并在氢气气氛下搅拌过夜。反应完成后过滤，滤液在减压条件下除去溶剂，得到目标产物4-((四氢-2H-噻喃-4-基)氧基)苯胺45c(500mg，白色固体)，产率：77％。Compound 4-(4-nitrophenoxy)tetrahydro-2H-thiopyran 45b (1 g, 4.18 mmol) was dissolved in ethanol (10 mL), then 10% palladium on carbon (200 mg) was added and stirred under hydrogen atmosphere overnight . After the completion of the reaction, the filtrate was filtered, and the solvent was removed from the filtrate under reduced pressure to obtain the target product 4-((tetrahydro-2H-thiopyran-4-yl)oxy)aniline 45c (500 mg, white solid), yield: 77% .
MS m/z(ESI):210[M+1]MS m/z(ESI): 210[M+1]
第三步third step
6-氯-4-((4-((四氢-2H-噻喃-4-基)氧基)苯基)氨基)哒嗪-3-羧酸甲酯Methyl 6-chloro-4-((4-((tetrahydro-2H-thiopyran-4-yl)oxy)phenyl)amino)pyridazine-3-carboxylate
将化合物4-((四氢-2H-噻喃-4-基)氧基)苯胺45c(200mg，0.955mmol)和4,6-二氯哒嗪-3-羧酸甲酯1a(200mg，0.97mmol)溶于乙醇(10mL)，在封管中加热到90℃并搅拌12小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝1/1至1/2)纯化，得到目标产物6-氯-4-((4-((四氢-2H-噻喃-4-基)氧基)苯基)氨基)哒嗪-3-羧酸甲酯45d(240mg，黄色固体)，产率：66％。Compound 4-((tetrahydro-2H-thiopyran-4-yl)oxy)aniline 45c (200 mg, 0.955 mmol) and methyl 4,6-dichloropyridazine-3-carboxylate 1a (200 mg, 0.97 mmol) was dissolved in ethanol (10 mL), heated to 90°C in a sealed tube and stirred for 12 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1 to 1/2) to obtain the target product 6-chloro-4-((4-(( Tetrahydro-2H-thiopyran-4-yl)oxy)phenyl)amino)pyridazine-3-carboxylate methyl ester 45d (240 mg, yellow solid), yield: 66%.
MS m/z(ESI):380[M+1]MS m/z(ESI): 380[M+1]
第四步the fourth step
6-(2,6-二氟苯基)-4-((4-((四氢-2H-噻喃-4-基)氧基)苯基)氨基)哒嗪- 3-羧酸甲酯6-(2,6-Difluorophenyl)-4-((4-((tetrahydro-2H-thiopyran-4-yl)oxy)phenyl)amino)pyridazine-3-carboxylate methyl ester
将化合物6-氯-4-((4-((四氢-2H-噻喃-4-基)氧基)苯基)氨基)哒嗪-3-羧酸甲酯45d(100mg，0.263mmol)、2,6-二氟苯硼酸(47mg，0.297mmol)、二异丙基乙基胺(64mg，0.496mmol)和四(三苯基膦)钯(30mg，0.026mmol)溶于1,4-二氧六环(10mL)，除氧后在氮气气氛下用微波反应器加热到110℃并搅拌1小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝1/1至1/2)纯化，得到目标产物6-(2,6-二氟苯基)-4-((4-((四氢-2H-噻喃-4-基)氧基)苯基)氨基)哒嗪-3-羧酸甲酯45e(86mg，黄色固体)，产率：72％。Compound 6-chloro-4-((4-((tetrahydro-2H-thiopyran-4-yl)oxy)phenyl)amino)pyridazine-3-carboxylate methyl ester 45d (100 mg, 0.263 mmol) , 2,6-difluorophenylboronic acid (47 mg, 0.297 mmol), diisopropylethylamine (64 mg, 0.496 mmol) and tetrakis(triphenylphosphine)palladium (30 mg, 0.026 mmol) were dissolved in 1,4- Dioxane (10 mL), deoxygenated and heated to 110°C in a microwave reactor under nitrogen atmosphere and stirred for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1 to 1/2) to obtain the target product 6-(2,6-difluorophenyl) -4-((4-((Tetrahydro-2H-thiopyran-4-yl)oxy)phenyl)amino)pyridazine-3-carboxylate methyl ester 45e (86 mg, yellow solid), yield: 72 %.
MS m/z(ESI):372[M+1]MS m/z(ESI): 372[M+1]
第五步the fifth step
6-(2,6-二氟苯基)-4-((4-((四氢-2H-噻喃-4-基)氧基)苯基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((4-((tetrahydro-2H-thiopyran-4-yl)oxy)phenyl)amino)pyridazine-3-carboxamide
将化合物6-(2,6-二氟苯基)-4-((4-((四氢-2H-噻喃-4-基)氧基)苯基)氨基)哒嗪-3-羧酸甲酯45e(86mg，0.189mmol)溶于四氢呋喃(10mL)，加入氨水(10mL)。室温下搅拌12小时后，减压除去溶剂，得到目标产物6-(2,6-二氟苯基)-4-((4-((四氢-2H-噻喃-4-基)氧基)苯基)氨基)哒嗪-3-甲酰胺45f(100mg，粗品)。该产品未经进一步纯化，直接用于下一步反应。The compound 6-(2,6-difluorophenyl)-4-((4-((tetrahydro-2H-thiopyran-4-yl)oxy)phenyl)amino)pyridazine-3-carboxylic acid Methyl ester 45e (86 mg, 0.189 mmol) was dissolved in tetrahydrofuran (10 mL), and aqueous ammonia (10 mL) was added. After stirring at room temperature for 12 hours, the solvent was removed under reduced pressure to give the desired product 6-(2,6-difluorophenyl)-4-((4-((tetrahydro-2H-thiopyran-4-yl)oxy) )phenyl)amino)pyridazine-3-carboxamide 45f (100 mg, crude). This product was used directly in the next reaction without further purification.
MS m/z(ESI):443[M+1]MS m/z(ESI): 443[M+1]
第六步Step 6
6-(2,6-二氟苯基)-4-((4-((1-氧化四氢-2H-噻喃-4-基)氧基)苯基)氨基)哒嗪-3-甲酰胺(45)和6-(2,6-二氟苯基)-4-((4-((1,1-二氧化四氢-2H-噻喃-4-基)氧基)苯基)氨基)哒嗪-3-甲酰胺(46)6-(2,6-Difluorophenyl)-4-((4-((1-oxytetrahydro-2H-thiopyran-4-yl)oxy)phenyl)amino)pyridazine-3-methyl Amide (45) and 6-(2,6-difluorophenyl)-4-((4-((1,1-dioxytetrahydro-2H-thiopyran-4-yl)oxy)phenyl) Amino)pyridazine-3-carboxamide (46)
将化合物6-(2,6-二氟苯基)-4-((4-((四氢-2H-噻喃-4-基)氧基)苯基)氨基)哒嗪-3-甲酰胺45f(100mg，粗品)溶于二氯甲烷(10mL)，然后加入间氯过氧苯甲酸(纯度80％，84mg，0.389mmol)。室温下搅拌1小时后过滤，滤液在减压条件下除去溶剂，残余物用反相制备液相色谱纯化，得到目标产物6-(2,6-二氟苯基)-4-((4-((1-氧化四氢-2H-噻喃-4-基)氧基)苯基)氨基)哒嗪-3-甲酰胺45(4.8mg，白色固体)，产率：4％；6-(2,6-二氟苯基)-4-((4-((1,1-二氧化四氢-2H-噻喃-4-基)氧基)苯基)氨基)哒嗪-3-甲酰胺46(35.4mg，白色固体)，产率：33％。The compound 6-(2,6-difluorophenyl)-4-((4-((tetrahydro-2H-thiopyran-4-yl)oxy)phenyl)amino)pyridazine-3-carboxamide 45f (100 mg, crude) was dissolved in dichloromethane (10 mL) and m-chloroperoxybenzoic acid (80% pure, 84 mg, 0.389 mmol) was added. After stirring at room temperature for 1 hour, the filtrate was filtered, and the solvent was removed from the filtrate under reduced pressure. The residue was purified by reverse-phase preparative liquid chromatography to obtain the target product 6-(2,6-difluorophenyl)-4-((4- ((1-Oxotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)amino)pyridazine-3-carboxamide 45 (4.8 mg, white solid), yield: 4%; 6-( 2,6-Difluorophenyl)-4-((4-((1,1-dioxytetrahydro-2H-thiopyran-4-yl)oxy)phenyl)amino)pyridazine-3-methyl Amide 46 (35.4 mg, white solid), yield: 33%.
6-(2,6-二氟苯基)-4-((4-((1-氧化四氢-2H-噻喃-4-基)氧基)苯基)氨基)哒嗪-3-甲酰胺456-(2,6-Difluorophenyl)-4-((4-((1-oxytetrahydro-2H-thiopyran-4-yl)oxy)phenyl)amino)pyridazine-3-methyl Amide 45
MS m/z(ESI):459[M+1]MS m/z(ESI): 459[M+1]
1H NMR(400MHz,DMSO-d 6)δ10.62(s,1H),8.73(s,1H),8.00(s,1H),7.75–7.51(m,2H),7.26–7.24(m,3H),7.16–6.91(m,2H),4.68(brs,1H),2.98–2.66(m,4H),2.24–1.94(m,4H)。 1 H NMR (400MHz, DMSO-d 6 )δ10.62(s,1H), 8.73(s,1H), 8.00(s,1H), 7.75-7.51(m,2H), 7.26-7.24(m,3H) ), 7.16–6.91 (m, 2H), 4.68 (brs, 1H), 2.98–2.66 (m, 4H), 2.24–1.94 (m, 4H).
6-(2,6-二氟苯基)-4-((4-((1,1-二氧化四氢-2H-噻喃-4-基)氧基)苯基) 氨基)哒嗪-3-甲酰胺466-(2,6-Difluorophenyl)-4-((4-((1,1-Dioxytetrahydro-2H-thiopyran-4-yl)oxy)phenyl)amino)pyridazine- 3-Carboxamide 46
MS m/z(ESI):475[M+1]MS m/z(ESI): 475[M+1]
1H NMR(400MHz,DMSO-d 6)δ10.63(s,1H),8.74(s,1H),8.01(s,1H),7.60–7.56(m,2H),7.30–7.22(m,3H),7.13–7.07(m,3H),4.70(dd,J＝6.4,3.1Hz,1H),3.4–3.17(m,4H),2.28–2.10(m,4H)。 1 H NMR (400MHz, DMSO-d 6 )δ10.63(s,1H), 8.74(s,1H), 8.01(s,1H), 7.60-7.56(m,2H), 7.30-7.22(m,3H) ), 7.13–7.07 (m, 3H), 4.70 (dd, J=6.4, 3.1 Hz, 1H), 3.4–3.17 (m, 4H), 2.28–2.10 (m, 4H).
实施例49Example 49
6-(2,6-二氟苯基)-4-((4-((1,1-二氧化硫代吗啉代)甲基)苯基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((4-((1,1-Dioxythiomorpholino)methyl)phenyl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000072
Figure PCTCN2020108468-appb-000072
第一步first step
6-氯-4-((4-(羟甲基)苯基)氨基)哒嗪-3-羧酸甲酯Methyl 6-chloro-4-((4-(hydroxymethyl)phenyl)amino)pyridazine-3-carboxylate
将化合物4,6-二氯哒嗪-3-羧酸甲酯1a(800mg，3.88mmol)、4-氨基苄醇(477mg，3.88mmol)、二异丙基乙基胺(500mg，3.88mmol)和乙醇(20mL)混合，加热到90℃并搅拌18小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(二氯甲烷/甲醇＝19/1)纯化，得到目标产物6-氯-4-((4-(羟甲基)苯基)氨基)哒嗪-3-羧酸甲酯49a(500mg，黄色固体)，产率：44％。Compound 4,6-dichloropyridazine-3-carboxylate methyl ester 1a (800 mg, 3.88 mmol), 4-aminobenzyl alcohol (477 mg, 3.88 mmol), diisopropylethylamine (500 mg, 3.88 mmol) Mixed with ethanol (20 mL), heated to 90°C and stirred for 18 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=19/1) to obtain the target product 6-chloro-4-((4-(hydroxymethyl)phenyl) )amino)pyridazine-3-carboxylate methyl ester 49a (500 mg, yellow solid), yield: 44%.
MS m/z(ESI):294[M+1]MS m/z(ESI): 294[M+1]
第二步second step
6-(2,6-二氟苯基)-4-((4-(羟甲基)苯基)氨基)哒嗪-3-羧酸甲酯Methyl 6-(2,6-difluorophenyl)-4-((4-(hydroxymethyl)phenyl)amino)pyridazine-3-carboxylate
将化合物6-氯-4-((4-(羟甲基)苯基)氨基)哒嗪-3-羧酸甲酯49a(450mg，1.54mmol)、2,6-二氟苯硼酸(728mg，4.61mmol)、二异丙基乙基胺(595mg，4.61mmol)和四(三苯基膦)钯(177mg，0.153mmol)溶于1,4-二氧六环(20mL)，除氧后在氮气气氛下用微波反应器加热到100℃并搅拌1小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱 层析(二氯甲烷/甲醇＝9/1)纯化，得到目标产物6-(2,6-二氟苯基)-4-((4-(羟甲基)苯基)氨基)哒嗪-3-羧酸甲酯49b(300mg，黄色固体)，产率：53％。Compound 6-chloro-4-((4-(hydroxymethyl)phenyl)amino)pyridazine-3-carboxylate methyl ester 49a (450 mg, 1.54 mmol), 2,6-difluorophenylboronic acid (728 mg, 4.61 mmol), diisopropylethylamine (595 mg, 4.61 mmol) and tetrakis(triphenylphosphine)palladium (177 mg, 0.153 mmol) were dissolved in 1,4-dioxane (20 mL), deoxygenated in The microwave reactor was heated to 100°C under nitrogen atmosphere and stirred for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=9/1) to obtain the target product 6-(2,6-difluorophenyl)-4-(( Methyl 4-(hydroxymethyl)phenyl)amino)pyridazine-3-carboxylate 49b (300 mg, yellow solid), yield: 53%.
MS m/z(ESI):372[M+1]MS m/z(ESI): 372[M+1]
第三步third step
4-((4-(氯甲基)苯基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯Methyl 4-((4-(chloromethyl)phenyl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxylate
将化合物6-(2,6-二氟苯基)-4-((4-(羟甲基)苯基)氨基)哒嗪-3-羧酸甲酯49b(300mg，0.81mmol)溶于二氯甲烷(20mL)，然后加入二氯亚砜(1mL)。室温下搅拌1小时后，减压除去溶剂，得到目标产物4-((4-(氯甲基)苯基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯49c(300mg，0.78mmol)，产率：95％。Compound 6-(2,6-difluorophenyl)-4-((4-(hydroxymethyl)phenyl)amino)pyridazine-3-carboxylate methyl ester 49b (300 mg, 0.81 mmol) was dissolved in two Chloromethane (20 mL) followed by thionyl chloride (1 mL). After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure to obtain the target product 4-((4-(chloromethyl)phenyl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxylate Acid methyl ester 49c (300 mg, 0.78 mmol), yield: 95%.
MS m/z(ESI):390[M+1]MS m/z(ESI): 390[M+1]
第四步the fourth step
6-(2,6-二氟苯基)-4-((4-((1,1-二氧化硫代吗啉代)甲基)苯基)氨基)哒嗪-3-羧酸甲酯Methyl 6-(2,6-difluorophenyl)-4-((4-((1,1-dioxythiomorpholino)methyl)phenyl)amino)pyridazine-3-carboxylate
将化合物4-((4-(氯甲基)苯基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯49c(100mg，0.26mmol)、硫代吗啉-1,1-二氧化物(35mg，0.26mmol)、二异丙基乙基胺(34mg，0.26mmol)和四氢呋喃(10mL)混合，室温下搅拌1小时后，减压除去溶剂，残余物用硅胶柱层析(二氯甲烷/甲醇＝9/1)纯化，得到目标产物6-(2,6-二氟苯基)-4-((4-((1,1-二氧化硫代吗啉代)甲基)苯基)氨基)哒嗪-3-羧酸甲酯49c(130mg，粗品)。该产品未经进一步纯化，直接用于下一步反应。Compound 4-((4-(chloromethyl)phenyl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxylate methyl ester 49c (100 mg, 0.26 mmol), thiol Morpholine-1,1-dioxide (35 mg, 0.26 mmol), diisopropylethylamine (34 mg, 0.26 mmol) and tetrahydrofuran (10 mL) were mixed, and after stirring at room temperature for 1 hour, the solvent was removed under reduced pressure, and the residue The compound was purified by silica gel column chromatography (dichloromethane/methanol=9/1) to obtain the target product 6-(2,6-difluorophenyl)-4-((4-((1,1-thiophene Lino)methyl)phenyl)amino)pyridazine-3-carboxylate methyl ester 49c (130 mg, crude). This product was used directly in the next reaction without further purification.
MS m/z(ESI):489[M+1]MS m/z(ESI): 489[M+1]
第五步the fifth step
6-(2,6-二氟苯基)-4-((4-((1,1-二氧化硫代吗啉代)甲基)苯基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((4-((1,1-Dioxythiomorpholino)methyl)phenyl)amino)pyridazine-3-carboxamide
将化合物6-(2,6-二氟苯基)-4-((4-((1,1-二氧化硫代吗啉代)甲基)苯基)氨基)哒嗪-3-羧酸甲酯49c(130mg，粗品)溶于四氢呋喃(15mL)，加入氨水(1mL)。室温下搅拌12小时后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2,6-二氟苯基)-4-((4-((1,1-二氧化硫代吗啉代)甲基)苯基)氨基)哒嗪-3-甲酰胺49(43mg，黄色固体)，产率：35％。The compound 6-(2,6-difluorophenyl)-4-((4-((1,1-dioxythiomorpholino)methyl)phenyl)amino)pyridazine-3-carboxylate methyl ester 49c (130 mg, crude) was dissolved in tetrahydrofuran (15 mL) and ammonia (1 mL) was added. After stirring at room temperature for 12 hours, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to obtain the target product 6-(2,6-difluorophenyl)-4-((4-(((1, 1-Dioxythiomorpholino)methyl)phenyl)amino)pyridazine-3-carboxamide 49 (43 mg, yellow solid), yield: 35%.
MS m/z(ESI):474[M+1]MS m/z(ESI): 474[M+1]
1H NMR(400MHz,CD 3OD)δ7.84(d,J＝8.3Hz,2H),7.81–7.75(m,1H),7.73(s,1H),7.62(d,J＝8.3Hz,2H),7.31(t,J＝8.6Hz,2H),4.56(s,2H),3.89–3.77(m,4H),3.72–3.54(m,4H)。 1 H NMR (400 MHz, CD 3 OD) δ 7.84 (d, J=8.3 Hz, 2H), 7.81-7.75 (m, 1H), 7.73 (s, 1H), 7.62 (d, J=8.3 Hz, 2H) ), 7.31 (t, J=8.6Hz, 2H), 4.56 (s, 2H), 3.89–3.77 (m, 4H), 3.72–3.54 (m, 4H).
以下实施例(实施例50、实施例51)均参照实施例49的操作方法合成，但在第四步中用不同的脂肪胺代替硫代吗啉-1,1-二氧化物。表征数据如下表所示：The following examples (Example 50, Example 51) are all synthesized according to the operation method of Example 49, but in the fourth step, different fatty amines are used instead of thiomorpholine-1,1-dioxide. Characterization data are shown in the following table:
Figure PCTCN2020108468-appb-000073
Figure PCTCN2020108468-appb-000073
实施例52Example 52
6-(2,6-二氟苯基)-4-((2-甲基-1-氧代异二氢吲哚-5-基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((2-methyl-1-oxoisoindol-5-yl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000074
Figure PCTCN2020108468-appb-000074
第一步first step
2-(溴甲基)-4-硝基苯甲酸甲酯Methyl 2-(bromomethyl)-4-nitrobenzoate
将化合物2-甲基-4-硝基苯甲酸甲酯52a(5g，25.6mmol)溶于四氯化碳(150mL)，然后加入N-溴代丁二酰亚胺(5.02g，28.2mmol)和偶氮二异丁腈(419mg，2.56mmol)，加热至80℃并搅拌15小时。反应完成后减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝100/1至5/1)纯化，得到目标产物2-(溴甲基)-4-硝基苯甲酸甲酯52b(3.7g，白色固体)，产率：53％。Compound 2-methyl-4-nitrobenzoic acid methyl ester 52a (5 g, 25.6 mmol) was dissolved in carbon tetrachloride (150 mL), then N-bromosuccinimide (5.02 g, 28.2 mmol) was added and azobisisobutyronitrile (419 mg, 2.56 mmol), heated to 80°C and stirred for 15 hours. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100/1 to 5/1) to obtain the target product 2-(bromomethyl)-4-nitrobenzoic acid Methyl ester 52b (3.7 g, white solid), yield: 53%.
1H NMR(400MHz,CDCl 3)δ8.34(d,J＝2.3Hz,1H),8.20(dd,J＝8.6,2.3Hz,1H),8.12(d,J＝8.6Hz,1H),4.97(s,2H),4.01(s,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.34 (d, J=2.3 Hz, 1H), 8.20 (dd, J=8.6, 2.3 Hz, 1H), 8.12 (d, J=8.6 Hz, 1H), 4.97 (s, 2H), 4.01 (s, 3H).
第二步second step
2-甲基-5-硝基异二氢吲哚-1-酮2-Methyl-5-nitroisoindol-1-one
将化合物2-(溴甲基)-4-硝基苯甲酸甲酯52b(1.2g，4.4mmol)溶于甲醇，然后加入甲胺的四氢呋喃溶液(2M，5mL，10mmol)。室温下搅拌12小时后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝100/1至5/1)纯化，得到目标产物2-甲基-5-硝基异二氢吲哚-1-酮52c(845mg，近白色固体)，产率：100％。Compound 2-(bromomethyl)-4-nitrobenzoic acid methyl ester 52b (1.2 g, 4.4 mmol) was dissolved in methanol followed by addition of methylamine in tetrahydrofuran (2M, 5 mL, 10 mmol). After stirring at room temperature for 12 hours, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100/1 to 5/1) to obtain the target product 2-methyl-5-nitroiso Indoline-1-one 52c (845 mg, off-white solid), yield: 100%.
MS m/z(ESI):193[M+1]MS m/z(ESI): 193[M+1]
第三步third step
5-氨基-2-甲基异二氢吲哚-1-酮5-Amino-2-methylisoindol-1-one
将化合物2-甲基-5-硝基异二氢吲哚-1-酮52c(920mg，4.8mmol)溶于乙酸乙酯(50mL)，然后加入10％钯炭(400mg)，在氢气气氛下室温搅拌2小时。反应完成后过滤，滤液在减压条件下除去溶剂，得到目标产物5-氨基-2-甲基异二氢吲哚-1-酮52d(630mg，近白色固体)，产率：81％。Compound 2-methyl-5-nitroisoindolin-1-one 52c (920 mg, 4.8 mmol) was dissolved in ethyl acetate (50 mL), then 10% palladium on carbon (400 mg) was added, and under hydrogen atmosphere Stir at room temperature for 2 hours. After the completion of the reaction, it was filtered, and the filtrate was removed from the solvent under reduced pressure to obtain the target product 5-amino-2-methylisoindol-1-one 52d (630 mg, nearly white solid), yield: 81%.
MS m/z(ESI):163[M+1]MS m/z(ESI): 163[M+1]
第四步the fourth step
6-氯-4-((2-甲基-1-氧代异二氢吲哚-5-基)氨基)哒嗪-3-羧酸甲酯Methyl 6-chloro-4-((2-methyl-1-oxoisoindol-5-yl)amino)pyridazine-3-carboxylate
将化合物4,6-二氯哒嗪-3-羧酸甲酯1a(310mg，1.50mmol)和5-氨基-2-甲基异二氢吲哚-1-酮52d(267mg，1.65mmol)溶于乙醇(20mL)，然后在微波反应器中加热到90℃并搅拌3小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(二氯甲烷/甲醇＝100/1至20/1)纯化，得到目标产物6-氯-4-((2-甲基-1-氧代异二氢吲哚-5-基)氨基)哒嗪-3-羧酸甲酯52e(120mg，淡黄色固体)，产率：24％。Compounds 4,6-dichloropyridazine-3-carboxylate methyl ester 1a (310 mg, 1.50 mmol) and 5-amino-2-methylisoindol-1-one 52d (267 mg, 1.65 mmol) were dissolved in ethanol (20 mL), then heated to 90 °C in a microwave reactor and stirred for 3 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=100/1 to 20/1) to obtain the target product 6-chloro-4-((2-methyl- 1-oxoisoindol-5-yl)amino)pyridazine-3-carboxylate methyl ester 52e (120 mg, pale yellow solid), yield: 24%.
MS m/z(ESI):333[M+1]MS m/z(ESI): 333[M+1]
第五步the fifth step
6-(2,6-二氟苯基)-4-((2-甲基-1-氧代异二氢吲哚-5-基)氨基)哒嗪-3-羧酸甲酯Methyl 6-(2,6-difluorophenyl)-4-((2-methyl-1-oxoisoindol-5-yl)amino)pyridazine-3-carboxylate
将化合物6-氯-4-((2-甲基-1-氧代异二氢吲哚-5-基)氨基)哒嗪-3-羧酸甲酯52e(120mg，0.36mmol)、2,6-二氟苯硼酸(171mg，1.08mmol)、二异丙基乙基胺(140mg，1.08mmol)和四(三苯基膦)钯(41mg，0.036mmol)溶于1,4-二氧六环(3mL)，除氧后在氮气气氛下用微波反应器加热到110℃并搅拌1小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝20/1至1/2)纯化，得到目标产物6-(2,6-二氟苯基)-4-((2-甲基-1-氧代异二氢吲哚-5-基)氨基)哒嗪-3-羧酸甲酯52d(90mg，黄色油状物)，产率：61％。The compound 6-chloro-4-((2-methyl-1-oxoisoindoline-5-yl)amino)pyridazine-3-carboxylate methyl ester 52e (120 mg, 0.36 mmol), 2, 6-Difluorophenylboronic acid (171 mg, 1.08 mmol), diisopropylethylamine (140 mg, 1.08 mmol) and tetrakis(triphenylphosphine)palladium (41 mg, 0.036 mmol) were dissolved in 1,4-dioxane The ring (3 mL) was deoxygenated and heated to 110°C in a microwave reactor under nitrogen atmosphere and stirred for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=20/1 to 1/2) to obtain the target product 6-(2,6-difluorophenyl) -4-((2-Methyl-1-oxoisoindol-5-yl)amino)pyridazine-3-carboxylate methyl ester 52d (90 mg, yellow oil), yield: 61%.
MS m/z(ESI):411[M+1]MS m/z(ESI): 411[M+1]
第六步Step 6
6-(2,6-二氟苯基)-4-((2-甲基-1-氧代异二氢吲哚-5-基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((2-methyl-1-oxoisoindol-5-yl)amino)pyridazine-3-carboxamide
将化合物6-(2,6-二氟苯基)-4-((2-甲基-1-氧代异二氢吲哚-5-基)氨基)哒嗪-3-羧酸甲酯52d(90mg，0.22mmol)溶于四氢呋喃(10mL)，然后加入氨水(1mL)。室温下搅拌15小时后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2,6-二氟苯基)-4-((2-甲基-1-氧代异二氢吲哚-5-基)氨基)哒嗪-3-甲酰胺52(50mg，黄色固体)，产率52％。The compound 6-(2,6-difluorophenyl)-4-((2-methyl-1-oxoisoindol-5-yl)amino)pyridazine-3-carboxylate methyl ester 52d (90 mg, 0.22 mmol) was dissolved in tetrahydrofuran (10 mL), then ammonia (1 mL) was added. After stirring at room temperature for 15 hours, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to obtain the target product 6-(2,6-difluorophenyl)-4-((2-methyl-1 -oxoisoindoline-5-yl)amino)pyridazine-3-carboxamide 52 (50 mg, yellow solid), 52% yield.
MS m/z(ESI):396[M+1]MS m/z(ESI): 396[M+1]
1H NMR(400MHz,CD 3OD)δ7.90(d,J＝8.1Hz,1H),7.80–7.67(m,3H),7.58(dd,J＝8.1,1.8Hz,1H),7.29(t,J＝8.5Hz,2H),4.57(s,2H),3.22(s,3H)。 1 H NMR (400 MHz, CD 3 OD) δ 7.90 (d, J=8.1 Hz, 1H), 7.80-7.67 (m, 3H), 7.58 (dd, J=8.1, 1.8 Hz, 1H), 7.29 (t , J=8.5Hz, 2H), 4.57(s, 2H), 3.22(s, 3H).
以下实施例(实施例53、实施例54)均参照实施例52的操作方法合成，但在第一步中用不同的脂肪胺代替N-溴代丁二酰亚胺。表征数据如下表所示：The following examples (Example 53, Example 54) are all synthesized with reference to the operation method of Example 52, but in the first step, different aliphatic amines are used to replace N-bromosuccinimide. Characterization data are shown in the following table:
Figure PCTCN2020108468-appb-000075
Figure PCTCN2020108468-appb-000075
实施例55Example 55
2-(4-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)苯基)乙酸2-(4-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)phenyl)acetic acid
Figure PCTCN2020108468-appb-000076
Figure PCTCN2020108468-appb-000076
第一步first step
2-(4-硝基苯基)乙酸叔丁酯2-(4-Nitrophenyl)acetate tert-butyl ester
将化合物2-(4-硝基苯基)乙酸55a(4.5g，20mmol)溶于二氯甲烷(30mL)，然后依次加入叔丁醇(20mL)、吡啶(10mL)和三氯氧磷(3mL)。室温下搅拌12小时后，加入水(150mL)，然后用乙酸乙酯萃取(50mL×3)。有机相合并后，用饱和食盐水(50mL×2)洗涤，然后用无水硫酸钠干燥。过滤后，滤液在减压条件下除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝100/0至4/1)纯化，得到目标产物2-(4-硝基苯基)乙酸叔丁酯55b(5.5g，无色油状物)，产率：93％。Compound 2-(4-nitrophenyl)acetic acid 55a (4.5 g, 20 mmol) was dissolved in dichloromethane (30 mL), followed by addition of tert-butanol (20 mL), pyridine (10 mL) and phosphorus oxychloride (3 mL) ). After stirring at room temperature for 12 hours, water (150 mL) was added, followed by extraction with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL×2), and then dried over anhydrous sodium sulfate. After filtration, the filtrate was removed from the solvent under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100/0 to 4/1) to obtain the target product 2-(4-nitrophenyl) tert-Butyl acetate 55b (5.5 g, colorless oil), yield: 93%.
1H NMR(400MHz,CDCl 3)δ8.22–8.15(m,2H),7.48–7.40(m,2H),3.64(s,2H),1.44(s,9H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.22-8.15 (m, 2H), 7.48-7.40 (m, 2H), 3.64 (s, 2H), 1.44 (s, 9H).
第二步second step
2-(4-氨基苯基)乙酸叔丁酯2-(4-Aminophenyl)acetate tert-butyl ester
将化合物2-(4-硝基苯基)乙酸叔丁酯55b(5g，21mmol)溶于甲醇(30mL)，然后加入10％钯炭(1g)并在氢气气氛下搅拌3小时。反应完成后过滤，滤液在减压条件下除去溶剂，得到目标产物2-(4-氨基苯基)乙酸叔丁酯55c(2.25g，黄色油状物)，产率：51％。Compound 2-(4-nitrophenyl)acetate tert-butyl ester 55b (5 g, 21 mmol) was dissolved in methanol (30 mL), then 10% palladium on carbon (1 g) was added and stirred under a hydrogen atmosphere for 3 hours. After completion of the reaction, filter the filtrate and remove the solvent under reduced pressure to obtain the target product 2-(4-aminophenyl)acetic acid tert-butyl ester 55c (2.25 g, yellow oil), yield: 51%.
MS m/z(ESI):208[M+1]MS m/z(ESI): 208[M+1]
第三步third step
4-((4-(2-叔丁氧基-2-氧代乙基)苯基)氨基)-6-氯哒嗪-3-羧酸甲酯Methyl 4-((4-(2-tert-butoxy-2-oxoethyl)phenyl)amino)-6-chloropyridazine-3-carboxylate
将化合物4,6-二氯哒嗪-3-羧酸甲酯1a(1g，5mmol)和2-(4-氨基 苯基)乙酸叔丁酯55c(1g，5mmol)溶于乙醇(10mL)，加热至90℃并搅拌5小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝100/0至7/3)纯化，得到目标产物4-((4-(2-叔丁氧基-2-氧代乙基)苯基)氨基)-6-氯哒嗪-3-羧酸甲酯55d(540mg，无色油状物)，产率：28％。Compound 4,6-dichloropyridazine-3-carboxylate methyl ester 1a (1 g, 5 mmol) and tert-butyl 2-(4-aminophenyl)acetate 55c (1 g, 5 mmol) were dissolved in ethanol (10 mL), Heat to 90°C and stir for 5 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100/0 to 7/3) to obtain the target product 4-((4-(2-tert-butoxy) Methyl-2-oxoethyl)phenyl)amino)-6-chloropyridazine-3-carboxylate 55d (540 mg, colorless oil), yield: 28%.
MS m/z(ESI):378[M+1]MS m/z(ESI): 378[M+1]
第四步the fourth step
4-((4-(2-叔丁氧基-2-氧代乙基)苯基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯Methyl 4-((4-(2-tert-butoxy-2-oxoethyl)phenyl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxylate
将化合物4-((4-(2-(叔-丁氧基)-2-氧代乙基)苯基)氨基)-6-氯哒嗪-3-羧酸甲酯55d(540mg，1.43mmol)、2,6-二氟苯硼酸(680mg，4.3mmol)、二异丙基乙基胺(0.9mL)和四(三苯基膦)钯(330mg，0.28mmol)溶于1,4-二氧六环(7mL)和水(1mL)的混合溶剂，除氧后在氮气气氛下用微波反应器加热到110℃并搅拌1小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝100/0至1/1)纯化，得到目标产物4-((4-(2-叔丁氧基-2-氧代乙基)苯基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯55e(170mg，棕色油状物)，产率：26％。Compound 4-((4-(2-(tert-butoxy)-2-oxoethyl)phenyl)amino)-6-chloropyridazine-3-carboxylate methyl ester 55d (540 mg, 1.43 mmol ), 2,6-difluorophenylboronic acid (680 mg, 4.3 mmol), diisopropylethylamine (0.9 mL) and tetrakis(triphenylphosphine)palladium (330 mg, 0.28 mmol) were dissolved in 1,4-diisopropylethylamine (0.9 mL) A mixed solvent of oxane (7 mL) and water (1 mL) was deoxygenated and heated to 110° C. with a microwave reactor under nitrogen atmosphere and stirred for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100/0 to 1/1) to obtain the target product 4-((4-(2-tert-butoxy) Methyl-2-oxoethyl)phenyl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxylate 55e (170 mg, brown oil), yield: 26% .
MS m/z(ESI):456[M+1]MS m/z(ESI): 456[M+1]
第五步the fifth step
2-(4-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)苯基)乙酸叔丁酯tert-Butyl 2-(4-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)phenyl)acetate
将化合物4-((4-(2-叔丁氧基-2-氧代乙基)苯基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯55e(170mg，0.373mmol)溶于四氢呋喃(1mL)，然后加入氨水(2mL)。室温下搅拌3小时后，减压除去溶剂，得到目标产物2-(4-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)苯基)乙酸叔丁酯55f(140mg，棕色油状物)，产率：82％。The compound 4-((4-(2-tert-butoxy-2-oxoethyl)phenyl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxylate methyl ester 55e (170 mg, 0.373 mmol) was dissolved in tetrahydrofuran (1 mL), then ammonia (2 mL) was added. After stirring at room temperature for 3 hours, the solvent was removed under reduced pressure to give the desired product 2-(4-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)benzene yl) tert-butyl acetate 55f (140 mg, brown oil), yield: 82%.
MS m/z(ESI):441[M+1]MS m/z(ESI): 441[M+1]
第六步Step 6
2-(4-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)苯基)乙酸2-(4-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)phenyl)acetic acid
将化合物2-(4-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)苯基)乙酸叔丁酯55f(100mg，0.227mmol)溶于三氟乙酸(2mL)，加热至80℃并搅拌1小时。冷却到室温后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物2-(4-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)苯基)乙酸55(41mg，黄色固体)，产率：两步36％。Compound 2-(4-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)phenyl)acetate tert-butyl ester 55f (100 mg, 0.227 mmol) Dissolve in trifluoroacetic acid (2 mL), heat to 80°C and stir for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to obtain the target product 2-(4-((3-carbamoyl-6-(2,6-difluorophenyl)) Pyridazin-4-yl)amino)phenyl)acetic acid 55 (41 mg, yellow solid), yield: 36% for two steps.
MS m/z(ESI):385[M+1]MS m/z(ESI): 385[M+1]
1H NMR(400MHz,DMSO-d 6)δ11.31(s,1H),8.77(s,1H),8.22(s,1H),7.74–7.58(m,1H),7.48–7.21(m,7H),3.61(s,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ11.31(s,1H), 8.77(s,1H), 8.22(s,1H), 7.74-7.58(m,1H), 7.48-7.21(m,7H) ), 3.61(s, 2H).
实施例56Example 56
6-(2,6-二氟苯基)-4-((4-(2-吗啉代-2-氧代乙基)苯基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((4-(2-morpholino-2-oxoethyl)phenyl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000077
Figure PCTCN2020108468-appb-000077
将化合物2-(4-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)苯基)乙酸55(137mg，0.356mmol)、O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓六氟磷酸盐(175mg，0.462mmol)和二异丙基乙基胺(230mg，1.2mmol)溶于N,N-二甲基甲酰胺(2mL)，然后加入吗啉(100mg，1.07mmol)。室温下搅拌1小时后，直接将反应混合物用反相制备高效液相色谱纯化，得到目标产物6-(2,6-二氟苯基)-4-((4-(2-吗啉代-2-氧代乙基)苯基)氨基)哒嗪-3-甲酰胺56(21.6mg，黄色固体)，产率：13％。Compound 2-(4-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)phenyl)acetic acid 55 (137 mg, 0.356 mmol), O- (7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (175 mg, 0.462 mmol) and diisopropylethylamine (230 mg , 1.2 mmol) was dissolved in N,N-dimethylformamide (2 mL), then morpholine (100 mg, 1.07 mmol) was added. After stirring at room temperature for 1 hour, the reaction mixture was directly purified by reverse-phase preparative high performance liquid chromatography to obtain the target product 6-(2,6-difluorophenyl)-4-((4-(2-morpholino- 2-Oxoethyl)phenyl)amino)pyridazine-3-carboxamide 56 (21.6 mg, yellow solid), yield: 13%.
MS m/z(ESI):454[M+1]MS m/z(ESI): 454[M+1]
1H NMR(400MHz,DMSO-d 6)δ11.17(s,1H),8.77(s,1H),8.17(s,1H),7.72–7.56(m,1H),7.46–7.09(m,7H),3.74(brs,2H),3.57–3.37(m,8H)。 1 H NMR (400MHz, DMSO-d 6 )δ11.17(s,1H), 8.77(s,1H), 8.17(s,1H), 7.72-7.56(m,1H), 7.46-7.09(m,7H) ), 3.74 (brs, 2H), 3.57–3.37 (m, 8H).
以下实施例(实施例57、实施例58、实施例59、实施例60)均参照实施例56的操作方法合成，但在第一步中用不同的脂肪胺代替吗啉。表征数据如下表所示：The following examples (Example 57, Example 58, Example 59, Example 60) were all synthesized according to the operation method of Example 56, but in the first step, different aliphatic amines were used instead of morpholine. Characterization data are shown in the following table:
Figure PCTCN2020108468-appb-000078
Figure PCTCN2020108468-appb-000078
Figure PCTCN2020108468-appb-000079
Figure PCTCN2020108468-appb-000079
实施例61Example 61
2-(4-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)苯基)-2-甲基丙酸2-(4-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)phenyl)-2-methylpropionic acid
Figure PCTCN2020108468-appb-000080
Figure PCTCN2020108468-appb-000080
第一步first step
2-甲基-2-(4-硝基苯基)丙酸叔丁酯2-Methyl-2-(4-nitrophenyl)propanoate tert-butyl ester
将化合物2-(4-硝基苯基)乙酸叔丁酯55b(2g，8.43mmol)溶于N,N-二甲基甲酰胺(20mL)中，冷却到0℃后加入氢化钠(60％，840mg，21mmol)。搅拌30分钟后，加入碘甲烷(5g，33.7mmol)，然后逐渐升到室温并搅拌12小时。反应完成后后加入水(100mL)，然后用乙酸乙酯萃取(100mL×2)。有机相合并后，用饱和食盐水洗涤(100mL×2)，然后用无水硫酸钠干燥。过滤后滤液在减压条件下除去溶剂，得到目标产物2-甲基-2-(4-硝基苯基)丙酸叔丁酯61a(2.5g，粗品)。该产品未经进一步纯化，直接用于下一步反应。Compound 2-(4-nitrophenyl)acetate tert-butyl ester 55b (2 g, 8.43 mmol) was dissolved in N,N-dimethylformamide (20 mL), cooled to 0 °C and then added with sodium hydride (60% , 840 mg, 21 mmol). After stirring for 30 minutes, iodomethane (5 g, 33.7 mmol) was added, then gradually warmed to room temperature and stirred for 12 hours. After the reaction was completed, water (100 mL) was added, followed by extraction with ethyl acetate (100 mL×2). The organic phases were combined, washed with saturated brine (100 mL×2), and then dried over anhydrous sodium sulfate. After filtration, the solvent was removed from the filtrate under reduced pressure to obtain the target product tert-butyl 2-methyl-2-(4-nitrophenyl)propanoate 61a (2.5 g, crude product). This product was used directly in the next reaction without further purification.
1H NMR(400MHz,CDCl 3)δ8.21–8.15(m,2H),7.53–7.47(m,2H),1.57(s,6H),1.38(s,9H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.21-8.15 (m, 2H), 7.53-7.47 (m, 2H), 1.57 (s, 6H), 1.38 (s, 9H).
第二步second step
2-(4-氨基苯基)-2-甲基丙酸叔丁酯2-(4-Aminophenyl)-2-methylpropionic acid tert-butyl ester
将化合物2-甲基-2-(4-硝基苯基)丙酸叔丁酯61a(2.5g，粗品)溶于乙醇(30mL)，然后加入10％钯炭(1g)并在氢气气氛下搅拌3小时。反应完成后过滤，滤液在减压条件下除去溶剂，得到目标产物2-(4-氨基苯基)-2-甲基丙酸叔丁酯61b(1.9g，黄色油状物)，产率：96％。Compound 2-methyl-2-(4-nitrophenyl)propanoate tert-butyl ester 61a (2.5 g, crude) was dissolved in ethanol (30 mL), then 10% palladium on carbon (1 g) was added and the mixture was heated under a hydrogen atmosphere Stir for 3 hours. After the completion of the reaction, the filtrate was filtered, and the solvent was removed from the filtrate under reduced pressure to obtain the target product 2-(4-aminophenyl)-2-methylpropionic acid tert-butyl ester 61b (1.9 g, yellow oil), yield: 96 %.
MS m/z(ESI):236[M+1]MS m/z(ESI): 236[M+1]
第三步third step
4-((4-(1-(叔-丁氧基)-2-甲基-1-氧代丙烷-2-基)苯基)氨基)-6-氯哒嗪-3-羧酸甲酯Methyl 4-((4-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)phenyl)amino)-6-chloropyridazine-3-carboxylate
将化合物4,6-二氯哒嗪-3-羧酸甲酯1a(1.1g，5.31mmol)、2-(4-氨基苯基)-2-甲基丙酸叔丁酯61b(1.25g，5.31mmol)和二异丙基乙基胺(2g，16mmol)溶于乙腈(10mL)，加热至90℃并搅拌15小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝100/0至7/3)纯化，得到目标产物4-((4-(1-(叔-丁氧基)-2-甲基-1-氧代丙烷-2-基)苯基)氨基)-6-氯哒嗪-3-羧酸甲酯61c(1.9g，黄色油状物)，产率：88％。Compound 4,6-dichloropyridazine-3-carboxylic acid methyl ester 1a (1.1 g, 5.31 mmol), 2-(4-aminophenyl)-2-methylpropionic acid tert-butyl ester 61b (1.25 g, 5.31 mmol) and diisopropylethylamine (2 g, 16 mmol) were dissolved in acetonitrile (10 mL), heated to 90°C and stirred for 15 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100/0 to 7/3) to obtain the target product 4-((4-(1-(tert- Butoxy)-2-methyl-1-oxopropan-2-yl)phenyl)amino)-6-chloropyridazine-3-carboxylic acid methyl ester 61c (1.9 g, yellow oil), yield : 88%.
MS m/z(ESI):406[M+1]MS m/z(ESI): 406[M+1]
第四步the fourth step
4-((4-(1-(叔-丁氧基)-2-甲基-1-氧代丙烷-2-基)苯基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯4-((4-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)phenyl)amino)-6-(2,6-difluorophenyl) Methyl pyridazine-3-carboxylate
将化合物4-((4-(1-(叔-丁氧基)-2-甲基-1-氧代丙烷-2-基)苯基)氨基)-6-氯哒嗪-3-羧酸甲酯61c(1.2g，2.96mmol)、2,6-二氟苯硼酸(1.4g，8.88mmol)、二异丙基乙基胺(1.5g，11.84mmol)和四(三苯基膦)钯(330mg，0.28mmol)溶于1,4-二氧六环(15mL)，除氧后在氮气气氛下用微波反应器加热到105℃并搅拌2小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝100/0至1/1)纯化，得到目标产物4-((4-(1-(叔-丁氧基)-2-甲基-1-氧代丙烷-2-基)苯基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯61d(520mg，棕色油状物)，产 率：31％。Compound 4-((4-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)phenyl)amino)-6-chloropyridazine-3-carboxylic acid Methyl ester 61c (1.2 g, 2.96 mmol), 2,6-difluorophenylboronic acid (1.4 g, 8.88 mmol), diisopropylethylamine (1.5 g, 11.84 mmol) and tetrakis(triphenylphosphine)palladium (330 mg, 0.28 mmol) was dissolved in 1,4-dioxane (15 mL), deoxygenated and heated to 105 °C in a microwave reactor under nitrogen atmosphere and stirred for 2 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100/0 to 1/1) to obtain the target product 4-((4-(1-(tert- Butoxy)-2-methyl-1-oxopropan-2-yl)phenyl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxylate methyl ester 61d (520 mg , brown oil), yield: 31%.
MS m/z(ESI):484[M+1]MS m/z(ESI): 484[M+1]
第五步the fifth step
2-(4-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)苯基)-2-甲基丙酸叔丁酯tert-Butyl 2-(4-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)phenyl)-2-methylpropanoate
将化合物4-((4-(1-(叔-丁氧基)-2-甲基-1-氧代丙烷-2-基)苯基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯61d(440mg，0.91mmol)溶于四氢呋喃(2mL)，然后加入氨水(4mL)。室温下搅拌3小时后，减压除去溶剂，得到目标产物2-(4-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)苯基)-2-甲基丙酸叔丁酯61e(440mg，棕色油状物)，产率：78％。Compound 4-((4-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)phenyl)amino)-6-(2,6-difluorobenzene yl)pyridazine-3-carboxylate methyl ester 61d (440 mg, 0.91 mmol) was dissolved in tetrahydrofuran (2 mL), then ammonia (4 mL) was added. After stirring at room temperature for 3 hours, the solvent was removed under reduced pressure to give the desired product 2-(4-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)benzene (440 mg, brown oil), yield: 78%.
MS m/z(ESI):469[M+1]MS m/z(ESI): 469[M+1]
第六步Step 6
2-(4-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)苯基)-2-甲基丙酸2-(4-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)phenyl)-2-methylpropionic acid
将化合物2-(4-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)苯基)-2-甲基丙酸叔丁酯61e(100mg，0.227mmol)溶于三氟乙酸(2mL)，加热至80℃并搅拌1小时。冷却到室温后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物2-(4-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)苯基)-2-甲基丙酸61(23mg，黄色固体)，产率：30％。Compound 2-(4-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)phenyl)-2-methylpropionic acid tert-butyl ester 61e (100 mg, 0.227 mmol) was dissolved in trifluoroacetic acid (2 mL), heated to 80°C and stirred for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to obtain the target product 2-(4-((3-carbamoyl-6-(2,6-difluorophenyl)) Pyridazin-4-yl)amino)phenyl)-2-methylpropionic acid 61 (23 mg, yellow solid), yield: 30%.
MS m/z(ESI):413[M+1]MS m/z(ESI): 413[M+1]
1H NMR(400MHz,DMSO-d 6)δ11.11(s,1H),8.78(s,1H),8.14(s,1H),7.74–7.54(m,1H),7.50–7.16(m,7H),1.48(s,6H)。 1 H NMR (400MHz, DMSO-d 6 )δ11.11(s,1H), 8.78(s,1H), 8.14(s,1H), 7.74-7.54(m,1H), 7.50-7.16(m,7H) ), 1.48(s, 6H).
实施例62Example 62
6-(2,6-二氟苯基)-4-((4-(2-甲基-1-(4-甲基哌嗪-1-基)-1-氧代丙烷-2-基)苯基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((4-(2-methyl-1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl) Phenyl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000081
Figure PCTCN2020108468-appb-000081
将化合物2-(4-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)苯基)-2-甲基丙酸61(200mg，0.485mmol)、O-(7-氮杂苯并三唑-1-基)- N,N,N’,N’-四甲基脲鎓六氟磷酸盐(240mg，0.63mmol)和二异丙基乙基胺(230mg，1.2mmol)溶于N,N-二甲基甲酰胺(3mL)，然后加入1-甲基哌嗪(150mg，1.45mmol)。室温下搅拌1小时后，直接将反应混合物用反相制备高效液相色谱纯化，得到目标产物6-(2,6-二氟苯基)-4-((4-(2-甲基-1-(4-甲基哌嗪-1-基)-1-氧代丙烷-2-基)苯基)氨基)哒嗪-3-甲酰胺62(42mg，黄色固体)，产率：17％。Compound 2-(4-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)phenyl)-2-methylpropionic acid 61 (200 mg, 0.485 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (240 mg, 0.63 mmol) and diisopropyl Ethyl amine (230 mg, 1.2 mmol) was dissolved in N,N-dimethylformamide (3 mL) and 1-methylpiperazine (150 mg, 1.45 mmol) was added. After stirring at room temperature for 1 hour, the reaction mixture was directly purified by reverse-phase preparative high performance liquid chromatography to obtain the target product 6-(2,6-difluorophenyl)-4-((4-(2-methyl-1). -(4-Methylpiperazin-1-yl)-1-oxopropan-2-yl)phenyl)amino)pyridazine-3-carboxamide 62 (42 mg, yellow solid), yield: 17%.
MS m/z(ESI):495[M+1]MS m/z(ESI): 495[M+1]
1H NMR(400MHz,DMSO-d 6)δ11.53(brs,1H),11.40(s,1H),8.79(s,1H),8.25(s,1H),7.76–7.59(m,1H),7.56–7.23(m,6H),3.51–2.67(m,8H),2.62(d,J＝4.3Hz,3H),1.45(s,6H)。 1 H NMR (400MHz, DMSO-d 6 )δ11.53(brs,1H), 11.40(s,1H), 8.79(s,1H), 8.25(s,1H), 7.76-7.59(m,1H), 7.56–7.23 (m, 6H), 3.51–2.67 (m, 8H), 2.62 (d, J=4.3Hz, 3H), 1.45 (s, 6H).
以下实施例(实施例63、实施例64、实施例65)均参照实施例62的操作方法合成，但在第一步中用不同的脂肪胺代替1-甲基哌嗪。表征数据如下表所示：The following examples (Example 63, Example 64, Example 65) are all synthesized according to the operation method of Example 62, but in the first step, different fatty amines are used instead of 1-methylpiperazine. Characterization data are shown in the following table:
Figure PCTCN2020108468-appb-000082
Figure PCTCN2020108468-appb-000082
实施例67Example 67
6-(2,6-二氟苯基)-4-((1-甲基-6-氧代-1,6-二氢吡啶-3-基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000083
Figure PCTCN2020108468-appb-000083
第一步first step
4-氯-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯Methyl 4-chloro-6-(2,6-difluorophenyl)pyridazine-3-carboxylate
将化合物4,6-二氯哒嗪-3-羧酸甲酯1a(600mg，2.90mmol)、2,6-二氟苯硼酸(1.37g，8.70mmol)，二异丙基乙基胺(3g，23.2mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(118mg，0.145mmol)和1,4-二氧六环(15mL)混合，除氧后在氮气气氛下用微波反应器加热到110℃并搅拌1小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝100/0至17/3)纯化，得到目标产物4-氯-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯67a(223mg，白色固体)，产率：27％。Compound 4,6-dichloropyridazine-3-carboxylate methyl ester 1a (600 mg, 2.90 mmol), 2,6-difluorophenylboronic acid (1.37 g, 8.70 mmol), diisopropylethylamine (3 g , 23.2 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (118 mg, 0.145 mmol) and 1,4-dioxane (15 mL) Mixed, deoxygenated, heated to 110°C in a microwave reactor under nitrogen atmosphere and stirred for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100/0 to 17/3) to obtain the target product 4-chloro-6-(2,6-di). Fluorophenyl)pyridazine-3-carboxylate methyl ester 67a (223 mg, white solid), yield: 27%.
MS m/z(ESI):285[M+1]MS m/z(ESI): 285[M+1]
第二步second step
6-(2,6-二氟苯基)-4-((1-甲基-6-氧代-1,6-二氢吡啶-3-基)氨基)哒嗪-3-羧酸甲酯Methyl 6-(2,6-difluorophenyl)-4-((1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino)pyridazine-3-carboxylate
将化合物4-氯-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯67a(200mg，0.702mmol)、5-氨基-1-甲基吡啶-2(1H)-酮(87mg，0.703mmol)、三(二亚苄基丙酮)二钯(32mg，0.035mmol)、2-二环己基膦-2,4,6-三异丙基联苯(32mg，0.056mmol)、碳酸铯(298mg，0.913mmol)和甲苯(15mL)混合，除氧后在氮气气氛下用微波反应器加热到110℃并搅拌1小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝100/0至1/1)纯化，得到目标产物6-(2,6-二氟苯基)-4-((1-甲基-6-氧代-1,6-二氢吡啶-3-基)氨基)哒嗪-3-羧酸甲酯67b(107mg，白色固体)，产率：40％。Compound 4-chloro-6-(2,6-difluorophenyl)pyridazine-3-carboxylate methyl ester 67a (200 mg, 0.702 mmol), 5-amino-1-methylpyridine-2(1H)- Ketone (87 mg, 0.703 mmol), tris(dibenzylideneacetone)dipalladium (32 mg, 0.035 mmol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (32 mg, 0.056 mmol) , cesium carbonate (298 mg, 0.913 mmol) and toluene (15 mL) were mixed, deoxygenated, heated to 110° C. with a microwave reactor under nitrogen atmosphere and stirred for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100/0 to 1/1) to obtain the target product 6-(2,6-difluorophenyl) - Methyl 4-((1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino)pyridazine-3-carboxylate 67b (107 mg, white solid), yield: 40 %.
MS m/z(ESI):373[M+1]MS m/z(ESI): 373[M+1]
第三步third step
6-(2,6-二氟苯基)-4-((1-甲基-6-氧代-1,6-二氢吡啶-3-基)氨基)哒嗪-3- 甲酰胺6-(2,6-Difluorophenyl)-4-((1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino)pyridazine-3-carboxamide
将化合物6-(2,6-二氟苯基)-4-((1-甲基-6-氧代-1,6-二氢吡啶-3-基)氨基)哒嗪-3-羧酸甲酯67b(107mg，0.287mmol)溶于四氢呋喃(5mL)，然后加入氨水(3mL)。室温搅拌5小时后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2,6-二氟苯基)-4-((1-甲基-6-氧代-1,6-二氢吡啶-3-基)氨基)哒嗪-3-甲酰胺67(3.3mg，白色固体)，产率：3％。The compound 6-(2,6-difluorophenyl)-4-((1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino)pyridazine-3-carboxylic acid Methyl ester 67b (107 mg, 0.287 mmol) was dissolved in tetrahydrofuran (5 mL), then ammonia (3 mL) was added. After stirring at room temperature for 5 hours, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to obtain the target product 6-(2,6-difluorophenyl)-4-((1-methyl-6- Oxo-1,6-dihydropyridin-3-yl)amino)pyridazine-3-carboxamide 67 (3.3 mg, white solid), yield: 3%.
MS m/z(ESI):358[M+1]MS m/z(ESI): 358[M+1]
1H NMR(400MHz,CD 3OD)δ8.06(s,1H),7.89(d,J＝4Hz,1H),7.77–7.84(m,1H),7.34(t,J＝8Hz,2H),6.69(s,1H),6.57–6.58(d,J＝4Hz,1H),3.64(s,3H)。 1 H NMR (400MHz, CD 3 OD) δ 8.06 (s, 1H), 7.89 (d, J=4Hz, 1H), 7.77-7.84 (m, 1H), 7.34 (t, J=8Hz, 2H), 6.69 (s, 1H), 6.57–6.58 (d, J=4Hz, 1H), 3.64 (s, 3H).
实施例68Example 68
6-(2,6-二氟苯基)-4-((2-甲基异二氢吲哚-5-基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((2-methylisoindol-5-yl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000084
Figure PCTCN2020108468-appb-000084
第一步first step
5-((6-氯-3-(甲氧羰基)哒嗪-4-基)氨基)异二氢吲哚-2-羧酸叔丁酯5-((6-Chloro-3-(methoxycarbonyl)pyridazin-4-yl)amino)isoindoline-2-carboxylate tert-butyl ester
将化合物4,6-二氯哒嗪-3-羧酸甲酯1a(300mg，1.45mmol)、5-氨基异二氢吲哚-2-羧酸叔丁酯(340mg，1.45mmol)、二异丙基乙基胺(375mg，2.91mmol)和乙醇(20mL)混合，加热到80℃并搅拌2小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(二氯甲烷/甲醇＝19/1)纯化，得到目标产物5-((6-氯-3-(甲氧羰基)哒嗪-4-基)氨基)异二氢吲哚-2-羧酸叔丁酯68a(500mg，黄色固体)，产率：85％。Compound 4,6-dichloropyridazine-3-carboxylic acid methyl ester 1a (300 mg, 1.45 mmol), 5-aminoisoindole-2-carboxylic acid tert-butyl ester (340 mg, 1.45 mmol), diiso Propylethylamine (375 mg, 2.91 mmol) and ethanol (20 mL) were mixed, heated to 80°C and stirred for 2 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=19/1) to obtain the target product 5-((6-chloro-3-(methoxycarbonyl)pyridazine) -4-yl)amino)isoindoline-2-carboxylate tert-butyl ester 68a (500 mg, yellow solid), yield: 85%.
MS m/z(ESI):405[M+1]MS m/z(ESI): 405[M+1]
第二步second step
5-((6-(2,6-二氟苯基)-3-(甲氧羰基)哒嗪-4-基)氨基)异二氢吲哚-2-羧 酸叔丁酯5-((6-(2,6-Difluorophenyl)-3-(methoxycarbonyl)pyridazin-4-yl)amino)isoindoline-2-carboxylic acid tert-butyl ester
将化合物5-((6-氯-3-(甲氧羰基)哒嗪-4-基)氨基)异二氢吲哚-2-羧酸叔丁酯68a(500mg，1.24mmol)、2,6-二氟苯硼酸(587mg，3.72mmol)、二异丙基乙基胺(480mg，3.72mmol)和四(三苯基膦)钯(144mg，0.124mmol)溶于1,4-二氧六环(20mL)，除氧后在氮气气氛下用微波反应器加热到100℃并搅拌1小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(二氯甲烷/甲醇＝19/1)纯化，得到目标产物5-((6-(2,6-二氟苯基)-3-(甲氧羰基)哒嗪-4-基)氨基)异二氢吲哚-2-羧酸叔丁酯68b(300mg，黄色固体)，产率：50％。Compound 5-((6-chloro-3-(methoxycarbonyl)pyridazin-4-yl)amino)isoindoline-2-carboxylate tert-butyl ester 68a (500 mg, 1.24 mmol), 2,6 - Difluorophenylboronic acid (587 mg, 3.72 mmol), diisopropylethylamine (480 mg, 3.72 mmol) and tetrakis(triphenylphosphine)palladium (144 mg, 0.124 mmol) in 1,4-dioxane (20 mL), deoxygenated and heated to 100°C in a microwave reactor under nitrogen atmosphere and stirred for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=19/1) to obtain the target product 5-((6-(2,6-difluorophenyl)- 3-(Methoxycarbonyl)pyridazin-4-yl)amino)isoindoline-2-carboxylate tert-butyl ester 68b (300 mg, yellow solid), yield: 50%.
MS m/z(ESI):483[M+1]MS m/z(ESI): 483[M+1]
第三步third step
5-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)异二氢吲哚-2-羧酸叔丁酯tert-Butyl 5-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)isoindoline-2-carboxylate
将化合物5-((6-(2,6-二氟苯基)-3-(甲氧羰基)哒嗪-4-基)氨基)异二氢吲哚-2-羧酸叔丁酯68b(300mg，0.62mmol)溶于四氢呋喃(30mL)，加入氨水(2mL)。室温下搅拌3小时后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物5-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)异二氢吲哚-2-羧酸叔丁酯68c(300mg，粗品)。该产品未经进一步纯化，直接用于下一步反应。Compound 5-((6-(2,6-difluorophenyl)-3-(methoxycarbonyl)pyridazin-4-yl)amino)isoindoline-2-carboxylate tert-butyl ester 68b ( 300 mg, 0.62 mmol) was dissolved in tetrahydrofuran (30 mL), and aqueous ammonia (2 mL) was added. After stirring at room temperature for 3 hours, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to obtain the target product 5-((3-carbamoyl-6-(2,6-difluorophenyl)pyridine) Azin-4-yl)amino)isoindoline-2-carboxylate tert-butyl ester 68c (300 mg, crude). This product was used directly in the next reaction without further purification.
MS m/z(ESI):468[M+1]MS m/z(ESI): 468[M+1]
第四步the fourth step
6-(2,6-二氟苯基)-4-(异二氢吲哚-5-基氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-(isoindoline-5-ylamino)pyridazine-3-carboxamide
将化合物5-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)异二氢吲哚-2-羧酸叔丁酯68c(300mg，粗品)溶于甲醇(10mL)，加入氯化氢的乙醇溶液(33％，2mL)。室温下搅拌2小时后，减压除去溶剂，得到目标产物6-(2,6-二氟苯基)-4-(异二氢吲哚-5-基氨基)哒嗪-3-甲酰胺68d(240mg，粗品)。该产品未经进一步纯化，直接用于下一步反应。Compound 5-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)isoindoline-2-carboxylate tert-butyl ester 68c (300 mg, crude product) was dissolved in methanol (10 mL) and hydrogen chloride in ethanol (33%, 2 mL) was added. After stirring at room temperature for 2 hours, the solvent was removed under reduced pressure to give the desired product 6-(2,6-difluorophenyl)-4-(isoindol-5-ylamino)pyridazine-3-carboxamide 68d (240 mg, crude). This product was used directly in the next reaction without further purification.
MS m/z(ESI):368[M+1]MS m/z(ESI): 368[M+1]
第五步the fifth step
6-(2,6-二氟苯基)-4-((2-甲基异二氢吲哚-5-基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((2-methylisoindol-5-yl)amino)pyridazine-3-carboxamide
将化合物6-(2,6-二氟苯基)-4-(异二氢吲哚-5-基氨基)哒嗪-3-甲酰胺68d(240mg，粗品)、多聚甲醛(39mg，1.3mmol)和甲醇(10mL)混合，然后加入氰基硼氢化钠(82mg，1.3mmol)。室温下搅拌2小时后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2,6-二氟苯基)-4-((2-甲基异二氢吲哚-5-基)氨基)哒嗪-3-甲酰胺68(123mg，白色固体)，产率：52％。Compound 6-(2,6-difluorophenyl)-4-(isoindoline-5-ylamino)pyridazine-3-carboxamide 68d (240 mg, crude), paraformaldehyde (39 mg, 1.3 mmol) and methanol (10 mL), then sodium cyanoborohydride (82 mg, 1.3 mmol) was added. After stirring at room temperature for 2 hours, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to obtain the target product, 6-(2,6-difluorophenyl)-4-((2-methylisodiol). Indol-5-yl)amino)pyridazine-3-carboxamide 68 (123 mg, white solid), yield: 52%.
MS m/z(ESI):382[M+1]MS m/z(ESI): 382[M+1]
1H NMR(400MHz,CD 3OD)δ7.60-7.51(m,1H),7.35(d,J＝7.9Hz,1H),7.25(s,1H),7.22–7.10(m,4H),3.95(brs,4H),2.60(s,3H)。 1 H NMR (400MHz, CD 3 OD) δ 7.60-7.51(m, 1H), 7.35(d, J=7.9Hz, 1H), 7.25(s, 1H), 7.22-7.10(m, 4H), 3.95 (brs, 4H), 2.60 (s, 3H).
实施例69Example 69
6-(2,6-二氟苯基)-4-((4-(3-甲氧基噁丁环-3-基)苯基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((4-(3-methoxyoxetan-3-yl)phenyl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000085
Figure PCTCN2020108468-appb-000085
第一步first step
N,N-二苯甲基-4-溴苯胺N,N-Diphenylmethyl-4-bromoaniline
将化合物4-溴苯胺69a(3.4g，20mmol)、苄溴(8.5g，50mmol)、碳酸钾(8.3g，60mmol)和乙腈(8mL)混合，加热到80℃并搅拌15小时。过滤后，滤液在减压条件下除去溶剂，残余物在硅胶柱层析(石油醚/乙酸乙酯＝300/1至50/1)纯化，得到目标产物N,N-二苯甲基-4-溴苯胺69b(6g，白色固体)，产率：85％。Compound 4-bromoaniline 69a (3.4 g, 20 mmol), benzyl bromide (8.5 g, 50 mmol), potassium carbonate (8.3 g, 60 mmol) and acetonitrile (8 mL) were mixed, heated to 80°C and stirred for 15 hours. After filtration, the filtrate was removed from the solvent under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=300/1 to 50/1) to obtain the target product N,N-benzyl-4 -Bromoaniline 69b (6 g, white solid), yield: 85%.
MS m/z(ESI):352[M+1]MS m/z(ESI): 352[M+1]
第二步second step
3-(4-(二苯甲基氨基)苯基)噁丁环-3-醇3-(4-(Dibenzylamino)phenyl)oxetan-3-ol
将化合物N,N-二苯甲基-4-溴苯胺69b(3g，8.5mmol)溶于无水四氢呋喃(3g，8.5mmol)，除氧后冷却到-78℃，加入正丁基锂的己烷溶液(2.4M，4.6mL，11mmol)。在此温度下搅拌1小时后，加入噁丁环-3-酮(795mg，11mmol)。逐渐升温到室温后继续搅拌30分钟，用水(5mL)淬灭反应，然后在减压条件下除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝50/1至1/1)纯化，得到目标产物3-(4-(二苯甲基氨基)苯基)噁丁环-3-醇69c(2.4g，黄色固体)，产率：82％。The compound 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. After gradually warming up to room temperature, stirring was continued for 30 minutes, the reaction was quenched with water (5 mL), and then the solvent was removed under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=50/1 to 1/1) Purification gave the target product 3-(4-(dibenzylamino)phenyl)oxetan-3-ol 69c (2.4 g, yellow solid), yield: 82%.
MS m/z(ESI):346[M+1]MS m/z(ESI): 346[M+1]
第三步third step
N,N-二苯甲基-4-(3-甲氧基噁丁环-3-基)苯胺N,N-Diphenylmethyl-4-(3-methoxyoxetan-3-yl)aniline
将化合物3-(4-(二苯甲基氨基)苯基)噁丁环-3-醇69c(1.5g，4.35mmol)溶于四氢呋喃(80mL)，冷却到0℃后加入氢化钠(60％，260mg，6.5mmol)。在此温度下搅拌30分钟后，加入碘甲烷(1.5mL)并逐渐升温到室温。搅拌15小时后，用水(1mL)淬灭反应，然后在减压条件下除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝50/1至1/2)纯化，得到目标产物N,N-二苯甲基-4-(3-甲氧基噁丁环-3-基)苯胺69d(1.45g，白色固体)，产率：92％。Compound 3-(4-(dibenzylamino)phenyl)oxetan-3-ol 69c (1.5 g, 4.35 mmol) was dissolved in tetrahydrofuran (80 mL), cooled to 0 °C and sodium hydride (60%) was added , 260 mg, 6.5 mmol). After stirring at this temperature for 30 minutes, iodomethane (1.5 mL) was added and the temperature was gradually warmed to room temperature. After stirring for 15 hours, the reaction was quenched with water (1 mL), then the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/1 to 1/2) to obtain the desired product N,N-Diphenylmethyl-4-(3-methoxyoxetan-3-yl)aniline 69d (1.45 g, white solid), yield: 92%.
MS m/z(ESI):360[M+1]MS m/z(ESI): 360[M+1]
第四步the fourth step
4-(3-甲氧基噁丁环-3-基)苯胺4-(3-Methoxyoxetan-3-yl)aniline
将化合物N,N-二苯甲基-4-(3-甲氧基噁丁环-3-基)苯胺69d(1.45g，4mmol)，10％钯炭(600mg)和乙醇(50mL)混合，然后在氢气气氛下室温搅拌5小时。用甲醇(50mL)稀释后过滤，滤液在减压条件下除去溶剂，得到目标产物4-(3-甲氧基噁丁环-3-基)苯胺69e(760mg，黄色固体)，产率：97％。Compound N,N-diphenylmethyl-4-(3-methoxyoxetan-3-yl)aniline 69d (1.45 g, 4 mmol), 10% palladium on carbon (600 mg) and ethanol (50 mL) were mixed, It was then stirred at room temperature for 5 hours under a hydrogen atmosphere. Diluted with methanol (50 mL) and filtered, the filtrate was removed from the solvent under reduced pressure to obtain the target product 4-(3-methoxyoxetan-3-yl)aniline 69e (760 mg, yellow solid), yield: 97 %.
MS m/z(ESI):180[M+1]MS m/z(ESI): 180[M+1]
第五步the fifth step
6-氯-4-((4-(3-甲氧基噁丁环-3-基)苯基)氨基)哒嗪-3-羧酸甲酯Methyl 6-chloro-4-((4-(3-methoxyoxetan-3-yl)phenyl)amino)pyridazine-3-carboxylate
将化合物4,6-二氯哒嗪-3-羧酸甲酯1a(1.22g，5.95mmol)、4-(3-甲氧基噁丁环-3-基)苯胺69e(760mg，4.25mmol)、二异丙基乙基胺(1.65g，12.75mmol)和乙腈(15mL)混合，在微波反应器中加热到90℃并搅拌3小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝50/1至1/2)纯化，得到目标产物6-氯-4-((4-(3-甲氧基噁丁环-3-基)苯基)氨基)哒嗪-3-羧酸甲酯69f(850mg，黄色固体)，产率：57％。Compound 4,6-dichloropyridazine-3-carboxylate methyl ester 1a (1.22 g, 5.95 mmol), 4-(3-methoxyoxetan-3-yl)aniline 69e (760 mg, 4.25 mmol) , diisopropylethylamine (1.65 g, 12.75 mmol) and acetonitrile (15 mL) were mixed, heated to 90°C in a microwave reactor and stirred for 3 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/1 to 1/2) to obtain the target product 6-chloro-4-((4-(3 -Methoxyoxetan-3-yl)phenyl)amino)pyridazine-3-carboxylate 69f (850 mg, yellow solid), yield: 57%.
MS m/z(ESI):350[M+1]MS m/z(ESI): 350[M+1]
第六步Step 6
6-(2,6-二氟苯基)-4-((4-(3-甲氧基噁丁环-3-基)苯基)氨基)哒嗪-3-羧酸甲酯Methyl 6-(2,6-difluorophenyl)-4-((4-(3-methoxyoxetan-3-yl)phenyl)amino)pyridazine-3-carboxylate
将化合物6-氯-4-((4-(3-甲氧基噁丁环-3-基)苯基)氨基)哒嗪-3-羧酸甲酯69f(850mg，2.43mmol)、2,6-二氟苯硼酸(1.15g，7.29mmol)、二异丙基乙基胺(940mg，7.29mmol)和四(三苯基膦)钯(231mg，0.2mmol)溶于1,4-二氧六环(8mL)，除氧后在氮气气氛下用微波反应器加热到110℃并搅拌1小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝50/1至1/5)纯化，得到目标产物6-(2,6-二氟苯基)-4-((4-(3-甲氧基噁丁环-3-基)苯基)氨基)哒嗪-3-羧酸甲酯69g(670mg，黄色油状物)，产率：73％。The compound 6-chloro-4-((4-(3-methoxyoxetan-3-yl)phenyl)amino)pyridazine-3-carboxylate methyl ester 69f (850 mg, 2.43 mmol), 2, 6-Difluorophenylboronic acid (1.15 g, 7.29 mmol), diisopropylethylamine (940 mg, 7.29 mmol) and tetrakis(triphenylphosphine)palladium (231 mg, 0.2 mmol) were dissolved in 1,4-dioxane Hexacyclic (8 mL), deoxygenated, heated to 110° C. in a microwave reactor under nitrogen atmosphere and stirred for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/1 to 1/5) to obtain the target product 6-(2,6-difluorophenyl) -Methyl 4-((4-(3-methoxyoxetan-3-yl)phenyl)amino)pyridazine-3-carboxylate 69 g (670 mg, yellow oil), yield: 73%.
MS m/z(ESI):428[M+1]MS m/z(ESI): 428[M+1]
第七步Step 7
6-(2,6-二氟苯基)-4-((4-(3-甲氧基噁丁环-3-基)苯基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((4-(3-methoxyoxetan-3-yl)phenyl)amino)pyridazine-3-carboxamide
将化合物6-(2,6-二氟苯基)-4-((4-(3-甲氧基噁丁环-3-基)苯基)氨基)哒嗪-3-羧酸甲酯69g(670mg，1.56mmol)溶于四氢呋喃(25mL)，加入氨水(10mL)。室温下搅拌3小时后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2,6-二氟苯基)-4-((4-(3-甲氧基噁丁环-3-基)苯基)氨基)哒嗪-3-羧酸甲酯69g(500mg，白色固体)，产率96％。Compound 6-(2,6-difluorophenyl)-4-((4-(3-methoxyoxetan-3-yl)phenyl)amino)pyridazine-3-carboxylate methyl ester 69g (670 mg, 1.56 mmol) was dissolved in tetrahydrofuran (25 mL), and aqueous ammonia (10 mL) was added. After stirring at room temperature for 3 hours, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to obtain the target product 6-(2,6-difluorophenyl)-4-((4-(3-methyl) Methyl oxyoxetan-3-yl)phenyl)amino)pyridazine-3-carboxylate 69 g (500 mg, white solid), 96% yield.
MS m/z(ESI):413[M+1]MS m/z(ESI): 413[M+1]
1H NMR(400MHz,CD 3OD)δ7.62–7.51(m,3H),7.46–7.40(m,2H),7.37(s,1H),7.16(t,J＝8.2Hz,2H),4.89(dd,J＝14.4,7.0Hz,4H),3.13(s,3H)。 1 H NMR (400 MHz, CD 3 OD) δ 7.62–7.51 (m, 3H), 7.46–7.40 (m, 2H), 7.37 (s, 1H), 7.16 (t, J=8.2Hz, 2H), 4.89 (dd, J=14.4, 7.0 Hz, 4H), 3.13 (s, 3H).
实施例70Example 70
6-(2,6-二氟苯基)-4-((5-(4-甲基-2-氧代哌嗪-1-基)吡啶-2-基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((5-(4-methyl-2-oxopiperazin-1-yl)pyridin-2-yl)amino)pyridazine-3-methyl Amide
Figure PCTCN2020108468-appb-000086
Figure PCTCN2020108468-appb-000086
第一步first step
4-(6-氯吡啶-3-基)-3-氧代哌嗪-1-羧酸叔丁酯4-(6-Chloropyridin-3-yl)-3-oxopiperazine-1-carboxylate tert-butyl ester
将化合物3-氧代哌嗪-1-甲酸叔丁酯(1.04g，5.2mmol)、2-氯-5-溴吡啶70a(1.00g，5.2mmol)、叔丁醇钾(1.17g，10.4mmol)、三(二亚苄基丙酮)二钯(476mg，0.52mmol)、2-二环己基膦-2,4,6-三异丙基联苯(495mg，1.04mmol)和1,4-二氧六环(5mL)混合，除氧后在氮气气氛下加热到90℃并搅拌15小时。冷却到室温后过滤，滤液 在减压条件下除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物4-(6-氯吡啶-3-基)-3-氧代哌嗪-1-羧酸叔丁酯70b(1.40g，黄色固体)，产率：86％。Compound 3-oxopiperazine-1-carboxylic acid tert-butyl ester (1.04 g, 5.2 mmol), 2-chloro-5-bromopyridine 70a (1.00 g, 5.2 mmol), potassium tert-butoxide (1.17 g, 10.4 mmol) ), tris(dibenzylideneacetone)dipalladium (476mg, 0.52mmol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (495mg, 1.04mmol) and 1,4-diisopropylbiphenyl (495mg, 1.04mmol) Oxane (5 mL) was mixed, deoxygenated, heated to 90°C under nitrogen atmosphere and stirred for 15 hours. After cooling to room temperature, the filtrate was filtered, and the solvent was removed from the filtrate under reduced pressure. 1-Carboxylic acid tert-butyl ester 70b (1.40 g, yellow solid), yield: 86%.
MS m/z(ESI):312[M+1]MS m/z(ESI): 312[M+1]
第二步second step
4-((5-(4-(叔丁氧羰基)-2-氧代哌嗪-1-基)吡啶-2-基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸4-((5-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)pyridin-2-yl)amino)-6-(2,6-difluorophenyl)pyridazine -3-Carboxylic acid
将化合物4-氨基-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯31c(1g，4.85mmol)、4-(6-氯吡啶-3-基)-3-氧代哌嗪-1-羧酸叔丁酯70b(1.5g，4.85mmol)、碳酸铯(3.08g，9.5mmol)、三(二亚苄基丙酮)二钯(444mg，0.485mmol)、2-二环己基膦-2,4,6-三异丙基联苯(452mg，0.95mmol)和1,4-二氧六环(5mL)混合，除氧后在氮气气氛下加热到90℃并搅拌15小时。冷却到室温后过滤，滤液在减压条件下除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物4-((5-(4-(叔丁氧羰基)-2-氧代哌嗪-1-基)吡啶-2-基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸70c(400mg，黄色固体)，产率：15％。Compound 4-amino-6-(2,6-difluorophenyl)pyridazine-3-carboxylate methyl ester 31c (1 g, 4.85 mmol), 4-(6-chloropyridin-3-yl)-3- Oxopiperazine-1-carboxylate tert-butyl ester 70b (1.5 g, 4.85 mmol), cesium carbonate (3.08 g, 9.5 mmol), tris(dibenzylideneacetone)dipalladium (444 mg, 0.485 mmol), 2- Dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (452 mg, 0.95 mmol) and 1,4-dioxane (5 mL) were mixed, heated to 90°C under nitrogen atmosphere after deoxygenation and stirred 15 hours. After cooling to room temperature, the filtrate was filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was purified by reverse-phase preparative high performance liquid chromatography to obtain the target product 4-((5-(4-(tert-butoxycarbonyl)-2-oxo) Piperazin-1-yl)pyridin-2-yl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxylic acid 70c (400 mg, yellow solid), yield: 15%.
MS m/z(ESI):527[M+1]MS m/z(ESI): 527[M+1]
第三步third step
4-(6-(3-氨基甲酰基-6-(2,6-二氟苯基)哒嗪-4-基)氨基吡啶-3-基)-3-氧代哌嗪-1-羧酸叔丁酯4-(6-(3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)aminopyridin-3-yl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester
将化合物4-((5-(4-(叔丁氧羰基)-2-氧代哌嗪-1-基)吡啶-2-基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸70c(400mg，0.76mmol)、二异丙基乙基胺(103mg，0.8mmol)、O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓六氟磷酸盐(304mg，0.8mmol)和N,N-二甲基甲酰胺(10mL)混合，室温下搅拌5分钟后加入氨水(5mL)，然后继续搅拌15小时。在减压条件下除去溶剂后，残余物用硅胶柱层析(二氯甲烷/甲醇＝20/1)纯化，得到目标产物4-(6-(3-氨基甲酰基-6-(2,6-二氟苯基)哒嗪-4-基)氨基吡啶-3-基)-3-氧代哌嗪-1-羧酸叔丁酯70d(350mg，黄色固体)，产率：87％。Compound 4-((5-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)pyridin-2-yl)amino)-6-(2,6-difluorophenyl) Pyridazine-3-carboxylic acid 70c (400 mg, 0.76 mmol), diisopropylethylamine (103 mg, 0.8 mmol), O-(7-azabenzotriazol-1-yl)-N,N, N',N'-Tetramethyluronium hexafluorophosphate (304 mg, 0.8 mmol) and N,N-dimethylformamide (10 mL) were mixed, stirred at room temperature for 5 minutes, then added with ammonia (5 mL), and then continued Stir for 15 hours. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane/methanol=20/1) to obtain the target product 4-(6-(3-carbamoyl-6-(2,6) -Difluorophenyl)pyridazin-4-yl)aminopyridin-3-yl)-3-oxopiperazine-1-carboxylate tert-butyl ester 70d (350 mg, yellow solid), yield: 87%.
MS m/z(ESI):526[M+1]MS m/z(ESI): 526[M+1]
第四步the fourth step
6-(2,6-二氟苯基)-4-((5-(2-氧代哌嗪-1-基)吡啶-2-基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((5-(2-oxopiperazin-1-yl)pyridin-2-yl)amino)pyridazine-3-carboxamide
将化合物4-(6-(3-氨基甲酰基-6-(2,6-二氟苯基)哒嗪-4-基)氨基吡啶-3-基)-3-氧代哌嗪-1-羧酸叔丁酯70d(350mg，0.66mmol)和氯化氢的1,4-二氧六环溶液(2M，10mL)混合，搅拌1小时，然后减压除去溶剂，得到目标产物6-(2,6-二氟苯基)-4-((5-(2-氧代哌嗪-1-基)吡啶-2-基)氨基)哒嗪-3-甲酰胺70e(250mg，黄色固体)，产率：89％。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%.
MS m/z(ESI):426[M+1]MS m/z(ESI): 426[M+1]
第五步the fifth step
6-(2,6-二氟苯基)-4-((5-(4-甲基-2-氧代哌嗪-1-基)吡啶-2-基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((5-(4-methyl-2-oxopiperazin-1-yl)pyridin-2-yl)amino)pyridazine-3-methyl Amide
将化合物6-(2,6-二氟苯基)-4-((5-(2-氧代哌嗪-1-基)吡啶-2-基)氨基)哒嗪-3-甲酰胺70e(250mg，0.587mmol)溶于二氯甲烷(10mL)，然后加入氰基硼氢化钠(68mg，1.08mmol)。室温搅拌1小时后过滤，滤液在减压条件下除去溶剂，得到目标产物6-(2,6-二氟苯基)-4-((5-(4-甲基-2-氧代哌嗪-1-基)吡啶-2-基)氨基)哒嗪-3-甲酰胺70(2.3mg，黄色固体)，产率：0.9％。Compound 6-(2,6-difluorophenyl)-4-((5-(2-oxopiperazin-1-yl)pyridin-2-yl)amino)pyridazine-3-carboxamide 70e( 250 mg, 0.587 mmol) was dissolved in dichloromethane (10 mL) and sodium cyanoborohydride (68 mg, 1.08 mmol) was added. After stirring at room temperature for 1 hour, the filtrate was filtered, and the solvent was removed from the filtrate under reduced pressure to obtain the target product 6-(2,6-difluorophenyl)-4-((5-(4-methyl-2-oxopiperazine). -1-yl)pyridin-2-yl)amino)pyridazine-3-carboxamide 70 (2.3 mg, yellow solid), yield: 0.9%.
MS m/z(ESI):440[M+1]MS m/z(ESI): 440[M+1]
1H NMR(400MHz,DMSO)δ12.03(s,1H),9.00(d,J＝48.8Hz,2H),8.28(d,J＝56.6Hz,2H),7.73(d,J＝60.7Hz,2H),7.27(d,J＝56.2Hz,3H),3.69(s,2H),3.16(brs,2H),2.75(brs,2H),2.31(s,3H)。 1 H NMR(400MHz, DMSO)δ12.03(s,1H),9.00(d,J=48.8Hz,2H),8.28(d,J=56.6Hz,2H),7.73(d,J=60.7Hz, 2H), 7.27(d, J=56.2Hz, 3H), 3.69(s, 2H), 3.16(brs, 2H), 2.75(brs, 2H), 2.31(s, 3H).
实施例72Example 72
2-(4-((3-氨基甲酰-6-(2-氯-6-氟苯基)哒嗪-4-基)氨基)苯基)-2-甲基丙酸2-(4-((3-carbamoyl-6-(2-chloro-6-fluorophenyl)pyridazin-4-yl)amino)phenyl)-2-methylpropionic acid
Figure PCTCN2020108468-appb-000087
Figure PCTCN2020108468-appb-000087
第一步first step
4-((4-(1-(叔-丁氧基)-2-甲基-1-氧代丙烷-2-基)苯基)氨基)-6-(2-氯-6-氟苯基)哒嗪-3-羧酸甲酯4-((4-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)phenyl)amino)-6-(2-chloro-6-fluorophenyl ) pyridazine-3-carboxylate methyl ester
将化合物4-((4-(1-(叔-丁氧基)-2-甲基-1-氧代丙烷-2-基)苯基)氨基)-6-氯哒嗪-3-羧酸甲酯61c(202mg，0.5mmol)、(2-氯-6-氟苯基)硼酸(261mg，1.5mmol)、二异丙基乙基胺(194mg，1.5mmol)和四(三苯基膦)钯(35mg，0.03mmol)溶于1,4-二氧六环(10mL)，除氧后在氮气气氛下用微波反应器加热到100℃并搅拌8小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(二氯甲烷/甲醇＝100/1至10/1)纯化， 得到目标产物4-((4-(1-(叔-丁氧基)-2-甲基-1-氧代丙烷-2-基)苯基)氨基)-6-(2-氯-6-氟苯基)哒嗪-3-羧酸甲酯72a(260mg，粗品)。该产品未经进一步纯化，直接用于下一步反应。Compound 4-((4-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)phenyl)amino)-6-chloropyridazine-3-carboxylic acid Methyl ester 61c (202 mg, 0.5 mmol), (2-chloro-6-fluorophenyl)boronic acid (261 mg, 1.5 mmol), diisopropylethylamine (194 mg, 1.5 mmol) and tetrakis(triphenylphosphine) Palladium (35 mg, 0.03 mmol) was dissolved in 1,4-dioxane (10 mL), deoxygenated and heated to 100 °C in a microwave reactor under nitrogen atmosphere and stirred for 8 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=100/1 to 10/1) to obtain the target product 4-((4-(1-(tert-butylene) Oxy)-2-methyl-1-oxopropan-2-yl)phenyl)amino)-6-(2-chloro-6-fluorophenyl)pyridazine-3-carboxylate methyl ester 72a (260 mg ,Crude). This product was used directly in the next reaction without further purification.
MS m/z(ESI):500[M+1]MS m/z(ESI): 500[M+1]
第二步second step
2-(4-((3-氨基甲酰-6-(2-氯-6-氟苯基)哒嗪-4-基)氨基)苯基)-2-甲基丙酸叔丁酯tert-Butyl 2-(4-((3-carbamoyl-6-(2-chloro-6-fluorophenyl)pyridazin-4-yl)amino)phenyl)-2-methylpropanoate
将化合物4-((4-(1-(叔-丁氧基)-2-甲基-1-氧代丙烷-2-基)苯基)氨基)-6-(2-氯-6-氟苯基)哒嗪-3-羧酸甲酯72a(260mg，粗品)溶于四氢呋喃(4mL)，加入氨水(4mL)，加热并回流2小时。冷却到室温后，减压除去溶剂，得到目标产物2-(4-((3-氨基甲酰-6-(2-氯-6-氟苯基)哒嗪-4-基)氨基)苯基)-2-甲基丙酸叔丁酯72b(260mg，粗品)。该产品未经进一步纯化，直接用于下一步反应。Compound 4-((4-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)phenyl)amino)-6-(2-chloro-6-fluoro Phenyl)pyridazine-3-carboxylate methyl ester 72a (260 mg, crude) was dissolved in tetrahydrofuran (4 mL), added with ammonia (4 mL), heated and refluxed for 2 hours. After cooling to room temperature, the solvent was removed under reduced pressure to give the target product 2-(4-((3-carbamoyl-6-(2-chloro-6-fluorophenyl)pyridazin-4-yl)amino)phenyl )-tert-butyl 2-methylpropanoate 72b (260 mg, crude). This product was used directly in the next reaction without further purification.
MS m/z(ESI):485[M+1]MS m/z(ESI): 485[M+1]
第三步third step
2-(4-((3-氨基甲酰-6-(2-氯-6-氟苯基)哒嗪-4-基)氨基)苯基)-2-甲基丙酸2-(4-((3-carbamoyl-6-(2-chloro-6-fluorophenyl)pyridazin-4-yl)amino)phenyl)-2-methylpropionic acid
将化合物2-(4-((3-氨基甲酰-6-(2-氯-6-氟苯基)哒嗪-4-基)氨基)苯基)-2-甲基丙酸叔丁酯72b(260mg，粗品)溶于二氯甲烷(4mL)，然后加入三氟乙酸(4mL)。室温下搅拌16小时后，用20％氢氧化钠溶液调节至pH＝12，然后用乙酸乙酯洗涤(20mL×2)。水相用1N盐酸调节至pH＝4，有固体析出。将此固体滤出后，用反相制备液相色谱纯化，得到目标产物2-(4-((3-氨基甲酰-6-(2-氯-6-氟苯基)哒嗪-4-基)氨基)苯基)-2-甲基丙酸73(11mg，淡黄色固体)，产率：三步5％。The compound 2-(4-((3-carbamoyl-6-(2-chloro-6-fluorophenyl)pyridazin-4-yl)amino)phenyl)-2-methylpropionic acid tert-butyl ester 72b (260 mg, crude) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (4 mL) was added. After stirring at room temperature for 16 hours, it was adjusted to pH=12 with 20% sodium hydroxide solution, then washed with ethyl acetate (20 mL x 2). The aqueous phase was adjusted to pH=4 with 1N hydrochloric acid, and a solid was precipitated. This solid was filtered off and purified by reverse-phase preparative liquid chromatography to give the target product 2-(4-((3-carbamoyl-6-(2-chloro-6-fluorophenyl)pyridazine-4- (yl)amino)phenyl)-2-methylpropionic acid 73 (11 mg, pale yellow solid), yield: 5% for three steps.
MS m/z(ESI):429[M+1]MS m/z(ESI): 429[M+1]
1H NMR(400MHz,CD 3OD)δ7.63–7.52(m,3H),7.48(d,J＝8.1Hz,1H),7.39–7.28(m,4H),1.60(s,6H)。 1 H NMR (400 MHz, CD 3 OD) δ 7.63-7.52 (m, 3H), 7.48 (d, J=8.1 Hz, 1 H), 7.39-7.28 (m, 4H), 1.60 (s, 6H).
实施例73Example 73
2-(6-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)吡啶-3-基)-2-甲基丙酸
Figure PCTCN2020108468-appb-000088
2-(6-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)pyridin-3-yl)-2-methylpropionic acid
Figure PCTCN2020108468-appb-000088
Figure PCTCN2020108468-appb-000089
Figure PCTCN2020108468-appb-000089
第一步first step
6-(2,6-二氟苯基)-4-((5-(1-乙氧基-2-甲基-1-氧代丙烷-2-基)吡啶-2-基)氨基)哒嗪-3-羧酸6-(2,6-Difluorophenyl)-4-((5-(1-ethoxy-2-methyl-1-oxopropan-2-yl)pyridin-2-yl)amino)pyridin oxazine-3-carboxylic acid
将化合物4-氨基-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯31c(2.50g，9.45mmol)、2-(6-氯吡啶-3-基)-2-甲基丙酸乙酯(2.14g，9.45mmol)、醋酸钯(215mg，0.95mmol)、2-二环己基膦-2,4,6-三异丙基联苯(820mg，1.4mmol)、碳酸铯(4.0g，12.2mmol)和1,4-二氧六环(50mL)混合，除氧后在氮气气氛下于微波反应器中加热至110℃并搅拌1小时。冷却到室温后过滤待用，滤液在减压条件下除去溶剂，得到目标产物6-(2,6-二氟苯基)-4-((5-(1-乙氧基-2-甲基-1-氧代丙烷-2-基)吡啶-2-基)氨基)哒嗪-3-羧酸73a(2.63g，粗品)。该产品未经进一步纯化，直接用于下一步反应。Compound 4-amino-6-(2,6-difluorophenyl)pyridazine-3-carboxylate methyl ester 31c (2.50 g, 9.45 mmol), 2-(6-chloropyridin-3-yl)-2 -ethyl methylpropionate (2.14g, 9.45mmol), palladium acetate (215mg, 0.95mmol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (820mg, 1.4mmol), Cesium carbonate (4.0 g, 12.2 mmol) and 1,4-dioxane (50 mL) were mixed, deoxygenated, heated to 110 °C in a microwave reactor under nitrogen atmosphere and stirred for 1 hour. After cooling to room temperature, it was filtered for later use, and the filtrate was removed from the solvent under reduced pressure to obtain the target product 6-(2,6-difluorophenyl)-4-((5-(1-ethoxy-2-methyl) -1-Oxopropan-2-yl)pyridin-2-yl)amino)pyridazine-3-carboxylic acid 73a (2.63 g, crude). This product was used directly in the next reaction without further purification.
MS m/z(ESI):443[M+1]MS m/z(ESI): 443[M+1]
第二步second step
2-(6-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)吡啶-3-基)-2-甲基丙酸乙酯Ethyl 2-(6-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)pyridin-3-yl)-2-methylpropanoate
将化合物6-(2,6-二氟苯基)-4-((5-(1-乙氧基-2-甲基-1-氧代丙烷-2-基)吡啶-2-基)氨基)哒嗪-3-羧酸73a(2.63g，粗品)溶于N,N-二甲基甲酰胺(20mL)，然后加入O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓六氟磷酸盐(7.20g，18.9mmol)。室温下搅拌过夜后，加入氨水(20mL)。继续搅拌5小时后，减压除去溶剂，残余物用硅胶柱层析(二氯甲烷)纯化，得到目标产物2-(6-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)吡啶-3-基)-2-甲基丙酸乙酯73b(1.76g，近白色固体)，产率：两步42％。The compound 6-(2,6-difluorophenyl)-4-((5-(1-ethoxy-2-methyl-1-oxopropan-2-yl)pyridin-2-yl)amino ) pyridazine-3-carboxylic acid 73a (2.63 g, crude) was dissolved in N,N-dimethylformamide (20 mL), followed by the addition of O-(7-azabenzotriazol-1-yl)-N , N,N',N'-tetramethyluronium hexafluorophosphate (7.20 g, 18.9 mmol). After stirring overnight at room temperature, aqueous ammonia (20 mL) was added. After stirring for 5 hours, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane) to obtain the target product 2-(6-((3-carbamoyl-6-(2,6-difluoro) Phenyl)pyridazin-4-yl)amino)pyridin-3-yl)-2-methylpropionic acid ethyl ester 73b (1.76 g, off-white solid), yield: 42% for two steps.
MS m/z(ESI):442[M+1]MS m/z(ESI): 442[M+1]
第三步third step
2-(6-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)吡啶-3-基)-2-甲基丙酸2-(6-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)pyridin-3-yl)-2-methylpropionic acid
将化合物2-(6-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)吡啶-3-基)-2-甲基丙酸乙酯73b(1.76g，3.99mmol)溶于乙醇(110mL)， 然后加入氢氧化钾(5.30g，94.4mmol)。室温下搅拌过夜后，用醋酸调节至pH＝7后过滤。滤液在减压条件下除去溶剂，残余物用硅胶柱层析(二氯甲烷/甲醇＝100/0至83/17)纯化，得到的粗品再用反相制备液相色谱纯化，得到目标产物2-(6-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)吡啶-3-基)-2-甲基丙酸73(133mg，淡黄色固体)，产率：8％。The compound 2-(6-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)pyridin-3-yl)-2-methylpropionic acid ethyl Ester 73b (1.76 g, 3.99 mmol) was dissolved in ethanol (110 mL) and potassium hydroxide (5.30 g, 94.4 mmol) was added. After stirring overnight at room temperature, it was adjusted to pH=7 with acetic acid and filtered. The filtrate was removed from the solvent under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane/methanol=100/0 to 83/17), and the obtained crude product was purified by reverse-phase preparative liquid chromatography to obtain the target product 2 -(6-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)pyridin-3-yl)-2-methylpropionic acid 73 (133 mg, pale yellow solid), yield: 8%.
MS m/z(ESI):429[M+1]MS m/z(ESI): 429[M+1]
1H NMR(400MHz,DMSO-d 6)δ12.51(s,1H),11.96(s,1H),9.12(s,1H),8.92(s,1H),8.35(s,1H),8.19(s,1H),7.76(dd,J＝8Hz,1H),7.62–7.70(m,1H),7.31–7.35(m,2H),7.10(d,J＝8Hz,1H),1.49(s,6H)。 1 H NMR (400MHz, DMSO-d 6 )δ12.51(s,1H), 11.96(s,1H), 9.12(s,1H), 8.92(s,1H), 8.35(s,1H), 8.19( s, 1H), 7.76 (dd, J=8Hz, 1H), 7.62–7.70 (m, 1H), 7.31–7.35 (m, 2H), 7.10 (d, J=8Hz, 1H), 1.49 (s, 6H) ).
实施例74Example 74
4-((5-(1-(吖丁啶-1-基)-2-甲基-1-氧代丙烷-2-基)吡啶-2-基)氨基)-6-(2,6-二氟苯基)哒嗪-3-甲酰胺4-((5-(1-(azetidin-1-yl)-2-methyl-1-oxopropan-2-yl)pyridin-2-yl)amino)-6-(2,6- Difluorophenyl)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000090
Figure PCTCN2020108468-appb-000090
将化合物2-(6-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)吡啶-3-基)-2-甲基丙酸73(70mg，0.17mmol)、二异丙基乙基胺(109mg，0.85mmol)和吖丁啶(29mg，0.51mmol)溶于N,N-二甲基甲酰胺(7mL)，然后加入O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸盐(97mg，0.25mmol)。室温下搅拌过夜后，减压除去溶剂，残余物用反相制备液相色谱纯化，得到目标产物4-((5-(1-(吖丁啶-1-基)-2-甲基-1-氧代丙烷-2-基)吡啶-2-基)氨基)-6-(2,6-二氟苯基)哒嗪-3-甲酰胺74(5.3mg，近白色固体)，产率：7％。Compound 2-(6-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)pyridin-3-yl)-2-methylpropionic acid 73 (70 mg, 0.17 mmol), diisopropylethylamine (109 mg, 0.85 mmol) and azetidine (29 mg, 0.51 mmol) were dissolved in N,N-dimethylformamide (7 mL) and O-( 7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (97 mg, 0.25 mmol). After stirring at room temperature overnight, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative liquid chromatography to give the desired product 4-((5-(1-(azetidin-1-yl)-2-methyl-1 -Oxopropan-2-yl)pyridin-2-yl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxamide 74 (5.3 mg, nearly white solid), yield: 7%.
MS m/z(ESI):453[M+1]MS m/z(ESI): 453[M+1]
1H NMR(400MHz,CD 3OD)δ9.22(s,1H),8.21(s,1H),7.69(dd,J＝8Hz,1H),7.48–7.53(m,1H),7.10(t,J＝8Hz,2H),6.99(d,J＝8Hz,1H),3.85–3.89(m,2H),3.50–3.54(m,2H),1.95–2.03(m,2H),1.42(s,6H)。 1 H NMR (400MHz, CD 3 OD) δ 9.22 (s, 1H), 8.21 (s, 1H), 7.69 (dd, J=8Hz, 1H), 7.48–7.53 (m, 1H), 7.10 (t, J＝8Hz,2H),6.99(d,J＝8Hz,1H),3.85-3.89(m,2H),3.50-3.54(m,2H),1.95-2.03(m,2H),1.42(s,6H) ).
实施例75Example 75
6-(2,6-二氟苯基)-4-((5-(3-氧代吗啉代)吡啶-2-基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((5-(3-oxomorpholino)pyridin-2-yl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000091
Figure PCTCN2020108468-appb-000091
第一步first step
4-(6-氯吡啶-3-基)吗啉-3-酮4-(6-Chloropyridin-3-yl)morpholin-3-one
将化合物2-氯-5-碘吡啶75a(1g，4.18mmol)、吗啉-3-酮(422mg，4.17mmol)、N 1,N 2-二甲基乙烷-1,2-二胺(220mg，2.50mmol)、碘化亚铜(318mg，0.67mmol)、碳酸钾(1.154g，8.35mmol)和1,4-二氧六环(15mL)混合，除氧后在氮气气氛下用微波反应器加热至110℃并搅拌1小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(二氯甲烷/甲醇＝100/0至19/1)纯化，得到目标产物4-(6-氯吡啶-3-基)吗啉-3-酮75b(363mg，橙色固体)，产率：41％。 Compound 2-chloro-5-iodopyridine 75a (1 g, 4.18 mmol), morpholin-3-one (422 mg, 4.17 mmol), N 1 ,N 2 -dimethylethane-1,2-diamine ( 220mg, 2.50mmol), cuprous iodide (318mg, 0.67mmol), potassium carbonate (1.154g, 8.35mmol) and 1,4-dioxane (15mL) were mixed, deoxygenated and reacted with microwave under nitrogen atmosphere was heated to 110°C and stirred for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=100/0 to 19/1) to obtain the target product 4-(6-chloropyridin-3-yl)? Linn-3-one 75b (363 mg, orange solid), yield: 41%.
MS m/z(ESI):213[M+1]MS m/z(ESI): 213[M+1]
第二步second step
6-(2,6-二氟苯基)-4-((5-(3-氧代吗啉代)吡啶-2-基)氨基)哒嗪-3-羧酸甲酯Methyl 6-(2,6-difluorophenyl)-4-((5-(3-oxomorpholino)pyridin-2-yl)amino)pyridazine-3-carboxylate
将化合物4-氨基-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯31c(366mg，1.38mmol)、4-(6-氯吡啶-3-基)吗啉-3-酮75b(293mg，1.38mmol)、碳酸钾(381mg，2.76mmol)、三(二亚苄基丙酮)二钯(126mg，0.14mmol)、2-(二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯(121mg，0.21mmol)和甲苯(15mL)混合，除氧后在氮气气氛下加热到110℃并搅拌1小时。冷却到室温后过滤，滤液在减压条件下除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝100/0至0/100)纯化，得到目标产物6-(2,6-二氟苯基)-4-((5-(3-氧代吗啉代)吡啶-2-基)氨基)哒嗪-3-羧酸甲酯75c(159mg，黄色油状物)，产率：26％。Compound 4-amino-6-(2,6-difluorophenyl)pyridazine-3-carboxylate methyl ester 31c (366 mg, 1.38 mmol), 4-(6-chloropyridin-3-yl)morpholine- 3-keto 75b (293 mg, 1.38 mmol), potassium carbonate (381 mg, 2.76 mmol), tris(dibenzylideneacetone)dipalladium (126 mg, 0.14 mmol), 2-(dicyclohexylphosphine)-3,6- Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (121 mg, 0.21 mmol) and toluene (15 mL) were mixed, deoxygenated and heated to 110°C under nitrogen atmosphere and stirred for 1 hour. After cooling to room temperature, the filtrate was filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100/0 to 0/100) to obtain the target product 6-(2,6- Difluorophenyl)-4-((5-(3-oxomorpholino)pyridin-2-yl)amino)pyridazine-3-carboxylate 75c (159 mg, yellow oil), yield: 26%.
MS m/z(ESI):442[M+1]MS m/z(ESI): 442[M+1]
第三步third step
6-(2,6-二氟苯基)-4-((5-(3-氧代吗啉代)吡啶-2-基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((5-(3-oxomorpholino)pyridin-2-yl)amino)pyridazine-3-carboxamide
将化合物6-(2,6-二氟苯基)-4-((5-(3-氧代吗啉代)吡啶-2-基)氨基)哒嗪-3-羧酸甲酯75c(159mg，0.36mmol)溶于四氢呋喃(5mL)，加入氨水(5mL)。室温下搅拌1小时后，减压除去溶剂，残余物用反相制 备高效液相色谱纯化，得到目标产物6-(2,6-二氟苯基)-4-((5-(3-氧代吗啉代)吡啶-2-基)氨基)哒嗪-3-甲酰胺75(34.6mg，白色固体)，产率23％。Compound 6-(2,6-difluorophenyl)-4-((5-(3-oxomorpholino)pyridin-2-yl)amino)pyridazine-3-carboxylate methyl ester 75c (159mg , 0.36 mmol) was dissolved in tetrahydrofuran (5 mL), and ammonia water (5 mL) was added. After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high performance liquid chromatography to obtain the target product 6-(2,6-difluorophenyl)-4-((5-(3-oxo) Morpholino)pyridin-2-yl)amino)pyridazine-3-carboxamide 75 (34.6 mg, white solid) in 23% yield.
MS m/z(ESI):427[M+1]MS m/z(ESI): 427[M+1]
1H NMR(400MHz,DMSO-d 6)δ12.04(s,1H),9.07(s,1H),8.94(s,1H),8.41(d,J＝4Hz,1H),8.21(s,1H),7.87(dd,J＝12Hz,1H),7.62–7.70(m,1H),7.33(t,J＝8Hz,2H),7.21(d,J＝12Hz,1H),4.22(s,2H),3.98(t,J＝4Hz,2H),3.76(t,J＝4Hz,2H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 12.04(s, 1H), 9.07(s, 1H), 8.94(s, 1H), 8.41(d, J=4Hz, 1H), 8.21(s, 1H) ), 7.87(dd, J＝12Hz, 1H), 7.62–7.70(m, 1H), 7.33(t, J＝8Hz, 2H), 7.21(d, J＝12Hz, 1H), 4.22(s, 2H) , 3.98 (t, J=4Hz, 2H), 3.76 (t, J=4Hz, 2H).
实施例77Example 77
6-(2,6-二氟苯基)-4-((1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000092
Figure PCTCN2020108468-appb-000092
第一步first step
4-((1-(1-(叔-丁氧基羰基)哌啶-4-基)-1H-吡唑-4-基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸4-((1-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-6-(2,6-difluorophenyl)pyridin oxazine-3-carboxylic acid
将化合物4-((1H-吡唑-4-基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯41b(331mg，1mmol)、4-碘哌啶-1-羧酸叔丁酯(940mg，3.02mmol)、碳酸钾(625mg，4.53mmol)和N,N-二甲基甲酰胺(20mL)混合，加热至100℃搅拌24小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(二氯甲烷/甲醇＝19/1)纯化，得到目标产物4-((1-(1-(叔-丁氧基羰基)哌啶-4-基)-1H-吡唑-4-基)氨基)-6-(2,6-二氟苯基)哒嗪-3-羧酸77a(100mg，黄色固体)，产率：6％。Compound 4-((1H-pyrazol-4-yl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxylate methyl ester 41b (331 mg, 1 mmol), 4-iodopiperidine tert-butyl pyridine-1-carboxylate (940 mg, 3.02 mmol), potassium carbonate (625 mg, 4.53 mmol) and N,N-dimethylformamide (20 mL) were mixed, heated to 100° C. and stirred for 24 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=19/1) to obtain the target product 4-((1-(1-(tert-butoxycarbonyl) Piperidin-4-yl)-1H-pyrazol-4-yl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxylic acid 77a (100 mg, yellow solid), yield: 6%.
MS m/z(ESI):501[M+1]MS m/z(ESI): 501[M+1]
第二步second step
6-(2,6-二氟苯基)-4-((1-(哌啶-4-基)-1H-吡唑-4-基)氨基)哒嗪-3-羧酸甲酯Methyl 6-(2,6-difluorophenyl)-4-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyridazine-3-carboxylate
将化合物4-((1-(1-(叔-丁氧基羰基)哌啶-4-基)-1H-吡唑-4-基)氨基)- 6-(2,6-二氟苯基)哒嗪-3-羧酸77a(100mg，0.2mmol)溶于甲醇(10mL)，然后加入氯化氢的1,4-二氧六环溶液(4M，2mL)。室温下搅拌3小时后，减压除去溶剂，得到目标产物6-(2,6-二氟苯基)-4-((1-(哌啶-4-基)-1H-吡唑-4-基)氨基)哒嗪-3-羧酸甲酯77b(80mg，粗品)。该产品未经进一步纯化，直接用于下一步反应。Compound 4-((1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-6-(2,6-difluorophenyl ) pyridazine-3-carboxylic acid 77a (100 mg, 0.2 mmol) was dissolved in methanol (10 mL), then hydrogen chloride in 1,4-dioxane (4 M, 2 mL) was added. After stirring at room temperature for 3 hours, the solvent was removed under reduced pressure to give the desired product 6-(2,6-difluorophenyl)-4-((1-(piperidin-4-yl)-1H-pyrazole-4- (methyl)amino)pyridazine-3-carboxylate 77b (80 mg, crude). This product was used directly in the next reaction without further purification.
MS m/z(ESI):415[M+1]MS m/z(ESI): 415[M+1]
第三步third step
6-(2,6-二氟苯基)-4-((1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)氨基)哒嗪-3-羧酸甲酯6-(2,6-Difluorophenyl)-4-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyridazine-3-carboxylic acid methyl ester
将化合物6-(2,6-二氟苯基)-4-((1-(哌啶-4-基)-1H-吡唑-4-基)氨基)哒嗪-3-羧酸甲酯77b(80mg，粗品)、碳酸钾(39mg，0.285mmol)和N,N-二甲基甲酰胺(5mL)混合，然后加入碘甲烷(32mg，0.228mmol)，加热到95℃并搅拌3小时。冷却到室温后过滤，滤液在减压条件下除去溶剂，得到目标产物6-(2,6-二氟苯基)-4-((1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)氨基)哒嗪-3-羧酸甲酯77c(80mg，粗品)。该产品未经进一步纯化，直接用于下一步反应。The compound 6-(2,6-difluorophenyl)-4-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyridazine-3-carboxylate methyl ester 77b (80 mg, crude), potassium carbonate (39 mg, 0.285 mmol) and N,N-dimethylformamide (5 mL) were combined, then iodomethane (32 mg, 0.228 mmol) was added, heated to 95 °C and stirred for 3 hours. After cooling to room temperature, the filtrate was filtered, and the solvent was removed from the filtrate under reduced pressure to obtain the target product 6-(2,6-difluorophenyl)-4-((1-(1-methylpiperidin-4-yl)- 1H-Pyrazol-4-yl)amino)pyridazine-3-carboxylate methyl ester 77c (80 mg, crude). This product was used directly in the next reaction without further purification.
MS m/z(ESI):429[M+1]MS m/z(ESI): 429[M+1]
第四步the fourth step
6-(2,6-二氟苯基)-4-((1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyridazine-3-carboxamide
将化合物6-(2,6-二氟苯基)-4-((1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)氨基)哒嗪-3-羧酸甲酯77c(80mg，粗品)溶于四氢呋喃(10mL)，加入氨水(2mL)。室温下搅拌1小时后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2,6-二氟苯基)-4-((1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)氨基)哒嗪-3-甲酰胺77(6.5mg，白色固体)，产率：三步7％。The compound 6-(2,6-difluorophenyl)-4-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyridazine-3- Methyl carboxylate 77c (80 mg, crude) was dissolved in tetrahydrofuran (10 mL), and aqueous ammonia (2 mL) was added. After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to obtain the target product 6-(2,6-difluorophenyl)-4-((1-(1-methyl) ylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyridazine-3-carboxamide 77 (6.5 mg, white solid), yield: 7% for three steps.
MS m/z(ESI):414[M+1]MS m/z(ESI): 414[M+1]
1H NMR(400MHz,CD 3OD)δ8.06–7.96(m,1H),7.71–7.61(m,2H),7.56–7.49(m,1H),7.20(t,J＝8.7Hz,2H),4.61–4.47(m,1H),3.58(d,J＝11.4Hz,2H),3.42–3.33(m,1H),3.18–3.10(m,1H),2.83(s,3H),2.47–2.22(m,4H)。 1 H NMR (400MHz, CD 3 OD) δ 8.06-7.96 (m, 1H), 7.71-7.61 (m, 2H), 7.56-7.49 (m, 1H), 7.20 (t, J=8.7Hz, 2H) , 4.61–4.47 (m, 1H), 3.58 (d, J=11.4Hz, 2H), 3.42–3.33 (m, 1H), 3.18–3.10 (m, 1H), 2.83 (s, 3H), 2.47–2.22 (m, 4H).
实施例79Example 79
6-(2,6-二氟苯基)-4-((4-(2-甲基-1-(甲基磺酰氨基)-1-氧代丙烷-2-基)苯基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((4-(2-methyl-1-(methylsulfonamido)-1-oxopropan-2-yl)phenyl)amino) Pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000093
Figure PCTCN2020108468-appb-000093
Figure PCTCN2020108468-appb-000094
Figure PCTCN2020108468-appb-000094
将化合物2-(4-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)苯基)-2-甲基丙酸61(50mg，0.121mmol)、甲基磺酰胺(23mg，0.242mmol)、二环己基碳二亚胺(50mg，0.242mmol)、4-二甲氨基吡啶(30mg，0.242mmol)和二氯甲烷(2mL)混合。室温下搅拌1小时后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2,6-二氟苯基)-4-((4-(2-甲基-1-(甲基磺酰氨基)-1-氧代丙烷-2-基)苯基)氨基)哒嗪-3-甲酰胺79(24mg，白色固体)，产率：40％。Compound 2-(4-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)phenyl)-2-methylpropionic acid 61 (50 mg, 0.121 mmol), methylsulfonamide (23 mg, 0.242 mmol), dicyclohexylcarbodiimide (50 mg, 0.242 mmol), 4-dimethylaminopyridine (30 mg, 0.242 mmol) and dichloromethane (2 mL) were combined. After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to obtain the target product 6-(2,6-difluorophenyl)-4-((4-(2-methyl) yl-1-(methylsulfonamido)-1-oxopropan-2-yl)phenyl)amino)pyridazine-3-carboxamide 79 (24 mg, white solid), yield: 40%.
MS m/z(ESI):490[M+1]MS m/z(ESI): 490[M+1]
1H NMR(400MHz,DMSO-d 6)δ11.40(brs,1H),10.90(s,1H),8.78(s,1H),8.05(s,1H),7.69–7.50(m,1H),7.44–7.17(m,5H),3.14(s,3H),1.47(s,6H)。 1 H NMR (400MHz, DMSO-d 6 )δ11.40(brs,1H), 10.90(s,1H), 8.78(s,1H), 8.05(s,1H), 7.69-7.50(m,1H), 7.44–7.17(m, 5H), 3.14(s, 3H), 1.47(s, 6H).
实施例85Example 85
6-(2,6-二氟苯基)-4-((3-氟-5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((3-fluoro-5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000095
Figure PCTCN2020108468-appb-000095
第一步first step
1-(6-氯-5-氟吡啶-3-基)-4-甲基哌嗪1-(6-Chloro-5-fluoropyridin-3-yl)-4-methylpiperazine
将化合物5-溴-2-氯-3-氟吡啶85a(1g，4.76mmol)、1-甲基哌嗪(480mg，4.76mmol)、三(二亚苄基丙酮)二钯(130mg，0.143mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(110mg，0.191mmol)、叔丁醇钠(600 mg，6.19mmol)和甲苯(10mL)混合，除氧后在氮气气氛下用微波反应器加热至80℃并搅拌1小时，冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝100/0至3/7)纯化，得到目标产物1-(6-氯-5-氟吡啶-3-基)-4-甲基哌嗪85b(850mg，白色固体)，产率：77％。Compound 5-bromo-2-chloro-3-fluoropyridine 85a (1 g, 4.76 mmol), 1-methylpiperazine (480 mg, 4.76 mmol), tris(dibenzylideneacetone)dipalladium (130 mg, 0.143 mmol) ), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (110 mg, 0.191 mmol), sodium tert-butoxide (600 mg, 6.19 mmol) and toluene (10 mL) were mixed, and after deoxygenation It was heated to 80°C with a microwave reactor under nitrogen atmosphere and stirred for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=100/0 to 3/7) Purification gave the desired product 1-(6-chloro-5-fluoropyridin-3-yl)-4-methylpiperazine 85b (850 mg, white solid), yield: 77%.
MS m/z(ESI):230[M+1]MS m/z(ESI): 230[M+1]
第二步second step
6-(2,6-二氟苯基)-4-((3-氟-5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)哒嗪-3-羧酸6-(2,6-Difluorophenyl)-4-((3-fluoro-5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyridazine-3-carboxylic acid
将化合物4-氨基-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯31c(100mg，0.375mmol)、1-(6-氯-5-氟吡啶-3-基)-4-甲基哌嗪85b(172mg，0.751mmol)、碳酸铯(245mg，0.751mmol)、三(二亚苄基丙酮)二钯(34mg，0.0375mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(43mg，0.075mmol)和1,4-二氧六环(3mL)混合，除氧后在氮气气氛下用微波反应器加热到90℃并搅拌1小时。冷却到室温后过滤，滤液在减压条件下除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2,6-二氟苯基)-4-((3-氟-5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)哒嗪-3-羧酸85c(30mg，黄色固体)，产率：18％。Compound 4-amino-6-(2,6-difluorophenyl)pyridazine-3-carboxylate methyl ester 31c (100 mg, 0.375 mmol), 1-(6-chloro-5-fluoropyridin-3-yl )-4-methylpiperazine 85b (172 mg, 0.751 mmol), cesium carbonate (245 mg, 0.751 mmol), tris(dibenzylideneacetone)dipalladium (34 mg, 0.0375 mmol), 4,5-bisdiphenyl Phosphine-9,9-dimethylxanthene (43 mg, 0.075 mmol) and 1,4-dioxane (3 mL) were mixed, deoxygenated, heated to 90 °C in a microwave reactor under nitrogen atmosphere and stirred for 1 Hour. After cooling to room temperature, the filtrate was filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to obtain the target product 6-(2,6-difluorophenyl)-4-((3-fluoro -5-(4-Methylpiperazin-1-yl)pyridin-2-yl)amino)pyridazine-3-carboxylic acid 85c (30 mg, yellow solid), yield: 18%.
MS m/z(ESI):445[M+1]MS m/z(ESI): 445[M+1]
第三步third step
6-(2,6-二氟苯基)-4-((3-氟-5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)哒嗪-3-羧酸甲酯6-(2,6-Difluorophenyl)-4-((3-fluoro-5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyridazine-3-carboxylic acid methyl ester
将化合物6-(2,6-二氟苯基)-4-((3-氟-5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)哒嗪-3-羧酸85c(30mg，0.067mmol)溶于甲醇(4mL)，然后加入氯化亚砜(0.5mL)，加热到90℃并搅拌12小时。冷却到室温后，得到目标产物6-(2,6-二氟苯基)-4-((3-氟-5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)哒嗪-3-羧酸甲酯85d(30mg，粗品)。该产品未经进一步纯化，直接用于下一步反应。The compound 6-(2,6-difluorophenyl)-4-((3-fluoro-5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyridazine-3- Carboxylic acid 85c (30 mg, 0.067 mmol) was dissolved in methanol (4 mL), then thionyl chloride (0.5 mL) was added, heated to 90°C and stirred for 12 hours. After cooling to room temperature, the target product 6-(2,6-difluorophenyl)-4-((3-fluoro-5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino was obtained ) pyridazine-3-carboxylate methyl ester 85d (30 mg, crude). This product was used directly in the next reaction without further purification.
MS m/z(ESI):459[M+1]MS m/z(ESI): 459[M+1]
第四步the fourth step
6-(2,6-二氟苯基)-4-((3-氟-5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((3-fluoro-5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyridazine-3-carboxamide
将化合物6-(2,6-二氟苯基)-4-((3-氟-5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)哒嗪-3-羧酸甲酯85d(30mg，粗品)溶于N,N-二甲基甲酰胺(2mL)，加入氨水(1mL)。室温下搅拌12小时后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2,6-二氟苯基)-4-((3-氟-5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)哒嗪-3-甲酰胺盐酸盐85(15.7mg，白色固体)，产率：两步52％。The compound 6-(2,6-difluorophenyl)-4-((3-fluoro-5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyridazine-3- Methyl carboxylate 85d (30 mg, crude) was dissolved in N,N-dimethylformamide (2 mL), and aqueous ammonia (1 mL) was added. After stirring at room temperature for 12 hours, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to obtain the target product 6-(2,6-difluorophenyl)-4-((3-fluoro-5- (4-Methylpiperazin-1-yl)pyridin-2-yl)amino)pyridazine-3-carboxamide hydrochloride 85 (15.7 mg, white solid), yield: 52% for two steps.
MS m/z(ESI):444[M+1]MS m/z(ESI): 444[M+1]
1H NMR(400MHz,DMSO-d 6)δ12.17(d,J＝1.8Hz,1H),10.20(brs,1H),9.00(s,1H),8.94(s,1H),8.19(s,1H),8.01–7.94(m,1H),7.72–7.62(m,2H),7.39–7.30(m,1H),7.27–6.99(m,1H),3.89(d,J＝11.0Hz,3H),3.22–3.02(m,5H),2.81(d,J＝4.6Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ12.17(d, J=1.8Hz, 1H), 10.20(brs, 1H), 9.00(s, 1H), 8.94(s, 1H), 8.19(s, 1H), 8.01–7.94 (m, 1H), 7.72–7.62 (m, 2H), 7.39–7.30 (m, 1H), 7.27–6.99 (m, 1H), 3.89 (d, J=11.0Hz, 3H) , 3.22–3.02 (m, 5H), 2.81 (d, J=4.6Hz, 3H).
以下实施例(实施例86、实施例87)均参照实施例85的操作方法合成，但在第一步中用不同的脂肪胺代替1-甲基哌嗪。表征数据如下表所示：The following examples (Example 86, Example 87) are all synthesized according to the operation method of Example 85, but in the first step, different fatty amines are used instead of 1-methylpiperazine. Characterization data are shown in the following table:
Figure PCTCN2020108468-appb-000096
Figure PCTCN2020108468-appb-000096
实施例89Example 89
6-(2,6-二氟苯基)-4-(5-吗啉代嘧啶-2-基)氨基吡啶-3-甲酰胺6-(2,6-Difluorophenyl)-4-(5-morpholinopyrimidin-2-yl)aminopyridine-3-carboxamide
Figure PCTCN2020108468-appb-000097
Figure PCTCN2020108468-appb-000097
Figure PCTCN2020108468-appb-000098
Figure PCTCN2020108468-appb-000098
第一步first step
5-溴-N,N-二(4-甲氧基苯甲基)嘧啶-2-胺5-Bromo-N,N-bis(4-methoxybenzyl)pyrimidin-2-amine
将化合物5-溴嘧啶-2-胺89a(2.6g，15mmol)溶于无水四氢呋喃(50mL)，冷却到0℃后加入氢化钠(纯度60％，1.32g，33mmol)。在此温度下搅拌30分钟后，加入对甲氧基苄氯(5.17g，33mmol)并逐渐升温到室温。搅拌15小时后，用水(2mL)淬灭反应，在减压条件下除去溶剂，残余物在硅胶柱层析(石油醚/乙酸乙酯＝50/1至2/1)纯化，得到目标产物5-溴-N,N-二(4-甲氧基苯甲基)嘧啶-2-胺89b(5.5g，淡黄色固体)，产率：89％。The compound 5-bromopyrimidin-2-amine 89a (2.6 g, 15 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), cooled to 0°C, and sodium hydride (purity 60%, 1.32 g, 33 mmol) was added. After stirring at this temperature for 30 minutes, p-methoxybenzyl chloride (5.17 g, 33 mmol) was added and the temperature was gradually warmed to room temperature. After stirring for 15 hours, the reaction was quenched with water (2 mL), the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/1 to 2/1) to give the target product 5 -Bromo-N,N-bis(4-methoxybenzyl)pyrimidin-2-amine 89b (5.5 g, pale yellow solid), yield: 89%.
MS m/z(ESI):414[M+1]MS m/z(ESI): 414[M+1]
第二步second step
N,N-二(4-甲氧基苯甲基)-5-吗啉代嘧啶-2-胺N,N-bis(4-methoxybenzyl)-5-morpholinopyrimidin-2-amine
将化合物5-溴-N,N-二(4-甲氧基苯甲基)嘧啶-2-胺89b(5.5g，13.3mmol)、吗啉(2.3g，26.6mmol)、叔丁醇钠(2.55g，26.6mmol)、1,1'-联萘-2,2'-双二苯膦(828mg，1.33mmol)、三(二亚苄基丙酮)二钯(609mg，0.67mmol)和甲苯(50mL)混合，除氧后在氮气气氛下加热到100℃并搅拌15小时。冷却到室温后，用乙酸乙酯(50mL)稀释，然后过滤。滤液在减压条件下除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝50/1至2/1)纯化，得到目标产物N,N-二(4-甲氧基苯甲基)-5-吗啉代嘧啶-2-胺89c(5.3g，棕色固体)，产率：95％。Compound 5-bromo-N,N-bis(4-methoxybenzyl)pyrimidin-2-amine 89b (5.5 g, 13.3 mmol), morpholine (2.3 g, 26.6 mmol), sodium tert-butoxide ( 2.55 g, 26.6 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (828 mg, 1.33 mmol), tris(dibenzylideneacetone)dipalladium (609 mg, 0.67 mmol) and toluene ( 50 mL), mixed, deoxygenated, heated to 100°C under nitrogen atmosphere and stirred for 15 hours. After cooling to room temperature, it was diluted with ethyl acetate (50 mL) and filtered. The filtrate was removed from the solvent under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/1 to 2/1) to obtain the target product N,N-bis(4-methoxybenzyl) yl)-5-morpholinopyrimidin-2-amine 89c (5.3 g, brown solid), yield: 95%.
MS m/z(ESI):421[M+1]MS m/z(ESI): 421[M+1]
第三步third step
5-吗啉代嘧啶-2-胺5-morpholinopyrimidin-2-amine
将化合物N,N-二(4-甲氧基苯甲基)-5-吗啉代嘧啶-2-胺89c(5.3g，12.6mmol)溶于三氟乙酸(50mL)，加热到50℃并搅拌3小时。冷却到室温后，减压除去溶剂，残余物溶于甲醇(50mL)。用饱和碳酸氢钠水溶液调节至pH＝8，然后在减压条件下除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝50/1至1/2)纯化，得到目标产物5-吗啉代嘧啶-2-胺89d(1.5g，黄色固体)，产率：66％。Compound N,N-bis(4-methoxybenzyl)-5-morpholinopyrimidin-2-amine 89c (5.3 g, 12.6 mmol) was dissolved in trifluoroacetic acid (50 mL), heated to 50 °C and heated to 50 °C. Stir for 3 hours. After cooling to room temperature, the solvent was removed under reduced pressure and the residue was dissolved in methanol (50 mL). Adjusted to pH=8 with saturated aqueous sodium bicarbonate solution, then the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/1 to 1/2) to obtain the target product 5 - Morpholinopyrimidin-2-amine 89d (1.5 g, yellow solid), yield: 66%.
MS m/z(ESI):181[M+1]MS m/z(ESI): 181[M+1]
第四步the fourth step
6-氯-4-((5-吗啉代嘧啶-2-基)氨基)哒嗪-3-羧酸甲酯Methyl 6-chloro-4-((5-morpholinopyrimidin-2-yl)amino)pyridazine-3-carboxylate
将化合物4,6-二氯哒嗪-3-羧酸甲酯1a(1.37g，6.66mmol)、5-吗啉代嘧啶-2-胺89d(1.2g，6.67mmol)和乙醇(80mL)混合，加热回流并搅拌4天。冷却到室温后，加入二异丙基乙基胺(1mL)，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝50/1至1/2)纯化，得到目标产物6-氯-4-((5-吗啉代嘧啶-2-基)氨基)哒嗪-3-羧酸甲酯89e(220mg，黄色油状物)，产率：9％。Compound 4,6-dichloropyridazine-3-carboxylate methyl ester 1a (1.37 g, 6.66 mmol), 5-morpholinopyrimidin-2-amine 89d (1.2 g, 6.67 mmol) and ethanol (80 mL) were mixed , heated to reflux and stirred for 4 days. After cooling to room temperature, diisopropylethylamine (1 mL) was added, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/1 to 1/2) to obtain the target product Methyl 6-chloro-4-((5-morpholinopyrimidin-2-yl)amino)pyridazine-3-carboxylate 89e (220 mg, yellow oil), yield: 9%.
MS m/z(ESI):351[M+1]MS m/z(ESI): 351[M+1]
第五步the fifth step
6-(2,6-二氟苯基)-4-(5-吗啉代嘧啶-2-基)氨基吡啶-3-羧酸甲酯6-(2,6-Difluorophenyl)-4-(5-morpholinopyrimidin-2-yl)aminopyridine-3-carboxylate methyl ester
将化合物6-氯-4-((5-吗啉代吡啶-2-基)氨基)哒嗪-3-羧酸甲酯89e(220mg，0.63mmol)、2,6-二氟苯硼酸(298mg，1.89mmol)、二异丙基乙基胺(244mg，1.89mmol)和四(三苯基膦)钯(69mg，0.2mmol)溶于1,4-二氧六环(8mL)，除氧后在氮气气氛下用微波反应器加热到110℃并搅拌1小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝50/1至1/2)纯化，得到目标产物6-(2,6-二氟苯基)-4-(5-吗啉代吡啶-2-基)氨基吡啶-3-羧酸甲酯89f(60mg，黄色油状物)，产率：22％。Compound 6-chloro-4-((5-morpholinopyridin-2-yl)amino)pyridazine-3-carboxylate methyl ester 89e (220mg, 0.63mmol), 2,6-difluorophenylboronic acid (298mg , 1.89 mmol), diisopropylethylamine (244 mg, 1.89 mmol) and tetrakis(triphenylphosphine)palladium (69 mg, 0.2 mmol) were dissolved in 1,4-dioxane (8 mL), and after deoxygenation The microwave reactor was heated to 110°C under nitrogen atmosphere and stirred for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/1 to 1/2) to obtain the target product 6-(2,6-difluorophenyl) -4-(5-Morpholinopyridin-2-yl)aminopyridine-3-carboxylate methyl ester 89f (60 mg, yellow oil), yield: 22%.
MS m/z(ESI):429[M+1]MS m/z(ESI): 429[M+1]
第六步Step 6
6-(2,6-二氟苯基)-4-(5-吗啉代嘧啶-2-基)氨基吡啶-3-甲酰胺6-(2,6-Difluorophenyl)-4-(5-morpholinopyrimidin-2-yl)aminopyridine-3-carboxamide
将化合物6-(2,6-二氟苯基)-4-(5-吗啉代吡啶-2-基)氨基吡啶-3-羧酸甲酯89f(60mg，0.14mmol)溶于四氢呋喃(10mL)，加入氨水(3mL)。室温下搅拌15小时后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2,6-二氟苯基)-4-(5-吗啉代吡啶-2-基)氨基吡啶-3-甲酰胺89(22mg，白色固体)，产率：23％。Compound 6-(2,6-difluorophenyl)-4-(5-morpholinopyridin-2-yl)aminopyridine-3-carboxylate methyl ester 89f (60 mg, 0.14 mmol) was dissolved in tetrahydrofuran (10 mL) ), and ammonia (3 mL) was added. After stirring at room temperature for 15 hours, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to obtain the target product 6-(2,6-difluorophenyl)-4-(5-morpholinopyridine- 2-yl)aminopyridine-3-carboxamide 89 (22 mg, white solid), yield: 23%.
MS m/z(ESI):414[M+1]MS m/z(ESI): 414[M+1]
1H NMR(400MHz,CDCl 3)δ12.04(s,1H),9.24(s,1H),8.27(s,3H),7.47(dd,J＝13.6,7.5Hz,1H),7.10(t,J＝8.0Hz,2H),5.74(s,1H),3.95–3.83(m,4H),3.21–3.09(m,4H)。 1 H NMR (400 MHz, CDCl 3 ) δ 12.04 (s, 1H), 9.24 (s, 1H), 8.27 (s, 3H), 7.47 (dd, J=13.6, 7.5 Hz, 1H), 7.10 (t, J = 8.0 Hz, 2H), 5.74 (s, 1H), 3.95–3.83 (m, 4H), 3.21–3.09 (m, 4H).
实施例91Example 91
6-(2,6-二氟苯基)-4-((4-氟-5-吗啉代吡啶-2-基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((4-fluoro-5-morpholinopyridin-2-yl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000099
Figure PCTCN2020108468-appb-000099
Figure PCTCN2020108468-appb-000100
Figure PCTCN2020108468-appb-000100
第一步first step
4-(6-氯-4-氟吡啶-3-基)吗啉4-(6-Chloro-4-fluoropyridin-3-yl)morpholine
将化合物2-氯-4-氟-5-碘吡啶91a(1g，3.88mmol)、三(二亚苄基丙酮)二钯(355mg，0.388mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(450mg，0.777mmol)、叔丁醇钾(566mg，5.04mmol)、吗啉(338mg，3.88mmol)和甲苯(10mL)混合，除氧后用微波反应器加热到70℃并搅拌1小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化，得到目标产物4-(6-氯-4-氟吡啶-3-基)吗啉91b(402mg，白色固体)，产率：47％。Compound 2-chloro-4-fluoro-5-iodopyridine 91a (1 g, 3.88 mmol), tris(dibenzylideneacetone)dipalladium (355 mg, 0.388 mmol), 4,5-bisdiphenylphosphine-9 , 9-dimethylxanthene (450mg, 0.777mmol), potassium tert-butoxide (566mg, 5.04mmol), morpholine (338mg, 3.88mmol) and toluene (10mL) were mixed, deoxygenated and heated in a microwave reactor to 70°C and stirred for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain the target product 4-(6-chloro-4-fluoropyridin-3-yl) Morpholine 91b (402 mg, white solid), yield: 47%.
MS m/z(ESI):217[M+1]MS m/z(ESI): 217[M+1]
第二步second step
6-(2,6-二氟苯基)-2-((4-氟-5-吗啉代吡啶-2-基)氨基)哒嗪-3-羧酸甲酯Methyl 6-(2,6-difluorophenyl)-2-((4-fluoro-5-morpholinopyridin-2-yl)amino)pyridazine-3-carboxylate
将化合物4-氨基-6-(2,6-二氟苯基)哒嗪-3-羧酸甲酯31c(132mg，0.5mmol)、4-(6-氯-4-氟吡啶-3-基)吗啉91b(293mg，1.38mmol)、碳酸铯(240mg，0.74mmol)、三(二亚苄基丙酮)二钯(42mg，0.037mmol)、2-(二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯(40mg，0.074mmol)和1,4-二氧六环(10mL)混合，除氧后在氮气气氛下加热到95℃并搅拌1小时。冷却到室温后过滤，滤液在减压条件下除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝50/1至1/2)纯化，得到目标产物6-(2,6-二氟苯基)-2-((4-氟-5-吗啉代吡啶-2-基)氨基)哒嗪-3-羧酸甲酯91c(25mg，近白色固体)，产率：15％。Compound 4-amino-6-(2,6-difluorophenyl)pyridazine-3-carboxylate methyl ester 31c (132 mg, 0.5 mmol), 4-(6-chloro-4-fluoropyridin-3-yl ) morpholine 91b (293 mg, 1.38 mmol), cesium carbonate (240 mg, 0.74 mmol), tris(dibenzylideneacetone)dipalladium (42 mg, 0.037 mmol), 2-(dicyclohexylphosphine)-3,6- Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (40 mg, 0.074 mmol) and 1,4-dioxane (10 mL) were mixed and deoxygenated in Heat to 95°C under nitrogen atmosphere and stir for 1 hour. After cooling to room temperature, the filtrate was filtered, and the solvent was removed from the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/1 to 1/2) to obtain the target product 6-(2,6- Difluorophenyl)-2-((4-fluoro-5-morpholinopyridin-2-yl)amino)pyridazine-3-carboxylate methyl ester 91c (25 mg, nearly white solid), yield: 15% .
MS m/z(ESI):446[M+1]MS m/z(ESI): 446[M+1]
第三步third step
6-(2,6-二氟苯基)-4-((4-氟-5-吗啉代吡啶-2-基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((4-fluoro-5-morpholinopyridin-2-yl)amino)pyridazine-3-carboxamide
将化合物6-(2,6-二氟苯基)-2-((4-氟-5-吗啉代吡啶-2-基)氨基)哒嗪-3-羧酸甲酯91c(25mg，0.056mmol)溶于四氢呋喃(10mL)，加入氨水(3mL)。室温下搅拌15小时后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2,6-二氟苯基)-4-((4-氟-5-吗啉代吡啶-2-基)氨基)哒嗪-3-甲酰胺91(8mg，白色固体)，产率23％。Compound 6-(2,6-difluorophenyl)-2-((4-fluoro-5-morpholinopyridin-2-yl)amino)pyridazine-3-carboxylate methyl ester 91c (25 mg, 0.056 mmol) was dissolved in tetrahydrofuran (10 mL), and aqueous ammonia (3 mL) was added. After stirring at room temperature for 15 hours, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to obtain the target product 6-(2,6-difluorophenyl)-4-((4-fluoro-5- Morpholinopyridin-2-yl)amino)pyridazine-3-carboxamide 91 (8 mg, white solid), 23% yield.
MS m/z(ESI):431[M+1]MS m/z(ESI): 431[M+1]
1H NMR(400MHz,CD 3OD)δ9.21(s,1H),8.08(d,J＝11.0Hz,1H),7.67–7.56(m,1H),7.21(t,J＝8.0Hz,2H),6.94(d,J＝13.1Hz,1H),3.88–3.81(m,2H),3.14–3.07(m,2H)。 1 H NMR (400 MHz, CD 3 OD) δ 9.21 (s, 1H), 8.08 (d, J=11.0 Hz, 1H), 7.67–7.56 (m, 1H), 7.21 (t, J=8.0 Hz, 2H) ), 6.94 (d, J=13.1 Hz, 1H), 3.88–3.81 (m, 2H), 3.14–3.07 (m, 2H).
实施例92Example 92
6-(2-氯-6-氟苯基)-4-((4-吗啉代苯基)氨基)哒嗪-3-甲酰胺6-(2-Chloro-6-fluorophenyl)-4-((4-morpholinophenyl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000101
Figure PCTCN2020108468-appb-000101
第一步first step
4-(4-硝基苯基)吗啉4-(4-Nitrophenyl)morpholine
将化合物对氟硝基苯92a(1.0g，7.09mmol)溶于乙腈(20mL)，然后加入吗啉(1.24g，14.17mmol)，在封管中加热至90℃并搅拌15小时。冷却到室温后，减压除去溶剂，残余物用石油醚和乙酸乙酯重结晶，得到目标产物4-(4-硝基苯基)吗啉92b(1.35g，黄色固体)，产率：91％.The compound p-fluoronitrobenzene 92a (1.0 g, 7.09 mmol) was dissolved in acetonitrile (20 mL), then morpholine (1.24 g, 14.17 mmol) was added, heated to 90°C in a sealed tube and stirred for 15 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was recrystallized from petroleum ether and ethyl acetate to obtain the target product 4-(4-nitrophenyl)morpholine 92b (1.35 g, yellow solid), yield: 91 %.
MS m/z(ESI):209[M+1]MS m/z(ESI): 209[M+1]
第二步second step
4-吗啉代苯胺4-morpholinoaniline
将化合物4-(4-硝基苯基)吗啉92b(1.01g，4.86mmol)溶于四氢呋喃(100mL)，加入10％钯炭(517mg)，然后在氢气气氛下搅拌2小时。反应完成后过滤，滤液在减压条件下除去溶剂，得到目标产物4-吗啉代苯胺92c(860mg，白色固体)，产率：99％。Compound 4-(4-nitrophenyl)morpholine 92b (1.01 g, 4.86 mmol) was dissolved in tetrahydrofuran (100 mL), and 10% palladium on carbon (517 mg) was added, followed by stirring under a hydrogen atmosphere for 2 hours. After the reaction was completed, it was filtered, and the filtrate was removed from the solvent under reduced pressure to obtain the target product 4-morpholinoaniline 92c (860 mg, white solid), yield: 99%.
MS m/z(ESI):179[M+1]MS m/z(ESI): 179[M+1]
第三步third step
6-氯-4-((4-吗啉代苯基)氨基)哒嗪-3-羧酸甲酯Methyl 6-chloro-4-((4-morpholinophenyl)amino)pyridazine-3-carboxylate
将化合物4,6-二氯哒嗪-3-羧酸甲酯1a(581mg，2.81mmol)、4-吗啉代苯胺92c(500mg，2.81mmol)、二异丙基乙基胺(3.63g，28mmol)和乙腈(10mL)混合，加热到90℃并搅拌18小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝100/0至1/4)纯化，得到目标产物6-氯-4-((4-吗啉代苯基)氨基)哒嗪-3-羧酸甲酯92d(768mg，棕色固体)，产率：78％。Compound 4,6-dichloropyridazine-3-carboxylate methyl ester 1a (581 mg, 2.81 mmol), 4-morpholinoaniline 92c (500 mg, 2.81 mmol), diisopropylethylamine (3.63 g, 28 mmol) and acetonitrile (10 mL), heated to 90°C and stirred for 18 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100/0 to 1/4) to obtain the target product 6-chloro-4-((4-morpholine) Substituted phenyl)amino)pyridazine-3-carboxylate methyl ester 92d (768 mg, brown solid), yield: 78%.
MS m/z(ESI):349[M+1]MS m/z(ESI): 349[M+1]
第四步the fourth step
6-(2-氯-6-氟苯基)-4-((4-吗啉代苯基)氨基)哒嗪-3-羧酸甲酯Methyl 6-(2-chloro-6-fluorophenyl)-4-((4-morpholinophenyl)amino)pyridazine-3-carboxylate
将化合物6-氯-4-((4-吗啉代苯基)氨基)哒嗪-3-羧酸甲酯92d(300mg，0.86mmol)、2-氟-6-氯苯硼酸(450mg，2.58mmol)、二异丙基乙基胺(1.12g，8.60mmol)和四(三苯基膦)钯(100mg，0.086mmol)溶于1,4-二氧六环(20mL)，除氧后在氮气气氛下用微波反应器加热到110℃并搅拌1小时。冷却到室温后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2-氯-6-氟苯基)-4-((4-吗啉代苯基)氨基)哒嗪-3-羧酸甲酯92e(76mg，黄色固体)，产率：20％。Compound 6-chloro-4-((4-morpholinophenyl)amino)pyridazine-3-carboxylate methyl ester 92d (300 mg, 0.86 mmol), 2-fluoro-6-chlorophenylboronic acid (450 mg, 2.58 g mmol), diisopropylethylamine (1.12 g, 8.60 mmol) and tetrakis(triphenylphosphine)palladium (100 mg, 0.086 mmol) were dissolved in 1,4-dioxane (20 mL) and deoxygenated in The microwave reactor was heated to 110°C under nitrogen atmosphere and stirred for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to obtain the target product 6-(2-chloro-6-fluorophenyl)-4-((4-morpholinophenyl) )amino)pyridazine-3-carboxylate methyl ester 92e (76 mg, yellow solid), yield: 20%.
MS m/z(ESI):443[M+1]MS m/z(ESI): 443[M+1]
第五步the fifth step
6-(2-氯-6-氟苯基)-4-((4-吗啉代苯基)氨基)哒嗪-3-甲酰胺6-(2-Chloro-6-fluorophenyl)-4-((4-morpholinophenyl)amino)pyridazine-3-carboxamide
将化合物6-(2-氯-6-氟苯基)-4-((4-吗啉代苯基)氨基)哒嗪-3-羧酸甲酯92e(76mg，0.17mmol)溶于四氢呋喃(4mL)，加入氨水(2mL)。室温下搅拌3小时后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2-氯-6-氟苯基)-4-((4-吗啉代苯基)氨基)哒嗪-3-甲酰胺92(28mg，黄色固体)，产率：38％。Compound 6-(2-chloro-6-fluorophenyl)-4-((4-morpholinophenyl)amino)pyridazine-3-carboxylate methyl ester 92e (76 mg, 0.17 mmol) was dissolved in tetrahydrofuran ( 4 mL), ammonia water (2 mL) was added. After stirring at room temperature for 3 hours, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to obtain the target product 6-(2-chloro-6-fluorophenyl)-4-((4-morpholino Phenyl)amino)pyridazine-3-carboxamide 92 (28 mg, yellow solid), yield: 38%.
MS m/z(ESI):428[M+1]MS m/z(ESI): 428[M+1]
1H NMR(400MHz,DMSO-d 6)δ11.11(s,1H),8.76(s,1H),8.19(s,1H),8.00–6.70(m,8H),4.14(m,4H),3.18(s,4H)。 1 H NMR (400MHz, DMSO-d 6 )δ11.11(s,1H), 8.76(s,1H), 8.19(s,1H), 8.00–6.70(m,8H), 4.14(m,4H), 3.18(s, 4H).
以下实施例(实施例96、实施例97、实施例98、实施例102)均参照实施例92的操作方法合成，但在第一步中用不同的脂肪胺代替吗啉。表征数据如下表所示：The following examples (Example 96, Example 97, Example 98, Example 102) are all synthesized according to the operation method of Example 92, but in the first step, different aliphatic amines are used instead of morpholine. Characterization data are shown in the following table:
Figure PCTCN2020108468-appb-000102
Figure PCTCN2020108468-appb-000102
Figure PCTCN2020108468-appb-000103
Figure PCTCN2020108468-appb-000103
实施例93Example 93
6-(2,6-二氟苯基)-4-((4-((甲基磺酰基)氨基甲酰基)苯基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((4-((methylsulfonyl)carbamoyl)phenyl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000104
Figure PCTCN2020108468-appb-000104
将化合物4-((3-氨基甲酰-6-(2,6-二氟苯基)哒嗪-4-基)氨基)苯甲酸19(400mg，1.08mmol)、甲基磺酰胺(103mg，1.08mmol)、1-(3-二甲 氨基丙基)-3-乙基碳二亚胺盐酸盐(310mg，1.62mmol)和二氯甲烷(10mL)混合。室温下搅拌1小时后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2,6-二氟苯基)-4-((4-((甲基磺酰基)氨基甲酰基)苯基)氨基)哒嗪-3-甲酰胺93(140.1mg，白色固体)，产率：27％。Compound 4-((3-carbamoyl-6-(2,6-difluorophenyl)pyridazin-4-yl)amino)benzoic acid 19 (400 mg, 1.08 mmol), methylsulfonamide (103 mg, 1.08 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (310 mg, 1.62 mmol) and dichloromethane (10 mL) were combined. After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to obtain the target product 6-(2,6-difluorophenyl)-4-((4-((methyl Sulfonyl)carbamoyl)phenyl)amino)pyridazine-3-carboxamide 93 (140.1 mg, white solid), yield: 27%.
MS m/z(ESI):448[M+1]MS m/z(ESI): 448[M+1]
1H NMR(400MHz,CD 3OD)δ8.09(d,J＝8.6Hz,2H),7.79–7.73(m,2H),7.63(d,J＝8.6Hz,2H),7.30(t,J＝8.6Hz,2H),3.39(s,3H)。 1 H NMR (400 MHz, CD 3 OD) δ 8.09 (d, J=8.6 Hz, 2H), 7.79-7.73 (m, 2H), 7.63 (d, J=8.6 Hz, 2H), 7.30 (t, J = 8.6 Hz, 2H), 3.39 (s, 3H).
实施例95Example 95
6-(2,6-二氟苯基)-4-((3-氟-4-(四氢-2H-吡喃-4-基)苯基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((3-fluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000105
Figure PCTCN2020108468-appb-000105
第一步first step
4-(3,6-二氢-2H-吡喃-4-基)-3-氟苯胺4-(3,6-Dihydro-2H-pyran-4-yl)-3-fluoroaniline
将化合物3-氟-4-溴苯胺95a(500mg，2.38mmol)、2-(3,6-二氢-2H-吡喃-4-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷(452mg，2.38mmol)、二(三苯基膦)二氯化钯(167mg，0.24mmol)、碳酸铯(1.55g，4.76mmol)和1,4-二氧六环(4mL)混合，除氧后在氮气气氛下用微波反应器加热至110℃并搅拌1小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝100/0至1/1)纯化，得到目标产物4-(3,6-二氢-2H-吡喃-4-基)-3-氟苯胺95b(143mg，白色固体)，产率：31％。Compound 3-fluoro-4-bromoaniline 95a (500 mg, 2.38 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl- 1,3,2-Dioxaborane (452 mg, 2.38 mmol), bis(triphenylphosphine)palladium dichloride (167 mg, 0.24 mmol), cesium carbonate (1.55 g, 4.76 mmol), and 1,4-dichloride Oxane (4 mL) was mixed, deoxygenated, heated to 110°C in a microwave reactor under nitrogen atmosphere and stirred for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100/0 to 1/1) to obtain the target product 4-(3,6-dihydro-2H- Pyran-4-yl)-3-fluoroaniline 95b (143 mg, white solid), yield: 31%.
MS m/z(ESI):194[M+1]MS m/z(ESI): 194[M+1]
第二步second step
3-氟-4-(四氢-2H-吡喃-4-基)苯胺3-Fluoro-4-(tetrahydro-2H-pyran-4-yl)aniline
将化合物4-(3,6-二氢-2H-吡喃-4-基)-3-氟苯胺95b(143mg，0.74 mmol)溶于四氢呋喃(50mL)，加入10％钯炭(78mg)，然后在氢气气氛下搅拌15小时。反应完成后过滤，滤液在减压条件下除去溶剂，得到目标产物3-氟-4-(四氢-2H-吡喃-4-基)苯胺95c(103mg，白色固体)，产率：71％。Compound 4-(3,6-dihydro-2H-pyran-4-yl)-3-fluoroaniline 95b (143 mg, 0.74 mmol) was dissolved in tetrahydrofuran (50 mL), 10% palladium on carbon (78 mg) was added, and then Stir under a hydrogen atmosphere for 15 hours. After the reaction was completed, the filtrate was filtered, and the solvent was removed from the filtrate under reduced pressure to obtain the target product 3-fluoro-4-(tetrahydro-2H-pyran-4-yl)aniline 95c (103 mg, white solid), yield: 71% .
MS m/z(ESI):196[M+1]MS m/z(ESI): 196[M+1]
第三步third step
6-氯-4-((3-氟-4-(四氢-2H-吡喃-4-基)苯基)氨基)哒嗪-3-羧酸甲酯Methyl 6-chloro-4-((3-fluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)pyridazine-3-carboxylate
将化合物4,6-二氯哒嗪-3-羧酸甲酯1a(109mg，0.53mmol)、3-氟-4-(四氢-2H-吡喃-4-基)苯胺95c(103mg，0.53mmol)、二异丙基乙基胺(682mg，5.28mmol)和乙腈(4mL)混合，加热到90℃并搅拌18小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝100/0至3/7)纯化，得到目标产物6-氯-4-((3-氟-4-(四氢-2H-吡喃-4-基)苯基)氨基)哒嗪-3-羧酸甲酯95d(67mg，橙色油状物)，产率：34％。Compound 4,6-dichloropyridazine-3-carboxylate methyl ester 1a (109 mg, 0.53 mmol), 3-fluoro-4-(tetrahydro-2H-pyran-4-yl)aniline 95c (103 mg, 0.53 mmol) mmol), diisopropylethylamine (682 mg, 5.28 mmol) and acetonitrile (4 mL) were mixed, heated to 90°C and stirred for 18 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100/0 to 3/7) to obtain the target product 6-chloro-4-((3-fluoro- Methyl 4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)pyridazine-3-carboxylate 95d (67 mg, orange oil), yield: 34%.
MS m/z(ESI):366[M+1]MS m/z(ESI): 366[M+1]
第四步the fourth step
6-(2,6-二氟苯基)-4-((3-氟-4-(四氢-2H-吡喃-4-基)苯基)氨基)哒嗪-3-羧酸甲酯Methyl 6-(2,6-difluorophenyl)-4-((3-fluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)pyridazine-3-carboxylate
将化合物6-氯-4-((3-氟-4-(四氢-2H-吡喃-4-基)苯基)氨基)哒嗪-3-羧酸甲酯95d(67mg，0.18mmol)、2，6-二氟苯硼酸(88mg，0.55mmol)、二异丙基乙基胺(237mg，1.83mmol)和二(三苯基膦)二氯化钯(13mg，0.03mmol)溶于1,4-二氧六环(3mL)，除氧后在氮气气氛下用微波反应器加热到110℃并搅拌1小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝1/4)纯化，得到目标产物6-(2,6-二氟苯基)-4-((3-氟-4-(四氢-2H-吡喃-4-基)苯基)氨基)哒嗪-3-羧酸甲酯95e(47mg，黄色油状物)，产率：58％。Compound 6-chloro-4-((3-fluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)pyridazine-3-carboxylate methyl ester 95d (67 mg, 0.18 mmol) , 2,6-difluorophenylboronic acid (88 mg, 0.55 mmol), diisopropylethylamine (237 mg, 1.83 mmol) and bis(triphenylphosphine)palladium dichloride (13 mg, 0.03 mmol) were dissolved in 1 , 4-dioxane (3 mL), was deoxygenated and heated to 110°C in a microwave reactor under nitrogen atmosphere and stirred for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/4) to obtain the target product 6-(2,6-difluorophenyl)-4-( (3-Fluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)pyridazine-3-carboxylate methyl ester 95e (47 mg, yellow oil), yield: 58%.
MS m/z(ESI):444[M+1]MS m/z(ESI): 444[M+1]
第五步the fifth step
6-(2,6-二氟苯基)-4-((3-氟-4-(四氢-2H-吡喃-4-基)苯基)氨基)哒嗪-3-甲酰胺6-(2,6-Difluorophenyl)-4-((3-fluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)pyridazine-3-carboxamide
将化合物6-(2,6-二氟苯基)-4-((3-氟-4-(四氢-2H-吡喃-4-基)苯基)氨基)哒嗪-3-羧酸甲酯95e(47mg，0.11mmol)溶于四氢呋喃(4mL)，加入氨水(2mL)。室温下搅拌15小时后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2,6-二氟苯基)-4-((3-氟-4-(四氢-2H-吡喃-4-基)苯基)氨基)哒嗪-3-甲酰胺95(10mg，黄色固体)，产率：22％。The compound 6-(2,6-difluorophenyl)-4-((3-fluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)pyridazine-3-carboxylic acid Methyl ester 95e (47 mg, 0.11 mmol) was dissolved in tetrahydrofuran (4 mL) and aqueous ammonia (2 mL) was added. After stirring at room temperature for 15 hours, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to obtain the target product 6-(2,6-difluorophenyl)-4-((3-fluoro-4- (Tetrahydro-2H-pyran-4-yl)phenyl)amino)pyridazine-3-carboxamide 95 (10 mg, yellow solid), yield: 22%.
MS m/z(ESI):429[M+1]MS m/z(ESI): 429[M+1]
1H NMR(400MHz,DMSO-d 6)δ10.99(s,1H),8.79(s,1H),8.11(s,1H),7.62(s,1H),7.18–7.46(m,6H),3.97–3.95(m,4H),3.07–3.02(m, 1H),1.71–1.68(m,4H)。 1 H NMR (400MHz, DMSO-d 6 )δ10.99(s,1H), 8.79(s,1H), 8.11(s,1H), 7.62(s,1H), 7.18–7.46(m,6H), 3.97–3.95 (m, 4H), 3.07–3.02 (m, 1H), 1.71–1.68 (m, 4H).
实施例99Example 99
4-((4-(2-(吖丁啶基-1-基)-2-氧代乙基)苯基)氨基)-2-(2-氯-6-氟苯基)哒嗪-3-甲酰胺4-((4-(2-(azetidinyl-1-yl)-2-oxoethyl)phenyl)amino)-2-(2-chloro-6-fluorophenyl)pyridazine-3-methyl Amide
Figure PCTCN2020108468-appb-000106
Figure PCTCN2020108468-appb-000106
第一步first step
4-((4-(2-(叔丁氧基)-2-氧代乙基)苯基)氨基)-2-(2-氯-6-氟苯基)哒嗪-3-羧酸甲酯4-((4-(2-(tert-butoxy)-2-oxoethyl)phenyl)amino)-2-(2-chloro-6-fluorophenyl)pyridazine-3-carboxylate methyl ester
将化合物4-((4-(2-(叔丁氧基)-2-氧代乙基)苯基)氨基)-6-氯吡啶-3-羧酸甲酯55d(500mg，1.33mmol)、2-氟-6-氯苯硼酸(923mg，5.3mmol)、二异丙基乙基胺(862mg，6.63mmol)和四(三苯基膦)钯(500mg，0.4mmol)溶于1,4-二氧六环(20mL)，除氧后在氮气气氛下用微波反应器加热到110℃并搅拌30分钟。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝100/0至3/7)纯化，得到目标产物4-((4-(2-(叔丁氧基)-2-氧代乙基)苯基)氨基)-2-(2-氯-6-氟苯基)哒嗪-3-羧酸甲酯99a(264mg，白色固体)，产率：42％。Compound 4-((4-(2-(tert-butoxy)-2-oxoethyl)phenyl)amino)-6-chloropyridine-3-carboxylate methyl ester 55d (500 mg, 1.33 mmol), 2-Fluoro-6-chlorophenylboronic acid (923 mg, 5.3 mmol), diisopropylethylamine (862 mg, 6.63 mmol) and tetrakis(triphenylphosphine)palladium (500 mg, 0.4 mmol) were dissolved in 1,4- Dioxane (20 mL), deoxygenated and heated to 110°C in a microwave reactor under nitrogen atmosphere and stirred for 30 minutes. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100/0 to 3/7) to obtain the target product 4-((4-(2-(tert-butyl). Oxy)-2-oxoethyl)phenyl)amino)-2-(2-chloro-6-fluorophenyl)pyridazine-3-carboxylic acid methyl ester 99a (264 mg, white solid), yield: 42%.
MS m/z(ESI):472[M+1]MS m/z(ESI): 472[M+1]
第二步second step
2-(4-(3-氨基甲酰基-6-(2-氯-6-氟苯基)哒嗪-4-基)氨基)苯基乙酸叔丁酯tert-Butyl 2-(4-(3-carbamoyl-6-(2-chloro-6-fluorophenyl)pyridazin-4-yl)amino)phenylacetate
将化合物4-((4-(2-(叔丁氧基)-2-氧代乙基)苯基)氨基)-2-(2-氯-6-氟苯基)哒嗪-3-羧酸甲酯99a(264mg，0.56mmol)溶于四氢呋喃(4mL)，加入氨水(3mL)。室温下搅拌5小时后，减压除去溶剂，得到目标产物2-(4-(3-氨基甲酰基-6-(2-氯-6-氟苯基)哒嗪-4-基)氨基)苯基乙酸叔丁酯99b(260mg，粗品)。Compound 4-((4-(2-(tert-butoxy)-2-oxoethyl)phenyl)amino)-2-(2-chloro-6-fluorophenyl)pyridazine-3-carboxylate Methyl acid 99a (264 mg, 0.56 mmol) was dissolved in tetrahydrofuran (4 mL) and ammonia (3 mL) was added. After stirring at room temperature for 5 hours, the solvent was removed under reduced pressure to give the desired product 2-(4-(3-carbamoyl-6-(2-chloro-6-fluorophenyl)pyridazin-4-yl)amino)benzene tert-Butyl acetate 99b (260 mg, crude).
MS m/z(ESI):457[M+1]MS m/z(ESI): 457[M+1]
第三步third step
2-(4-((3-氨基甲酰基-6-(2-氯-6-氟苯基)哒嗪-4-基)氨基)苯基)乙酸2-(4-((3-carbamoyl-6-(2-chloro-6-fluorophenyl)pyridazin-4-yl)amino)phenyl)acetic acid
将化合物2-(4-(3-氨基甲酰基-6-(2-氯-6-氟苯基)哒嗪-4-基)氨基)苯基乙酸叔丁酯99b(260mg，粗品)溶于四氢呋喃(4mL)，然后加入氯化氢的1,4-二氧六环溶液(2M，10mL，20mmol)。室温下搅拌2小时后，减压除去溶剂，残余物用反相制备液相色谱纯化，得到目标产物2-(4-((3-氨基甲酰基-6-(2-氯-6-氟苯基)哒嗪-4-基)氨基)苯基)乙酸99c(265mg，粗品)。该产品未经进一步纯化，直接用于下一步反应。Compound 2-(4-(3-carbamoyl-6-(2-chloro-6-fluorophenyl)pyridazin-4-yl)amino)phenylacetic acid tert-butyl ester 99b (260 mg, crude) was dissolved in Tetrahydrofuran (4 mL), then hydrogen chloride in 1,4-dioxane (2M, 10 mL, 20 mmol) was added. After stirring at room temperature for 2 hours, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative liquid chromatography to give the target product 2-(4-((3-carbamoyl-6-(2-chloro-6-fluorobenzene) yl)pyridazin-4-yl)amino)phenyl)acetic acid 99c (265 mg, crude). This product was used directly in the next reaction without further purification.
MS m/z(ESI):401[M+1]MS m/z(ESI): 401[M+1]
第四步the fourth step
4-((4-(2-(吖丁啶基-1-基)-2-氧代乙基)苯基)氨基)-2-(2-氯-6-氟苯基)哒嗪-3-甲酰胺4-((4-(2-(azetidinyl-1-yl)-2-oxoethyl)phenyl)amino)-2-(2-chloro-6-fluorophenyl)pyridazine-3-methyl Amide
将化合物2-(4-((3-氨基甲酰基-6-(2-氯-6-氟苯基)哒嗪-4-基)氨基)苯基)乙酸99c(265mg，粗品)、二异丙基乙基胺(450mg，3.3mmol)和吖丁啶(200mg，3.3mmol)溶于N,N-二甲基甲酰胺(4mL)，然后加入O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸盐(250mg，0.66mmol)。室温下搅拌过夜后，减压除去溶剂，残余物用反相制备液相色谱纯化，得到目标产物4-((4-(2-(吖丁啶-1-基)-2-氧代乙基)苯基)氨基)-2-(2-氯-6-氟苯基)哒嗪-3-甲酰胺99(8.9mg，近白色固体)，产率：三步3％。Compound 2-(4-((3-carbamoyl-6-(2-chloro-6-fluorophenyl)pyridazin-4-yl)amino)phenyl)acetic acid 99c (265 mg, crude), diiso Propylethylamine (450 mg, 3.3 mmol) and azetidine (200 mg, 3.3 mmol) were dissolved in N,N-dimethylformamide (4 mL), then O-(7-azabenzotriazole- 1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (250 mg, 0.66 mmol). After stirring at room temperature overnight, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative liquid chromatography to give the desired product, 4-((4-(2-(azetidin-1-yl)-2-oxoethyl) )phenyl)amino)-2-(2-chloro-6-fluorophenyl)pyridazine-3-carboxamide 99 (8.9 mg, off-white solid), yield: 3% for three steps.
MS m/z(ESI):440[M+1]MS m/z(ESI): 440[M+1]
1H NMR(400MHz,DMSO-d 6)δ10.84(s,1H),8.78(s,1H),8.05(s,1H),7.60–7.53(m,1H),7.48(d,J＝8.1Hz,1H),7.41–7.35(m,1H),7.30–7.21(m,4H),4.20–4.12(m,2H),3.87–3.78(m,2H),3.38(s,2H),2.22–2.11(m,2H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 10.84(s, 1H), 8.78(s, 1H), 8.05(s, 1H), 7.60-7.53(m, 1H), 7.48(d, J=8.1 Hz, 1H), 7.41–7.35 (m, 1H), 7.30–7.21 (m, 4H), 4.20–4.12 (m, 2H), 3.87–3.78 (m, 2H), 3.38 (s, 2H), 2.22– 2.11 (m, 2H).
实施例100参照实施例99的操作方法合成，但在第四步中用3-氯-1-丙胺代替吖丁啶。表征数据如下表所示：Example 100 was synthesized according to the procedure of Example 99, but in the fourth step, 3-chloro-1-propylamine was used instead of azetidine. Characterization data are shown in the following table:
Figure PCTCN2020108468-appb-000107
Figure PCTCN2020108468-appb-000107
实施例101Example 101
4-(4-(1-(吖丁啶-1-基)-2-甲基-1-氧代丙烷-2-基)苯基)氨基)-6-(2-氯-6-氟苯基)哒嗪-3-甲酰胺4-(4-(1-(azetidin-1-yl)-2-methyl-1-oxopropan-2-yl)phenyl)amino)-6-(2-chloro-6-fluorobenzene yl)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000108
Figure PCTCN2020108468-appb-000108
将化合物2-(4-((3-氨基甲酰-6-(2-氯-6-氟苯基)哒嗪-4-基)氨基)苯基)-2-甲基丙酸72(170mg，0.397mmol)、二异丙基乙基胺(260mg，1.99mmol)和吖丁啶(70mg，1.2mmol)溶于N,N-二甲基甲酰胺(3mL)，然后加入O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓六氟磷酸盐(200mg，0.51mmol)。室温下搅拌过夜后，减压除去溶剂，残余物用反相制备液相色谱纯化，得到目标产物4-(4-(1-(吖丁啶-1-基)-2-甲基-1-氧代丙烷-2-基)苯基)氨基)-6-(2-氯-6-氟苯基)哒嗪-3-甲酰胺101(58.8mg，近白色固体)，产率：31％。Compound 2-(4-((3-carbamoyl-6-(2-chloro-6-fluorophenyl)pyridazin-4-yl)amino)phenyl)-2-methylpropionic acid 72 (170 mg , 0.397 mmol), diisopropylethylamine (260 mg, 1.99 mmol) and azetidine (70 mg, 1.2 mmol) were dissolved in N,N-dimethylformamide (3 mL), then O-(7- Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (200 mg, 0.51 mmol). After stirring at room temperature overnight, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative liquid chromatography to give the desired product 4-(4-(1-(azetidin-1-yl)-2-methyl-1- Oxopropan-2-yl)phenyl)amino)-6-(2-chloro-6-fluorophenyl)pyridazine-3-carboxamide 101 (58.8 mg, off-white solid), yield: 31%.
MS m/z(ESI):468[M+1]MS m/z(ESI): 468[M+1]
1H NMR(400MHz,DMSO-d 6)δ10.91(s,1H),8.80(s,1H),8.07(s,1H),7.61–7.24(m,7H),3.86–3.71(m,2H),3.44–3.34(m,2H),1.99–1.86(m,2H),1.39(s,6H)。 1 H NMR (400MHz, DMSO-d 6 )δ10.91(s,1H), 8.80(s,1H), 8.07(s,1H), 7.61-7.24(m,7H), 3.86-3.71(m,2H) ), 3.44–3.34 (m, 2H), 1.99–1.86 (m, 2H), 1.39 (s, 6H).
实施例123参照实施例101的操作方法合成，但在第一步中用吗啉代替吖丁啶。表征数据如下表所示：Example 123 was synthesized following the procedure of Example 101, but in the first step, morpholine was used instead of azetidine. Characterization data are shown in the following table:
Figure PCTCN2020108468-appb-000109
Figure PCTCN2020108468-appb-000109
实施例103Example 103
6-(2-氯-6-氟苯基)-4-((4-(4-甲基-2-氧代哌嗪-1-基)苯基)氨基)哒嗪-3-甲酰胺6-(2-Chloro-6-fluorophenyl)-4-((4-(4-methyl-2-oxopiperazin-1-yl)phenyl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000110
Figure PCTCN2020108468-appb-000110
第一步first step
6-氯-4-((4-(4-甲基-2-氧代哌嗪-1-基)苯基)氨基)哒嗪-3-羧酸甲酯Methyl 6-chloro-4-((4-(4-methyl-2-oxopiperazin-1-yl)phenyl)amino)pyridazine-3-carboxylate
将化合物4,6-二氯哒嗪-3-羧酸甲酯1a(199mg，0.96mmol)、1-(4-氨基苯基)-4-甲基哌嗪-2-酮(197mg，0.96mmol)、二异丙基乙基胺(1.24g，9.60mmol)和乙腈(5mL)混合，加热到90℃并搅拌6小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(乙酸乙酯/甲醇＝100/0至1/1)纯化，得到目标产物6-氯-4-((4-(4-甲基-2-氧代哌嗪-1-基)苯基)氨基)哒嗪-3-羧酸甲酯103a(97mg，黄色油状物)，产率：27％。Compound 4,6-dichloropyridazine-3-carboxylate methyl ester 1a (199 mg, 0.96 mmol), 1-(4-aminophenyl)-4-methylpiperazin-2-one (197 mg, 0.96 mmol) ), diisopropylethylamine (1.24 g, 9.60 mmol) and acetonitrile (5 mL) were mixed, heated to 90°C and stirred for 6 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0 to 1/1) to obtain the target product 6-chloro-4-((4-(4- Methyl-2-oxopiperazin-1-yl)phenyl)amino)pyridazine-3-carboxylate methyl ester 103a (97 mg, yellow oil), yield: 27%.
MS m/z(ESI):376[M+1]MS m/z(ESI): 376[M+1]
第二步second step
6-(2-氯-6-氟苯基)-4-((4-(4-甲基-2-氧代哌嗪-1-基)苯基)氨基)哒嗪-3-羧酸甲酯6-(2-Chloro-6-fluorophenyl)-4-((4-(4-methyl-2-oxopiperazin-1-yl)phenyl)amino)pyridazine-3-carboxylate methyl ester
将化合物6-氯-4-((4-(4-甲基-2-氧代哌嗪-1-基)苯基)氨基)哒嗪-3-羧酸甲酯103a(387mg，0.82mmol)、2-氟-6-氯苯硼酸(574mg，3.29mmol)、二异丙基乙基胺(1.06g，8.24mmol)和四(三苯基膦)钯(238mg，0.21mmol)溶于1,4-二氧六环(6mL)，除氧后在氮气气氛下用微波反应器加热到115℃并搅拌1小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝100/0至0/100)纯化，得到目标产物6-(2-氯-6-氟苯基)-4-((4-(4-甲基-2-氧代哌嗪-1-基)苯基)氨基)哒嗪-3-羧酸甲酯103b(182mg，黄色油状物)，产率：47％。Compound 6-chloro-4-((4-(4-methyl-2-oxopiperazin-1-yl)phenyl)amino)pyridazine-3-carboxylate methyl ester 103a (387 mg, 0.82 mmol) , 2-fluoro-6-chlorobenzeneboronic acid (574mg, 3.29mmol), diisopropylethylamine (1.06g, 8.24mmol) and tetrakis(triphenylphosphine)palladium (238mg, 0.21mmol) were dissolved in 1, 4-Dioxane (6 mL), deoxygenated, heated to 115°C in a microwave reactor under nitrogen atmosphere and stirred for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100/0 to 0/100) to obtain the target product 6-(2-chloro-6-fluorophenyl) )-4-((4-(4-methyl-2-oxopiperazin-1-yl)phenyl)amino)pyridazine-3-carboxylate methyl ester 103b (182 mg, yellow oil), yield : 47%.
MS m/z(ESI):470[M+1]MS m/z(ESI): 470[M+1]
第三步third step
6-(2-氯-6-氟苯基)-4-((4-(4-甲基-2-氧代哌嗪-1-基)苯基)氨基)哒嗪-3- 甲酰胺6-(2-Chloro-6-fluorophenyl)-4-((4-(4-methyl-2-oxopiperazin-1-yl)phenyl)amino)pyridazine-3-carboxamide
将化合物6-(2-氯-6-氟苯基)-4-((4-(4-甲基-2-氧代哌嗪-1-基)苯基)氨基)哒嗪-3-羧酸甲酯103b(182mg，0.39mmol)溶于四氢呋喃(5mL)，加入氨水(5mL)。室温下搅拌3小时后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2-氯-6-氟苯基)-4-((4-(4-甲基-2-氧代哌嗪-1-基)苯基)氨基)哒嗪-3-甲酰胺103(28.5mg，黄色固体)，产率：16％。The compound 6-(2-chloro-6-fluorophenyl)-4-((4-(4-methyl-2-oxopiperazin-1-yl)phenyl)amino)pyridazine-3-carboxylate Methyl acid 103b (182 mg, 0.39 mmol) was dissolved in tetrahydrofuran (5 mL), and aqueous ammonia (5 mL) was added. After stirring at room temperature for 3 hours, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to obtain the target product 6-(2-chloro-6-fluorophenyl)-4-((4-(4- Methyl-2-oxopiperazin-1-yl)phenyl)amino)pyridazine-3-carboxamide 103 (28.5 mg, yellow solid), yield: 16%.
MS m/z(ESI):455[M+1]MS m/z(ESI): 455[M+1]
1H NMR(400MHz,CD 3OD)δ7.39–7.68(m,8H),4.17(brs,4H),3.85(brs,2H),3.12(s,3H)。 1 H NMR (400 MHz, CD 3 OD) δ 7.39-7.68 (m, 8H), 4.17 (brs, 4H), 3.85 (brs, 2H), 3.12 (s, 3H).
实施例104Example 104
6-(2-氯-6-氟苯基)-4-((4-(吗啉-4-羰基)苯基)氨基)哒嗪-3-甲酰胺6-(2-Chloro-6-fluorophenyl)-4-((4-(morpholine-4-carbonyl)phenyl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000111
Figure PCTCN2020108468-appb-000111
第一步first step
5-(2-氯-6-氟苯基)-5-羟基-3-氧代戊甲酸甲酯Methyl 5-(2-chloro-6-fluorophenyl)-5-hydroxy-3-oxopentanoate
在氮气气氛下将氢化钠(纯度60％，720mg，18mmol)和无水四氢呋喃(10mL)混合，冷却到0℃后，加入乙酰乙酸甲酯104a(1.74g，15mmol)。逐渐升温到室温后继续搅拌30分钟，然后冷却到-15℃。逐滴加入丁基锂的正己烷溶液(2.5M，7.2mL，18mmol)并继续搅拌30分钟后，加入2-氟-6-氯苯甲醛(2.85g，18mmol，溶于3mL四氢呋喃)，然后逐渐升温至室温。搅拌1小时后，加入饱和氯化铵水溶液(50mL)，然后用乙酸乙酯(3×50mL)萃取。有机相合并后用无水硫酸钠干燥，过滤后滤液在减压条件下除去溶剂，残余物用硅胶柱层析 (石油醚/乙酸乙酯＝3/2)纯化，得到目标产物5-(2-氯-6-氟苯基)-5-羟基-3-氧代戊甲酸甲酯104b(3.08g，黄色油状物)，产率：75％。Sodium hydride (purity 60%, 720 mg, 18 mmol) and anhydrous tetrahydrofuran (10 mL) were mixed under nitrogen atmosphere, and after cooling to 0°C, methyl acetoacetate 104a (1.74 g, 15 mmol) was added. After gradually warming to room temperature, stirring was continued for 30 minutes, and then cooled to -15°C. A solution of butyllithium in n-hexane (2.5 M, 7.2 mL, 18 mmol) was added dropwise and stirring continued for 30 minutes, 2-fluoro-6-chlorobenzaldehyde (2.85 g, 18 mmol, dissolved in 3 mL of tetrahydrofuran) was added, and then gradually Warm to room temperature. After stirring for 1 hour, saturated aqueous ammonium chloride solution (50 mL) was added, followed by extraction with ethyl acetate (3 x 50 mL). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was filtered and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=3/2) to obtain the target product 5-(2 -Chloro-6-fluorophenyl)-5-hydroxy-3-oxopentanoate methyl ester 104b (3.08 g, yellow oil), yield: 75%.
MS m/z(ESI):297[M+Na]MS m/z(ESI): 297[M+Na]
1H NMR(400MHz,CDCl 3)δ7.25–7.16(m,2H),7.04–6.98(m,1H),5.78(ddd,J＝9.7,3.3,0.9Hz,1H),3.75(s,3H),3.55(s,2H),3.46(ddd,J＝17.4,9.7,0.7Hz,1H),2.96(dd,J＝17.5,3.3Hz,1H)。 1 H NMR (400MHz, CDCl 3 ) δ 7.25-7.16 (m, 2H), 7.04-6.98 (m, 1H), 5.78 (ddd, J=9.7, 3.3, 0.9Hz, 1H), 3.75 (s, 3H) ), 3.55 (s, 2H), 3.46 (ddd, J=17.4, 9.7, 0.7Hz, 1H), 2.96 (dd, J=17.5, 3.3Hz, 1H).
第二步second step
5-(2-氯-6-氟苯基)-2-重氮-5-羟基-3-氧代戊甲酸甲酯Methyl 5-(2-chloro-6-fluorophenyl)-2-diazo-5-hydroxy-3-oxopentanoate
将化合物5-(2-氯-6-氟苯基)-5-羟基-3-氧代戊甲酸甲酯104b(3.08g，11.23mmol)溶于乙腈(50mL)，然后依次加入三乙胺(2.275g，22.46mmol)和4-乙酰氨基苯磺酰叠氮(2.698g，11.23mmol)。室温下搅拌1小时后，加入饱和氯化铵水溶液(100mL)，然后用乙酸乙酯萃取(2×100mL)。有机相合并后，用饱和食盐水(100mL)洗涤，然后用无水硫酸钠干燥。过滤后，滤液在减压条件下除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝3/1至3/2)纯化，得到目标产物5-(2-氯-6-氟苯基)-2-重氮-5-羟基-3-氧代戊甲酸甲酯104c(2.99g，黄色油状物)，产率：88％。The compound 5-(2-chloro-6-fluorophenyl)-5-hydroxy-3-oxopentanoate methyl ester 104b (3.08 g, 11.23 mmol) was dissolved in acetonitrile (50 mL), and then triethylamine ( 2.275 g, 22.46 mmol) and 4-acetamidobenzenesulfonyl azide (2.698 g, 11.23 mmol). After stirring at room temperature for 1 hour, saturated aqueous ammonium chloride solution (100 mL) was added, followed by extraction with ethyl acetate (2 x 100 mL). The organic phases were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. After filtration, the solvent of the filtrate was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=3/1 to 3/2) to obtain the target product 5-(2-chloro-6-fluoro). Phenyl)-2-diazo-5-hydroxy-3-oxopentanoate methyl ester 104c (2.99 g, yellow oil), yield: 88%.
MS m/z(ESI):323[M+Na]MS m/z(ESI): 323[M+Na]
1H NMR(400MHz,CDCl 3)δ7.24–7.13(m,2H),7.01(ddd,J＝10.7,7.5,2.0Hz,1H),5.78(ddd,J＝10.0,3.2,0.9Hz,1H),3.85(s,3H),3.80(ddd,J＝16.8,10.0,0.8Hz,1H),3.17(dd,J＝16.8,3.3Hz,1H)。 1 H NMR (400MHz, CDCl 3 ) δ 7.24-7.13 (m, 2H), 7.01 (ddd, J=10.7, 7.5, 2.0Hz, 1H), 5.78 (ddd, J=10.0, 3.2, 0.9Hz, 1H ), 3.85 (s, 3H), 3.80 (ddd, J=16.8, 10.0, 0.8 Hz, 1H), 3.17 (dd, J=16.8, 3.3 Hz, 1H).
第三步third step
5-(2-氯-6-氟苯基)-2-重氮-3,5-二氧代戊甲酸甲酯Methyl 5-(2-chloro-6-fluorophenyl)-2-diazo-3,5-dioxopentanoate
将化合物5-(2-氯-6-氟苯基)-2-重氮-5-羟基-3-氧代戊甲酸甲酯104c(2.71g，9mmol)溶于二氯甲烷(50mL)，冷却到0℃后，加入戴斯-马丁氧化剂(5.73g，13.52mmol)。室温下搅拌3小时后，用饱和亚硫酸钠水溶液(100mL)淬灭反应，然后用二氯甲烷(2×100mL)萃取。有机相合并后，用无水硫酸钠干燥。过滤后，滤液在减压条件下除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化，得到目标产物5-(2-氯-6-氟苯基)-2-重氮-3,5-二氧代戊甲酸甲酯104d(1.3g，近白色固体)，产率：48％。Compound 5-(2-chloro-6-fluorophenyl)-2-diazo-5-hydroxy-3-oxopentanoic acid methyl ester 104c (2.71 g, 9 mmol) was dissolved in dichloromethane (50 mL), cooled After reaching 0°C, Dess-Martin oxidant (5.73 g, 13.52 mmol) was added. After stirring at room temperature for 3 hours, the reaction was quenched with saturated aqueous sodium sulfite (100 mL), then extracted with dichloromethane (2 x 100 mL). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was removed from the solvent under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the target product 5-(2-chloro-6-fluorophenyl)- Methyl 2-diazo-3,5-dioxopentanoate 104d (1.3 g, off-white solid), yield: 48%.
MS m/z(ESI):299[M+1]MS m/z(ESI): 299[M+1]
1H NMR(400MHz,CDCl 3)δ14.96(s,1H),7.33(td,J＝8.2,5.8Hz,1H),7.24(dd,J＝5.0,4.1Hz,1H),7.09–7.03(m,1H),6.74(s,1H),3.84(s,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 14.96 (s, 1H), 7.33 (td, J=8.2, 5.8 Hz, 1H), 7.24 (dd, J=5.0, 4.1 Hz, 1H), 7.09-7.03 ( m, 1H), 6.74 (s, 1H), 3.84 (s, 3H).
第四步the fourth step
6-(2-氯-6-氟苯基)-4-羟基哒嗪-3-羧酸甲酯6-(2-Chloro-6-fluorophenyl)-4-hydroxypyridazine-3-carboxylate methyl ester
将化合物5-(2-氯-6-氟苯基)-2-重氮-3,5-二氧代戊甲酸甲酯104d(505mg，1.69mmol)溶于异丙醚(20mL)，然后在氮气气氛下加入三丁基膦(342mg，1.69mmol)。室温下搅拌30分钟后，将析出的固 体滤出，得到目标产物6-(2-氯-6-氟苯基)-4-羟基哒嗪-3-羧酸甲酯104e(192mg，黄色固体)，产率：40％。Compound 5-(2-chloro-6-fluorophenyl)-2-diazo-3,5-dioxopentanoic acid methyl ester 104d (505 mg, 1.69 mmol) was dissolved in isopropyl ether (20 mL), followed by Tributylphosphine (342 mg, 1.69 mmol) was added under nitrogen atmosphere. After stirring at room temperature for 30 minutes, the precipitated solid was filtered off to obtain the target product, methyl 6-(2-chloro-6-fluorophenyl)-4-hydroxypyridazine-3-carboxylate 104e (192 mg, yellow solid) , Yield: 40%.
MS m/z(ESI):283[M+1]MS m/z(ESI): 283[M+1]
第五步the fifth step
4-氯-6-(2-氯-6-氟苯基)哒嗪-3-羧酸甲酯Methyl 4-chloro-6-(2-chloro-6-fluorophenyl)pyridazine-3-carboxylate
将化合物6-(2-氯-6-氟苯基)-4-羟基哒嗪-3-羧酸甲酯104e(192mg，0.679mmol)与三氯氧磷(5mL)混合，加热到100℃并搅拌1小时。冷却到室温后，减压除去溶剂，残余物溶于二氯甲烷(20mL)，然后加入饱和碳酸氢钠溶液(20mL)。搅拌10分钟后，用二氯甲烷(2×20mL)萃取。有机相合并后，用无水硫酸钠干燥。过滤后，滤液在减压条件下除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝2/1)纯化，得到目标产物4-氯-6-(2-氯-6-氟苯基)哒嗪-3-羧酸甲酯104f(187mg，黄色油状物)，产率：92％。Compound 6-(2-chloro-6-fluorophenyl)-4-hydroxypyridazine-3-carboxylate methyl ester 104e (192 mg, 0.679 mmol) was mixed with phosphorus oxychloride (5 mL), heated to 100 °C and heated to 100°C. Stir for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, the residue was dissolved in dichloromethane (20 mL), and saturated sodium bicarbonate solution (20 mL) was added. After stirring for 10 minutes, it was extracted with dichloromethane (2 x 20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was removed from the solvent under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to obtain the target product 4-chloro-6-(2-chloro-6-fluoro). Phenyl)pyridazine-3-carboxylate methyl ester 104f (187 mg, yellow oil), yield: 92%.
MS m/z(ESI):301[M+1]MS m/z(ESI): 301[M+1]
第六步Step 6
6-(2-氯-6-氟苯基)-4-((4-(吗啉-4-羰基)苯基)氨基)哒嗪-3-羧酸甲酯Methyl 6-(2-chloro-6-fluorophenyl)-4-((4-(morpholine-4-carbonyl)phenyl)amino)pyridazine-3-carboxylate
将化合物4-氯-6-(2-氯-6-氟苯基)哒嗪-3-羧酸甲酯104f(1.5g，5mmol)、(4-氨基苯基)(吗啉代)甲酮(1.24g，6mmol)，对甲基苯磺酸(95mg，0.1mmol)和甲醇(50mL)混合，加热回流并搅拌2.5小时。冷却到室温后，加入饱和碳酸氢钠溶液(100mL)，然后用乙酸乙酯(3×100mL)萃取。有机相合并后，用饱和食盐水(100mL)洗涤，然后用无水硫酸钠干燥。过滤后，滤液在减压条件下除去溶剂，残余物用硅胶柱层析(二氯甲烷/甲醇＝100/1至94/6)纯化，得到目标产物6-(2-氯-6-氟苯基)-4-((4-(吗啉-4-羰基)苯基)氨基)哒嗪-3-羧酸甲酯104g(1.09g，黄色固体)，产率：46％。Compound 4-chloro-6-(2-chloro-6-fluorophenyl)pyridazine-3-carboxylate methyl ester 104f (1.5g, 5mmol), (4-aminophenyl)(morpholino)methanone (1.24 g, 6 mmol), p-toluenesulfonic acid (95 mg, 0.1 mmol) and methanol (50 mL) were mixed, heated to reflux and stirred for 2.5 hours. After cooling to room temperature, saturated sodium bicarbonate solution (100 mL) was added, followed by extraction with ethyl acetate (3 x 100 mL). The organic phases were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. After filtration, the solvent of the filtrate was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=100/1 to 94/6) to obtain the target product 6-(2-chloro-6-fluorobenzene) yl)-4-((4-(morpholine-4-carbonyl)phenyl)amino)pyridazine-3-carboxylate 104 g (1.09 g, yellow solid), yield: 46%.
MS m/z(ESI):471[M+1]MS m/z(ESI): 471[M+1]
第七步Step 7
6-(2-氯-6-氟苯基)-4-((4-(吗啉-4-羰基)苯基)氨基)哒嗪-3-甲酰胺6-(2-Chloro-6-fluorophenyl)-4-((4-(morpholine-4-carbonyl)phenyl)amino)pyridazine-3-carboxamide
将化合物6-(2-氯-6-氟苯基)-4-((4-(吗啉-4-羰基)苯基)氨基)哒嗪-3-羧酸甲酯104g(1.09g，2.31mmol)溶于四氢呋喃(8mL)，然后加入氨水(8mL)，加热到40℃并搅拌1小时。冷却到室温后，加入水(50mL)，然后用乙酸乙酯(3×50mL)萃取。有机相合并后，用饱和食盐水(100mL)洗涤，然后用无水硫酸钠干燥。过滤后，滤液在减压条件下除去溶剂，残余物用硅胶柱层析(二氯甲烷/甲醇＝100/1至49/1)纯化，得到的产物与稀盐酸(1N，3mL)混合并冻干后，得到目标产物6-(2-氯-6-氟苯基)-4-((4-(吗啉-4-羰基)苯基)氨基)哒嗪-3-甲酰胺盐酸盐104(603.5mg，黄色固体)，产率：57％。Compound 6-(2-chloro-6-fluorophenyl)-4-((4-(morpholine-4-carbonyl)phenyl)amino)pyridazine-3-carboxylate 104g (1.09g, 2.31 g) mmol) was dissolved in tetrahydrofuran (8 mL), then aqueous ammonia (8 mL) was added, heated to 40° C. and stirred for 1 hour. After cooling to room temperature, water (50 mL) was added, followed by extraction with ethyl acetate (3 x 50 mL). The organic phases were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was freed of solvent under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane/methanol=100/1 to 49/1), and the obtained product was mixed with dilute hydrochloric acid (1N, 3 mL) and frozen After drying, the target product 6-(2-chloro-6-fluorophenyl)-4-((4-(morpholine-4-carbonyl)phenyl)amino)pyridazine-3-carboxamide hydrochloride 104 was obtained (603.5 mg, yellow solid), yield: 57%.
MS m/z(ESI):456[M+1]MS m/z(ESI): 456[M+1]
1H NMR(400MHz,CD 3OD)δ11.36(s,1H),9.83(s,1H),8.84(s,1H), 8.22(s,1H),7.69–7.27(m,8H),3.59(brs,4H),3.50(brs,4H)。 1 H NMR (400MHz, CD 3 OD) δ 11.36(s, 1H), 9.83(s, 1H), 8.84(s, 1H), 8.22(s, 1H), 7.69–7.27(m, 8H), 3.59 (brs, 4H), 3.50 (brs, 4H).
以下实施例(实施例109、实施例113、实施例114、实施例115、实施例126、实施例127)均参照实施例104的操作方法合成，但在第六步中用不同的胺代替(4-氨基苯基)(吗啉代)甲酮。表征数据如下表所示：The following examples (Example 109, Example 113, Example 114, Example 115, Example 126, Example 127) were all synthesized with reference to the operation method of Example 104, but in the sixth step, different amines were used instead ( 4-Aminophenyl)(morpholino)methanone. Characterization data are shown in the following table:
Figure PCTCN2020108468-appb-000112
Figure PCTCN2020108468-appb-000112
Figure PCTCN2020108468-appb-000113
Figure PCTCN2020108468-appb-000113
实施例105Example 105
6-(2-氯-6-氟苯基)-4-((4-(4-环丙基-2-氧代哌嗪-1-基)苯基)氨基)哒嗪-3-甲酰胺6-(2-Chloro-6-fluorophenyl)-4-((4-(4-cyclopropyl-2-oxopiperazin-1-yl)phenyl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000114
Figure PCTCN2020108468-appb-000114
Figure PCTCN2020108468-appb-000115
Figure PCTCN2020108468-appb-000115
第一步first step
4-(4-硝基苯基)-3-氧代哌嗪-1-甲酸叔丁酯4-(4-Nitrophenyl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester
将化合物对硝基溴苯105a(1.0g，4.95mmol)、3-氧代哌嗪-1-甲酸叔丁酯(1.0g，5.0mmol)、N 1,N 2-二甲基-1,2-乙二胺(88mg，1.0mmol)、碘化亚铜(190mg，1.0mmol)和甲苯(20mL)混合，除氧后在氮气气氛下加热回流15小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝100/1至1/1)纯化，得到目标产物4-(4-硝基苯基)-3-氧代哌嗪-1-甲酸叔丁酯105b(550mg，黄色固体)，产率：34％。 Compound p-nitrobromobenzene 105a (1.0 g, 4.95 mmol), tert-butyl 3-oxopiperazine-1-carboxylate (1.0 g, 5.0 mmol), N 1 ,N 2 -dimethyl-1,2 - Ethylenediamine (88 mg, 1.0 mmol), cuprous iodide (190 mg, 1.0 mmol) and toluene (20 mL) were mixed and heated to reflux under nitrogen atmosphere for 15 hours after deoxygenation. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100/1 to 1/1) to obtain the target product 4-(4-nitrophenyl)-3 - tert-butyl oxopiperazine-1-carboxylate 105b (550 mg, yellow solid), yield: 34%.
MS m/z(ESI):344[M+Na]MS m/z(ESI): 344[M+Na]
第二步second step
1-(4-硝基苯基)哌嗪-2-酮1-(4-Nitrophenyl)piperazin-2-one
将化合物4-(4-硝基苯基)-3-氧代哌嗪-1-甲酸叔丁酯105b(550mg，1.7mmol)溶于二氯甲烷(20mL)，然后加入三氟乙酸(3mL)。室温下搅拌3小时后，减压除去溶剂，残余物溶于甲醇(20mL)，然后用饱和碳酸氢钠溶液调节至pH＝8～9。减压除去溶剂后，残余物用硅胶柱层析(二氯甲烷/甲醇＝100/1至20/1)纯化，得到目标产物1-(4-硝基苯基)哌嗪-2-酮105c(320mg，近白色固体)，产率：85％。Compound 4-(4-nitrophenyl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester 105b (550 mg, 1.7 mmol) was dissolved in dichloromethane (20 mL), then trifluoroacetic acid (3 mL) was added . After stirring at room temperature for 3 hours, the solvent was removed under reduced pressure and the residue was dissolved in methanol (20 mL), then adjusted to pH=8-9 with saturated sodium bicarbonate solution. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane/methanol=100/1 to 20/1) to obtain the target product 1-(4-nitrophenyl)piperazin-2-one 105c (320 mg, off-white solid), yield: 85%.
MS m/z(ESI):222[M+1]MS m/z(ESI): 222[M+1]
第三步third step
4-环丙基-1-(4-硝基苯基)哌嗪-2-酮4-Cyclopropyl-1-(4-nitrophenyl)piperazin-2-one
将化合物1-(4-硝基苯基)哌嗪-2-酮105c(442mg，2.0mmol)、乙酸(1.2g，20mmol)、(1-乙氧基环丙氧基)三甲基硅烷(2.09g，12mmol)和甲醇(20mL)混合，然后加入氰基硼氢化钠(629mg，10mmol)。室温下搅拌6小时后过滤，滤液在减压条件下除去溶剂，残余物用硅胶柱层析(二氯甲烷/甲醇＝100/1至10/1)纯化，得到目标产物4-环丙基-1-(4-硝基苯基)哌嗪-2-酮105d(530mg，黄色固体)，产率：100％。Compound 1-(4-nitrophenyl)piperazin-2-one 105c (442 mg, 2.0 mmol), acetic acid (1.2 g, 20 mmol), (1-ethoxycyclopropoxy)trimethylsilane ( 2.09 g, 12 mmol) and methanol (20 mL) were mixed, then sodium cyanoborohydride (629 mg, 10 mmol) was added. After stirring at room temperature for 6 hours, the filtrate was filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=100/1 to 10/1) to obtain the target product 4-cyclopropyl- 1-(4-Nitrophenyl)piperazin-2-one 105d (530 mg, yellow solid), yield: 100%.
MS m/z(ESI):262[M+1]MS m/z(ESI): 262[M+1]
第四步the fourth step
1-(4-氨基苯基)-4-环丙基哌嗪-2-酮1-(4-Aminophenyl)-4-cyclopropylpiperazin-2-one
将化合物4-环丙基-1-(4-硝基苯基)哌嗪-2-酮105d(530mg，2.0mmol)溶于乙酸乙酯(30mL)，加入10％钯炭(200mg)，然后在氢气气氛下搅拌15小时。反应完成后用甲醇(50mL)稀释，然后过滤。滤液在减压条件下除去溶剂，得到目标产物1-(4-氨基苯基)-4-环丙基哌嗪-2-酮105e(450mg，淡黄色固体)，产率：97％。Compound 4-cyclopropyl-1-(4-nitrophenyl)piperazin-2-one 105d (530 mg, 2.0 mmol) was dissolved in ethyl acetate (30 mL), 10% palladium on carbon (200 mg) was added, and then Stir under a hydrogen atmosphere for 15 hours. After completion of the reaction, it was diluted with methanol (50 mL) and filtered. The filtrate was removed under reduced pressure to obtain the target product 1-(4-aminophenyl)-4-cyclopropylpiperazin-2-one 105e (450 mg, pale yellow solid), yield: 97%.
MS m/z(ESI):232[M+1]MS m/z(ESI): 232[M+1]
第五步the fifth step
6-氯-4-((4-(4-环丙基-2-氧代哌嗪-1-基)苯基)氨基)哒嗪-3-羧酸甲酯Methyl 6-chloro-4-((4-(4-cyclopropyl-2-oxopiperazin-1-yl)phenyl)amino)pyridazine-3-carboxylate
将化合物4,6-二氯哒嗪-3-羧酸甲酯1a(621mg，3.0mmol)、1-(4-氨基苯基)-4-环丙基哌嗪-2-酮105e(347mg，1.5mmol)、二异丙基乙基胺(580mg，4.5mmol)和乙腈(15mL)混合，加热到100℃并搅拌15小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝50/1至1/5)纯化，得到目标产物6-氯-4-((4-(4-环丙基-2-氧代哌嗪-1-基)苯基)氨基)哒嗪-3-羧酸甲酯105f(220mg，黄色固体)，产率：36％。Compound 4,6-dichloropyridazine-3-carboxylate methyl ester 1a (621 mg, 3.0 mmol), 1-(4-aminophenyl)-4-cyclopropylpiperazin-2-one 105e (347 mg, 1.5 mmol), diisopropylethylamine (580 mg, 4.5 mmol) and acetonitrile (15 mL) were mixed, heated to 100°C and stirred for 15 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/1 to 1/5) to obtain the target product 6-chloro-4-((4-(4 -Cyclopropyl-2-oxopiperazin-1-yl)phenyl)amino)pyridazine-3-carboxylate methyl ester 105f (220 mg, yellow solid), yield: 36%.
MS m/z(ESI):402[M+1]MS m/z(ESI): 402[M+1]
第六步Step 6
6-(2-氯-6-氟苯基)-4-((4-(4-环丙基-2-氧代哌嗪-1-基)苯基)氨基)哒嗪-3-羧酸甲酯6-(2-Chloro-6-fluorophenyl)-4-((4-(4-cyclopropyl-2-oxopiperazin-1-yl)phenyl)amino)pyridazine-3-carboxylic acid methyl ester
将化合物6-氯-4-((4-(4-环丙基-2-氧代哌嗪-1-基)苯基)氨基)哒嗪-3-羧酸甲酯105f(220mg，0.55mmol)、2-氟-6-氯苯硼酸(287mg，1.65mmol)、二异丙基乙基胺(212mg，1.65mmol)和四(三苯基膦)钯(63mg，0.055mmol)溶于1,4-二氧六环(8mL)，除氧后在氮气气氛下加热到110℃并搅拌15小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝50/1至1/5)纯化，得到目标产物6-(2-氯-6-氟苯基)-4-((4-(4-环丙基-2-氧代哌嗪-1-基)苯基)氨基)哒嗪-3-羧酸甲酯105g(200mg，黄色油状物)，产率：73％。Compound 6-chloro-4-((4-(4-cyclopropyl-2-oxopiperazin-1-yl)phenyl)amino)pyridazine-3-carboxylate methyl ester 105f (220 mg, 0.55 mmol ), 2-fluoro-6-chlorophenylboronic acid (287mg, 1.65mmol), diisopropylethylamine (212mg, 1.65mmol) and tetrakis(triphenylphosphine)palladium (63mg, 0.055mmol) were dissolved in 1, 4-Dioxane (8 mL), deoxygenated, heated to 110°C under nitrogen atmosphere and stirred for 15 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/1 to 1/5) to obtain the target product 6-(2-chloro-6-fluorophenyl) )-4-((4-(4-cyclopropyl-2-oxopiperazin-1-yl)phenyl)amino)pyridazine-3-carboxylate methyl ester 105g (200mg, yellow oil), yielded Rate: 73%.
MS m/z(ESI):496[M+1]MS m/z(ESI): 496[M+1]
第七步Step 7
6-(2-氯-6-氟苯基)-4-((4-(4-环丙基-2-氧代哌嗪-1-基)苯基)氨基)哒嗪-3-甲酰胺6-(2-Chloro-6-fluorophenyl)-4-((4-(4-cyclopropyl-2-oxopiperazin-1-yl)phenyl)amino)pyridazine-3-carboxamide
将化合物6-(2-氯-6-氟苯基)-4-((4-(4-环丙基-2-氧代哌嗪-1-基)苯基)氨基)哒嗪-3-羧酸甲酯105g(200mg，0.40mmol)溶于四氢呋喃(15mL)，加入氨水(5mL)。室温下搅拌3小时后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2-氯-6-氟苯基)-4-((4-(4-环丙基-2-氧代哌嗪-1-基)苯基)氨基)哒嗪-3-甲酰胺105(47mg，黄色固体)，产率：23％。The compound 6-(2-chloro-6-fluorophenyl)-4-((4-(4-cyclopropyl-2-oxopiperazin-1-yl)phenyl)amino)pyridazine-3- 105 g (200 mg, 0.40 mmol) of methyl carboxylate was dissolved in tetrahydrofuran (15 mL), and ammonia water (5 mL) was added. After stirring at room temperature for 3 hours, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to obtain the target product 6-(2-chloro-6-fluorophenyl)-4-((4-(4- Cyclopropyl-2-oxopiperazin-1-yl)phenyl)amino)pyridazine-3-carboxamide 105 (47 mg, yellow solid), yield: 23%.
MS m/z(ESI):481[M+1]MS m/z(ESI): 481[M+1]
1H NMR(400MHz,CD 3OD)δ7.72(td,J＝8.4,6.1Hz,1H),7.65–7.53(m,6H),7.41(t,J＝8.9Hz,1H),4.28(s,2H),4.14(s,2H),3.96(t,J＝5.4Hz,2H),3.17–3.06(m,1H),1.30(q,J＝6.4Hz,2H),1.08(t,J＝6.7Hz,2H)。 1 H NMR (400 MHz, CD 3 OD) δ 7.72 (td, J=8.4, 6.1 Hz, 1H), 7.65-7.53 (m, 6H), 7.41 (t, J=8.9 Hz, 1H), 4.28 (s ,2H),4.14(s,2H),3.96(t,J＝5.4Hz,2H),3.17–3.06(m,1H),1.30(q,J＝6.4Hz,2H),1.08(t,J＝ 6.7Hz, 2H).
实施例106Example 106
6-(2-氯-6-氟苯基)-4-((4-(4-(噁丁环-3-基)-2-氧代哌嗪-1-基)苯基)氨基)哒嗪-3-甲酰胺6-(2-Chloro-6-fluorophenyl)-4-((4-(4-(oxetan-3-yl)-2-oxopiperazin-1-yl)phenyl)amino)pyridin oxazine-3-carboxamide
Figure PCTCN2020108468-appb-000116
Figure PCTCN2020108468-appb-000116
第一步first step
1-(4-硝基苯基)-4-(噁丁环-3-基)哌嗪-2-酮1-(4-Nitrophenyl)-4-(oxetan-3-yl)piperazin-2-one
将化合物1-(4-硝基苯基)哌嗪-2-酮105c(442mg，2.0mmol)、噁丁环-3-酮(293mg，4.08mmol)、乙酸(1mL)和二氯甲烷(20mL)混合，然后加入三乙酰氧基硼氢化钠(2.88g，13.6mmol)。室温下搅拌1小时后，用二氯甲烷(100mL)稀释，然后依次用饱和碳酸氢钠溶液(50mL)和饱和食盐水(50mL)洗涤。有机相用无水硫酸钠干燥，过滤后滤液在减压条件下除去溶剂，残余物用硅胶柱层析(二氯甲烷/甲醇＝100/1至20/1)纯化，得到目标产物1-(4-硝基苯基)-4-(噁丁环-3-基)哌嗪-2-酮106a(340mg，黄色固体)，产率：90％。Compound 1-(4-nitrophenyl)piperazin-2-one 105c (442 mg, 2.0 mmol), oxetan-3-one (293 mg, 4.08 mmol), acetic acid (1 mL) and dichloromethane (20 mL) were combined ) and mixed, then sodium triacetoxyborohydride (2.88 g, 13.6 mmol) was added. After stirring at room temperature for 1 hour, it was diluted with dichloromethane (100 mL), and washed with saturated sodium bicarbonate solution (50 mL) and saturated brine (50 mL) in this order. The organic phase was dried over anhydrous sodium sulfate, and the filtrate was filtered to remove the solvent under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=100/1 to 20/1) to obtain the target product 1-( 4-Nitrophenyl)-4-(oxetan-3-yl)piperazin-2-one 106a (340 mg, yellow solid), yield: 90%.
MS m/z(ESI):278[M+1]MS m/z(ESI): 278[M+1]
第二步至第五步Steps 2 to 5
6-(2-氯-6-氟苯基)-4-((4-(4-(噁丁环-3-基)-2-氧代哌嗪-1-基)苯基)氨基)哒嗪-3-甲酰胺6-(2-Chloro-6-fluorophenyl)-4-((4-(4-(oxetan-3-yl)-2-oxopiperazin-1-yl)phenyl)amino)pyridin oxazine-3-carboxamide
参照实施例105中第四步至第七步的合成步骤合成106，但在操作 中用1-(4-硝基苯基)-4-(噁丁环-3-基)哌嗪-2-酮106a代替4-环丙基-1-(4-硝基苯基)哌嗪-2-酮105d。106 was synthesized by referring to the synthetic steps from the fourth step to the seventh step in Example 105, but using 1-(4-nitrophenyl)-4-(oxetan-3-yl)piperazine-2- Ketone 106a replaced 4-cyclopropyl-1-(4-nitrophenyl)piperazin-2-one 105d.
MS m/z(ESI):497[M+1]MS m/z(ESI): 497[M+1]
1H NMR(400MHz,CD 3OD)δ7.72(td,J＝8.4,6.1Hz,1H),7.60(dt,J＝15.4,6.8Hz,6H),7.41(t,J＝8.8Hz,1H),4.40(d,J＝7.8Hz,2H),4.29–3.99(m,8H),3.97–3.91(m,1H)。 1 H NMR (400 MHz, CD 3 OD) δ 7.72 (td, J=8.4, 6.1 Hz, 1H), 7.60 (dt, J=15.4, 6.8 Hz, 6H), 7.41 (t, J=8.8 Hz, 1H) ), 4.40 (d, J=7.8Hz, 2H), 4.29–3.99 (m, 8H), 3.97–3.91 (m, 1H).
实施例107Example 107
6-(2-氟-6-氯苯基)-4-((4-(噁丁环-3-基)苯基)氨基)哒嗪-3-甲酰胺6-(2-Fluoro-6-chlorophenyl)-4-((4-(oxetan-3-yl)phenyl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000117
Figure PCTCN2020108468-appb-000117
第一步first step
N,N-二苯甲基-4-(噁丁环-3-基)苯胺N,N-Diphenylmethyl-4-(oxetan-3-yl)aniline
将化合物3-(4-(二苯甲基氨基)苯基)噁丁环-3-醇69c(400mg，1.156mmol)溶于二氯甲烷(10mL)，冷却到0℃后依次加入三乙基甲硅烷(148mg，1.27mmol)和三氟乙酸(396mg，3.47mmol)。逐渐升至室温后，继续搅拌16小时后，加入饱和碳酸氢钠溶液(10mL)，然后用二氯甲烷萃取(10mL×3)。有机相合并后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝1/3)纯化，得到目标产物N,N-二苯甲基-4-(噁丁环-3-基)苯胺107a(300mg，黄色固体)，产率：79％。Compound 3-(4-(dibenzylamino)phenyl)oxetan-3-ol 69c (400 mg, 1.156 mmol) was dissolved in dichloromethane (10 mL), cooled to 0 °C, and triethyl was added sequentially Monosilane (148 mg, 1.27 mmol) and trifluoroacetic acid (396 mg, 3.47 mmol). After gradually warming to room temperature, stirring was continued for 16 hours, and saturated sodium bicarbonate solution (10 mL) was added, followed by extraction with dichloromethane (10 mL×3). After the organic phases were combined, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/3) to obtain the target product N,N-diphenylmethyl-4-(oxetane- 3-yl)aniline 107a (300 mg, yellow solid), yield: 79%.
MS m/z(ESI):330[M+1]MS m/z(ESI): 330[M+1]
第二步second step
4-(噁丁环-3-基)苯胺4-(oxetan-3-yl)aniline
将化合物N,N-二苯甲基-4-(噁丁环-3-基)苯胺107a(300mg，0.91mmol)，10％钯炭(200mg)和乙醇(10mL)混合，然后在氢气气氛下室温搅拌5小时。用甲醇(50mL)稀释后过滤，滤液在减压条件下除去溶剂，得到目标产物4-(噁丁环-3-基)苯胺107b(110mg，黄色固体)，产率：81％。Compound N,N-diphenylmethyl-4-(oxetan-3-yl)aniline 107a (300 mg, 0.91 mmol), 10% palladium on carbon (200 mg) and ethanol (10 mL) were mixed, then under hydrogen atmosphere Stir at room temperature for 5 hours. It was diluted with methanol (50 mL) and filtered, and the filtrate was removed from the solvent under reduced pressure to obtain the target product 4-(oxbutan-3-yl)aniline 107b (110 mg, yellow solid), yield: 81%.
MS m/z(ESI):150[M+1]MS m/z(ESI): 150[M+1]
第三步third step
6-(2-氯-6-氟苯基)-4-((4-(噁丁环-3-基)苯基)氨基)哒嗪-3-羧酸甲酯Methyl 6-(2-chloro-6-fluorophenyl)-4-((4-(oxetan-3-yl)phenyl)amino)pyridazine-3-carboxylate
将化合物4-(噁丁环-3-基)苯胺107b(70mg，0.469mmol)、4-氯-6-(2-氯-6-氟苯基)哒嗪-3-羧酸甲酯104f(104mg，0.469mmol)、对甲苯磺酸(8mg，0.0469mmol)和乙醇(10mL)混合，加热到70℃并搅拌4小时。冷却到室温后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化，得到目标产物6-(2-氯-6-氟苯基)-4-((4-(噁丁环-3-基)苯基)氨基)哒嗪-3-羧酸甲酯107c(100mg，白色固体)，产率：51％。Compound 4-(oxetan-3-yl)aniline 107b (70 mg, 0.469 mmol), methyl 4-chloro-6-(2-chloro-6-fluorophenyl)pyridazine-3-carboxylate 104f ( 104 mg, 0.469 mmol), p-toluenesulfonic acid (8 mg, 0.0469 mmol) and ethanol (10 mL) were mixed, heated to 70°C and stirred for 4 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain the target product 6-(2-chloro-6-fluorophenyl)-4- Methyl ((4-(oxetan-3-yl)phenyl)amino)pyridazine-3-carboxylate 107c (100 mg, white solid), yield: 51%.
MS m/z(ESI):414[M+1]MS m/z(ESI): 414[M+1]
第四步the fourth step
6-(2-氟-6-氯苯基)-4-((4-(噁丁环-3-基)苯基)氨基)哒嗪-3-甲酰胺6-(2-Fluoro-6-chlorophenyl)-4-((4-(oxetan-3-yl)phenyl)amino)pyridazine-3-carboxamide
将化合物6-(2-氯-6-氟苯基)-4-((4-(噁丁环-3-基)苯基)氨基)哒嗪-3-羧酸甲酯107c(100mg，0.242mmol)溶于四氢呋喃(2mL)，加入氨水(2mL)。室温下搅拌1小时后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2-氟-6-氯苯基)-4-((4-(噁丁环-3-基)苯基)氨基)哒嗪-3-甲酰胺107(43.8mg，白色固体)，产率：44％。Compound 6-(2-chloro-6-fluorophenyl)-4-((4-(oxetan-3-yl)phenyl)amino)pyridazine-3-carboxylate methyl ester 107c (100 mg, 0.242 mmol) was dissolved in tetrahydrofuran (2 mL), and ammonia (2 mL) was added. After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to obtain the target product, 6-(2-fluoro-6-chlorophenyl)-4-((4-(oxobutan). Cyclo-3-yl)phenyl)amino)pyridazine-3-carboxamide 107 (43.8 mg, white solid), yield: 44%.
MS m/z(ESI):399[M+1]MS m/z(ESI): 399[M+1]
1H NMR(400MHz,DMSO-d 6)δ10.86(s,1H),8.79(s,1H),8.05(s,1H),7.60–7.53(m,1H),7.51–7.43(m,3H),7.42–7.30(m,3H),7.24(s,1H),4.92(dd,J＝8.3,5.9Hz,2H),4.60(t,J＝6.3Hz,2H),4.25(t,J＝7.5Hz,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ10.86(s,1H), 8.79(s,1H), 8.05(s,1H), 7.60-7.53(m,1H), 7.51-7.43(m,3H) ), 7.42–7.30(m, 3H), 7.24(s, 1H), 4.92(dd, J=8.3, 5.9Hz, 2H), 4.60(t, J=6.3Hz, 2H), 4.25(t, J= 7.5Hz, 1H).
实施例108Example 108
6-(2-氯-6-氟苯基)-4-((4-(4-环丙基哌嗪-1-羰基)苯基)氨基)哒嗪-3-甲酰胺6-(2-Chloro-6-fluorophenyl)-4-((4-(4-cyclopropylpiperazine-1-carbonyl)phenyl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000118
Figure PCTCN2020108468-appb-000118
第一步first step
4-((4-(叔-丁氧基羰基)苯基)氨基)-6-(2-氯-6-氟苯基)哒嗪-3-羧酸甲酯Methyl 4-((4-(tert-butoxycarbonyl)phenyl)amino)-6-(2-chloro-6-fluorophenyl)pyridazine-3-carboxylate
将化合物4-氯-6-(2-氯-6-氟苯基)哒嗪-3-羧酸甲酯104f(800mg，2.66mmol)、对氨基苯甲酸叔丁酯(667mg，3.46mmol)、对甲苯磺酸(54mg，0.27mmol)和异丙醇(50mL)混合，加热至80℃并搅拌5小时。冷却到室温后，加入三乙胺(2mL)，然后在减压条件下除去溶剂。残余物用硅胶柱层析(石油醚/乙酸乙酯＝50/1至1/1)纯化，得到目标产物4-((4-(叔-丁氧基羰基)苯基)氨基)-6-(2-氯-6-氟苯基)哒嗪-3-羧酸甲酯108a(1g，黄色油状物)，产率：82％。Compound 4-chloro-6-(2-chloro-6-fluorophenyl)pyridazine-3-carboxylate methyl ester 104f (800 mg, 2.66 mmol), tert-butyl p-aminobenzoate (667 mg, 3.46 mmol), P-toluenesulfonic acid (54 mg, 0.27 mmol) and isopropanol (50 mL) were mixed, heated to 80°C and stirred for 5 hours. After cooling to room temperature, triethylamine (2 mL) was added and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/1 to 1/1) to obtain the target product 4-((4-(tert-butoxycarbonyl)phenyl)amino)-6- Methyl (2-chloro-6-fluorophenyl)pyridazine-3-carboxylate 108a (1 g, yellow oil), yield: 82%.
MS m/z(ESI):458[M+1]MS m/z(ESI): 458[M+1]
第二步second step
4-((3-氨基甲酰-6-(2-氯-6-氟苯基)哒嗪-4-基)氨基)苯甲酸叔丁酯tert-Butyl 4-((3-carbamoyl-6-(2-chloro-6-fluorophenyl)pyridazin-4-yl)amino)benzoate
将化合物4-((4-(叔-丁氧基羰基)苯基)氨基)-6-(2-氯-6-氟苯基)哒嗪-3-羧酸甲酯108a(1g，2.18mmol)溶于四氢呋喃(30mL)，然后加入氨水(15mL)。室温下搅拌1小时后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝50/1至1/1)纯化，得到目标产物4-((3-氨基甲酰-6-(2-氯-6-氟苯基)哒嗪-4-基)氨基)苯甲酸叔丁酯108b(930mg，黄色油状物)，产率：96％。Compound 4-((4-(tert-butoxycarbonyl)phenyl)amino)-6-(2-chloro-6-fluorophenyl)pyridazine-3-carboxylate methyl ester 108a (1 g, 2.18 mmol ) was dissolved in tetrahydrofuran (30 mL), then ammonia (15 mL) was added. After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/1 to 1/1) to obtain the target product 4-((3-carbamoyl- tert-Butyl 6-(2-chloro-6-fluorophenyl)pyridazin-4-yl)amino)benzoate 108b (930 mg, yellow oil), yield: 96%.
MS m/z(ESI):443[M+1]MS m/z(ESI): 443[M+1]
第三步third step
4-((3-氨基甲酰-6-(2-氯-6-氟苯基)哒嗪-4-基)氨基)苯甲酸4-((3-carbamoyl-6-(2-chloro-6-fluorophenyl)pyridazin-4-yl)amino)benzoic acid
将化合物4-((3-氨基甲酰-6-(2-氯-6-氟苯基)哒嗪-4-基)氨基)苯甲酸叔丁酯108b(930mg，2.1mmol)溶于二氯甲烷(10mL)，然后加入三氟乙酸(15mL)。室温下搅拌3小时后，减压除去溶剂，残余物用反相制备液相色谱纯化，得到目标产物4-((3-氨基甲酰-6-(2-氯-6-氟苯基)哒嗪-4-基)氨基)苯甲酸108c(620mg，黄色固体)，产率：76％。Compound 4-((3-carbamoyl-6-(2-chloro-6-fluorophenyl)pyridazin-4-yl)amino)benzoic acid tert-butyl ester 108b (930 mg, 2.1 mmol) was dissolved in dichloro Methane (10 mL) followed by trifluoroacetic acid (15 mL). After stirring at room temperature for 3 hours, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative liquid chromatography to give the desired product 4-((3-carbamoyl-6-(2-chloro-6-fluorophenyl)pyridine) Azin-4-yl)amino)benzoic acid 108c (620 mg, yellow solid), yield: 76%.
MS m/z(ESI):387[M+1]MS m/z(ESI): 387[M+1]
第四步the fourth step
6-(2-氯-6-氟苯基)-4-((4-(4-环丙基哌嗪-1-羰基)苯基)氨基)哒嗪-3-甲酰胺6-(2-Chloro-6-fluorophenyl)-4-((4-(4-cyclopropylpiperazine-1-carbonyl)phenyl)amino)pyridazine-3-carboxamide
将化合物4-((3-氨基甲酰-6-(2-氯-6-氟苯基)哒嗪-4-基)氨基)苯甲酸108c(520mg，1.35mmol)、1-环丙基哌嗪盐酸盐(328mg，2.02mmol)和二异丙基乙基胺(782mg，6.06mmol)溶于N,N-二甲基甲酰胺(10mL)，然后加入O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓六氟磷酸盐(760mg，2mmol)。室温下搅拌30分钟后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2-氯-6-氟苯基)-4-((4-(4-环丙基哌嗪-1-羰基)苯基)氨基)哒嗪-3-甲酰胺盐酸盐108(537mg，淡黄色固体)，产率：75％。Compound 4-((3-carbamoyl-6-(2-chloro-6-fluorophenyl)pyridazin-4-yl)amino)benzoic acid 108c (520 mg, 1.35 mmol), 1-cyclopropylpiperidine Azine hydrochloride (328 mg, 2.02 mmol) and diisopropylethylamine (782 mg, 6.06 mmol) were dissolved in N,N-dimethylformamide (10 mL), followed by O-(7-azabenzone) Triazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (760 mg, 2 mmol). After stirring at room temperature for 30 minutes, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to obtain the target product 6-(2-chloro-6-fluorophenyl)-4-((4-(4- Cyclopropylpiperazine-1-carbonyl)phenyl)amino)pyridazine-3-carboxamide hydrochloride 108 (537 mg, pale yellow solid), yield: 75%.
MS m/z(ESI):495[M+1]MS m/z(ESI): 495[M+1]
1H NMR(400MHz,DMSO-d 6)δ11.36(s,1H),11.20(s,1H),8.85(s,1H),8.15(d,J＝4.0Hz,1H),7.64–7.48(m,5H),7.47–7.37(m,3H),4.71–3.10(m,8H),2.81(brs,1H),1.16(s,2H),0.80(d,J＝7.1Hz,2H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 11.36(s, 1H), 11.20(s, 1H), 8.85(s, 1H), 8.15(d, J=4.0Hz, 1H), 7.64-7.48( m, 5H), 7.47–7.37 (m, 3H), 4.71–3.10 (m, 8H), 2.81 (brs, 1H), 1.16 (s, 2H), 0.80 (d, J=7.1 Hz, 2H).
以下实施例(实施例116、实施例117、实施例118、实施例119、实施例120、实施例121)均参照实施例108的操作方法合成，但在第四步中用不同的胺代替1-环丙基哌嗪盐酸盐。表征数据如下表所示：The following examples (Example 116, Example 117, Example 118, Example 119, Example 120, Example 121) are all synthesized according to the operation method of Example 108, but in the fourth step, different amines are used instead of 1 -Cyclopropylpiperazine hydrochloride. Characterization data are shown in the following table:
Figure PCTCN2020108468-appb-000119
Figure PCTCN2020108468-appb-000119
Figure PCTCN2020108468-appb-000120
Figure PCTCN2020108468-appb-000120
实施例110Example 110
6-(2-氯-6-氟苯基)-4-((4-((4-环丙基哌嗪-1-基)磺酰)苯基)氨基)哒嗪-3-甲酰胺
Figure PCTCN2020108468-appb-000121
6-(2-Chloro-6-fluorophenyl)-4-((4-((4-cyclopropylpiperazin-1-yl)sulfonyl)phenyl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000121
第一步first step
1-环丙基-4-((4-硝基苯基)磺酰)哌嗪1-Cyclopropyl-4-((4-nitrophenyl)sulfonyl)piperazine
将化合物4-硝基苯磺酰氯110a(1g，4.42mmol)溶于二氯甲烷，然后依次加入1-环丙基哌嗪(610mg，4.86mmol)和三乙胺(3mL)。室温下搅拌1小时后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝100/0至1/1)纯化，得到目标产物1-环丙基-4-((4-硝基苯基)磺酰)哌嗪110b(1.5g，粗品)。该产品未经进一步纯化，直接用于下一步反应。Compound 4-nitrobenzenesulfonyl chloride 110a (1 g, 4.42 mmol) was dissolved in dichloromethane, then 1-cyclopropylpiperazine (610 mg, 4.86 mmol) and triethylamine (3 mL) were added sequentially. After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100/0 to 1/1) to obtain the target product 1-cyclopropyl-4-(( 4-Nitrophenyl)sulfonyl)piperazine 110b (1.5 g, crude). This product was used directly in the next reaction without further purification.
MS m/z(ESI):312[M+1]MS m/z(ESI): 312[M+1]
第二步second step
4-((4-环丙基哌嗪-1-基)磺酰)苯胺4-((4-Cyclopropylpiperazin-1-yl)sulfonyl)aniline
将化合物1-环丙基-4-((4-硝基苯基)磺酰)哌嗪110b(1.5g，粗品)溶于乙醇(15mL)，然后加入10％钯炭(500mg)。在氢气气氛下搅拌 12小时后过滤，滤液在减压条件下除去溶剂，得到目标产物4-((4-环丙基哌嗪-1-基)磺酰)苯胺110c(1g，黄色固体)，产率：两步80％。Compound 1-cyclopropyl-4-((4-nitrophenyl)sulfonyl)piperazine 110b (1.5 g, crude) was dissolved in ethanol (15 mL), and then 10% palladium on carbon (500 mg) was added. After stirring under a hydrogen atmosphere for 12 hours, the filtrate was filtered, and the solvent was removed from the filtrate under reduced pressure to obtain the target product 4-((4-cyclopropylpiperazin-1-yl)sulfonyl)aniline 110c (1 g, yellow solid), Yield: 80% for two steps.
MS m/z(ESI):282[M+1]MS m/z(ESI): 282[M+1]
第三步third step
6-(2-氯-6-氟苯基)-4-((4-((4-环丙基哌嗪-1-基)磺酰)苯基)氨基)哒嗪-3-羧酸甲酯6-(2-Chloro-6-fluorophenyl)-4-((4-((4-cyclopropylpiperazin-1-yl)sulfonyl)phenyl)amino)pyridazine-3-carboxylate methyl ester
将化合物4-氯-6-(2-氯-6-氟苯基)哒嗪-3-羧酸甲酯104f(120mg，0.39mmol)、对甲苯磺酸(85mg，0.49mmol)，4-((4-环丙基哌嗪-1-基)磺酰)苯胺110c(100mg，0.35m mol)和异丙醇(2mL)混合，加热至80℃并搅拌12小时。冷却到室温后，在减压条件下除去溶剂，得到目标产物6-(2-氯-6-氟苯基)-4-((4-((4-环丙基哌嗪-1-基)磺酰)苯基)氨基)哒嗪-3-羧酸甲酯110c(330mg，粗品)。该产品未经进一步纯化，直接用于下一步反应。Compound 4-chloro-6-(2-chloro-6-fluorophenyl)pyridazine-3-carboxylate methyl ester 104f (120 mg, 0.39 mmol), p-toluenesulfonic acid (85 mg, 0.49 mmol), 4-( (4-Cyclopropylpiperazin-1-yl)sulfonyl)aniline 110c (100 mg, 0.35 mmol) and isopropanol (2 mL) were mixed, heated to 80°C and stirred for 12 hours. After cooling to room temperature, the solvent was removed under reduced pressure to give the target product 6-(2-chloro-6-fluorophenyl)-4-((4-((4-cyclopropylpiperazin-1-yl) Sulfonyl)phenyl)amino)pyridazine-3-carboxylic acid methyl ester 110c (330 mg, crude). This product was used directly in the next reaction without further purification.
MS m/z(ESI):546[M+1]MS m/z(ESI): 546[M+1]
第四步the fourth step
6-(2-氯-6-氟苯基)-4-((4-((4-环丙基哌嗪-1-基)磺酰)苯基)氨基)哒嗪-3-甲酰胺6-(2-Chloro-6-fluorophenyl)-4-((4-((4-cyclopropylpiperazin-1-yl)sulfonyl)phenyl)amino)pyridazine-3-carboxamide
将化合物6-(2-氯-6-氟苯基)-4-((4-((4-环丙基哌嗪-1-基)磺酰)苯基)氨基)哒嗪-3-羧酸甲酯110c(330mg，粗品)溶于N,N-二甲基甲酰胺(6mL)，然后加入氨水(2mL)。室温下搅拌1小时后，减压除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物6-(2-氯-6-氟苯基)-4-((4-((4-环丙基哌嗪-1-基)磺酰)苯基)氨基)哒嗪-3-甲酰胺盐酸盐110(44.6mg，白色固体)，产率：两步11％。The compound 6-(2-chloro-6-fluorophenyl)-4-((4-((4-cyclopropylpiperazin-1-yl)sulfonyl)phenyl)amino)pyridazine-3-carboxylate Methyl acid 110c (330 mg, crude) was dissolved in N,N-dimethylformamide (6 mL), followed by addition of ammonia (2 mL). After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to obtain the target product 6-(2-chloro-6-fluorophenyl)-4-((4-((4 -Cyclopropylpiperazin-1-yl)sulfonyl)phenyl)amino)pyridazine-3-carboxamide hydrochloride 110 (44.6 mg, white solid), yield: 11% for two steps.
MS m/z(ESI):531[M+1]MS m/z(ESI): 531[M+1]
1H NMR(400MHz,DMSO-d 6)δ11.44(s,1H),11.02(brs,1H),8.90(s,1H),8.20(s,1H),7.77(d,J＝8.7Hz,2H),7.71(s,1H),7.65–7.56(m,3H),7.52(d,J＝8.1Hz,1H),7.46–7.39(m,1H),3.76–3.64(m,2H),3.58–3.22(m,4H),2.92–2.71(m,3H),1.11–0.95(m,2H),0.82–0.69(m,2H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 11.44(s, 1H), 11.02(brs, 1H), 8.90(s, 1H), 8.20(s, 1H), 7.77(d, J=8.7Hz, 2H), 7.71 (s, 1H), 7.65–7.56 (m, 3H), 7.52 (d, J=8.1Hz, 1H), 7.46–7.39 (m, 1H), 3.76–3.64 (m, 2H), 3.58 – 3.22 (m, 4H), 2.92 – 2.71 (m, 3H), 1.11 – 0.95 (m, 2H), 0.82 – 0.69 (m, 2H).
以下实施例(实施例111、实施例112)均参照实施例110的操作方法合成，但在第一步中用不同的胺代替1-环丙基哌嗪。表征数据如下表所示：The following examples (Example 111, Example 112) are all synthesized according to the operation method of Example 110, but in the first step, different amines are used instead of 1-cyclopropylpiperazine. Characterization data are shown in the following table:
Figure PCTCN2020108468-appb-000122
Figure PCTCN2020108468-appb-000122
Figure PCTCN2020108468-appb-000123
Figure PCTCN2020108468-appb-000123
实施例125Example 125
6-(2-氯-6-氟苯基)-4-((4-(3-异丙氧基噁丁环-3-基)苯基)氨基)哒嗪-3-甲酰胺6-(2-Chloro-6-fluorophenyl)-4-((4-(3-isopropoxyoxetan-3-yl)phenyl)amino)pyridazine-3-carboxamide
Figure PCTCN2020108468-appb-000124
Figure PCTCN2020108468-appb-000124
6-(2-氯-6-氟苯基)-4-((4-(3-异丙氧基噁丁环-3-基)苯基)氨基)哒嗪-3-甲酰胺125是实施例124合成过程中发现的副产物，其表征数据如下：6-(2-Chloro-6-fluorophenyl)-4-((4-(3-isopropoxyoxetan-3-yl)phenyl)amino)pyridazine-3-carboxamide 125 was implemented Example 124 by-products found in the synthesis process, its characterization data are as follows:
MS m/z(ESI):457[M+1]MS m/z(ESI): 457[M+1]
1H NMR(400MHz,DMSO-d 6)δ10.99(s,1H),8.82(s,1H),8.08(s,1H),7.53(ddd,J＝20.0,9.9,7.1Hz,4H),7.42–7.35(m,4H),4.81–4.74(m,4H),3.51–3.43(m,1H),0.93(d,J＝6.1Hz,6H)。 1 H NMR (400MHz, DMSO-d 6 )δ10.99(s,1H),8.82(s,1H),8.08(s,1H),7.53(ddd,J=20.0,9.9,7.1Hz,4H), 7.42–7.35 (m, 4H), 4.81–4.74 (m, 4H), 3.51–3.43 (m, 1H), 0.93 (d, J=6.1 Hz, 6H).
生物学实验biological experiment
JAK1的活性抑制测试Activity inhibition test of JAK1
使用体外激酶检测实验评估本发明的化合物对JAK1活性的影响Evaluation of the effect of compounds of the invention on JAK1 activity using an in vitro kinase assay
实验方法概述如下：The experimental method is outlined as follows:
使用均相时间分辨荧光(HTRF)激酶检测试剂盒(Cisbio，62TK0PEC)，通过检测激酶反应中底物的磷酸化水平来测定JAK1的体外活性。反应缓冲液包含以下组分：试剂盒自带酶反应缓冲液(1×)、5mM mgCl 2、1mM DTT、60nM SEB(试剂盒自带)、0.625mM EGTA和0.01％Brij35；人源重组JAK1蛋白(Carna Biosciences，08-144)用反应缓冲液稀释成0.25ng/μL的激酶溶液；底物反应溶液包括用反应缓冲液稀释成1.5μM的生物素标记的酪氨酸激酶底物和25μM ATP；检测缓冲液包括用反应缓冲液稀释成0.1ng/μL的Eu 3+标记的笼状抗体(Cisbio，61T66KLB)和100nM链霉亲和素标记的XL665(Cisbio，610SAXLB)。 The in vitro activity of JAK1 was determined by measuring the phosphorylation level of the substrate in the kinase reaction using a Homogeneous Time-Resolved Fluorescence (HTRF) Kinase Detection Kit (Cisbio, 62TKOPEC). The reaction buffer contains the following components: enzyme reaction buffer (1×), 5 mM mgCl 2 , 1 mM DTT, 60 nM SEB (included in the kit), 0.625 mM EGTA and 0.01% Brij35; human recombinant JAK1 protein (Carna Biosciences, 08-144) diluted with reaction buffer to 0.25 ng/μL kinase solution; substrate reaction solution includes biotinylated tyrosine kinase substrate diluted to 1.5 μM with reaction buffer and 25 μM ATP; Detection buffer included Eu3 + -labeled caged antibody (Cisbio, 61T66KLB) and 100 nM Streptavidin-labeled XL665 (Cisbio, 610SAXLB) diluted to 0.1 ng/μL in reaction buffer.
将化合物在100％DMSO中溶解稀释至10μM，然后用DMSO进行4倍的系列稀释至最低浓度为0.61nM，每个浓度点再使用反应缓冲液稀释40倍。Compounds were dissolved and diluted to 10 [mu]M in 100% DMSO, followed by 4-fold serial dilutions in DMSO to a minimum concentration of 0.61 nM, each concentration point being further diluted 40-fold with reaction buffer.
向384孔检测板(Corning，3674)中添加4μL化合物溶液和2μL JAK1激酶溶液，混合均匀后室温孵育15分钟。随后加入4μL底物反应溶液，将反应混合物在室温孵育60分钟。随后加入与反应等体积的10μL检测缓冲液，混合均匀并在室温条件下静置30分钟后，用Envision读板机(Perkin Elmer)在620nm和665nm波长下检测反应进程。信号值(吸光度 665nm/吸光度 620nm)与底物的磷酸化程度呈正相关性，从而检测出JAK1激酶的活性。该实验中，未加JAK1激酶蛋白组作为100％抑制组，加JAK1激酶蛋白但是未加化合物组作为0％抑制组。化合物对JAK1活性抑制百分比可以用以下公式计算： 4 μL of compound solution and 2 μL of JAK1 kinase solution were added to a 384-well assay plate (Corning, 3674), mixed well, and incubated at room temperature for 15 minutes. 4 μL of substrate reaction solution was then added and the reaction mixture was incubated at room temperature for 60 minutes. Then, an equal volume of 10 μL detection buffer was added to the reaction, mixed well and allowed to stand at room temperature for 30 minutes, and then the progress of the reaction was detected with an Envision plate reader (Perkin Elmer) at 620 nm and 665 nm wavelengths. The signal value (absorbance 665nm /absorbance 620nm ) was positively correlated with the phosphorylation degree of the substrate, thus detecting the activity of JAK1 kinase. In this experiment, the group without JAK1 kinase protein was regarded as a 100% inhibition group, and the group with JAK1 kinase protein but no compound was added as a 0% inhibition group. The percent inhibition of JAK1 activity by a compound can be calculated using the following formula:
抑制百分比＝100-100*(待测化合物特定浓度下信号值-100％抑制组信号值)/(0％抑制组信号值-100％抑制组信号值)Inhibition percentage=100-100*(signal value at a specific concentration of the test compound-100% inhibition group signal value)/(0% inhibition group signal value-100% inhibition group signal value)
化合物IC 50值由8个浓度点用XLfit(ID Business Solutions Ltd.，UK)软件通过以下公式计算： Compound IC50 values were calculated from 8 concentration points using XLfit (ID Business Solutions Ltd., UK) software by the following formula:
Y＝Bottom+(Top-Bottom)/(1+10^((logIC 50-X)×slope factor)) Y=Bottom+(Top-Bottom)/(1+10^((logIC 50 -X)×slope factor))
其中Y为抑制百分比，X为待测化合物浓度的对数值，Bottom为最大抑制百分比，Top为最小抑制百分比，slope factor为曲线斜率系数。where Y is the percentage of inhibition, X is the logarithm of the concentration of the compound to be tested, Bottom is the maximum percentage of inhibition, Top is the minimum percentage of inhibition, and slope factor is the slope coefficient of the curve.
JAK2的活性抑制测试Activity inhibition test of JAK2
使用体外激酶检测实验评估本发明的化合物对JAK2活性的影响Evaluation of the Effects of Compounds of the Invention on JAK2 Activity Using In Vitro Kinase Assays
实验方法概述如下：The experimental method is outlined as follows:
使用HTRF激酶检测试剂盒(Cisbio，62TK0PEC)，通过检测激酶反应中底物的磷酸化水平来测定JAK2的体外活性。反应缓冲液包含以下组分：试剂盒自带酶反应缓冲液(1×)、5mM mgCl 2、1mM DTT和0.01％Brij35；人源重组JAK2蛋白(Carna Biosciences，08-045)用反应缓冲液稀释成0.03ng/μL的激酶溶液；底物反应溶液包括用反应缓冲液稀释成0.1μM的生物素标记的酪氨酸激酶底物和1μM ATP；检测缓冲液包括用反应缓冲液稀释成0.1ng/μL的Eu 3+标记的笼状抗体(Cisbio，61T66KLB)和6.25nM链霉亲和素标记的XL665(Cisbio，610SAXLB)。 The in vitro activity of JAK2 was determined by measuring the phosphorylation level of the substrate in the kinase reaction using the HTRF Kinase Assay Kit (Cisbio, 62TKOPEC). The reaction buffer contains the following components: the kit comes with enzyme reaction buffer (1×), 5 mM mgCl 2 , 1 mM DTT and 0.01% Brij35; human recombinant JAK2 protein (Carna Biosciences, 08-045) is diluted with the reaction buffer to 0.03ng/μL kinase solution; Substrate reaction solution includes biotinylated tyrosine kinase substrate and 1 μM ATP diluted to 0.1 μM with Reaction Buffer; Detection Buffer includes 0.1 ng/μM of ATP diluted with Reaction Buffer μL of Eu 3+ -labeled caged antibody (Cisbio, 61T66KLB) and 6.25 nM Streptavidin-labeled XL665 (Cisbio, 610SAXLB).
将化合物在100％DMSO中溶解稀释至10μM，然后用DMSO进行4倍的系列稀释至最低浓度为0.61nM，每个浓度点再使用反应缓冲液稀释40倍。Compounds were dissolved and diluted to 10 [mu]M in 100% DMSO, followed by 4-fold serial dilutions in DMSO to a minimum concentration of 0.61 nM, each concentration point being further diluted 40-fold with reaction buffer.
向384孔检测板(Corning，3674)中添加4μL化合物溶液和2μL JAK2激酶溶液，混合均匀后室温孵育15分钟。随后加入4μL底物反应溶液，将反应混合物在室温孵育40分钟。随后加入与反应等体积的10μL检测缓冲液，混合均匀并在室温条件下静置30分钟后，用 Envision读板机(Perkin Elmer)在620nm和665nm波长下检测反应进程。信号值(吸光度 665nm/吸光度 620nm)与底物的磷酸化程度呈正相关性，从而检测出JAK2激酶的活性。该实验中，未加JAK2激酶蛋白组作为100％抑制组，加JAK2激酶蛋白但是未加化合物组作为％抑制组。化合物对JAK2活性抑制百分比可以用以下公式计算： 4 μL of compound solution and 2 μL of JAK2 kinase solution were added to a 384-well assay plate (Corning, 3674), mixed well, and incubated at room temperature for 15 minutes. 4 μL of substrate reaction solution was then added and the reaction mixture was incubated for 40 minutes at room temperature. Then, an equal volume of 10 μL detection buffer was added to the reaction, mixed well and allowed to stand at room temperature for 30 minutes, and then the progress of the reaction was detected with an Envision plate reader (Perkin Elmer) at 620 nm and 665 nm wavelengths. The signal value (absorbance 665nm /absorbance 620nm ) was positively correlated with the phosphorylation degree of the substrate, thereby detecting the activity of JAK2 kinase. In this experiment, the group without JAK2 kinase protein was regarded as the 100% inhibition group, and the group with JAK2 kinase protein but no compound was added as the % inhibition group. The percent inhibition of JAK2 activity by a compound can be calculated using the following formula:
抑制百分比＝100-100*(待测化合物特定浓度下信号值-100％抑制组信号值)/(0％抑制组信号值-100％抑制组信号值)Inhibition percentage=100-100*(signal value at a specific concentration of the test compound-100% inhibition group signal value)/(0% inhibition group signal value-100% inhibition group signal value)
化合物IC 50值由8个浓度点用XLfit(ID Business Solutions Ltd.，UK)软件通过以下公式计算： Compound IC50 values were calculated from 8 concentration points using XLfit (ID Business Solutions Ltd., UK) software by the following formula:
Y＝Bottom+(Top-Bottom)/(1+10^((logIC 50-X)×slope factor)) Y=Bottom+(Top-Bottom)/(1+10^((logIC 50 -X)×slope factor))
其中Y为抑制百分比，X为待测化合物浓度的对数值，Bottom为最大抑制百分比，Top为最小抑制百分比，slope factor为曲线斜率系数。where Y is the percentage of inhibition, X is the logarithm of the concentration of the compound to be tested, Bottom is the maximum percentage of inhibition, Top is the minimum percentage of inhibition, and slope factor is the slope coefficient of the curve.
JAK3的活性抑制测试Activity inhibition test of JAK3
使用体外激酶检测实验评估本发明的化合物对JAK3活性的影响Evaluation of the Effects of Compounds of the Invention on JAK3 Activity Using In Vitro Kinase Assays
实验方法概述如下：The experimental method is outlined as follows:
使用均相时间分辨荧光(HTRF)激酶检测试剂盒(Cisbio，62TK0PEC)，通过检测激酶反应中底物的磷酸化水平来测定JAK3的体外活性。反应缓冲液包含以下组分：试剂盒自带酶反应缓冲液(1×)、5mM mgCl 2、1mM DTT和0.01％Brij35；人源重组JAK3蛋白(Carna Biosciences，08-046)用反应缓冲液稀释成0.05ng/μL的激酶溶液；底物反应溶液包括用反应缓冲液稀释成0.2μM的生物素标记的酪氨酸激酶底物和1μM ATP；检测缓冲液包括用反应缓冲液稀释成0.1ng/μL的Eu 3+标记的笼状抗体(Cisbio，61T66KLB)和12.5nM链霉亲和素标记的XL665(Cisbio，610SAXLB)。 The in vitro activity of JAK3 was determined by measuring the phosphorylation level of the substrate in the kinase reaction using a Homogeneous Time-Resolved Fluorescence (HTRF) Kinase Detection Kit (Cisbio, 62TKOPEC). The reaction buffer contains the following components: the kit comes with enzyme reaction buffer (1×), 5 mM mgCl 2 , 1 mM DTT and 0.01% Brij35; human recombinant JAK3 protein (Carna Biosciences, 08-046) is diluted with the reaction buffer into 0.05ng/μL kinase solution; substrate reaction solution includes biotinylated tyrosine kinase substrate and 1 μM ATP diluted to 0.2 μM with reaction buffer; detection buffer includes diluted to 0.1 ng/μM with reaction buffer μL of Eu 3+ -labeled caged antibody (Cisbio, 61T66KLB) and 12.5 nM Streptavidin-labeled XL665 (Cisbio, 610SAXLB).
将化合物在100％DMSO中溶解稀释至10μM，然后用DMSO进行4倍的系列稀释至最低浓度为0.61nM，每个浓度点再使用反应缓冲液稀释40倍。Compounds were dissolved and diluted to 10 [mu]M in 100% DMSO, followed by 4-fold serial dilutions in DMSO to a minimum concentration of 0.61 nM, each concentration point being further diluted 40-fold with reaction buffer.
向384孔检测板(Corning，3674)中添加4μl化合物溶液和2μL JAK3激酶溶液，混合均匀后室温孵育15分钟。随后加入4μL底物反应溶液，将反应混合物在室温孵育30分钟。随后加入与反应等体积的10μL检测缓冲液，混合均匀并在室温条件下静置30分钟后，用Envision读板机(Perkin Elmer)在620nm和665nm波长下检测反应进程。信号值(吸光度 665nm/吸光度 620nm)与底物的磷酸化程度呈正相关性，从而检测出JAK3激酶的活性。该实验中，未加JAK3激酶蛋白组作为100％抑制组，加JAK3激酶蛋白但是未加化合物组作为0％抑制组。化合物对JAK3活性抑制百分比可以用以下公式计算： 4 μl of compound solution and 2 μl of JAK3 kinase solution were added to a 384-well assay plate (Corning, 3674), mixed well and incubated at room temperature for 15 minutes. 4 μL of substrate reaction solution was then added and the reaction mixture was incubated at room temperature for 30 minutes. Then, an equal volume of 10 μL detection buffer was added to the reaction, mixed well and allowed to stand at room temperature for 30 minutes, and then the progress of the reaction was detected with an Envision plate reader (Perkin Elmer) at 620 nm and 665 nm wavelengths. The signal value (absorbance 665nm /absorbance 620nm ) was positively correlated with the phosphorylation degree of the substrate, thereby detecting the activity of JAK3 kinase. In this experiment, the group without JAK3 kinase protein was regarded as a 100% inhibition group, and the group with JAK3 kinase protein but no compound was added as a 0% inhibition group. The percent inhibition of JAK3 activity by a compound can be calculated using the following formula:
抑制百分比＝100-100*(待测化合物特定浓度下信号值-100％抑制组信号值)/(0％抑制组信号值-100％抑制组信号值)Inhibition percentage=100-100*(signal value at a specific concentration of the test compound-100% inhibition group signal value)/(0% inhibition group signal value-100% inhibition group signal value)
化合物IC 50值由8个浓度点用XLfit(ID Business Solutions Ltd.，UK)软件通过以下公式计算： Compound IC50 values were calculated from 8 concentration points using XLfit (ID Business Solutions Ltd., UK) software by the following formula:
Y＝Bottom+(Top-Bottom)/(1+10^((logIC 50-X)×slope factor)) Y=Bottom+(Top-Bottom)/(1+10^((logIC 50 -X)×slope factor))
其中Y为抑制百分比，X为待测化合物浓度的对数值，Bottom为最大抑制百分比，Top为最小抑制百分比，slope factor为曲线斜率系数。where Y is the percentage of inhibition, X is the logarithm of the concentration of the compound to be tested, Bottom is the maximum percentage of inhibition, Top is the minimum percentage of inhibition, and slope factor is the slope coefficient of the curve.
TYK2的活性抑制测试Activity inhibition test of TYK2
使用体外激酶检测实验评估本发明的化合物对TYK2活性的影响Evaluation of the Effects of Compounds of the Invention on TYK2 Activity Using In Vitro Kinase Assays
实验方法概述如下：The experimental method is outlined as follows:
使用HTRF激酶检测试剂盒(Cisbio，62TK0PEC)，通过检测激酶反应中底物的磷酸化水平来测定TYK2的体外活性。反应缓冲液包含以下组分：试剂盒自带酶反应缓冲液(1×)、5mM mgCl 2、1mM DTT和0.01％Brij35；人源重组TYK2蛋白(Carna Biosciences，08-147)用反应缓冲液稀释成0.03ng/μL的激酶溶液；底物反应溶液包括用反应缓冲液稀释成0.1μM的生物素标记的酪氨酸激酶底物和1μM ATP；检测缓冲液包括用反应缓冲液稀释成0.1ng/μL的Eu 3+标记的笼状抗体(Cisbio，61T66KLB)和6.25nM链霉亲和素标记的XL665(Cisbio，610SAXLB)。 The in vitro activity of TYK2 was determined by measuring the phosphorylation level of the substrate in the kinase reaction using the HTRF Kinase Assay Kit (Cisbio, 62TKOPEC). The reaction buffer contains the following components: the kit comes with enzyme reaction buffer (1×), 5 mM mgCl 2 , 1 mM DTT and 0.01% Brij35; human recombinant TYK2 protein (Carna Biosciences, 08-147) is diluted with the reaction buffer to 0.03ng/μL kinase solution; Substrate reaction solution includes biotinylated tyrosine kinase substrate and 1 μM ATP diluted to 0.1 μM with Reaction Buffer; Detection Buffer includes 0.1 ng/μM of ATP diluted with Reaction Buffer μL of Eu 3+ -labeled caged antibody (Cisbio, 61T66KLB) and 6.25 nM Streptavidin-labeled XL665 (Cisbio, 610SAXLB).
将化合物在100％DMSO中溶解稀释至1μM，然后用DMSO进行4倍的系列稀释至最低浓度为0.061nM，每个浓度点再使用反应缓冲液稀释40倍。Compounds were dissolved and diluted to 1 μM in 100% DMSO, followed by 4-fold serial dilutions in DMSO to a minimum concentration of 0.061 nM, each concentration point being diluted 40-fold with reaction buffer.
向384孔检测板(Corning，3674)中添加4μL化合物溶液和2μL TYK2激酶溶液，混合均匀后室温孵育15分钟。随后加入4μL底物反应溶液，将反应混合物在室温孵育40分钟。随后加入与反应等体积的10μL检测缓冲液，混合均匀并在室温条件下静置30分钟后，用Envision读板机(Perkin Elmer)在620nm和665nm波长下检测反应进程。信号值(吸光度 665nm/吸光度 620nm)与底物的磷酸化程度呈正相关性，从而检测出TYK2激酶的活性。该实验中，未加TYK2激酶蛋白组作为100％抑制组，加TYK2激酶蛋白但是未加化合物组作为0％抑制组。化合物对TYK2活性抑制百分比可以用以下公式计算： 4 μL of compound solution and 2 μL of TYK2 kinase solution were added to a 384-well assay plate (Corning, 3674), mixed well, and incubated at room temperature for 15 minutes. 4 μL of substrate reaction solution was then added and the reaction mixture was incubated for 40 minutes at room temperature. Then, an equal volume of 10 μL detection buffer was added to the reaction, mixed well and allowed to stand at room temperature for 30 minutes, and then the progress of the reaction was detected with an Envision plate reader (Perkin Elmer) at 620 nm and 665 nm wavelengths. The signal value (absorbance 665nm /absorbance 620nm ) was positively correlated with the phosphorylation degree of the substrate, thereby detecting the activity of TYK2 kinase. In this experiment, the group without TYK2 kinase protein was regarded as a 100% inhibition group, and the group with TYK2 kinase protein added but no compound was regarded as a 0% inhibition group. The percent inhibition of TYK2 activity by a compound can be calculated using the following formula:
抑制百分比＝100-100*(待测化合物特定浓度下信号值-100％抑制组信号值)/(0％抑制组信号值-100％抑制组信号值)Inhibition percentage=100-100*(signal value at a specific concentration of the test compound-100% inhibition group signal value)/(0% inhibition group signal value-100% inhibition group signal value)
化合物IC 50值由8个浓度点用XLfit(ID Business Solutions Ltd.,UK)软件通过以下公式计算： Compound IC50 values were calculated from 8 concentration points using XLfit (ID Business Solutions Ltd., UK) software by the following formula:
Y＝Bottom+(Top-Bottom)/(1+10^((logIC 50-X)×slope factor)) Y=Bottom+(Top-Bottom)/(1+10^((logIC 50 -X)×slope factor))
其中Y为抑制百分比，X为待测化合物浓度的对数值，Bottom为最大抑制百分比，Top为最小抑制百分比，slope factor为曲线斜率系数。where Y is the percentage of inhibition, X is the logarithm of the concentration of the compound to be tested, Bottom is the maximum percentage of inhibition, Top is the minimum percentage of inhibition, and slope factor is the slope coefficient of the curve.
Figure PCTCN2020108468-appb-000125
Figure PCTCN2020108468-appb-000125
Figure PCTCN2020108468-appb-000126
Figure PCTCN2020108468-appb-000126
Figure PCTCN2020108468-appb-000127
Figure PCTCN2020108468-appb-000127
Figure PCTCN2020108468-appb-000128
Figure PCTCN2020108468-appb-000128
本发明的实施例化合物对TYK2的活性具有显著抑制效应，优选IC 50为10至100nM，更优选IC 50小于10nM，最优选IC 50小于1nM。 The example compounds of the present invention have a significant inhibitory effect on 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.
NK92细胞中IL-12诱导的IFN-γ分泌量抑制的测定Determination of IL-12-induced inhibition of IFN-γ secretion in NK92 cells
通过酶联免疫吸附(ELISA)方法评估本发明的化合物对IL-12诱导的NK92细胞中IFN-γ分泌量的影响。The effect of the compounds of the present invention on IL-12-induced IFN-γ secretion in NK92 cells was evaluated by enzyme-linked immunosorbent assay (ELISA).
实验原理概述如下：IL-12R主要由活化的T细胞、NK细胞(NK92是一株NK细胞株)、DC细胞和B细胞表达，与IL-12结合，激活NK细胞和活化的T淋巴细胞中的JAK2/TYK2信号转导通路，从而诱导INF-γ的产生。The experimental principle is summarized as follows: IL-12R is mainly expressed by activated T cells, NK cells (NK92 is a NK cell line), DC cells and B cells, combined with IL-12, activated NK cells and activated T lymphocytes. The JAK2/TYK2 signal transduction pathway induces the production of INF-γ.
实验方法概述如下：The experimental method is outlined as follows:
将化合物用DMSO(Sigma，D5879)溶解稀释至10mM，然后用DMSO进行4倍的系列稀释至最低浓度为1.22μM，每个浓度点再使用不含FBS的MEMα培养基(Thermofisher，12561-056)稀释50倍。Compounds were dissolved and diluted to 10 mM in DMSO (Sigma, D5879), followed by 4-fold serial dilutions in DMSO to a minimum concentration of 1.22 μM, using FBS-free MEMα medium (Thermofisher, 12561-056) at each concentration point. Dilute 50 times.
NK92细胞(南京科佰，CBP60980)在含有12.5％FBS(Ausbian，VS500T)、12.5％马血清(Thermofisher，16050-122)、0.02mM叶酸(Sigma，F8758)、0.2mM肌醇(Sigma，17850)、0.55mMβ-巯基乙醇(Thermofish，21985-023)、200U/mL IL-2(R&D Systems，202-1L)和100U/mL青链霉素混合液(Thermofisher，15140122)的MEMα完全培养基中培养，当细胞在培养容器中覆盖率达80-90％时，将细胞吹散后种植于96孔板(Thermofish，167425)，每孔100000细胞(80μL不含IL-2的MEMα完全培养基)，然后将96孔板置于37℃、5％CO 2的培养箱中培养过夜。 NK92 cells (Nanjing Kebai, CBP60980) were cultured in cells containing 12.5% FBS (Ausbian, VS500T), 12.5% horse serum (Thermofisher, 16050-122), 0.02 mM folic acid (Sigma, F8758), 0.2 mM inositol (Sigma, 17850) , 0.55mM β-mercaptoethanol (Thermofish, 21985-023), 200U/mL IL-2 (R&D Systems, 202-1L) and 100U/mL penicillin-streptomycin mixture (Thermofisher, 15140122) in MEMα complete medium , when the cells covered 80-90% in the culture vessel, the cells were blown and planted in a 96-well plate (Thermofish, 167425), with 100,000 cells per well (80 μL of IL-2-free MEMα complete medium), The 96-well plate was then placed in a 37°C, 5% CO2 incubator overnight.
过夜后每孔加入10μL稀释后的化合物，以及10μL 20ng/mL的IL-12(R&D Systems，219-1L)，轻轻混匀，然后将96孔板置于37℃、5％CO 2的培养箱中继续培养。24小时后取出于室温800rpm离心10分钟，将50μL上清液转移至已包被了抗IFN-γ的抗体的96孔板(Sigma，CLS3695)，按照Human IFN-gamma DuoSet ELISA检测试剂盒(R&D Systems，DY285B)的方法检测IFN-γ的分泌量。其中，无刺激对照组不加IL-12和测试的化合物，用MEMα培养基替代(100％抑制)；刺激对照组加IL-12和0.2％DMSO(0％抑制)。 After overnight, 10 μL of the diluted compound and 10 μL of 20 ng/mL IL-12 (R&D Systems, 219-1L) were added to each well, mixed gently, and then the 96-well plate was incubated at 37 °C, 5% CO 2 . continue to grow in the box. 24 hours later, centrifuge at 800 rpm for 10 minutes at room temperature, transfer 50 μL of the supernatant to a 96-well plate (Sigma, CLS3695) coated with anti-IFN-γ antibody, according to Human IFN-gamma DuoSet ELISA detection kit (R&D Systems, DY285B) method to detect the secretion of IFN-γ. Among them, the unstimulated control group did not add IL-12 and the test compound, and was replaced with MEMα medium (100% inhibition); the stimulated control group added IL-12 and 0.2% DMSO (0% inhibition).
化合物对NK92细胞中IL-12诱导的IFN-γ分泌量抑制的百分比可以用以下公式计算：The percentage inhibition of IL-12-induced IFN-γ secretion in NK92 cells by compounds can be calculated using the following formula:
抑制百分比＝100-100*(信号值 化合物-信号值 无刺激对照)/(信号值 刺激对照-信号值 无刺激对照) Percent Inhibition = 100-100*(Signal Value Compound -Signal Value No Stimulation Control )/(Signal Value Stimulated Control -Signal Value No Stimulation Control )
化合物IC 50值由8个浓度点用XLfit(ID Business Solutions Ltd.,UK)软件通过以下公式计算： Compound IC50 values were calculated from 8 concentration points using XLfit (ID Business Solutions Ltd., UK) software by the following formula:
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50-X)×slope factor)) Y=Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)×slope factor))
其中Y为抑制百分比，Bottom为S型曲线的底部平台值，Top S为型曲线的顶部平台值，X为待测化合物浓度的对数值，slope factor为曲线斜率系数。where Y is the percentage of inhibition, Bottom is the bottom plateau value of the S-shaped curve, Top S is the top plateau value of the S-shaped curve, X is the logarithm of the concentration of the compound to be tested, and slope factor is the slope coefficient of the curve.
化合物编号Compound number IC50(NK92_IL12/IFNγ)(μM)IC50(NK92_IL12/IFNγ)(μM)
2828 0.720.72
3333 0.210.21
3838 0.080.08
5353 1.011.01
6969 0.400.40
7070 0.150.15
7474 0.480.48
7575 0.300.30
7676 2.842.84
7777 1.641.64
7878 0.200.20
8080 1.661.66
8181 0.940.94
8282 0.850.85
8383 0.710.71
8686 0.630.63
8888 0.840.84
9191 0.300.30
9292 0.400.40
9494 1.211.21
9696 0.460.46
101101 1.041.04
102102 0.660.66
103103 0.850.85
104104 0.080.08
105105 0.300.30
106106 1.911.91
107107 3.003.00
108108 0.780.78
111111 1.281.28
112112 3.533.53
116116 0.690.69
117117 1.051.05
118118 0.690.69
119119 0.580.58
120120 0.600.60
121121 0.510.51
本发明的实施例化合物对NK92细胞中IL-12诱导的IFN-γ分泌量具有抑制效应。Example compounds of the present invention have inhibitory effects on IL-12-induced IFN-γ secretion in NK92 cells.

Claims (10)

  1. 一种通式(I)所示的化合物：A compound represented by general formula (I):
    Figure PCTCN2020108468-appb-100001
    Figure PCTCN2020108468-appb-100001
    或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式，其中：or in the form of pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers and mixtures thereof, wherein:
    Z为N或CR 1； Z is N or CR 1 ;
    环A为任选取代的C 6-10芳环或5-10元杂芳环； Ring A is an optionally substituted C 6-10 aromatic ring or a 5-10 membered heteroaromatic ring;
    L为键或任选取代的C 1-6亚烷基，其中所述亚烷基中的一个或多个-CH 2-任选被选自-N(R 2)-、-N(R 2)C(O)-、-C(O)N(R 2)-、-N(R 2)S(O) 2-、-S(O) 2N(R 2)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-和-S(O) m-的基团所代替； 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选自H、卤素、氰基、-SF 5、-OR 3、-SR 3、-NR 3R 4、-S(O) mR 3、-S(O) 2NR 3R 4、-C(O)R 3、-C(O)OR 3、-C(O)NR 3R 4、-C(O)N(R 3)OR 4、-OC(O)R 3、-OC(O)NR 3R 4、-N(R 3)C(O)OR 4、-N(R 3)C(O)R 4、-N(R 2)C(O)NR 3R 4、-C(O)N(R 3)S(O) 2R 4、-N(R 3)S(O) 2R 4，或任选取代的C 1- 6烷基、C 3-7环烷基、4-7元杂环基、苯基或5-6元杂芳基； 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)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, C 3-7 cycloalkyl , 4- 7-membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
    R a、R b、R c、R d和R e各自独立地选自H、卤素、氰基、-SF 5、-OR 3、-S(O) mR 3、-S(O) 2NR 3R 4、-C(O)NR 3R 4，或任选取代的C 1-6烷基、C 3-7环烷基、4-7元杂环基、苯基或5-6元杂芳基； 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选自H、卤素、氰基或任选取代的C 1-6烷基； R 1 is selected from H, halogen, cyano or optionally substituted C 1-6 alkyl;
    R 2、R 3和R 4各自独立地选自H或任选取代的C 1-6烷基、C 3-7环烷基、4-7元杂环基、苯基或5-6元杂芳基；或者，在同一个氮原子上的R 3和R 4任选与它们连接的氮原子共同形成一任选含有另外的杂原子的4-7元杂环，所述杂环任选被取代；且 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; and
    m为1或2。m is 1 or 2.
  2. 根据权利要求1所述的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式，其中Z为CH。The compound of claim 1, wherein Z is CH, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, and mixture thereof form thereof.
  3. 根据权利要求1或2所述的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式，其为以下通式(II)的化合物：A compound according to claim 1 or 2 or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer and mixture thereof form thereof, which is a compound of the following general formula (II):
    Figure PCTCN2020108468-appb-100002
    Figure PCTCN2020108468-appb-100002
    其中：in:
    环A为任选被一个或多个选自卤素、氰基、C 1-4烷基、C 1-4卤代烷基、氧代、-C(O)OR 3、-OC 1-4烷基、-OC 1-4卤代烷基和-SO 2C 1-4烷基的取代基取代的C 6-10芳环或5-10元杂芳环； 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为键或任选取代的C 1-6亚烷基，其中所述亚烷基中的一个或多个-CH 2-任选被选自-N(R 2)-、-O-和-C(O)-的基团所代替； 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选自H、卤素、氰基、-SF 5、-OR 3、-NR 3R 4、-S(O) 2R 3、-S(O)R 3、-S(O) 2NR 3R 4、-C(O)OR 3、-C(O)R 3、-C(O)NR 3R 4、-N(R 3)C(O)OR 4、-N(R 3)C(O)R 4、-C(O)N(R 3)S(O) 2R 4，或任选取代的C 1-6烷基、C 3-7环烷基、4-7元杂环基、苯基或5-6元杂芳基； 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;
    R a和R e各自独立地选自卤素； Ra and Re are each independently selected from halogen;
    R 2选自H或C 1-6烷基； R 2 is selected from H or C 1-6 alkyl;
    R 3和R 4各自独立地选自H或任选取代的C 1-6烷基、C 3-7环烷基、4-7元杂环基、苯基或5-6元杂芳基；或者，在同一个氮原子上的R 3和R 4任选与它们连接的氮原子共同形成一任选含有另外的杂原子的4-7元杂环，所述杂环任选被取代。 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.
  4. 根据前述权利要求任一项所述的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式，其中：A compound according to any preceding claim, or in the form of a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer and mixtures thereof, wherein:
    环A为任选被一个或两个选自卤素、氰基、C 1-4烷基、氧代、-C(O)OH、-OC 1-4烷基和-SO 2C 1-4烷基的取代基取代的C 6-10芳环或5-10元杂芳环； 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为键或任选被C 1-6烷基取代的C 1-6亚烷基或-O-C 1-4亚烷基； 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选自H、氰基、-SF 5、-OR 3、-S(O) 2R 3、-S(O)R 3、-S(O) 2NR 3R 4、-C(O)OR 3、-C(O)R 3、-C(O)NR 3R 4、-C(O)N(R 3)S(O) 2R 4、C 1-6烷基，或任选被选自-OH、C 1-4烷基、氧代、-O-C 1-4烷基、C 3-6环烷基和4-6元杂环基的取代基取代的C 3-7环烷基、4-7元杂环基、苯基或5-6元杂芳基； 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;
    R a和R e各自独立地选自卤素； Ra and Re are each independently selected from halogen;
    R 3和R 4各自独立地选自H或任选被选自卤素、-OH、氧代和C 1-4烷基的取代基取代的C 1-6烷基、C 3-7环烷基、4-7元杂环基、苯基或5-6元杂芳基；或者，在同一个氮原子上的R 3和R 4任选与它们连接的氮原子共同形成一任选含有另外的杂原子的4-7元杂环，所述杂环任选被选自-OH、C 1-4烷基、-O-C 1-4烷基、氧代、C 3-6环烷基和4-6元杂环基的取代基取代。 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 A 4-7 membered heterocycle of heteroatoms optionally selected from -OH, C1-4alkyl , -OC1-4alkyl , oxo, C3-6cycloalkyl and 4- Substituent substitution of 6-membered heterocyclic group.
  5. 根据前述权利要求任一项所述的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式，其中：A compound according to any preceding claim, or in the form of a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer and mixtures thereof, wherein:
    环A为任选被一个或两个选自卤素、C 1-4烷基、氧代、-COOH、-OC 1- 4烷基和-SO 2C 1-4烷基的取代基取代的C 6-10芳环或5-6元杂芳环； 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为键或任选被C 1-4烷基取代的C 1-6亚烷基或-O-C 1-4亚烷基； 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独立地选自H、氰基、-SF 5、-OR 3、-S(O) 2C 1-6烷基、-S(O)C 1-6烷基、-S(O) 2NR 3R 4、-C(O)OH、-C(O)NR 3R 4、-C(O)NHS(O) 2C 1-6烷基、C 1- 6烷基，任选被选自-OH、C 1-4烷基、氧代、-O-C 1-4烷基、C 3-6环烷基和4-6元杂环基的取代基取代的4-7元杂环基，或任选被C 1-4烷基取代的5-6元杂芳基； 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;
    R a和R e各自独立地选自卤素； Ra and Re are each independently selected from halogen;
    R 3和R 4各自独立地选自H，任选被卤素或-OH取代的C 1-6烷基，任选被-OH取代的C 3-7环烷基，或任选被氧代或C 1-4烷基取代的4-7元杂环基；或者，在同一个氮原子上的R 3和R 4任选与它们连接的氮原子共同形成一任选含有另外的选自N、O和S的杂原子的4-7元杂环，所述杂环任选被选自-OH、C 1-4烷基、-O-C 1-4烷基、氧代、C 3-6环烷基和4-6元杂环基的取代基取代。 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.
  6. 根据前述权利要求任一项所述的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式，其中环A为任选被一个或两个选自卤素、C 1-4烷基、氧代、-COOH、-OC 1-4烷基和-SO 2C 1-4烷基的取代基取代的苯环、吡啶环、嘧啶环、二氢吲哚环、异二氢吲哚环或吡唑环，优选为苯环或吡啶环。 A compound according to any preceding claim, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer and mixture thereof form thereof, wherein Ring A is optionally selected from the group consisting of one or two halogens, Substituents of C 1-4 alkyl, oxo, -COOH, -OC 1-4 alkyl and -SO 2 C 1-4 alkyl substituted benzene ring, pyridine ring, pyrimidine ring, indoline ring, The isoindoline ring or the pyrazole ring is preferably a benzene ring or a pyridine ring.
  7. 根据前述权利要求1-5任一项所述的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式，其为以下通式(IIIa)或(IIIb)的化合物：A compound according to any one of the preceding claims 1-5, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, and mixture thereof, in the form of general formula (IIIa) or (IIIb) below compound of:
    Figure PCTCN2020108468-appb-100003
    Figure PCTCN2020108468-appb-100003
    其中：in:
    X 1、X 2和X 3各自独立地选自N或CG 1； X 1 , X 2 and X 3 are each independently selected from N or CG 1 ;
    G 1选自H、卤素、C 1-4烷基、氧代、-COOH、-OC 1-4烷基或-SO 2C 1- 4烷基； 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、R a和R e的定义如前述权利要求中所述。 L, R, Ra and Re are as defined in the preceding claims.
  8. 根据前述权利要求任一项所述的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式，所述化合物选自：A compound according to any preceding claim, or in the form of a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, and mixtures thereof, selected from the group consisting of:
    Figure PCTCN2020108468-appb-100004
    Figure PCTCN2020108468-appb-100004
    Figure PCTCN2020108468-appb-100005
    Figure PCTCN2020108468-appb-100005
    Figure PCTCN2020108468-appb-100006
    Figure PCTCN2020108468-appb-100006
    Figure PCTCN2020108468-appb-100007
    Figure PCTCN2020108468-appb-100007
  9. 药物组合物，所述药物组合物包含根据权利要求1-8任一项所述的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式和药学上可接受的载体和赋形剂。A pharmaceutical composition comprising a compound according to any one of claims 1-8 or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer and mixture thereof, and a pharmaceutically acceptable salt thereof. Accepted carriers and excipients.
  10. 根据权利要求1-8任一项所述的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式或根据权利要求9所述的药物组合物在制备用于治疗和/或预防TYK2介导的相关性疾病的药物中的用途，其中所述疾病选自自身免疫性疾病、炎性疾病、癌症、皮肤疾病、糖尿病、眼病、神经退行性疾病、过敏反应、哮喘和其他阻塞性气道疾病、移植排斥。The compound according to any one of claims 1-8 or the pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers and mixtures thereof or the pharmaceutical composition according to claim 9 is used in the preparation Use in medicines for the treatment and/or prevention of TYK2-mediated related diseases, wherein the diseases are selected from autoimmune diseases, inflammatory diseases, cancer, skin diseases, diabetes, eye diseases, neurodegenerative diseases, allergic reactions , asthma and other obstructive airway diseases, transplant rejection.
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