WO2019223777A1 - Composé pyrrolopyrimidine contenant une substitution arylamine, son procédé de préparation et son application - Google Patents

Composé pyrrolopyrimidine contenant une substitution arylamine, son procédé de préparation et son application Download PDF

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WO2019223777A1
WO2019223777A1 PCT/CN2019/088316 CN2019088316W WO2019223777A1 WO 2019223777 A1 WO2019223777 A1 WO 2019223777A1 CN 2019088316 W CN2019088316 W CN 2019088316W WO 2019223777 A1 WO2019223777 A1 WO 2019223777A1
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methyl
amino
ethyl
alkyl
propyl
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PCT/CN2019/088316
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English (en)
Chinese (zh)
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张强
王中祥
冯守业
张宏波
杨海龙
周利凯
徐占强
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北京赛特明强医药科技有限公司
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Priority to CN201980017096.3A priority Critical patent/CN111836819A/zh
Publication of WO2019223777A1 publication Critical patent/WO2019223777A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the technical field of medicine and relates to a pyrrolopyrimidine compound containing an arylamino group, a preparation method and an application thereof.
  • Protein kinase is an important signal messenger of cell life activity, which can catalyze the transfer of the ⁇ -phosphate group at the ATP terminus to the hydroxyl receptor in the amino acid residues of the substrate (serine, threonine, tyrosine), thereby activating the target Protein (Johnson LN, Lewis RJ, Structural basis for control by phosphorylation, Cheminform, 2001, 101,2209.). Protein kinases are involved in numerous physiological processes, including cell proliferation, survival, apoptosis, metabolism, transcription, and differentiation (Adams J.A., Kinetic and Catalytic Mechanisms of Protein Kinases, Chemical reviews, 2001, 101,2271.). Among the existing human drug targets, protein kinase family members account for up to 10% (Santos R., Ursu O., Gaulton A., et al., A comprehensive map of drug targets, Nature Reviews Drug Discovery, 2017, 16,19.).
  • Epidermal growth factor receptor (ErbB) tyrosine kinases can regulate cell proliferation, migration, differentiation, apoptosis, and cell migration through a variety of pathways. In various forms of malignant tumors, members of the ErbB family and their partial distributors are often overexpressed, amplified, or mutated, which makes them important therapeutic targets.
  • This family of protein kinases includes: ErbB1 / EGFR / HER1, ErbB2 / HER2, ErbB3 / HER3, and ErbB4 / HER4.
  • EGFR is an important target for the development of non-small cell lung cancer (dicamann, R., et.al., Personalizing, Therapy with Targeted Agents, Non-Small Cell, Cancer, ONCOTARGET, 2001, 2 (3), 165.).
  • Gefitinib, Erlotinib, and Icotinib are the first generation of EGFR-targeting reversible kinase inhibitors for the treatment of non-small cell cancer. These inhibitors have inhibitory effects on both wild-type and activated mutant EGFR, and have achieved great clinical success, but the resistance of the recipient patients after taking it for a period of time, especially the resistance caused by the T790M mutation Sex makes the effect less effective or ineffective.
  • Afatinib a second-generation EGFR inhibitor, is a non-reversible inhibitor that contains a Michael receptor and can covalently bond with a cysteine residue (Cys797) located at the entrance of the ATP-binding pocket.
  • the inhibitor shows strong activity against both T790M mutant EGFR kinase and wild-type EGFR kinase, and its inhibitory activity against T790M mutant EGFR kinase is higher than that of wild-type EGFR kinase, which makes the therapeutic window of the drug narrower in clinical application
  • the use effect is not ideal (Camidge, DR, et.al., Acquired, Resistance, TKIs, Solid Tumours: learning from cancer. Nature Reviews, Clinical Oncology, 2014, 11, 473.).
  • the third-generation EGFR kinase inhibitors Osimertinib and Olmutinib have achieved highly selective inhibition of T790M mutant EGFR kinase compared to wild-type EGFR kinase, widening the clinical use window, Effective treatment of patients with T790M mutation has been achieved.
  • three generations of EGFR kinase inhibitors have also developed resistance after a period of clinical use.
  • One of the reasons is the secondary mutation of C797S caused by EGFR.
  • Cruatinib is a targeted ALK inhibitor developed by Ariad Pharmaceuticals and approved by the US FDA in 2017 for the treatment of ALK-positive non-small cell lung cancer. According to the literature, Brigatinib has a certain inhibitory effect on C797S mutant EGFR kinase.
  • the present invention aims to provide an arylamine-substituted pyrrolopyrimidine compound, an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutical combination thereof. And their use in the preparation of a medicament as a kinase inhibitor.
  • One aspect of the present invention provides a compound represented by formula (I), an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt thereof, and a prodrug thereof,
  • X is CH or N
  • Y is CH or N
  • R 1 is -NHR 5
  • R 5 is unsubstituted or substituted aryl, heteroaryl, cycloalkyl, cycloalkyl bridged ring structure, and ring structure,
  • R 6 and R 7 are each independently -H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl,
  • the parallel ring structure is selected from the group consisting of an aromatic ring and a 5-6 membered heteroaryl ring group, a 5-6 membered heteroaryl ring and a 5-6 member heteroaryl ring group, an aromatic ring and a 5-6 membered cycloalkyl group, and an aromatic ring 5-6 membered heterocyclic group, 5-6 membered heteroaryl ring and 5-6 membered cycloalkyl group or 5-6 membered heteroaryl ring and 5-6 membered heterocyclic group;
  • R 2 is -H, -CF 3 , -CH 2 CF 3 , C 1- C 6 alkyl, C 3- C 6 cycloalkyl, C 3- C 4 cycloalkyl substituted C 1- C 2 alkyl , A 4- to 6-membered heterocyclic group containing one oxygen atom, or-(CH 2 ) m R 8 , where m is an integer of 1, 2, 3,
  • R 3 and R 4 are each independently -H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group containing one nitrogen atom or one oxygen atom, or-(CH 2 ) n R 9 , where n is an integer of 1, 2, 3,
  • the 4-6 membered heterocyclic ring containing one nitrogen atom or one oxygen atom is unsubstituted or substituted with a C 1 -C 3 alkyl group
  • R 3 , R 4 and the nitrogen atom to which it is attached form a 4-6 membered heterocyclic ring or a 6-9 membered spiro ring
  • the 4- to 6-membered heterocyclic ring formed by R 3 and R 4 and the nitrogen atom to which R 3 and R 4 are connected is unsubstituted or 1-2 members selected from halogen, cyano, hydroxyl, amino, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halo C 1 -C 3 alkyl, cyano substituted C 1 -C 3 alkyl, hydroxy substituted C 1 -C 3 alkyl, C 1 -C 3 alkoxy Substituted with substituted C 1 -C 3 alkyl,
  • the 6-9 membered spiro ring formed by R 3 and R 4 and the nitrogen atom connected to it is a single spiro ring containing one nitrogen atom.
  • R 1 is -NHR 5 and R 5 is selected from the following groups:
  • T is NH, O or S
  • R 10 is selected from -H, -OH, -F, -Cl, -Br, -CN, -CF 3 , -OCF 3 , methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl , Methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, or the following groups:
  • R 11 is -H, methyl, ethyl, propyl, isopropyl
  • R 12 is -H, -F, -Cl, -Br, hydroxyl, cyano, trifluoromethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or Isopropoxy.
  • X is CH; Y is CH.
  • R 1 is
  • R 2 is selected from -H, -CF 3 , -CH 2 CF 3 , methyl, ethyl, propyl, isopropyl, 1-methylpropyl, 2-methylpropyl Base, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, propylene oxide-3-yl, tetrahydrofuran-3-yl, tetrahydropyridine Uran-4-yl, tetrahydropyran-3-yl, methylthioethyl, methylthiopropyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl , Isopropoxyethyl, isopropoxypropyl, aminoacetyl, aminopropionyl, methanesulfony
  • R 2 is selected from n-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl.
  • R 3 and R 4 are each independently selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, propylene oxide-3-yl, and tetrahydrofuran.
  • the substituted or unsubstituted 4-6 membered heterocyclic ring composed of the nitrogen atom to which R 3 and R 4 are connected is selected from the following ring structures:
  • R 13 is selected from -H, methylamino, ethylamino, dimethylamino,
  • R 14 is selected from -H, methyl, ethyl, propyl, isopropyl, formyl, acetyl or methanesulfonyl,
  • R 15 and R 16 are each independently selected from -H, -F, -CF 3 , hydroxyl, amino, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and propoxy Methyl, isopropyloxy, cyanomethyl, cyanoethyl, methoxymethyl, methoxyethyl, methoxypropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl,
  • the 6-9 membered spiro ring formed by R 3 and R 4 and the nitrogen atom to which it is connected is selected from the following spiro ring structures:
  • R 3 is selected from -H, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, iso Amyl, neopentyl, n-hexyl, isohexyl, cyclopropyl, cyclobutyl, cyclopentyl, propylene oxide-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, tetrahydro Pyran-3-yl, N-methylpiperidin-3-yl, N-methylpiperidin-4-yl, N-methylpyrrolidin-3-yl, N-methylazepine Alk-3-yl, methylthioethyl, methylthiopropyl, methoxyethyl, methoxypropyl, eth
  • R 4 is selected from n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl.
  • Another aspect of the present invention provides a compound represented by formula (I), an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt thereof, and a prodrug thereof,
  • X is CH or N; Y is CH or N; preferably, X is CH; Y is CH;
  • R 1 is -NHR 5 and R 5 is selected from the following groups:
  • T is NH, O or S
  • R 10 is selected from -H, -OH, -F, -Cl, -Br, -CN, -CF 3 , -OCF 3 , methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl , Methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, or the following groups:
  • R 11 is -H, methyl, ethyl, propyl, isopropyl
  • R 12 is -H, -F, -Cl, -Br, hydroxyl, cyano, trifluoromethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or Isopropoxy
  • R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 2 is selected from -H, -CF 3 , -CH 2 CF 3 , methyl, ethyl, propyl, isopropyl, 1-methylpropyl, 2-methylpropyl, cyclopropyl, cyclobutyl Group, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, Tetrahydropyran-3-yl, methylthioethyl, methylthiopropyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, isopropoxyethyl Methyl, isopropyloxypropyl, aminoacetyl, aminopropionyl, methanesulfonylethy
  • R 3 is selected from -H, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl , Isohexyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, tetrahydropyran-3-yl, N-methylpiperidin-3-yl, N-methylpiperidin-4-yl, N-methylpyrrolidin-3-yl, N-methylaza (hetero) cyclobutane-3-yl;
  • R 4 is selected from-(CH 2 ) n R 17 , where n is an integer of 1, 2, 3,
  • R 17 is Or C 3 -C 6 cycloalkyl, and R 18 is -OH, -CN, -C (O) NH 2 ,
  • Another aspect of the present invention provides a compound represented by formula (I), an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt thereof, and a prodrug thereof,
  • X is CH or N
  • Y is CH or N
  • R 1 is -NHR 5 and R 5 is selected from the following groups:
  • T is NH, O or S
  • R 10 is selected from -H, -OH, -F, -Cl, -Br, -CN, -CF 3 , -OCF 3 , methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl , Methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, or the following groups:
  • R 11 is -H, methyl, ethyl, propyl, isopropyl
  • R 12 is -H, -F, -Cl, -Br, hydroxyl, cyano, trifluoromethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or Isopropoxy
  • R 2 is -H, C 1- C 6 alkyl, C 3- C 6 cycloalkyl, halo C 1- C 6 alkyl;
  • R 3 and R 4 are each independently -H, C 3 -C 8 cycloalkyl, or from 1 to 3 selected from C 1 -C 6 alkoxy, hydroxyl, halogen, C 3 -C 6 cycloalkyl C 1- C 9 alkyl substituted or substituted by
  • the 4- to 8-membered heterocyclic ring formed by R 3 and R 4 and the nitrogen atom to which they are connected is unsubstituted or 1-2 selected from halogen, cyano, hydroxyl, amino, C 1 -C 3 alkyl, C 1- C 3 alkoxy, halo C 1 -C 3 alkyl, cyano substituted C 1 -C 3 alkyl, hydroxy substituted C 1 -C 3 alkyl, C 1 -C 3 alkoxy substituted the C 1 -C 3 alkyl.
  • R 2 is -H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, isopentyl, pentyl, neopentyl, hexyl, isohexyl, cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, trifluoromethyl, fluoroethyl;
  • R 3 and R 4 are each independently selected from -H, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, Neopentyl, n-hexyl, isohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, Tetrahydropyran-3-yl, N-methylpiperidin-3-yl, N-methylpiperidin-4-yl, N-methylpyrrolidin-3-yl, N-methyl nitrogen (hetero) Cyclobutane-3-yl, methylthioethyl, methylthiopropyl, methoxymethyl, methoxyethyl
  • the substituted or unsubstituted 4-8 membered heterocyclic ring composed of the nitrogen atom to which R 3 and R 4 are connected is selected from the following ring structures:
  • R 13 is selected from -H, methylamino, ethylamino, dimethylamino,
  • R 14 is selected from -H, methyl, ethyl, propyl, isopropyl, formyl, acetyl or methanesulfonyl,
  • R 15 and R 16 are each independently selected from -H, -F, -CF 3 , hydroxyl, amino, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and propoxy Methyl, isopropyloxy, cyanomethyl, cyanoethyl, methoxymethyl, methoxyethyl, methoxypropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl.
  • a method for preparing the compound, an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt thereof, and a prodrug thereof including the following steps,
  • PG is selected from the group consisting of trimethylsilylethoxymethyl, tert-butoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, benzenesulfonyl, acetyl, trifluoroacetyl, fluorenylmethoxycarbonyl, benzyl; preferably trimethyl Silylethoxymethyl (SEM group),
  • R 1 , R 2 , R 3 , and R 4 are as described above.
  • the present application provides a pharmaceutical composition for treating a disease associated with tyrosine kinase EGFR, HER2, or ALK mutation or overexpression, which comprises the compound of formula (I) or a pharmaceutically acceptable compound thereof.
  • the salt or its hydrate or its solvate or its prodrug is composed of a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof as an active ingredient, as described, One or more other therapeutic agents, and one or more pharmaceutically acceptable carriers or excipients.
  • the application also relates to the compound of formula (I), its isomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs in the preparation of treatments with tyrosine kinase EGFR, HER2, or ALK mutations or Application of an overexpression-related cancer and an autoimmune disease drug, wherein the cancer and autoimmune disease include fundus disease, dry eye, psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, Multiple sclerosis, systemic lupus erythematosus, Crohn's disease, atherosclerosis, pulmonary fibrosis, liver fibrosis, bone marrow fibrosis, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, Glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer,
  • the application also relates to a method for treating a kinase-mediated disease or condition such as EGFR, HER2 or ALK, which comprises administering to a patient (human or other mammal, especially human) a therapeutically effective amount of the formula (I ) Compounds or salts thereof, said EGFR, HER2 or ALK-mediated diseases or conditions include those mentioned above.
  • substituted as referred to herein includes complex substituents (for example, aryl (such as phenyl), heteroalkyl, heteroaryl), more preferably 1 to 5 substituents, more preferably 1 There are three to three, preferably one to two, which can be freely selected from the substituent list.
  • complex substituents for example, aryl (such as phenyl), heteroalkyl, heteroaryl
  • substituents for example, aryl (such as phenyl), heteroalkyl, heteroaryl
  • substituents for example, aryl (such as phenyl), heteroalkyl, heteroaryl
  • alkyl refers to a saturated straight-chain, branched-chain hydrocarbon group having a specified number of carbon atoms
  • C 1 -C 10 alkyl refers to an alkyl moiety containing 1 to 10 carbon atoms
  • C 1 -C 3 Alkyl refers to an alkyl moiety containing 1 to 3 carbon atoms.
  • C 1 -C 6 alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl Base, tert-butyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methyl Pentyl and others.
  • Alkoxy is an alkyl-O- group formed from a linear or branched alkyl group previously described with -O-, such as methoxy, ethoxy, and the like.
  • an alkylthio group is an alkyl-S- group formed from a linear or branched alkyl group previously described with -S-, such as methylthio, ethylthio, and the like.
  • Alkenyl and alkynyl include straight-chain, branched-chain alkenyl or alkynyl, and the term C 2 -C 6 alkenyl or C 2 -C 6 alkynyl means a straight-chain or branched hydrocarbon group having at least one alkenyl or alkynyl group.
  • Cycloalkyl means a non-aromatic, saturated, cyclic hydrocarbon group containing a specified number of carbon atoms.
  • (C3-C6) cycloalkyl refers to a non-aromatic cyclic hydrocarbon ring having 3-6 ring carbon atoms.
  • Exemplary "(C3-C6) cycloalkyl” includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • aryl refers to an unsubstituted or substituted aromatic group, such as phenyl, naphthyl, anthracenyl.
  • aroyl refers to -C (O) -aryl.
  • heterocyclyl represents an unsubstituted or substituted stable 3 to 8 membered monocyclic saturated ring system, which is selected from carbon atoms and selected from N, O, and S It consists of 1 to 3 heteroatoms, of which N, S heteroatoms can be oxidized at will, and N heteroatoms can also be quaternized at will. Heterocyclic rings can be combined with any heteroatom or carbon atom to form a stable structure.
  • heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, piperazinyl oxide, piperidinyl oxide, tetrahydrofuranyl, dioxolane Radicals, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiamorpholinyl sulfone and oxadiazolyl.
  • heteroaryl represents an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system, and may also represent an unsubstituted or substituted 9 or 10-membered benzene benzene heteroaromatic ring system or bicyclic heteroaromatic ring system, which consists of carbon atoms and from 1 to 4 heteroatoms selected from N, O, S, of which N, S heteroatoms can be oxidized at will N heteroatoms can also be optionally quaternized.
  • Heteroaryl groups can adhere to any heteroatom or carbon atom to form a stable structure.
  • heteroaryl groups include, but are not limited to, thiathranyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl , Pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzoisoxazolyl, benzoxazolyl, Benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adenine, quinolinyl or isoquinolinyl.
  • carbonyl refers to a C (O) group.
  • alkyl or “aryl” or any of their prefixes appears in the name of a substituent (eg, aralkyl, dialkylamino), it will be considered to include the above as “alkane” And “aryl”.
  • a specified number of carbon atoms (for example, C1-C6) will independently represent the number of carbon atoms in an alkyl moiety or an alkyl moiety in which a alkyl group is used as its prefix stem.
  • solvated form may be a water-soluble form.
  • the invention includes all of these solvated and unsolvated forms.
  • the compounds of the present invention may have asymmetric carbon atoms. Based on their physical and chemical differences, such diastereomeric mixtures can be separated by known methods, such as chromatography or fractional crystallization. Into a single diastereomer. Enantiomers can be separated by first reacting with an appropriate optically active compound to convert the enantiomeric mixture into a diastereomeric mixture, separating the diastereomers, and then converting the single diastereomer Enantiomers are converted (hydrolyzed) to the corresponding pure enantiomers. All such isomers, including diastereomeric mixtures and pure enantiomers, are considered to be part of the invention.
  • the compound of the present invention as an active ingredient, and a method for preparing the same are the contents of the present invention.
  • the crystalline forms of some compounds can exist as polycrystals, and this form can also be included in the current invention.
  • some compounds can form solvates with water (ie, hydrates) or common organic solvents, and such solvates are also included in the scope of this invention.
  • the compounds of the present invention can be used for treatment in free form or, where appropriate, in the form of a pharmaceutically acceptable salt or other derivative.
  • pharmaceutically acceptable salt refers to the organic and inorganic salts of the compounds of the present invention. This salt is suitable for humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and is reasonable. Benefit / risk ratio.
  • Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates, and other types of compounds are well known in the art.
  • the salt can be formed by reacting a compound of the present invention with a suitable free base or acid.
  • salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, Alternatively, these salts can be obtained by using methods well known in the art, such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, and camphoric acid Salt, camphor sulfonate, citrate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glyceryl phosphate, gluconic acid Salt, hemisulfate, hexanoate, hydroiodate, 2-hydroxyethanesulfonate, lactate, lactate, laurate, lauryl sulfate, malate, maleate, methane Sulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, per-3-phenylpropionate, Phosphate, picrate, propionate
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Other pharmaceutically acceptable salts include appropriate non-toxic ammonium, quaternary ammonium, and use such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate and arylsulfonate Amine cations.
  • prodrug as used herein means that a compound can be converted into a compound represented by formula (I) of the present invention in vivo. This conversion is affected by the hydrolysis of the prodrug in the blood or the enzymatic conversion into the parent compound in the blood or tissue.
  • the pharmaceutical composition of the present invention comprises a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, a kinase inhibitor (small molecule, polypeptide, antibody, etc.), an immunosuppressive agent, an anticancer drug, an antiviral agent, an antiviral agent Inflammatory agents, antifungal agents, antibiotics or additional active agents of anti-hyperplasia compounds; and any pharmaceutically acceptable carrier, adjuvant or excipient.
  • a kinase inhibitor small molecule, polypeptide, antibody, etc.
  • an immunosuppressive agent an anticancer drug
  • an antiviral agent an antiviral agent
  • Inflammatory agents antifungal agents
  • antibiotics or additional active agents of anti-hyperplasia compounds any pharmaceutically acceptable carrier, adjuvant or excipient.
  • the compounds of the invention can be used alone or in combination with one or more other compounds of the invention or with one or more other agents.
  • the therapeutic agents can be formulated to be administered simultaneously or sequentially at different times, or the therapeutic agents can be administered as a single composition.
  • the so-called "combination therapy" refers to the use of the compound of the present invention together with another agent.
  • the mode of administration is the simultaneous administration of each agent or the sequential administration of each agent. In either case, the purpose is to To achieve the best results of the drug.
  • Co-administration includes simultaneous delivery of the dosage forms, as well as separate dosage forms for each compound.
  • the administration of the compound of the present invention can be used concurrently with other known therapies in the art, for example, the use of radiation therapy or additional therapies such as cytostatic agents, cytotoxic agents, other anticancer agents in cancer treatment to improve Symptoms of cancer.
  • additional therapies such as cytostatic agents, cytotoxic agents, other anticancer agents in cancer treatment to improve Symptoms of cancer.
  • the invention is not limited to the order of administration; the compounds of the invention may be administered previously, concomitantly, or after other anticancer or cytotoxic agents.
  • one or more compounds or salts of formula (I) as its active ingredient can be intimately mixed with the pharmaceutical carrier, which is performed according to the traditional pharmaceutical ingredient technology,
  • the carrier can adopt various forms according to the preparation form designed according to different administration modes (for example, oral or parenteral administration).
  • Suitable pharmaceutically acceptable carriers are well known in the art. A description of some of these pharmaceutically acceptable carriers can be found in the Handbook of Pharmaceutical Excipients, a book jointly published by the American Pharmaceutical Association and the British Pharmaceutical Society.
  • the pharmaceutical composition of the present invention may have the following forms, for example, suitable for oral administration, such as tablets, capsules, pills, powders, sustained release forms, solutions or suspensions; for parenteral injections such as clear liquids, suspensions, Emulsions; or for topical application such as creams, creams; or as suppositories for rectal administration.
  • Pharmaceutical ingredients may also be suitable for precise single-dose administration in unit dosage form.
  • the pharmaceutical ingredient will include a traditional pharmaceutical carrier or excipient and a compound made as an active ingredient according to the current invention, and may also include other medical or pharmaceutical preparations, carriers, adjuvants, and the like.
  • Therapeutic compounds can also be administered to mammals rather than humans.
  • the dosage of a drug administered to a mammal will depend on the species of the animal and its disease status or its disorder.
  • the therapeutic compound can be administered to animals in the form of capsules, boluses, or tablet potions.
  • Therapeutic compounds can also be introduced into animals by injection or infusion. We prepare these medicinal forms in a traditional way that meets the standards of veterinary practice.
  • pharmaceutical synthetic drugs can be mixed with animal feed and fed to animals. Therefore, concentrated feed additives or premixes can be prepared to mix ordinary animal feed.
  • Yet another object of the present invention is to provide a method for treating cancer in a subject in need, comprising administering to the subject a method of treating a therapeutically effective amount of a composition containing a compound of the present invention.
  • the present invention also includes the use of the compound of the present invention or a pharmaceutically acceptable derivative thereof for the preparation of a medicament for treating cancers related to tyrosine kinases EGFR, HER2, ALK and autoimmune diseases.
  • the cancers including non-solid tumors, solid tumors, primary or metastatic cancers, as indicated elsewhere herein and including one or more other treatments that are resistant or refractory to the cancer
  • other diseases including but It is not limited to agents for fundus diseases, psoriasis, atherosclerosis, pulmonary fibrosis, liver fibrosis, bone marrow fibrosis, etc.).
  • the cancer includes, but is not limited to, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, intrauterine Membrane cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myelogenous leukemia, acute myeloid leukemia, non-Hodgkin lymphoma, nasopharyngeal cancer, esophageal cancer, brain Tumor, B-cell and T-cell lymphoma, lymphoma, multiple myeloma, biliary sarcoma, and bile duct cancer.
  • the present invention also provides a method for preparing the corresponding compound.
  • a variety of synthetic methods can be used to prepare the compounds described herein, including the following methods.
  • the compound of the present invention or a pharmaceutically acceptable salt, isomer or hydrate thereof may be The following methods are used to synthesize synthetic methods known in the field of organic chemical synthesis, or by those skilled in the art to understand variations of these methods. Preferred methods include, but are not limited to, the following methods.
  • a method for preparing a compound of the present invention, an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt thereof, and a prodrug thereof, comprising the following steps:
  • R 1 , R 2 , R 3 , and R 4 are as defined above.
  • step 1) The compound represented by formula (IV) in step 1) and the compound represented by formula (III) are sufficiently contacted to obtain the compound represented by formula (II);
  • the reaction can be performed in an organic solvent, including, but not limited to, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N- One or a combination of two or more of methyl-2-pyrrolidone (NMP), ethylene glycol dimethyl ether, isopropanol, n-butanol, 2-butanol (sec-butanol), and tert-butanol;
  • NMF N, N-dimethylformamide
  • DMA N-dimethylacetamide
  • NMP N- One or a combination of two or more of methyl-2-pyrrolidone
  • ethylene glycol dimethyl ether isopropanol, n-butanol, 2-butanol (sec-butanol), and tert-butanol
  • NMP N-dimethyl-2-pyrrolidone
  • the reaction can be performed in the presence of a base, which includes but is not limited to: potassium carbonate, sodium carbonate, sodium acetate, triethylamine, diisopropylethylamine, triethylenediamine, pyridine, One or a combination of two or more of 4-dimethylaminopyridine, 1,8-diazabicycloundec-7-ene or N-methylmorpholine;
  • a base which includes but is not limited to: potassium carbonate, sodium carbonate, sodium acetate, triethylamine, diisopropylethylamine, triethylenediamine, pyridine, One or a combination of two or more of 4-dimethylaminopyridine, 1,8-diazabicycloundec-7-ene or N-methylmorpholine;
  • the reaction can be performed in the presence of an acid, which includes but is not limited to: trifluoroacetic acid, p-toluenesulfonic acid;
  • the reaction can be performed under the conditions of a palladium metal-catalyzed coupling reaction condition, wherein the palladium metal-catalyzed coupling reaction conditions are the palladium ligands, solvents, and bases used in common Buchward-Hartwig reactions;
  • Step 2 The compound represented by formula (II) in the presence of tetrabutylammonium fluoride is used to obtain a compound represented by formula (I).
  • Step 1) (2-((2-((4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -7-((2- (trimethyl Silyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) phenyl) dimethylphosphine
  • Step 2) (2-((2-((4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -7H-pyrrolo [2,3- d) Preparation of pyrimidin-4-yl) amino) phenyl) dimethylphosphine
  • Step 4) and Step 5) (2-((2-((4- (4- (dimethylamino) piperidin-1-yl) -3-isobutoxyphenyl) amino) -7H pyrrolo Preparation of [2,3-d] pyrimidin-4-yl) amino) phenyl) dimethylphosphine
  • Reference Example 1 was prepared in steps 1) and 2).
  • the starting material was equimolar equivalent of 1- (4-amino-2-isobutoxyphenyl) -N, N-dimethylpiperidine- 4-amine replaces 1- (4-amino-2-methoxyphenyl) -N, N-dimethylpiperidine-4-amine.
  • Example 7 For the preparation of Example 7, refer to Step 1) to Step 5) of Example 6, and replace the 1-iodo-2-methylpropane with an equimolar equivalent of iodocyclobutane in the starting material in step 1).
  • Example 8 refers to steps 1) to 5) of the preparation route of Reference Example 6, wherein the starting material in step 1) is replaced by 1-iodo-2-methylpropane with an equimolar equivalent of methyl iodide, and step 2 ) In place of N, N-dimethylpiperazin-4-amine with equimolar equivalent of 1-methyl-4- (piperidin-4-yl) piperazine.
  • Example 9 For the preparation of Example 9, refer to steps 1) to 5) of the preparation route of Example 6, wherein in step 2), equimolar equivalent of 1-methyl-4- (piperidin-4-yl) piperazine was used instead of N. , N-dimethylpiperazine-4-amine.
  • Example 10 For the preparation of Example 10, refer to steps 1) to 5) of the preparation route of Example 7, wherein in step 2), the molar equivalent of 1-methyl-4- (piperidin-4-yl) piperazine was used instead of N. , N-dimethylpiperazine-4-amine.
  • step 1) equimolar equivalent of bromoisopropane is used instead of 1-iodo-2-methylpropane
  • step 2) The equivalent molar equivalent of 2-methyl-1- (methyl (piperidin-4-yl) amino) propan-2-ol was used in place of N, N-dimethylpiperazin-4-amine.
  • step 1) equimolar equivalent of bromoisopropane is used instead of 1-iodo-2-methylpropane
  • step 2) In the equimolar equivalent of N- (2-methoxyethyl) -N-methylpiperidine-4-amine, N, N-dimethylpiperazine-4-amine was replaced.
  • Example 13 For the preparation of Example 13, refer to steps 1) to 5) of the preparation route of Example 6, wherein in step 1), equimolar equivalent of bromoisopropane is used instead of 1-iodo-2-methylpropane, and step 2) In the equimolar equivalent of N- (cyclopropylmethyl) -N-methylpiperidine-4-amine, N, N-dimethylpiperazine-4-amine was replaced.
  • Example 14 For the preparation of Example 14, refer to steps 1) to 5) of the preparation route of Example 6, wherein in step 2), an equimolar equivalent of 1-isopropyl-4- (piperidin-4-yl) piperazine was substituted. N, N-dimethylpiperazin-4-amine.
  • Step 7) (2-((2-((3-ethoxy-4- (4-((2-hydroxy-2-methylpropyl) (methyl) amino) piperidin-1-yl) benzene ) Amino) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) phenyl) dimethylphosphine
  • Example 18 For the preparation method of Example 18, refer to the preparation steps 1) to 7) of Example 17, wherein in step 2), equimolar equivalent of 1-bromopropane is used instead of bromoethane.
  • Example 19 For the preparation method of Example 19, refer to the preparation steps 1) to 7) of Example 17, wherein in step 2), an equimolar equivalent of 1-bromo-2-methylpropane is used instead of bromoethane.
  • Example 20 For the preparation method of Example 20, refer to the preparation steps 1) to 7) of Example 17, wherein in step 2), equimolar equivalent of 1-bromobutane is used instead of bromoethane.
  • Example 21 For the preparation method of Example 21, refer to the preparation steps 1) to 7) of Example 17, wherein in step 2), equimolar equivalent of 1-bromo-3-methylbutane is used instead of bromoethane.
  • Example 28 For the preparation method of Example 28, refer to the preparation steps 1) to 7) of Example 17, wherein in step 2), an equimolar equivalent of bromocyclobutane is used instead of bromoethane.
  • Example 30 For the preparation method of Example 30, refer to the preparation steps 1) to 7) of Example 17, wherein in step 2), an equimolar equivalent of bromocyclopentane is used instead of bromoethane.
  • Step 3) to Step 5) (2-((2-((4- (4- (ethyl (2-hydroxy-2-methylpropyl) amino) piperidin-1-yl) -3-isopropyl Preparation of oxyphenyl) amino) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) phenyl) dimethylphosphine
  • Step 3) to Step 5) Referring to Step 5) to Step 7) in the preparation method of Example 17, the starting material is equimolar equivalent of 1- (ethyl (1- (2-isopropoxy-4- Nitrophenyl) piperidin-4-yl) amino) -2-methylpropan-2-ol instead of 1-((1- (2-ethoxy-4-nitrophenyl) piperidine-4- (Methyl) (methyl) amino) -2-methylpropan-2-ol.
  • Example 32 For the preparation method of Example 32, refer to the preparation steps 1) to 7) of Example 17, wherein in step 2), an equimolar equivalent of bromocyclohexane is used instead of bromoethane.
  • Step 2) to Step 4) (2-((2-((4- (4- (azacyclooctane-1-yl) piperidin-1-yl) -3-isopropoxyphenyl) amino ) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) phenyl) dimethylphosphine
  • Step 2) to Step 4) Referring to Step 5) to Step 7) in the preparation method of Example 17, the starting material is equimolar equivalent of 1- (1- (2-isopropoxy-4-nitrobenzene) (Yl) piperidin-4-yl) azacyclooctane instead of 1-((1- (2-ethoxy-4-nitrophenyl) piperidin-4-yl) (methyl) amino) -2 -Methylpropan-2-ol.
  • Step 7) (2-((2-((4- (4-(((1-hydroxycyclopropyl) methyl) (methyl) amino) piperidin-1-yl) -3-isopropoxy Phenyl) amino) -7-((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) phenyl) di
  • step 6 For the preparation method, refer to step 6) in Example 17, wherein in an equimolar amount of 1-(((1- (4-amino-2-isopropoxyphenyl) piperidin-4-yl) (methyl) Amino) methyl) cyclopropane-1-ol instead of 1-((1- (4-amino-2-ethoxyphenyl) piperidin-4-yl) (methyl) amino) -2-methylpropane -2-ol.
  • Step 8) (2-((2-((4- (4-(((1-hydroxycyclopropyl) methyl) (methyl) amino) piperidin-1-yl) -3-isopropoxy Preparation of phenyl) amino) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) phenyl) dimethylphosphine
  • Step 4) (2-((2-((4- (4-(((1-hydroxycyclobutyl) methyl) (methyl) amino) piperidin-1-yl) -3-isopropoxy Phenyl) amino) -7-((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) phenyl) di
  • step 6 For the preparation method, refer to step 6) in Example 17, wherein in an equimolar amount of 1-(((1- (4-amino-2-isopropoxyphenyl) piperidin-4-yl) (methyl) Amino) methyl) cyclobut-1-ol instead of 1-((1- (4-amino-2-ethoxyphenyl) piperidin-4-yl) (methyl) amino) -2-methylpropane -2-ol.
  • Step 5 (2-((2-((4- (4-(((1-hydroxycyclobutyl) methyl) (methyl) amino) piperidin-1-yl) -3-isopropoxy Preparation of phenyl) amino) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) phenyl) dimethylphosphine
  • Step 2) to Step 4) (2-((2-((4- (4- (cyclopropyl (methyl) amino) piperidin-1-yl) -3-isopropoxyphenyl) amino) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) phenyl) dimethylphosphine
  • Step 2) to Step 4) Referring to Step 5) to Step 7) in the preparation method of Example 17, the starting material is equimolar equivalent of N-cyclopropyl-1- (2-isopropoxy-4- Nitrophenyl) -N-methylpiperidine-4-amine instead of 1-((1- (2-ethoxy-4-nitrophenyl) piperidin-4-yl) (methyl) amino) 2-methylpropan-2-ol.
  • Example 38 (2-((2-((4- (4- (4-((2-hydroxy-2-methylpropyl) (methyl) amino) piperidin-1-yl) -3- (trifluoro Preparation of methoxy) phenyl) amino) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) phenyl) dimethylphosphine
  • Step 3 Dimethyl (2-((2-((4- (4- (methylamino) piperidin-1-yl) -3- (trifluoromethoxy) phenyl) amino) -7H- Preparation of pyrrolo [2,3-d] pyrimidin-4-yl) amino) phenyl) phosphine oxide
  • Step 4) (2-((2-((4- (4-((2-hydroxy-2-methylpropyl) (methyl) amino) piperidin-1-yl) -3- (trifluoromethyl Preparation of oxy) phenyl) amino) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) phenyl) dimethylphosphine
  • Example 39 For the preparation method of Example 39, refer to the preparation steps 1) to 3) of Example 38, wherein in step 1), an equimolar equivalent of N, N-dimethylpiperidine-4-amine is used instead of tert-butylmethyl (piperidine Pyridin-4-yl) carbamate.
  • Step 3) to Step 5) (2-((2-((4- (4-((2-fluoroethyl) (methyl) amino) piperidin-1-yl) -3-isopropoxybenzene ) Amino) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) phenyl) dimethylphosphine
  • Step 3) to Step 5) Referring to Step 5) to Step 7) in the preparation method of Example 17, the starting material is equimolar equivalent of N- (2-fluoroethyl) -1- (2-isopropoxy 4-nitrophenyl) -N-methylpiperidine-4-amine instead of 1-((1- (2-ethoxy-4-nitrophenyl) piperidin-4-yl) (methyl Group) amino) -2-methylpropan-2-ol.
  • Step 5) to Step 7) (2-((2-((3- (2-fluoroethoxy) -4- (4-((2-hydroxy-2-methylpropyl) (methyl) amino ) Piperidin-1-yl) phenyl) amino) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) phenyl) dimethylphosphine
  • Step 5) to Step 7) Referring to Step 5) to Step 7) in the preparation method of Example 17, the starting material is an equimolar equivalent of 1-((1- (2- (2-fluoroethoxy)- 4-nitrophenyl) piperidin-4-yl) (methyl) amino) -2-methylprop-2-ol instead of 1-((1- (2-ethoxy-4-nitrophenyl ) Piperidin-4-yl) (methyl) amino) -2-methylpropan-2-ol.
  • EDTA (0.5M pH8.0) solution preparation accurately weigh 14.612g of EDTA powder, add ultrapure water and make up to 100mL (if insoluble, heat to 37 °C, adjust pH to 8.0 with NaOH solution)
  • 1 ⁇ Kinase Assay Buffer Add 25mL HEPES solution (1M), 190.175mg EGTA, 5mL MgCl 2 solution (1M), 1mL DTT, 50 ⁇ L Tween-20 to the reagent bottle, add ultrapure water to volume to 500mL (adjust pH) To 7.5).
  • 1 ⁇ Detection Buffer Take 1 mL of 10 ⁇ Detection Buffer and add 9 mL of water to mix.
  • EGFR T790M kinase solution Dilute the kinase stock solution to a concentration of 0.2nM with 1 ⁇ Kinase Assay Buffer, mix well, and store on ice.
  • substrate solution Dilute the substrate ULight TM -PolyGT stock solution to 400 nM with 1 ⁇ Kinase Assay Buffer and mix.
  • 4 ⁇ ATP solution Dilute the ATP stock solution to a concentration of 20 ⁇ M with 1 ⁇ Kinase Assay buffer, and mix well.
  • test method is as follows:
  • a 96-well plate a the compound with a concentration of 10 mM was diluted 3 times with DMSO solution to form 11 gradients, and the 12th gradient was a pure DMSO solution (as a positive control); a new 96-well plate b was taken, The above solution was diluted 25-fold with ultrapure water (DMSO concentration was 4%).
  • Add 2 ⁇ substrate / ATP mixed solution Use a row gun to take 5 ⁇ l of the above 2 ⁇ substrate / ATP mixed solution into the corresponding reaction wells of a 384-well plate.
  • Negative control set a negative control well in a 384-well plate, and add 2.5 ⁇ l 4 ⁇ substrate, 2.5 ⁇ l 4 ⁇ enzyme solution, 2.5 ⁇ l 1 ⁇ Kinase Assay Buffer and 2.5 ⁇ l ultrapure water containing 4% DMSO .
  • Inhibition rate (read value of positive control well-read value of experimental well) / (read value of positive control well-read value of negative control well) * 100%
  • test compound inhibition of EGFR T790M- L858R-C797S enzymatic reaction by calculating inhibition of EGFR T790M-L858R-C797S IC 50 to an enzymatic reaction Screen for compounds with biochemical inhibitory activity.
  • the specific method of the test is the same as the method of Experimental Example 1 above, only the following conditions need to be adjusted: 1).
  • the final concentration of the ATP solution in the reaction is 1 ⁇ M; 2).
  • the final concentration of the substrate ULight TM -PolyGT is 50 nM;
  • the final concentration of EGFR L858R-T790M-C797S kinase is 0.5 nM.
  • Table 2 lists the measurement results of the EGFR T790M kinase and EGFR L858R-T790M-C797S tyrosine kinase inhibitory activity of the compounds of the examples in the present application, where A represents an IC 50 of less than or equal to 5 nM, and B represents an IC 50 of greater than 5 nM but less than Or equal to 50nM, C means IC 50 is greater than 50nM, NT means no corresponding kinase was tested.
  • Table 4 lists the test results of the compounds of the embodiments of the present invention on Ba / F3 EGFR-L858R / T790M and Ba / F3 EGFR-L858R / T790M / C797S cells, where A represents an IC 50 of 50 nM or less, and B represents IC 50 is greater than 50 nM but less than or equal to 100 nM, C means IC 50 is greater than 100 nM but less than or equal to 200 nM, and D means IC 50 is greater than 200 nM.
  • test of small molecule compounds inhibiting ALK kinase activity is as follows:
  • Perkin Elmer Ultra TR-FRET technology measures the activity of ALK kinase substrate phosphorylation in the reaction.
  • LANCE Ultra enzyme activity analysis Eu-labeled specific anti-phospho antibodies were used to detect phosphorylation of Ulight-substrate. When the detection antibody binds to the phosphorylated substrate, Eu and Ulight are close to each other. After receiving laser radiation at a wavelength of 320 or 340 nm, the energy emitted by Eu is transferred to Ulight and a 665 nm optical signal is excited. The intensity of the light signal is positively correlated with the phosphorylation level of Ulight-substrate in the reaction, enabling the quantitative determination of kinase activity.
  • the enzyme detection experiment uses ALK kinase provided by Carna Biosciences, ATP provided by Promega, and Perkin Elmer's Ultra Ulight TM- Poly GT substrate, Eu-W1024-anti-phosphotyrosine detection antibody, LANCE TM Detection Buffer, white OptiPlate-384 well plate, sealing membrane and Envison multi-function plate reader were used for experiments and detection.
  • the preparation method of the kinase buffer solution, stop solution, and color development solution, and the method of compound dilution are as follows:
  • test solution Eu-W1024-anti-phosphotyrosine detection antibody was formulated at a concentration of 8 nM with 1 ⁇ Detection Buffer.
  • stop solution 0.8mL of EDTA (0.5M, pH8.0) aqueous solution, 1mL of 10 ⁇ Detection buffer and 8.2mL of ultrapure water were mixed.
  • ALK kinase, ATP, and Ultra Ulight TM- Poly GT substrate was prepared with kinase buffers at 4 ⁇ intermediate concentrations of 2.8nM, 4 ⁇ M, and 200nM, respectively.
  • the complete enzymatic reaction system includes the above 2.5 ⁇ L ALK kinase, 2.5 ⁇ L ATP, and 2.5 ⁇ L after dilution. 4 ⁇ intermediate concentration compounds and 2.5 ⁇ L Ultra Ulight TM- Poly GT substrate.
  • the reaction was protected from light at room temperature for 2 hours.
  • 5 ⁇ L of the stop solution was added to stop the enzymatic reaction, and then 5 ⁇ L of the color detection solution was added to the reaction for 1 hour.
  • Use Envison multi-function plate reader to call the corresponding program to read the plate.
  • Percent inhibition (read from positive control well-read from experimental well) / (read from positive control well-read from negative control well)] * 100%.
  • the drug concentration and the corresponding inhibition rate were input to GraphPad and Prism5 to calculate the corresponding IC50.
  • Table 5 lists the results of determination of ALK kinase inhibitory activity of some of the compounds of the examples in the present application, where A means that the IC50 is less than or equal to 5nM, B means that the IC50 is greater than 5nM but less than or equal to 50nM, and C means that the IC50 is greater than 50nM.

Abstract

La présente invention concerne un composé de pyrrolopyrimidine contenant une substitution arylamine, un procédé de préparation et une application de celui-ci, qui se rapportent spécifiquement à un composé représenté par la formule (I), un isomère de celui-ci, un hydrate, un solvate, un sel pharmaceutiquement acceptable de celui-ci, et un promédicament de celui-ci, son procédé de préparation et son application dans la préparation d'un médicament qui agit en tant qu'inhibiteur de kinase.
PCT/CN2019/088316 2018-05-24 2019-05-24 Composé pyrrolopyrimidine contenant une substitution arylamine, son procédé de préparation et son application WO2019223777A1 (fr)

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