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WO2017190637A1 - Composé de pyrimidine condensé pour inhiber l'activité de la protéine tyrosine kinase - Google Patents

Composé de pyrimidine condensé pour inhiber l'activité de la protéine tyrosine kinase Download PDF

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Publication number
WO2017190637A1
WO2017190637A1 PCT/CN2017/082682 CN2017082682W WO2017190637A1 WO 2017190637 A1 WO2017190637 A1 WO 2017190637A1 CN 2017082682 W CN2017082682 W CN 2017082682W WO 2017190637 A1 WO2017190637 A1 WO 2017190637A1
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compound
mmol
group
ring
added
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PCT/CN2017/082682
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English (en)
Chinese (zh)
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王义汉
李焕银
任兴业
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深圳市塔吉瑞生物医药有限公司
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Priority to CN201780004361.5A priority Critical patent/CN108473473A/zh
Publication of WO2017190637A1 publication Critical patent/WO2017190637A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of medicine.
  • the present invention relates to fused pyrimidine compounds which have an inhibitory effect on protein tyrosine kinase activity, pharmaceutical compositions containing them, and processes for their preparation and use.
  • the epidermal growth factor receptor (ie, EGFR, ErbB-1 or HER1) is a member of the ErbB receptor family, and the ErbB receptor family includes four closely related receptor tyrosine kinase members: EGFR (ErbB-1), HER2/c-neu (ErbB-2), Her3 (ErbB-3) and Her4 (ErbB-4).
  • EGFR is a cell surface receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands. Mutations that affect EGFR expression or activity may result in cancer. It has been reported that EGFR is in an dysregulated state in most solid tumors such as lung cancer, breast cancer and brain tumors. It is estimated that 30% of epithelial cancers are associated with mutations, amplification or disorders of EGFR or family members.
  • EGFR-TKI EGFR kinase inhibitors
  • gefitinib and erlotinib EGFR kinase inhibitors
  • EGFR-TKI was subsequently found to treat non-small cells.
  • Primary or secondary drug resistance in lung cancer is a new challenge for us in the treatment of advanced non-small cell lung cancer. It is necessary to carry out new explorations and find countermeasures.
  • Third-generation and subsequent EGFR inhibitors include compounds such as AZD9291 and CO-1686, which irreversibly inhibit EGFR and are more efficient in patients with T790M-resistant mutations, but still have an inhibitory effect on wild-type EGFR.
  • the present invention provides a novel fused pyrimidine compound and a composition comprising the same, and a use thereof, which have better EGFR kinase inhibitory activity and high selectivity for the resistant mutations T790M, L858R and both thereof It can be used to treat, prevent, and alleviate EGFR kinase-mediated diseases.
  • R 1 is selected from H, -OH, halogen, -CN, -NO 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkoxy base;
  • L is selected from the group consisting of a bond, NR, O, CR 2 or S; wherein R is independently selected from H, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
  • R 2 is selected from a C 1 -C 6 alkyl group or a 3- to 6-membered heterocyclic group containing 1-2 hetero atoms selected from N and O, wherein the above group is unsubstituted or substituted by 1 to 3 substituents Substituents: halogen, -OH, -CN, -NO 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 6 R 7 ; wherein R 6 , R 7 are each independently selected from C 1 - C 6 alkyl, C 1 -C 6 alkoxy or C 3 -C 6 carbocyclyl;
  • R 3 , R 4 and R 5 are independently selected from H, halogen, -CN, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl;
  • Ring A is selected from a C 3 -C 6 carbocyclic group, a 3 to 10 membered heterocyclic group, a C 6 -C 14 aryl group or a C 5 -C 10 heteroaryl group;
  • Ring B is selected from the following structures:
  • each X 1 is independently selected from the group consisting of C, N, O and S atoms, each X 2 and X 3 being independently selected from C and N atoms, wherein the ring containing X 1 , X 2 and X 3 is optionally 1- 3 R 8 substituents substituted;
  • Ring C is selected from a C 3 -C 6 carbocyclic group, a 3 to 10 membered heterocyclic group, a C 6 -C 14 aryl group or a C 5 -C 10 heteroaryl group, which is optionally substituted by 1 to 3 R 8 Base substitution
  • R 8 is independently selected from H, halogen, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkoxy;
  • the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient.
  • a compound of the invention is provided in the pharmaceutical composition in an effective amount.
  • the compounds of the invention are provided in a therapeutically effective amount.
  • the compounds of the invention are provided in a prophylactically effective amount.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient, further comprising other therapeutic agents.
  • the invention provides a compound, a pharmaceutically acceptable salt, a stereoisomer, a solvate, a hydrate, a crystal form, a prodrug or an isotopic derivative thereof, and other therapeutic agents, and a pharmaceutically acceptable compound, A kit of acceptable carriers, adjuvants or vehicles.
  • the invention provides a method of treating cancer caused by EGFR (including cancer caused by EGFR mutation, eg, a cancer with a T790M mutation, a L858R mutation, and a L858R/T790M double mutation) in a subject in need thereof
  • a method comprising: administering to a subject an effective amount of a compound of the invention.
  • the EGFR-induced cancer is selected from the group consisting of: non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cancer, Gastrointestinal stromal tumors, leukemia, histiocytic lymphoma, nasopharyngeal carcinoma, etc.
  • the compound is administered orally, subcutaneously, intravenously or intramuscularly. In a specific embodiment, the compound is administered chronically.
  • C 1 -C 6 alkyl includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1 -C 6 , C 1 -C 5 , C 1 -C 4 , C 1 - C 3 , C 1 -C 2 , C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 C 4 -C 6 , C 4 -C 5 and C 5 -C 6 alkyl.
  • C 1 -C 6 alkyl refers to a straight or branched saturated hydrocarbon group having from 1 to 6 carbon atoms, also referred to herein as “lower alkyl.” In some embodiments, a C 1 -C 4 alkyl group is particularly preferred.
  • alkyl group examples include, but are not limited to, methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), uncle Butyl (C 4 ), sec-butyl (C 4 ), isobutyl (C 4 ), n-pentyl (C 5 ), 3-pentyl (C 5 ), pentyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butyl (C 5 ), tert-amyl (C 5 ) and n-hexyl (C 6 ).
  • each alkyl group is independently optionally substituted, ie, unsubstituted (“unsubstituted alkyl") or substituted with one or more substituents (“substituted alkyl”) For example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent.
  • the alkyl group is unsubstituted C 1 -C 6 alkyl (e.g., -CH 3).
  • the alkyl group is a substituted C 1 -C 6 alkyl.
  • C 1 -C 6 alkoxy refers to the group -OR wherein R is a substituted or unsubstituted C 1 -C 6 alkyl group. In some embodiments, a C 1 -C 4 alkoxy group is particularly preferred. Specific alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, N-Hexyloxy and 1,2-dimethylbutoxy.
  • Halo or halogen refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).
  • the halo group is F, Cl or Br.
  • the halogen group is F or Cl.
  • the halogen group is F.
  • C 1 -C 6 haloalkyl and “C 1 -C 6 haloalkoxy” mean the above-mentioned “C 1 -C 6 alkyl” and "C 1 -C 6 alkoxy", which are one or Multiple halogen groups are substituted.
  • a C 1 -C 4 haloalkyl group is particularly preferred, more preferably a C 1 -C 2 haloalkyl group.
  • a C 1 -C 4 haloalkoxy group is particularly preferred, more preferably a C 1 -C 2 haloalkoxy group.
  • Exemplary haloalkyl groups include, but the are not limited to: -CF 3, -CH 2 F, -CHF 2, -CHFCH 2 F, -CH 2 CHF 2, -CF 2 CF 3, -CCl 3, -CH 2 Cl , -CHCl 2 , 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like.
  • Exemplary haloalkoxy groups include, but are not limited to, -OCH 2 F, -OCHF 2 , -OCF 3 , and the like.
  • C 3 -C 6 carbocyclyl refers to a non-aromatic cyclic hydrocarbon group having 3 to 6 ring carbon atoms and zero heteroatoms. In some embodiments, a C 5 -C 6 carbocyclic group is preferred.
  • Carbocyclyl also includes ring systems wherein the above carbocyclyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the carbocyclic ring, and in such cases, the number of carbons continues to be represented The number of carbons in the carbocyclic system.
  • Exemplary such carbocyclic groups include, but are not limited to, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl ( C 5 ), cyclopentenyl (C 5 ), cyclopentadienyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), etc. Wait.
  • each of the carbocyclic groups is independently optionally substituted, ie, unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclic ring"base").
  • the carbocyclic group is unsubstituted C 3 -C 6 carbocyclyl.
  • the carbocyclyl is substituted with C 3 -C 6 carbocyclyl.
  • the "3- to 10-membered heterocyclic group” means a group of a 3- to 10-membered non-aromatic ring system having a ring carbon atom and 1 to 4 ring hetero atoms, wherein each hetero atom is independently selected from nitrogen, oxygen, Sulfur, boron, phosphorus and silicon.
  • the point of attachment may be a carbon or nitrogen atom as long as the valence permits.
  • a 3- to 6-membered heterocyclic group is particularly preferred, which is a 3- to 6-membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms; more preferably a 5- to 6-membered heterocyclic ring. a group which is a 5 to 6 membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring hetero atoms.
  • each of the heterocyclic groups is independently optionally substituted, ie, unsubstituted ("unsubstituted heterocyclic") or substituted with one or more substituents ("substituted hetero Ring base").
  • the heterocyclyl is an unsubstituted 3-10 membered heterocyclyl.
  • a heterocyclic group is a substituted 3-10 membered heterocyclyl.
  • the heterocyclic group further includes a ring system in which the above heterocyclic ring is fused to one or more carbocyclic groups, wherein the point of attachment is on the carbocyclic ring, or wherein the above heterocyclic ring is bonded to one or more aryl groups or A heteroaryl fused ring system wherein the point of attachment is on a heterocyclyl ring; and in such cases, the number of ring members continues to indicate the number of ring members in the heterocyclyl ring system.
  • Exemplary 3-membered heterocyclic groups containing one hetero atom include, but are not limited to, aziridine, oxacyclopropane, thicyclopropyl.
  • Exemplary 4-membered heterocyclic groups containing one hetero atom include, but are not limited to, azetidinyl, oxetanyl and thietane.
  • Exemplary 5-membered heterocyclic groups containing one hetero atom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione.
  • Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolyl, oxathiolanyl, oxathiolanyl (1,2-oxothio) Cyclopentenyl, 1,3-oxathiolanyl, dithiolanyl, dihydropyrazolyl, dihydroimidazolyl, dihydrothiazolyl, dihydroisothiazolyl, dihydrogen Oxazolyl, dihydroisoxazolyl, dihydrooxadiazolyl and oxazolidin-2-one.
  • Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 6-membered heterocyclic groups containing one hetero atom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridyl and thiacyclohexane.
  • Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dihydropyrazinyl, piperazinyl, morpholinyl, dithianyl, dioxoalkyl.
  • Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, hexahydrotriazinyl.
  • Exemplary 7-membered heterocyclic groups containing one hetero atom include, but are not limited to, azepanyl, oxaheptyl and thiaheptanyl.
  • Exemplary 8-membered heterocyclic groups containing one hetero atom include, but are not limited to, azacyclooctyl, oxacyclooctyl, and thicyclooctyl.
  • Exemplary 5-membered heterocyclic groups (also referred to herein as 5,6-bicyclic heterocyclyl) fused to a C6 aryl ring include, but are not limited to, indanyl, isoindoline , dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, and the like.
  • Exemplary 6-membered heterocyclic groups fused to a C 6 aryl ring include, but are not limited to, tetrahydroquinolyl, tetrahydroisoquinolinyl, and many more.
  • C 6 -C 14 aryl refers to a monocyclic or polycyclic (eg, bicyclic or tricyclic) 4n+2 aromatic ring system having 6 to 14 ring carbon atoms and zero heteroatoms (eg, having A group of 6, 10 or 14 ⁇ electrons shared in a ring arrangement.
  • an aryl group having six ring carbon atoms ( "C 6 aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms (" C10 aryl”; for example, naphthyl, eg, 1-naphthyl and 2-naphthyl).
  • an aryl group has fourteen ring carbon atoms (" C14 aryl"; for example, fluorenyl).
  • C14 aryl for example, fluorenyl
  • a C 6-10 aryl group is particularly preferred, more preferably a C 6 aryl group.
  • the aryl group also includes a ring system in which the above aryl ring is fused to one or more carbocyclic or heterocyclic groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to be represented. The number of carbon atoms in the aryl ring system.
  • each of the aryl groups is independently optionally substituted, that is, unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl").
  • the aryl group is an unsubstituted C 6 -C 14 aryl group.
  • the aryl group is a substituted C 6 -C 14 aryl group.
  • C 5 -C 10 heteroaryl means a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms (for example, having a ring-like arrangement) a group of 6 or 10 ⁇ electrons, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the point of attachment may be a carbon or nitrogen atom as long as the valence permits.
  • Heteroaryl bicyclic systems may include one or more heteroatoms in one or both rings.
  • Heteroaryl also includes ring systems wherein the above heteroaryl ring is fused to one or more carbocyclic or heterocyclic groups, and the point of attachment is on the heteroaryl ring, in this case a carbon atom The number continues to indicate the number of carbon atoms in the heteroaryl ring system.
  • a C 5 -C 6 heteroaryl group is particularly preferred, which is a 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms. .
  • each of the heteroaryl groups is independently optionally substituted, ie, unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"base").
  • the heteroaryl is an unsubstituted 5-10 membered heteroaryl.
  • the heteroaryl is a substituted 5-10 membered heteroaryl.
  • Exemplary 5-membered heteroaryl groups containing one hetero atom include, but are not limited to, pyrrolyl, furyl and thienyl.
  • Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing one hetero atom include, but are not limited to, pyridyl.
  • Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing one hetero atom include, but are not limited to, azepandinyl, oxepanethylene, and thiephenylene.
  • Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, mercapto, isodecyl, oxazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl , benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzooxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, Pyridazinyl and fluorenyl.
  • Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, acridinyl, quinolyl, isoquinolinyl, fluorenyl, quinoxalinyl, pyridazinyl and quinazolinyl .
  • pharmaceutically acceptable salt means that, within the scope of sound medical judgment, it is suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergies, etc., and with reasonable benefits/dangers. Those salts that are proportionate.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., pharmaceutically acceptable salts as described in detail in J. Pharmaceutical Sciences (1977) 66: 1-19.
  • Pharmaceutically acceptable salts of the compounds of the invention include those derived from suitable inorganic and organic acids and bases.
  • non-toxic acid addition salts are salts of amino and inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or salts with organic acids, such as acetic acid, oxalic acid, Maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or a salt formed using methods used in the art, for example, an ion exchange method.
  • amino and inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, Maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or a salt formed using methods used in the art, for example, an ion exchange method.
  • adipic acid salts alginate, ascorbate, aspartate, besylate, benzoate, disulfate, borate, butyrate, camphor Acid salt, camphor sulfonate, citrate, cyclopentanoate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, gluconate, glycerol Phosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate , malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate Salt, pectin
  • Pharmaceutically acceptable salts derived from suitable bases include the alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, and the like.
  • Further pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts and amine cations formed using counterions, counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, Nitrate, lower alkyl sulfonate and aryl sulfonate.
  • Subjects for administration include, but are not limited to, humans (ie, males or females of any age group, eg, pediatric subjects (eg, infants, children, adolescents) or adult subjects (eg, young Adults, middle-aged adults or older adults) and/or non-human animals, for example, mammals, for example, primates (eg, cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep , goats, rodents, cats and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • treatment includes the effect of a subject having a particular disease, disorder, or condition that reduces the severity of the disease, disorder, or condition, or delays or slows the disease, disorder. Or the development of a condition ("therapeutic treatment"), but also the effect that occurs before the subject begins to have a particular disease, disorder or condition (“prophylactic treatment”).
  • an "effective amount" of a compound refers to an amount sufficient to cause a target biological response.
  • an effective amount of a compound of the invention can vary depending on, for example, the biological target, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age of the subject. Health conditions and symptoms. Effective amounts include therapeutically and prophylactically effective amounts.
  • a "therapeutically effective amount" of a compound as used herein is in the course of treating a disease, disorder or condition. To provide or limit the likelihood of a therapeutic benefit, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition.
  • a therapeutically effective amount of a compound refers to the amount of a therapeutic agent used alone or in combination with other therapies that provides a therapeutic benefit in the treatment of a disease, disorder or condition.
  • the term "therapeutically effective amount” can include an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of other therapeutic agents.
  • a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder, or condition, or a quantity sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or to prevent disease, unless otherwise stated. The number of relapses of a disorder or condition.
  • a prophylactically effective amount of a compound refers to the amount of a therapeutic agent used alone or in combination with other agents that provides a prophylactic benefit in the prevention of a disease, disorder or condition.
  • the term “prophylactically effective amount” can include an amount that improves the overall amount of prevention, or enhances the prophylactic efficacy of other prophylactic agents.
  • Combination and related terms mean the simultaneous or sequential administration of a therapeutic agent of the invention.
  • a compound of the invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or together with another therapeutic agent in a single unit dosage form.
  • Cancer-induced cancer refers to a cancer characterized by an unsuitable high expression of the EGFR gene or a mutation of the EGFR gene that alters the biological activity of the EGFR nucleic acid molecule or polypeptide. Cancers caused by EGFR can occur in any tissue including brain, blood, connective tissue, liver, mouth, muscle, spleen, stomach, testes, and trachea.
  • Cancers caused by EGFR include, but are not limited to, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia , tissue cell lymphoma, nasopharyngeal cancer.
  • an "EGFR mutation” or “EGFR mutant” includes one or more deletions, substitutions or additions in the amino acid or nucleotide sequence of the EGFR protein or EGFR coding sequence.
  • the EGFR mutation may also include one or more deletions, substitutions or additions, or fragments thereof, so long as the mutant retains or increases tyrosine kinase activity relative to wild-type EGFR.
  • the kinase or phosphorylation activity can be increased or decreased relative to wild-type EGFR (eg, at least 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70). %, 80%, 90% or even 100%).
  • Exemplary EGFR mutations include, but are not limited to, the T790M mutation, the L858R mutation, and the L858R/T790M double mutation.
  • a compound of the invention refers to a compound of formula (I) below, a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotopic derivative thereof.
  • the invention relates to a compound of formula (I):
  • R 1 is selected from H, halogen, -OH, -CN, -NO 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkoxy base;
  • L is selected from the group consisting of a bond, NR, O, CR 2 or S; wherein R is independently selected from H, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
  • R 2 is selected from a C 1 -C 6 alkyl group or a 3- to 6-membered heterocyclic group containing 1-2 hetero atoms selected from N and O, wherein the above group is unsubstituted or substituted by 1 to 3 substituents Substituents: halogen, -OH, -CN, -NO 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 6 R 7 ; wherein R 6 , R 7 are each independently selected from C 1 - C 6 alkyl, C 1 -C 6 alkoxy or C 3 -C 6 carbocyclyl;
  • R 3 , R 4 and R 5 are independently selected from H, halogen, -CN, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl;
  • Ring A is selected from a C 3 -C 6 carbocyclic group, a 3 to 10 membered heterocyclic group, a C 6 -C 14 aryl group or a C 5 -C 10 heteroaryl group;
  • Ring B is selected from the following structures:
  • each X 1 is independently selected from the group consisting of C, N, O and S atoms, each X 2 and X 3 being independently selected from C and N atoms, wherein the ring containing X 1 , X 2 and X 3 is optionally 1- 3 R 8 substituents substituted;
  • Ring C is selected from a C 3 -C 6 carbocyclic group, a 3 to 10 membered heterocyclic group, a C 6 -C 14 aryl group or a C 5 -C 10 heteroaryl group, which is optionally substituted by 1 to 3 R 8 Base substitution
  • R 8 is independently selected from H, halogen, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkoxy;
  • R 1 is independently selected from halogen, -OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy or C 1 -C 6 Haloalkoxy. More preferably, R 1 is independently selected from halogen, -OH, C 1 -C 6 alkoxy or C 1 -C 6 haloalkoxy. More preferably, R 1 is a C 1 -C 6 alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, N-pentyloxy, n-hexyloxy and 1,2-dimethylbutoxy.
  • R 1 is a C 1 -C 4 alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy and sec-butoxy. More preferably, R 1 is a halogen such as Cl or Br. More preferably, R 1 is Cl or methoxy. Most preferably, R 1 is methoxy.
  • L is selected from the group consisting of a bond, NR, O, CR 2 , or S, wherein R is selected from H or C 1 -C 6 alkyl. More preferably, L is selected from NR, O, or S, wherein R is selected from C 1 -C 6 alkyl. Most preferably, L is selected from NR and R is a methyl group.
  • R 2 is selected from a C 1 -C 6 alkyl group substituted with 1 to 3 substituents or a 3 to 6 membered heterocyclic ring having 1 to 2 hetero atoms selected from N and O. And wherein the substituent is halogen, -OH, -CN, -NO 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 6 R 7 . More preferably, R 2 is selected from C 1 -C 6 alkyl substituted with 1 to 3 substituents, wherein the substituent is NR 6 R 7 .
  • R 2 is selected from a substituent-substituted C 1 -C 4 alkyl group, wherein the substituent is NR 6 R 7 . Most preferably, R 2 is selected from the group consisting of a substituent substituted ethyl group wherein the substituent is N(CH 3 ) 2 .
  • R 3 , R 4 and R 5 are independently selected from H, halogen or C 1 -C 6 alkyl. More preferably, R 3 , R 4 and R 5 are both H.
  • Ring A is selected from a C 5 -C 6 carbocyclic group, a 5 to 6 membered heterocyclic group, a C 6 aryl group or a C 5 -C 6 heteroaryl group. More preferably, Ring A is selected from a 5 to 6 membered heterocyclic group or a C 5 -C 6 heteroaryl group. More preferably, ring A is selected from a C 5 -C 6 heteroaryl group. Most preferably, Ring A is selected from C 5 heteroaryl groups.
  • Ring A has the following structure:
  • Each Y 1 is independently selected from C, N, O or S atoms
  • each Y 2 is independently selected from a C or N atom, which is optionally substituted with an R 9 substituent selected from the group consisting of H, halogen, -CN, C 1- C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy or C 1 -C 6 alkylsulfonyl, wherein said C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy or C 1 -C 6 alkylsulfonyl optionally substituted by one or more -OH .
  • Ring A has the following structure:
  • R 9 is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy or C 1 -C 6 alkyl a sulfonyl group, wherein the C 1 -C 6 alkyl group, a C 1 -C 6 haloalkyl group, a C 1 -C 6 alkoxy group, a C 1 -C 6 haloalkoxy group or a C 1 -C 6 alkylsulfonyl group The ground is replaced by one or more -OH.
  • Ring A has the following structure:
  • R 9 is independently selected from H, C 1 -C 6 alkyl, substituted with one or more -OH, C 1 -C 6 alkyl.
  • Ring B has the following structure:
  • each X 1 is independently selected from the group consisting of C, N, O and S atoms, each X 2 and X 3 being independently selected from C and N atoms, wherein the ring containing X 1 , X 2 and X 3 is optionally 1- 3 R 8 substituents substituted;
  • Ring C is selected from a C 5 -C 6 carbocyclic group, a 5 to 6 membered heterocyclic group, a C 6 -C 10 aryl group or a C 5 -C 6 heteroaryl group, which is optionally substituted with from 1 to 3 R 8 Base substitution
  • R 8 is independently selected from H, halogen, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkoxy;
  • X 1 is a C atom. In a more preferred embodiment of the above technical solution, X 1 is an N atom. In a more preferred embodiment of the above technical solution, X 1 is an O atom. In a more preferred embodiment of the above technical solution, X 1 is an S atom.
  • X 2 is a C atom. In a more preferred embodiment of the above technical solution, X 2 is an N atom.
  • X 3 is a C atom. In a more preferred embodiment of the above technical solution, X 3 is an N atom.
  • Ring C is selected from a C 5 -C 6 carbocyclic group, a 5- to 6-membered heterocyclic group, a C 6 aryl group or a C 5 -C 6 heteroaryl group.
  • ring C is selected from the group consisting of cyclopentadienyl, cyclohexadienyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, dihydropyridyl, pyrimidine Base, pyrazinyl, dihydropyrazinyl.
  • R 8 is independently selected from the group consisting of H, F, oxo and C 1 -C 6 alkyl.
  • two R 8 on the ring together form -(CH 2 ) 2 -, -(CH 2 ) 3 -, -OCH 2 -, -O(CH 2 ) 2 - Or -CH 2 OCH 2 -.
  • the ring B has the following structure:
  • each ring is optionally substituted with from 1 to 3 R 8 substituents, and R 8 , X 1 and X 2 are as defined above.
  • two R 8 on the same ring together form -Z m -.
  • two R 8 on different rings together form -Z m -.
  • the ring B has the following structure:
  • each ring is optionally substituted with 1-2 R 8 substituents, and R 8 , Z, m, X 1 and X 2 are as defined above.
  • Ring B is selected from the group consisting of:
  • R 8 is as defined above.
  • the invention relates to the following compounds:
  • the compounds of the invention may include one or more asymmetric centers, and thus may exist in a variety of stereoisomeric forms, for example, enantiomeric and/or diastereomeric forms.
  • the compounds of the invention may be in the form of individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, A racemic mixture and a mixture rich in one or more stereoisomers are included.
  • the isomers can be separated from the mixture by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of a chiral salt; or preferred isomers can be passed Prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • the invention also includes all suitable isotopic derivatives of the compounds of the invention.
  • An isotope derivative of a compound of the invention is defined as wherein at least one atom is replaced by an atom having the same atomic number but differing in atomic mass from the atomic mass typically found in nature.
  • isotopes which may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, for example 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, respectively. 18 F, 31 P, 32 P, 35 S and 36 Cl.
  • isotopic derivatives of the compounds of the invention are useful in drug and/or substrate tissue distribution studies.
  • Deuterated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability.
  • substitution with isotopes e.g., hydrazine, i.e., 2 H
  • Isotopic derivatives of the compounds of the invention can generally be prepared by conventional procedures, for example by descriptive methods or by the preparations described in the Examples below, using appropriate isotopic derivatives of the appropriate reagents.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof may be in an amorphous or crystalline form.
  • the compounds of the invention may exist in one or more crystalline forms. Accordingly, the invention includes within its scope all amorphous or crystalline forms of the compounds of the invention.
  • prodrugs are also included within the context of the present invention.
  • the term "prodrug” as used herein refers to a compound which is converted in vivo to an active form thereof having a medical effect by, for example, hydrolysis in blood.
  • Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ACSSymposium Series Vol. 14, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon, and H. Barbra "Improved oral drug delivery: Solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each This article is incorporated herein by reference.
  • a prodrug is any covalently bonded carrier which, when administered to a patient, releases the compound of formula (I) in vivo.
  • Prodrugs are typically prepared by modifying functional groups in such a way that the modifications can be cleaved by routine manipulation or in vivo to yield the parent compound.
  • Prodrugs include, for example, compounds of the invention wherein a hydroxy, amine or sulfhydryl group is bonded to any group which, when administered to a patient, can be cleaved to form a hydroxy, amine or sulfhydryl group.
  • prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol, mercapto and amine functional groups of the compounds of formula (I).
  • an ester such as a methyl ester, an ethyl ester or the like can be used.
  • the ester itself may be active and/or may hydrolyze under conditions in humans.
  • Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those groups which readily decompose in the human body to release the parent acid or a salt thereof.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention (also referred to as "active ingredient") and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises an effective amount of the active component.
  • the pharmaceutical composition comprises a therapeutically effective amount of the active component.
  • the pharmaceutical composition comprises a prophylactically effective amount of the active component.
  • a pharmaceutically acceptable excipient for use in the present invention refers to a non-toxic carrier, adjuvant or vehicle which does not destroy the pharmacological activity of the compound formulated together.
  • Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (eg, human serum white) Protein), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated plant fatty acids, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate , sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene - Block
  • kits e.g., pharmaceutical packs.
  • Kits provided may include a compound of the invention, other therapeutic agents, and first and second containers (eg, vials, ampoules, bottles, syringes, and/or dispersible packages or other materials containing the compounds of the invention, other therapeutic agents) Suitable container).
  • first and second containers eg, vials, ampoules, bottles, syringes, and/or dispersible packages or other materials containing the compounds of the invention, other therapeutic agents
  • kits can also optionally include a third container containing a pharmaceutically acceptable excipient for diluting or suspending a compound of the invention and/or other therapeutic agent.
  • a compound of the invention provided in a first container and a second container is combined with other therapeutic agents to form a unit dosage form.
  • formulation examples illustrate representative pharmaceutical compositions that can be prepared in accordance with the present invention.
  • the invention is not limited to the following pharmaceutical compositions.
  • Exemplary Formulation 1 - Tablet The compound of the present invention in dry powder form can be mixed with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 0.3-30 mg tablets (each tablet contains 0.1-10 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 2 - Tablet The compound of the present invention in dry powder form can be mixed with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is formed into a 30-90 mg tablet (each tablet contains 10-30 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 3 - Tablet The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 90-150 mg tablets (30-50 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 4-Tablet The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is formed into a 150-240 mg tablet (each tablet contains 50-80 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 5 - Tablet The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 240-270 mg tablets (each tablet contains 80-90 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 6-Tablet The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into a 270-450 mg tablet (each tablet contains 90-150 mg of active compound) in a tablet press.
  • Exemplary Formulation 7-Tablet The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 450-900 mg tablets (each tablet contains 150-300 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 8-Capsule The compound of the present invention in dry powder form can be mixed with a starch diluent in a weight ratio of about 1:1. The mixture was filled into 250 mg capsules (each capsule containing 125 mg of active compound).
  • Exemplary Formulation 9-Liquid The compound of the present invention (125 mg) can be mixed with sucrose (1.75 g) and xanthan gum (4 mg), and the resulting mixture can be blended, passed through a No. 10 mesh U.S. sieve, and then With previously prepared microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg) of the aqueous solution was mixed. Sodium benzoate (10 mg), flavor and color are diluted with water and added with stirring. Then, sufficient water can be added to give a total volume of 5 mL.
  • Exemplary Formulation 10 - Injection The compound of the invention may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of about 5 mg/mL.
  • the pharmaceutical composition provided by the present invention can be administered by a variety of routes including, but not limited to, oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration.
  • parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intrasynovial administration, intrasternal administration. , intracerebroventricular administration, intralesional administration, and intracranial injection or infusion techniques.
  • an effective amount of a compound provided herein is administered.
  • the amount of compound actually administered can be determined by the physician. .
  • the compound provided herein is administered to a subject at risk of developing the condition, typically based on a physician's recommendation and administered under the supervision of a physician, at the dosage level as described above.
  • Subjects at risk of developing a particular condition typically include subjects with a family history of the condition, or those subjects that are particularly susceptible to developing the condition by genetic testing or screening.
  • long-term administration can also be administered chronically.
  • Long-term administration refers to administration of a compound or a pharmaceutical composition thereof for a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or can be continuously administered indefinitely, For example, the rest of the subject.
  • chronic administration is intended to provide a constant level of the compound in the blood over a prolonged period of time, for example, within a therapeutic window.
  • a pharmaceutical composition of the present invention can be further delivered using various methods of administration.
  • a pharmaceutical composition can be administered by bolus injection, for example, to increase the concentration of the compound in the blood to an effective level.
  • the bolus dose depends on the target systemic level of the active ingredient through the body, for example, an intramuscular or subcutaneous bolus dose that causes a slow release of the active ingredient, while a bolus that is delivered directly to the vein (eg, via IV IV drip) ) can be delivered more quickly, so that the concentration of the active ingredient in the blood is rapidly increased to an effective level.
  • the pharmaceutical composition can be administered in a continuous infusion form, for example, by IV intravenous drip to provide a steady state concentration of the active ingredient in the subject's body.
  • a bolus dose of the pharmaceutical composition can be administered first, followed by continued infusion.
  • Oral compositions can be in the form of a bulk liquid solution or suspension or bulk powder. More generally, however, the composition is provided in unit dosage form for ease of precise dosing.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active ingredient suitable to produce the desired therapeutic effect with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, pre-measured ampoules or syringes of liquid compositions, or in solids Pills, tablets, capsules and the like in the case of a body composition.
  • the compound will generally be a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being useful for forming the desired form of administration.
  • a carrier or excipient and a processing aid is provided in unit dosage form for ease of precise dosing.
  • a representative regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses.
  • each dose provides from about 0.01 to about 20 mg/kg of a compound of the invention, each preferably providing from about 0.1 to about 10 mg/kg, especially from about 1 to about 5 mg/kg.
  • a transdermal dose is generally selected in an amount of from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably about 0.1. To about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • the injection dose level ranges from about 1 mg/kg/hr to at least 10 mg/kg/hr from about 1 to about 120 hours, especially 24 to 96 hours.
  • a preload bolus of about 0.1 mg/kg to about 10 mg/kg or more can also be administered.
  • the maximum total dose cannot exceed about 2 g/day.
  • Liquid forms suitable for oral administration may include suitable aqueous or nonaqueous vehicles as well as buffers, suspending and dispersing agents, coloring agents, flavoring agents, and the like.
  • the solid form may include, for example, any of the following components, or a compound having similar properties: a binder, for example, microcrystalline cellulose, tragacanth or gelatin; an excipient such as starch or lactose, a disintegrant, For example, alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silica; a sweetener such as sucrose or saccharin; or a flavoring agent such as mint, water Methyl salicylate or orange flavoring.
  • a binder for example, microcrystalline cellulose, tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrant, For example, alginic acid, Primogel or corn star
  • Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art.
  • the active compound will typically be a minor component, often from about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.
  • transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient.
  • the active component When formulated as an ointment, the active component is typically combined with a paraffin or water miscible ointment base.
  • the active ingredient can be formulated as a cream with, for example, an oil-in-water cream base.
  • Such transdermal formulations are well known in the art and generally include other ingredients for enhancing stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope of the invention.
  • transdermal administration can be accomplished using a reservoir or a porous membrane type, or a patch of a plurality of solid matrices.
  • compositions for oral administration, injection or topical administration are merely representative.
  • Other materials and processing techniques, etc. are set forth in Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, part 8 of which is incorporated herein by reference.
  • the compounds of the invention may also be administered in sustained release form or from a sustained release delivery system.
  • sustained release materials can be found in Remington's Pharmaceutical Sciences.
  • the invention further relates to pharmaceutically acceptable formulations of the compounds of the invention.
  • the formulation comprises water.
  • the formulation comprises a cyclodextrin derivative.
  • the most common cyclodextrins are alpha-, beta- and gamma-cyclodextrins consisting of 6, 7 and 8 alpha-1,4-linked glucose units, respectively, optionally including one on the attached sugar moiety. Or a plurality of substituents including, but not limited to, methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substituted.
  • the cyclodextrin is a sulfoalkyl ether beta-cyclodextrin, eg, sulfobutylether beta-cyclodextrin, also known as Captisol. See, for example, U.S. 5,376,645.
  • the formulation comprises hexapropyl- ⁇ -cyclodextrin (eg, 10-50% in water).
  • the compounds of the invention or compositions thereof may be administered in combination with other therapeutic agents to treat the disease.
  • therapeutic agents include, but are not limited to, Adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan ( Topotecan), taxol, interferon, platinum derivatives, taxanes (eg, paclitaxel), vinca alkaloids (eg, vinblastine), anthracycline ( Anthracycline) (eg, doxorubicin), epipodophyllotoxin (eg, etoposide), cisplatin, mTOR inhibitor (eg, rapamycin), Methotrexate, actinomycin D, dolastatin 10, colchicine, emetine, trimetrexate, chlorobenzene Metoprine, cyclosporine, daunorubicin, teniposide, amphotericin, alkylating agent (eg chlorambucil
  • a compound of the invention or a composition thereof can be administered in combination with any one or more anti-proliferative or chemotherapeutic agents selected from the group consisting of: abarelix, aldileukin (aldesleukin), alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, anastrozole, arsenic trioxide, day Asparaginase, azacitidine, BCG Live, bevacuzimab, fluorouracil, bexarotene, bleomycin, bortezomib, white Busulfan, calbuterone, capecitabine, camptothecin, carboplatin, carmustine, celecoxib, cetuximab Antibiotic (cetuximab), chlorambucil, cladribine, clofarabine, cyclophosphamide, cytarabine, actinomycin D, darbepo
  • therapeutic agents to which the compounds of the invention may also be combined include, but are not limited to, therapeutic agents for Alzheimer's Disease, such as donepezil hydrochloride and rivastigmine. ; therapeutic agents for Parkinson's Disease, such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole ( Pramipexole), bromocriptine, pergolide, trihexephendyl, and amantadine; a therapeutic agent for multiple sclerosis (MS), Such as beta interferon, glatiramer acetate and mitoxantrone; therapeutic agents for asthma, such as albuterol and montelukast; therapeutic agents for schizophrenia, such as Zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1RA, azathioprine , cyclophosphamide and sulfasala
  • those other active agents can be administered separately from the compositions containing the compounds of the invention as part of a multiple dosing regimen.
  • those active agents may be part of a single dosage form, mixed with a compound of the invention in a single composition. If administered as multiple doses If a portion of the regimen is administered, then the two active agents can be provided simultaneously, sequentially, or at intervals from one another (usually within 5 hours of each other).
  • the invention provides a method for inhibiting a protein tyrosine kinase (such as EGFR kinase) or treating a disease (such as cancer, cell proliferative disease, inflammation, infection, immune disease, organ transplantation, viral disease, cardiovascular disease or A method of metabolic disease comprising the steps of administering a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug thereof, to a subject in need of treatment Or an isotope derivative, or a pharmaceutical composition of the invention.
  • a protein tyrosine kinase such as EGFR kinase
  • a disease such as cancer, cell proliferative disease, inflammation, infection, immune disease, organ transplantation, viral disease, cardiovascular disease or A method of metabolic disease comprising the steps of administering a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug thereof, to a subject in need of treatment Or
  • the compounds of the invention are useful in the treatment of cancer caused by EGFR.
  • the compounds are useful for treating cancer caused by EGFR expressing an EGFR mutant and for treating cancer caused by EGFR that is refractory to RTKI therapy (eg, erlotinib or gefitinib).
  • the compounds of the invention are inhibitors of at least one mutant of EGFR and are therefore suitable for treatment with one or more EGFR mutants (eg, deletion mutations, activating mutations, resistance mutations, or combinations thereof, specific examples include T790M mutations, One or more disorders associated with the activity of the L858R mutation and the L858R/T790M double mutation.
  • the invention provides a method of treating a mutant EGFR mediated disorder comprising administering a compound of the invention, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, to a patient in need thereof a solvate, hydrate, crystal form, prodrug or isotope derivative, or a step of administering a pharmaceutical composition of the invention.
  • Cancers treatable by the compounds of the invention include, but are not limited to, non-small cell lung cancer (NSCLS), small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, Hyperproliferative diseases such as gastrointestinal stromal tumors, leukemia, histiocytic lymphoma, and nasopharyngeal carcinoma.
  • the compounds of the invention may also be used to maintain the maintenance of cancer recurrence in patients in need of such treatment.
  • an effective amount of a compound of the invention will generally be administered in a single or multiple doses at an average daily dose of from 0.01 mg to 50 mg of compound per kilogram of patient body weight, preferably from 0.1 mg to 25 mg of compound per kilogram of patient body weight.
  • the compounds of the invention may be administered to a patient in need of such treatment in a daily dosage range of from about 1 mg to about 3500 mg per patient, preferably from 10 mg to 1000 mg.
  • the daily dose per patient can be 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 500, 600, 700, 800, 900 or 1000 mg. It can be administered one or more times daily, weekly (or several days apart) or on an intermittent schedule.
  • the compound can be administered one or more times per day on a weekly basis (e.g., every Monday), continually or for several weeks, such as 4-10 weeks.
  • the administration may be continued for several days (e.g., 2-10 days), followed by a few days (e.g., 1-30 days) without administration of the compound, and the cycle may be repeated indefinitely or repeated for a given number of times, such as 4-10 Cycles.
  • the compounds of the invention may be administered daily for 5 days, then intermittently for 9 days, then administered daily for 5 days, then intermittent for 9 days, and so on, optionally repeating the cycle or repeating 4-10 times.
  • EGFR-TKI e.g., erlotinib or gefitinib
  • the individual components of the combination therapy can be administered at their dosage level and regimen for monotherapy.
  • erlotinib has been orally administered at a dose of 150 mg per day for the treatment of non-small cell lung cancer, and has been orally administered at a dose of 100 mg per day for pancreatic cancer.
  • gefitinib is used to treat non- Small cell lung cancer has been administered orally at 250 mg per day.
  • EGFR-TKI e.g., erlotinib or gefitinib
  • the dosage level of one or both components is reduced compared to when used alone.
  • the compounds of the present invention can be prepared according to conventional methods in the art and using suitable reagents, starting materials, and purification methods known to those skilled in the art.
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (e.g., 0 ° C to 100 ° C, preferably 0 ° C to 80 ° C).
  • the reaction time is usually from 0.1 to 60 hours, preferably from 0.5 to 24 hours.
  • Iron powder (80 mg, 1.4 mmol) and ammonium chloride (23 mg, 0.44 mmol) were added to a solution of compound 34 (160 mg, 0.29 mmol) in ethanol (3 mL) and water (1 mL). After reacting for 2 hours at ° C, the reaction mixture was cooled to room temperature, and the ethanol was removed under reduced pressure.
  • Trifluoroacetic acid (3 mL) was added to a solution of compound 66 (160 mg, 0.24 mmol) in dichloromethane (6 mL), and the reaction was allowed to react at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. EtOAc EtOAc m. The reaction mixture was concentrated under reduced pressure, diluted with water (20 mL), dichloromethane (30 mL??
  • Triethylsilane (0.29 g, 2.54 mmol) and trifluoroacetic acid (1.0 g, 8.89 mmol) were added dropwise to a solution of Compound 133 (100 mg, 0.127 mmol) in dichloromethane (3 mL). The reaction was stirred for 2 h. Saturated NaHCO 3 (20mL) The reaction was quenched, (30mL x 3) and extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated and the residue was subjected to silica gel column to give a white solid 30mg, yield 43.6%.
  • LC-MS (APCI): m / z 543.2 (M + 1) +.
  • Triethylsilane (1.16 g, 10 mmol) and trifluoroacetic acid (3.42 g, 30 mmol) were added dropwise to a solution of Compound 129 (528 mg, 1.0 mmol) in dichloromethane (5 mL). 2h. Saturated NaHCO 3 (20mL) The reaction was quenched, (30mL x 3) and extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated and the residue was subjected to silica gel column to give a white solid 200mg, yield 69.9%.
  • LC-MS (APCI): m / z 287.1 (M + 1) +.
  • WT EGFR (Carna, Cat. No. 08-115), EGFR [L858R] (Carna, Cat. No. 08-502) EGFR [L858R/T790M] (Carna, Cat. No. 08-510), ATP (Sigma, Cat. No. A7699-1G) ), DMSO (Sigma, Cat. No. D2650), 96-well plate (Corning, Cat. No. 3365), 384-well plate (Greiner, Cat. No. 784076), HTRF Kinase TK Kit (Cisbio, Cat. No. 62TK0PEJ), Erlotinib (Selleckchem, Cat. No. S7787), EGFR [d746-750] (Life Technologies, Cat.
  • test compound was dissolved in DMSO to make a 20 mM mother liquor. Then, it was diluted 3 times in a medium gradient of DMSO and diluted 10 times. When dosing, dilute with buffer for 10 times.
  • WT EGFR, EGFR [L858R] and EGFR [L858R/T790M] kinase assays WT EGFR, EGFR [L858R] or EGFR [L858R/T790M] kinases in pre-diluted compounds at 5x kinase buffer A Mix for 10 minutes, double wells per concentration. The corresponding substrate and ATP in the kit were added and reacted at room temperature for 20 minutes (where a positive control was set: negative for blank control and positive for erlotinib).
  • the detection reagent (the reagent in the HTRF Kinase TK kit) was added, and after incubation at room temperature for 30 minutes, the enzyme activity in the presence of the compound of the present invention at each concentration was measured by an Evnvision microplate reader, and the compound concentrations of different concentrations were calculated.
  • A means IC 50 ⁇ 1 nM
  • B means IC 50 It is 1-10 nM
  • C means that the IC 50 is 10-50 nM
  • D means that the IC 50 is 50-100 nM.
  • the compounds of the present invention were tested in the above kinase inhibition assay, and the compounds of the present invention were found to have potent activity against EGFR [L858R] and EGFR [L858R/T790M] and superior selectivity to WT EGFR.
  • the results for the example compounds are summarized in Table 1 below.
  • the anti-proliferative activity of the compound of the present invention against three tumor cells cultured in vitro was examined by MTS method.
  • the experimental results show that the compound of the present invention has an inhibitory effect on the in vitro proliferation of cancer cells cultured in vitro; wherein the inhibition of proliferation of lung cancer cells in vitro is stronger than that of skin cancer cells in vitro.
  • Skin cancer cell line A431 (purchased from the American Standard Collection of Biological Products (ATCC)); lung cancer cells NCI-H1975 (purchased from the American Standard Collection of Biological Products (ATCC)) and HCC827 (purchased from the American Standard Collection of Biological Products (ATCC) Both were cultured in RPMI1640 medium containing 10% fetal bovine serum, 100 U/ml penicillin, and 100 ⁇ g/ml streptomycin.
  • RPMI-1640 (GIBCO, catalog number A10491-01); fetal bovine serum (GIBCO, catalog number 10099141); 0.25% trypsin-EDTA (GIBCO, catalog number 25200); penicillin-streptomycin, liquid (GIBCO, catalog number 15140-122); DMSO (Sigma, Cat. No. D2650); MTS Test Kit (Promega, Cat. No. G3581), 96-well plate (Corning, Cat. No. 3365).
  • test compound preparation The test compound was dissolved in DMSO to prepare a 20 mM mother liquor and stored at -20 °C. When used, it was diluted 3 times with a gradient of DMSO and diluted 10 times. The drug medium was further diluted 4 times with the cell culture medium RPMI-1640.
  • MTS cell viability assay 0.25% trypsin-EDTA digested logarithmic growth phase cells, inoculated with 150 ⁇ l in 96-well plates at an optimized density, and added to the medium RPMI-1640 diluted 4 times after 24 hours, 50 ⁇ l/well (general Ten concentrations were selected: 100, 33.3, 11.1, 3.70, 1.23, 0.412, 0.137, 0.0457, 0.0152, 0.00508 ⁇ M). A well of the same volume of 0.5% DMSO was added as a control. After the cells were cultured for 72 hours, MTS was assayed for cell viability.
  • the compounds of the invention were tested in the above cytotoxicity assay and found to be compounds of the invention against lung cancer cells NCI-H1975 and HCC827 has potent activity and superior selectivity to skin cancer cells A431.
  • the results of the inhibition of in vitro proliferation of cancer cells by the examples are summarized in Table 2 below.
  • Microsomal experiments human liver microsomes: 0.5 mg/mL, BD Gentest; rat liver microsomes: 0.5 mg/mL, Xenotech; mouse liver microsomes: 0.5 mg/mL, Xenotech; coenzyme (NADPH/NADH): 1 mM, Sigma Life Science; magnesium chloride: 5 mM, 100 mM phosphate buffer (pH 7.4).
  • Preparation of stock solution A certain amount of the compound powder of the example was accurately weighed and dissolved to 5 mM with DMSO.
  • phosphate buffer 100 mM, pH 7.4.
  • the pH was adjusted to 7.4, diluted 5 times with ultrapure water before use, and magnesium chloride was added to obtain a phosphate buffer (100 mM) containing 100 mM potassium phosphate, 3.3 mM magnesium chloride, and a pH of 7.4.
  • NADPH regeneration system containing 6.5 mM NADP, 16.5 mM G-6-P, 3 U/mL G-6-P D, 3.3 mM magnesium chloride was prepared and placed on wet ice before use.
  • Formulation stop solution acetonitrile solution containing 50 ng/mL propranolol hydrochloride and 200 ng/mL tolbutamide (internal standard). Take 25057.5 ⁇ L of phosphate buffer (pH 7.4) into a 50 mL centrifuge tube, add 812.5 ⁇ L of human liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg/mL. Take 25057.5 ⁇ L of phosphate buffer (pH 7.4) into a 50 mL centrifuge tube, add 812.5 ⁇ L of rat liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg/mL.
  • liver microsome dilution having a protein concentration of 0.625 mg/mL.
  • the corresponding compound had a reaction concentration of 1 ⁇ M and a protein concentration of 0.5 mg/mL.
  • 100 ⁇ L of the reaction solution was taken at 10, 30, and 90 min, respectively, and added to the stopper, and the reaction was terminated by vortexing for 3 min.
  • the plate was centrifuged at 5000 x g for 10 min at 4 °C.
  • 100 ⁇ L of the supernatant was taken into a 96-well plate to which 100 ⁇ L of distilled water was previously added, mixed, and sample analysis was performed by LC-MS/MS.
  • the compounds of the present invention were tested in the above microsomal experiments and found to have superior metabolic stability.
  • the results of the human liver microsome experiment and the rat liver microsome experiment of the representative examples are summarized in Table 3 below.
  • Rats were fed a standard diet and given water. Fasting began 16 hours before the test.
  • the drug was dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the eyelids at a time point of 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration.
  • Rats were briefly anesthetized after inhalation of ether, and 300 ⁇ L of blood samples were collected from the eyelids in test tubes. There was 30 ⁇ L of 1% heparin salt solution in the test tube. The tubes were dried overnight at 60 ° C before use. After the blood sample collection was completed at a later time point, the rats were anesthetized with ether and sacrificed.
  • Plasma samples were centrifuged at 5000 rpm for 5 minutes at 4 ° C to separate plasma from red blood cells. Pipette 100 ⁇ L of plasma into a clean plastic centrifuge tube, indicating the name and time of the compound. Plasma was stored at -80 °C prior to analysis. The concentration of the compound of the invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points.
  • the compounds of the invention were tested in the above pharmacokinetic experiments in rats and found to have certain pharmacokinetic properties in animals.
  • the results of the pharmacokinetic experiments of the representative Example 2 and the rat of Example 29 are summarized in Table 4 below.

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Abstract

L'invention concerne un composé de pyrimidine condensé tel que présenté dans la formule (I), une préparation de celui-ci et une composition pharmaceutique comprenant le composé, un sel pharmaceutiquement acceptable, un stéréoisomère, un solvate, un hydrate, une forme cristalline, un promédicament ou un dérivé d'isotope de celui-ci. Le composé peut être utilisé pour le traitement et/ou la prévention de maladies liées aux protéines tyrosine kinases telles que des maladies liées à la prolifération de cellules, des cancers et des maladies immunologiques.
PCT/CN2017/082682 2016-05-06 2017-05-02 Composé de pyrimidine condensé pour inhiber l'activité de la protéine tyrosine kinase WO2017190637A1 (fr)

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CN113956259A (zh) * 2021-11-05 2022-01-21 华北水利水电大学 一种丙烯酰胺类药物的制备方法
CN114846003A (zh) * 2019-08-09 2022-08-02 阿提奥斯医药有限公司 用于治疗癌症的氘代化合物

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CN115246822B (zh) * 2021-04-27 2024-10-29 中国科学院上海药物研究所 嘧啶类化合物及其制备方法和用途

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WO2016133935A1 (fr) * 2015-02-17 2016-08-25 Neupharma, Inc. Entités chimiques, compositions et méthodes particulières
CN106496196A (zh) * 2016-10-20 2017-03-15 南京雷科星生物技术有限公司 一种喹唑啉、吡啶并嘧啶或则双并嘧啶衍生物表皮生长因子抑制剂及其制备方法与用途

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US10435388B2 (en) 2016-01-07 2019-10-08 Cs Pharmatech Limited Selective inhibitors of clinically important mutants of the EGFR tyrosine kinase
CN110078732A (zh) * 2018-01-26 2019-08-02 沈阳药科大学 嘌呤类化合物及其用途
CN114846003A (zh) * 2019-08-09 2022-08-02 阿提奥斯医药有限公司 用于治疗癌症的氘代化合物
CN113956259A (zh) * 2021-11-05 2022-01-21 华北水利水电大学 一种丙烯酰胺类药物的制备方法

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