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WO2020088390A1 - Composés de pyrimidopyrazole utilisés en tant qu'inhibiteurs d'egfr de quatrième génération - Google Patents

Composés de pyrimidopyrazole utilisés en tant qu'inhibiteurs d'egfr de quatrième génération Download PDF

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Publication number
WO2020088390A1
WO2020088390A1 PCT/CN2019/113608 CN2019113608W WO2020088390A1 WO 2020088390 A1 WO2020088390 A1 WO 2020088390A1 CN 2019113608 W CN2019113608 W CN 2019113608W WO 2020088390 A1 WO2020088390 A1 WO 2020088390A1
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reaction
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room temperature
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English (en)
Chinese (zh)
Inventor
桑迎霞
谷晓辉
诸舜伟
薛黎婷
于晓虹
任晋生
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Jiangsu Simcere Pharmaceutical Co Ltd
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Jiangsu Simcere Pharmaceutical Co Ltd
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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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D403/14—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 three or more hetero rings

Definitions

  • the present invention relates to novel pyrimidine pyrazole compounds as fourth-generation (T790M / C797S mutation) EGFR kinase inhibitors and their medical applications, and specifically discloses compounds represented by formula (I), their stereoisomers, racemates, Tautomers, isotopic labels, nitrogen oxides or pharmaceutically acceptable salts thereof.
  • EGFR Epithelial growth factor Receptor
  • EGF epithelial growth factor
  • EGFR belongs to a family of ErbB receptors, which includes EGFR (ErbB-1), HER2 / c-neu (ErbB-2), HER3 (ErbB-3) and HER4 (ErbB-4).
  • EGFR is also called HER1, ErbB1.
  • EGFR is widely distributed on the cell surface of mammalian epithelial cells, fibroblasts, glial cells, keratinocytes, etc.
  • EGFR signaling pathway plays an important role in the physiological processes of cell growth, proliferation and differentiation.
  • EGFR is divided into three regions: extracellular ligand binding region, transmembrane region and intracellular kinase region.
  • extracellular ligand binding region When the EGFR is bound by the corresponding ligand, it will induce the formation of homo- or heterodimers, thereby activating the intracellular tyrosine kinase pathway to phosphorylate itself, thereby guiding downstream phosphorylation, including MAPK, Akt and JNK Pathway to induce cell proliferation.
  • EGFR tyrosine kinase inhibitor (Tyrosine Kinase Inhibitor, TKI) is to block endogenous ATP binding to the intracellular kinase region, thereby inhibiting receptor phosphorylation and the activation of downstream signal transduction molecules, blocking tumors Cell proliferation.
  • TKI Tyrosine Kinase Inhibitor
  • EGFR targeted therapy has successfully entered the clinical stage and drugs have been marketed, EGFR gene mutations have led to drug resistance.
  • the mutations mainly occur in exons 18-21, of which the deletion of exon 19 and the point mutation of L858R in exon 21 are the most common mutation subtypes, accounting for 90% of all mutation types. With the development and use of drugs, most drug resistance appears in the second mutation of T790M in the gatekeeper region of kinases.
  • the present invention provides the compound represented by formula (I), its stereoisomers, racemates, and Variant isomers, isotope labels, nitrogen oxides or pharmaceutically acceptable salts thereof,
  • E is selected from Y is selected from O or S;
  • R 1 , R 2 , R 3 , R 4 are the same or different, and are independently selected from C 1-12 alkyl;
  • A is selected from N or C-Q;
  • B is selected from N or C-D
  • Q and D are the same or different and are independently selected from H, halogen, cyano, hydroxy, amino, unsubstituted or optionally substituted with one, two or more R a of the following groups: C 1-12 alkane group, C 1-12 heteroalkyl, C 2 - 12 alkenyl group, C 2-12 alkenyl, heteroaryl, C 2 - 12 alkynyl group, C 2-12 heteroaryl alkynyl, C 1-12 alkoxy, C 3 --20 cycloalkyl, 3-20 membered heterocyclyl, C 6 - 20 aryl, 5-20 membered heteroaryl, -COOC 1-12 alkyl, -COC 1-12 alkyl;
  • Each R a is the same or different and is independently selected from halogen, cyano, amino, hydroxy, unsubstituted or optionally substituted with one, two or more Rs of the following groups: C 1-12 alkyl, C 1-12 heteroalkyl, C 1-12 alkoxy, C 3 - 20 cycloalkyl, 3-20 membered heterocyclyl, -COOC 1-12 alkyl, -COC 1-12 alkyl;
  • V and Z are the same or different and are independently selected from H, halogen, cyano, hydroxy, amino, unsubstituted or optionally substituted with one, two or more R b of the following groups: C 1-12 alkane group, C 1-12 heteroalkyl, C 2 - 12 alkenyl group, C 2-12 alkenyl, heteroaryl, C 2 - 12 alkynyl group, C 2-12 heteroaryl alkynyl, C 1-12 alkoxy, C 3 --20 cycloalkyl, 3-20 membered heterocyclyl, C 6 - 20 aryl, 5-20 membered heteroaryl, -COOC 1-12 alkyl, -COC 1-12 alkyl, -N (C 1 -12 alkyl) 2 , -NHC 1-12 alkyl;
  • Each R b is the same or different and is independently selected from halogen, cyano, hydroxy, amino, unsubstituted or optionally substituted with one, two or more Rs of the following groups: C 1-12 alkyl, C 1-12 alkoxy, C 1-12 heteroalkyl, C 3 - 20 cycloalkyl, 3-20 membered heterocyclyl;
  • Each Rs is the same or different and is independently selected from halogen, CN, OH, C 1-12 alkyl;
  • W is selected from the group consisting of hydrogen, unsubstituted or optionally substituted with one, two or more R c : C 1-12 alkyl, C 1-12 heteroalkyl, C 1-12 alkanoyl, C 1-12 alkanoyl heteroaryl, 3-20 membered heterocyclyl group, C 3 - 20 cycloalkyl, 3-20 membered heterocyclyl, C 6 - 18 aryl, 5-20 membered heteroaryl, C 3 - 20 cycloalkyl and C 3 - 20 cycloalkyl group formed spiro cycloalkyl group, C 3 - 20 cycloalkyl group spiro ring and 3-20 membered heterocyclic group formed, 3-20 membered heterocyclic group 3-20 membered Spirocyclic group formed by heterocyclic group, C3-20 cycloalkyl and C3-20 cycloalkyl cyclic group, C3-20 cycloalkyl and 3-20 membered hetero
  • Q and D are identical or different and independently selected from H, halo, cyano, hydroxy, amino, unsubstituted or optionally substituted with one, two or more of the following R a substituents group Group: C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 alkenyl, C 1-6 heteroalkenyl, C 1-6 alkynyl, C 1-6 heteroalkynyl, C 3- 6 cycloalkyl, C 3-6 heterocycloalkyl, phenyl and 5-6 membered heteroaryl;
  • V and Z are the same or different and are independently selected from H, halogen, cyano, hydroxy, amino, unsubstituted or optionally substituted with one, two or more R b of the following groups: C 1-6 alkane Group, C 1-6 heteroalkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, phenyl and 5-6 membered heteroaryl, the C 1-6 alkyl, C 1 -6 heteroalkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, phenyl and 5-6 membered heteroaryl;
  • W is selected from the group consisting of hydrogen, unsubstituted or optionally substituted with one, two or more R c : C 1-6 alkyl, C 1-6 heteroalkyl, C 1-3 alkanoyl, C 1-3 Heteroalkanoyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 3-6 cycloalkyl and C 3-6 cycloalkyl spiro, C 3-6 cycloalkyl Spirocyclic group with C 3-6 heterocyclic group, C 3-6 cycloalkyl group and C 3-6 cycloalkyl group, C 3-6 cycloalkyl group and C 3-6 heterocyclic group Cyclocyclic group, C 3-6 heterocyclic group and C 3-6 heterocyclic group, C 5-14 bridge ring group, C 5-14 hetero bridge ring group;
  • each R a, R b, R c identical or different, each independently selected from -F, -Cl, -Br, -I, -OH, -CN, -NH 2, -CH 3 , CH 3 CH 2- , -CF 3 , -CHF 2 , -CH 2 F, NH 2 CH 2- , -NH (CH 3 ) 2 , -OCH 3 , CH 3 CH 2 O-, CH 3 OCH 2 -, MeSO 2- , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 C (CH 3 ) 2 OH, -CH 2 CH 2 SO 2 Me, -CH 2 OH, -CH 2 CH 2 OH , -CH 2 CH 2 CN, -CH 2 CH 2 OCH 3 , -COOCH (CF 3 ) 2 , -COCH 2 OH, -CH 2 COOH, -CH 2 CONH 2 , 2- (1-morpholin
  • each Rs is the same or different and is independently selected from halogen, CN, OH, C 1-6 alkyl;
  • E is selected from Y is selected from O or S;
  • R 1 , R 2 , R 3 , and R 4 are the same or different, and are independently selected from C 1-6 alkyl;
  • A is selected from N or CQ;
  • B is selected from N or CD;
  • a and At least one of B is N, and A and B are not N at the same time;
  • Q and D are the same or different and are independently selected from H, halogen, cyano, C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 alkoxy group, C 3 - 12 cycloalkyl, 3-12 membered heterocyclyl, -COOC 1-6 alkyl, -COC 1-6 alkyl;
  • V and Z identical or different, independently selected from H, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3 - 6 cycloalkyl;
  • W is selected from unsubstituted or optionally substituted by one, two or more R c is the group: C 1-6 alkyl, C 1-6 heteroalkyl, C 3 - 12 cycloalkyl group, 3- 12-membered heterocyclic, C 6 - 12 aryl, 5-12 membered heteroaryl, C 3 - 6 cycloalkyl and C 3 - 6 cycloalkyl group formed spiro cycloalkyl group, C 3 - 12 cycloalkyl and The spirocyclic group formed by the 3-12 membered heterocyclic group, the spirocyclic group formed by the 3-12 membered heterocyclic group and the 3-12 membered heterocyclic group, the combination of the C 3-6 cycloalkyl group and the C3-6 heterocyclic group cycloalkyl group, C3-6 heterocyclyl and C3-6 cycloalkyl and heterocyclyl group, C 5 - 14 bridged cycloalkyl groups, 5-14
  • each R a and R b are the same or different and are independently selected from each other.
  • R is selected from -F, -Cl, -Br, -I, -OH, -CN, -NH 2 , and -CH 3 , CH 3 CH 2- , -CF 3 , -CHF 2 , -CH 2 F, NH 2 CH 2- , -NH (CH 3 ) 2 , -OCH 3 , CH 3 CH 2 O-, CH 3 OCH 2 -, MeSO 2- , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 C (CH 3 ) 2 OH, -CH 2 CH 2 SO 2 Me, -CH 2 OH, -CH 2 CH 2 OH , -CH 2 CH 2 CN, -CH 2 CH 2 OCH 3 , -COOCH (CF 3 ) 2 , -COCH 2 OH, -CH 2 COOH, 1-tetrahydro
  • E is selected from Y is selected from O or S;
  • At least one of A and B is N, and A and B are not N at the same time;
  • Q and D are the same or different, and are independently selected from H, F, Cl, Br, trifluoromethyl, cyano, isopropyl, methoxy, cyclopropyl, -COOC 2 H 5 ;
  • V and Z are the same or different, and are independently selected from H, F, Cl, Br, methyl, methoxy, cyclopropyl;
  • W is selected from: tert-butyl
  • the compound of formula (I) is selected from the following compounds or pharmaceutically acceptable salts thereof:
  • the salt is hydrochloride, trifluoroacetate or formate.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound represented by formula (I), its stereoisomer, racemate, tautomer, isotope label, nitrogen oxide or At least one of pharmaceutically acceptable salts.
  • the pharmaceutical composition further includes a pharmaceutically acceptable excipient.
  • the present invention also provides at least one of the compound represented by formula (I), its stereoisomer, racemate, tautomer, isotopic label, nitrogen oxide, or pharmaceutically acceptable salt thereof.
  • the cancer is non-small cell lung cancer, glioblastoma, pancreatic cancer, head and neck cancer, breast cancer, colorectal cancer, epithelial cancer, ovarian cancer, prostate cancer, adenocarcinoma or squamous cell carcinoma.
  • the present invention also provides at least one of the compound represented by formula (I), its stereoisomer, racemate, tautomer, isotopic label, nitrogen oxide, or a pharmaceutically acceptable salt thereof Application in preparing medicine for treating diseases caused by EGFR mutation.
  • the EGFR mutation is one, two or more mutations selected from: (1) Del19; (2) T790M; (3) C797S; (4) L858R; (5) T790M; (6) C797S .
  • the present invention also provides a method for treating cancer, comprising: combining a compound represented by formula (I), its stereoisomer, racemate, tautomer, isotope label, nitrogen oxide, or its pharmaceutical At least one of the acceptable salts is administered to individuals in need.
  • the position indicates the connection site.
  • halogen refers to F, Cl, Br and I. In other words, F, Cl, Br and I can be described as "halogen" in this specification.
  • C 1-12 alkyl group is understood to mean preferably a linear or branched saturated monovalent hydrocarbon group having 1 to 12 carbon atoms, preferably a C 1-10 alkyl group.
  • C 1-10 alkyl is understood to preferably mean a linear or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.
  • the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Group, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, 1,2-dimethylbutyl, etc.
  • the group has 1, 2, 3, 4, 5, 6, carbon atoms ("C 1-6 alkyl”), such as methyl, ethyl, propyl, butyl, isopropyl , Isobutyl, sec-butyl, tert-butyl, more particularly, the group has 1, 2 or 3 carbon atoms ("C 1-3 alkyl”), such as methyl, ethyl, n-propyl Base or isopropyl.
  • C 1-3 alkyl such as methyl, ethyl, n-propyl Base or isopropyl.
  • C 2-12 alkenyl is understood to mean preferably a linear or branched monovalent hydrocarbon group which contains one or more double bonds and has 2 to 12 carbon atoms, preferably “C 2-10 alkenyl” , Further preferably, “C 2-6 alkenyl”.
  • C 2-10 alkenyl is understood to mean preferably a linear or branched monovalent hydrocarbon group, which contains one or more double bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 Carbon atoms, especially 2 or 3 carbon atoms (“C 2-3 alkenyl”), it should be understood that in the case where the alkenyl group contains more than one double bond, the double bonds may be separated from each other yoke.
  • the alkenyl group is, for example, vinyl, allyl, (E) -2-methylvinyl, (Z) -2-methylvinyl, (E) -but-2-enyl, (Z)- But-2-enyl, (E) -but-1-enyl, (Z) -but-1-enyl, pent-4-enyl, (E) -pent-3-enyl, (Z) -Pent-3-enyl, (E) -pent-2-enyl, (Z) -pent-2-enyl, (E) -pent-1-enyl, (Z) -pent-1-ene Group, hex-5-enyl, (E) -hex-4-enyl, (Z) -hex-4-enyl, (E) -hex-3-enyl, (Z) -hex-3- Alkenyl, (E) -hex-2-enyl, (Z) -hex
  • C 1-n alkenyl for example, “C 1-12 alkenyl” or “C 1-6 alkenyl”
  • C 2-n alkenyl Eg C 2-12 alkenyl
  • C 2 - 12 alkynyl group is understood to mean a linear or branched divalent hydrocarbon chain comprising one or more triple bonds and having 2 to 12 carbon atoms, preferably “C 2 -C 10 alkynyl” , Further preferably, “C 2 -C 6 alkynyl”.
  • C 2 -C 10 alkynyl is understood to mean preferably a linear or branched monovalent hydrocarbon group, which contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9 Or 10 carbon atoms, especially 2 or 3 carbon atoms ("C 2 -C 3 -alkynyl").
  • the alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl , Pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, Hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl , 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpentane -4-ynyl, 2-methylpent-3-yn
  • alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.
  • C 1-n alkynyl for example, “C 1-12 alkynyl” or “C 1-6 alkynyl”
  • C 2-n alkynyl Eg C 2-12 alkynyl
  • C 1-12 alkyl C 2-12 alkenyl
  • C 2-12 alkynyl also apply to “C 1-12 heteroalkane group ",” C 2-12 alkenyl heteroaryl ",” C 2-12 alkynyl heteroaryl "relates to alkyl, alkenyl, alkynyl moieties.
  • C 3-20 cycloalkyl is understood to mean a saturated or unsaturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 20 carbon atoms, preferably “C 3-10 cycloalkyl”.
  • C 3-10 cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • the C 3-10 cycloalkyl group may be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or bicyclic Hydrocarbon groups such as decalin ring.
  • the "C 3-20 cycloalkyl group” may further include, for example, a C 1-8 cycloalkyl group, a C 3-8 cycloalkyl group, a C 3-6 cycloalkyl group, or the like.
  • 3-20 membered heterocyclic group means a saturated or unsaturated monovalent monocyclic or bicyclic hydrocarbon ring, which contains 1-5 heteroatoms independently selected from N, O, and S, preferably “3-10 membered” Heterocyclyl ".
  • the term “3-10 membered heterocyclic group” means a saturated monovalent monocyclic or bicyclic hydrocarbon ring, which contains 1-5, preferably 1-3 heteroatoms selected from N, O, and S.
  • the heterocyclic group may be connected to the rest of the molecule through any of the carbon atoms or nitrogen atom (if present).
  • the heterocyclic group may include, but is not limited to: a 4-membered ring, such as azetidine, oxetanyl; a 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithialkyl, thiomorpholinyl, piperazinyl Or trithiane; or a 7-membered ring, such as diazacycloheptanyl.
  • a 4-membered ring such as azetidine, oxetanyl
  • a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidinyl, pyrazolidinyl,
  • the heterocyclic group may be benzo-fused.
  • the heterocyclic group may be bicyclic, such as but not limited to a 5,5 membered ring, such as hexahydrocyclopenta [c] pyrrole-2 (1H) -yl ring, or a 5,6 membered bicyclic ring, such as hexahydropyrrole And [1,2-a] pyrazine-2 (1H) -yl ring.
  • the nitrogen-containing ring may be partially unsaturated, ie it may contain one or more double bonds, such as but not limited to 2,5-dihydro-1H-pyrrolyl, 4H- [1,3,4] thiadi Azinyl, 4,5-dihydrooxazolyl, or 4H- [1,4] thiazinyl, or it may be benzo-fused, such as but not limited to dihydroisoquinolinyl.
  • the heterocyclic group is non-aromatic.
  • C3-6 heterocycloalkyl and C3-6 heterocyclyl correspond to a heterocyclic group having 3 to 6 C atoms, and are also covered by the above-mentioned “3-20 membered heterocyclic group”.
  • C 6-20 aryl is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, preferably “C 6-14 aryl” .
  • the term “C 6-14 aryl” is understood to preferably mean a monovalent aromatic or partially aromatic monocyclic, bicyclic or monocyclic aromatic ring having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms Tricyclic hydrocarbon rings (“C 6-14 aryl”), especially those with 6 carbon atoms (“C 6 aryl”), such as phenyl; or biphenyl, or those with 9 carbon atoms Ring (“C 9 aryl”), such as indanyl or indenyl, or a ring having 10 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl, Either a ring with 13 carbon atoms ("C 13 aryl)
  • 5-20 membered heteroaryl should be understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5 to 20 ring atoms and containing 1 to 5 independently selected from N, O And S heteroatoms, such as "5-14 membered heteroaryl".
  • the term “5-14 membered heteroaryl” is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, especially 5 or 6 or 9 or 10 carbon atoms, and it contains 1-5, preferably 1-3 heteroatoms independently selected from N, O and S and, in addition, in each case The bottom can be benzo fused.
  • the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thio Diazolyl, thi-4H-pyrazolyl, etc.
  • heterocyclyl, heteroaryl or heteroarylene includes all possible isomeric forms thereof, such as positional isomers.
  • pyridyl or pyridinylene includes pyridin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl, pyridin-4-yl And pyridin-4-yl;
  • thienyl or thienylene includes thien-2-yl, thien-2-yl, thien-3-yl and thien-3-yl.
  • C 5-14 bridged cyclic group refers to a 5- to 14-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected. These may contain one or more double bonds, but none of them The ring has a completely conjugated ⁇ electron system. Including 7 to 10 yuan.
  • the number of constituent rings it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridge cycloalkyl.
  • C 5-14 heterobridge ring group refers to a polycyclic group of 5 to 14 members, any two rings sharing two atoms that are not directly connected, these may contain one or more double bonds, but none of the rings has A completely conjugated ⁇ -electron system in which one or more ring atoms are selected from nitrogen, oxygen, or S (O) n (where n is an integer from 0 to 2) heteroatom, and the remaining ring atoms are carbon. It is preferably 7 to 10 yuan. E.g:
  • bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include heavy hydrogen and hydrogen variants, as long as the valence state of the particular atom is normal and the compound after substitution is stable of.
  • keto group O
  • two hydrogen atoms are substituted.
  • Ketone substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted. Unless otherwise specified, the types of substituents and trees may be arbitrary on the basis that they are chemically achievable.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and / or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues, and No excessive toxicity, irritation, allergic reactions or other problems or function concurrently, commensurate with a reasonable benefit / risk ratio.
  • “Pharmaceutically acceptable salts” means those salts that retain the biological effectiveness and properties of the parent compound. Such salts include: (1) Forming a salt with an acid, which is obtained by reacting the free base of the parent compound with an inorganic acid or an organic acid.
  • the inorganic acid includes hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, and sulfurous acid
  • organic acids include acetic acid, trifluoroacetic acid, propionic acid, acrylic acid, hexanoic acid, cyclopentane propionic acid, glycolic acid, pyruvic acid, oxalic acid, (D) or (L) malic acid, fumaric acid , Maleic acid, benzoic acid, hydroxybenzoic acid, ⁇ -hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid , P-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, cinnamic acid, dodecyl
  • the salts of acid protons present in the parent compound are replaced by metal ions or coordinated with organic bases.
  • metals are alkali metal ions, alkaline earth metal ions, or aluminum ions.
  • Organic bases are ethanolamine, diethanolamine, and triethanolamine. Ethanolamine, tromethamine, N-methylglucamine, etc.
  • the compounds provided by the invention also exist in prodrug forms.
  • the prodrugs of the compounds described herein easily undergo chemical changes under victory conditions to transform the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in the in vivo environment.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated form is equivalent to the unsolvated form and is included in the scope of the present invention.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)-and (+)-enantiomers, (R)-and (S) -enantiomers, non- Enantiomers, (D) -isomers, (L) -isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of these Mixtures are within the scope of the present invention.
  • Substituents such as alkyl groups may have additional asymmetric carbon atoms. All these isomers and mixtures thereof are included in the scope of the present invention.
  • optically active (R)-and (S) -isomers and (D)-and (L) -isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, where the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • a salt of a diastereomer is formed with an appropriate optically active acid or base, and then known by the art
  • the conventional method is used for resolution, and then the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with chemical derivatization methods (for example, the formation of carbamate from amines) Acid salt).
  • the compound of the present invention may contain unnatural proportions of atomic isotopes in one or more atoms constituting the compound.
  • compounds can be labeled with radioactive isotopes, such as tritium, iodine-125, C-14. All changes in isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • “Pharmaceutical composition” refers to combining one or more of the compounds of the present invention or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof with other chemical components, such as a pharmaceutically acceptable carrier, carrier Form or diluent mixed.
  • the purpose of the pharmaceutical composition is to facilitate the process of administration to animals.
  • “Pharmaceutically acceptable carrier” means an inactive ingredient in a pharmaceutical composition that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the administered compound, such as but not limited to: calcium carbonate, calcium phosphate , Various sugars (such as lactose, mannitol, etc.), starch, cyclodextrin, magnesium stearate, cellulose, magnesium carbonate, acrylic polymer or methacrylic polymer, gel, water, polyethylene glycol, Propylene glycol, ethylene glycol, castor oil or hydrogenated castor oil or polyethoxylated hydrogenated castor oil, sesame oil, corn oil, peanut oil, etc.
  • Excipient refers to an inert substance added to the pharmaceutical composition to further facilitate administration of the compound.
  • excipients include (but are not limited to) calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oil, and polyethylene glycol.
  • the aforementioned pharmaceutical composition may also include adjuvants commonly used in medicine (agents), for example: antibacterial agents, antifungal agents, antimicrobial agents, shelf-stable agents, Colorants, solubilizers, thickeners, surfactants, complexing agents, proteins, amino acids, fats, sugars, vitamins, minerals, trace elements, sweeteners, colors, flavors, or combinations thereof.
  • adjuvants commonly used in medicine for example: antibacterial agents, antifungal agents, antimicrobial agents, shelf-stable agents, Colorants, solubilizers, thickeners, surfactants, complexing agents, proteins, amino acids, fats, sugars, vitamins, minerals, trace elements, sweeteners, colors, flavors, or combinations thereof.
  • the compounds of the present invention can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the implementation methods formed by the combination with other chemical synthetic methods, and the well known to those skilled in the art Equivalently, preferred embodiments include but are not limited to the embodiments of the present invention.
  • the solvent used in the present invention is commercially available.
  • the present invention uses the following abbreviations:
  • the total elution time is shown in each spectrum (2-10 minutes).
  • HPLC gradient general formula: AxBy or CxDy (x + y 100), A, C: water (acid: containing 0.1% trifluoroacetic acid, basic: containing 0.1% ammonium bicarbonate), B, D: acetonitrile (acid: Containing 0.1% trifluoroacetic acid, alkaline: containing 0.1% ammonium bicarbonate), gradient conditions: acetonitrile y% ⁇ 95%. The total elution time is shown in each spectrum (generally 16 minutes).
  • the aqueous phase was separated with ethyl acetate (20 mL X 3) Extraction, the organic phases are combined, washed with saturated aqueous sodium chloride solution (50 mL), then dried and filtered with anhydrous sodium sulfate, and the filtrate is concentrated under reduced pressure to obtain the target intermediate D23 (100 mg, yield: 76.9%, yellow liquid) ) Used directly in the next step.
  • compound D33 200 mg, 0.54 mmol, compound cyclopropylboronic acid (52 mg, 0.61 mmol), K 2 CO 3 (228 mg, 1.662 mmol) and Pd (dppf) Cl 2 (40 mg, 0.054 mmol) were added to 1, 4In dioxane (5mL) and H 2 O (0.1mL). After replacing the reaction solution with argon three times, heat to 100 ° C and stir the reaction for 8 hours. The reaction was completed by LCMS. After the reaction solution was cooled to room temperature, water was added ( 20 mL) diluted, the mixture was extracted with dichloromethane (20 mL ⁇ 3).
  • the aqueous phase was extracted with ethyl acetate (20 mL).
  • the ethyl acetate phases were combined and dried over anhydrous sodium sulfate. It was dried and filtered, and the filtrate was concentrated under reduced pressure.
  • tert-butyl 3-hydroxypiperidine-1-carboxylate 10 g, 49.7 mmol
  • triethylamine 15 g, 149 mmol
  • the mixture was replaced with argon three times and then cooled to -20 ° C.
  • Methanesulfonyl chloride 11.38g, 99.4mmol was slowly added dropwise to the system. After the addition, the reaction was stirred at room temperature for 4 hours.
  • HPLC 99.79% (214nm), 99.89% (254nm)

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Abstract

L'invention concerne de nouveaux composés de pyrimidopyrazole utilisés en tant qu'inhibiteurs de kinase EGFR de quatrième génération (mutation T790M/C797S) et leur utilisation pharmaceutique. Plus particulièrement, l'invention concerne un composé représenté par la formule (I), un stéréoisomère, un racémate, un tautomère, un marqueur isotopique, un N-oxyde ou un sel pharmaceutiquement acceptable de celui-ci. Lesdits composés ont une bonne efficacité dans le traitement de maladies provoquées par une mutation anormale de L'EGFR Del19/T790M/C797S et L858R/T790M/C797S.
PCT/CN2019/113608 2018-10-29 2019-10-28 Composés de pyrimidopyrazole utilisés en tant qu'inhibiteurs d'egfr de quatrième génération Ceased WO2020088390A1 (fr)

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CN119019454A (zh) * 2023-05-23 2024-11-26 广州智睿医药科技有限公司 一种杂芳基衍生物的制备及用途

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