CN116655600A - Substituted 2-arylamino pyrimidine compound, pharmaceutical composition and application thereof - Google Patents

Substituted 2-arylamino pyrimidine compound, pharmaceutical composition and application thereof Download PDF

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CN116655600A
CN116655600A CN202310581835.XA CN202310581835A CN116655600A CN 116655600 A CN116655600 A CN 116655600A CN 202310581835 A CN202310581835 A CN 202310581835A CN 116655600 A CN116655600 A CN 116655600A
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cycloalkyl
alkyl
pharmaceutically acceptable
compound
membered heterocyclyl
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唐春雷
王杰
王栋
王华冰
桂豫乐
王霞
范为正
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Jiangnan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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

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Abstract

The invention discloses a substituted 2-arylamino pyrimidine compound, a pharmaceutical composition and application thereof, and belongs to the field of chemical medicines. The invention provides a novel 2-arylamino pyrimidine compound with a structure shown in a general formula (I), which has enhanced metabolic stability and longer metabolic half-life, shows higher inhibition activity to EGFR in an activated or drug-resistant mutant form than that of wild EGFR, and can effectively reduce side effects.

Description

Substituted 2-arylamino pyrimidine compound, pharmaceutical composition and application thereof
Technical Field
The invention belongs to the field of chemical medicines, and relates to a substituted 2-arylamino pyrimidine compound, a pharmaceutical composition and application thereof.
Background
The Epidermal Growth Factor Receptor (EGFR) belongs to the family of receptor tyrosine kinases that together with HER2, HER3 and HER4 constitute the ErbB receptor family. Upon binding to ligands such as Epidermal Growth Factor (EGF), the receptor is activated and forms dimers, further activating phosphorylation of critical tyrosine residues within the cell, and finally activating downstream signaling pathways within the cell, such as: the PI3K-AKT-mTOR pathway involved in apoptosis, the RAS-RAF-MEK pathway involved in cell cycle progression and proliferation. When EGFR domains undergo genetic mutations, downstream signaling pathways are over-expressed, ultimately leading to tumor cell formation, proliferation, invasion and migration, as represented by non-small cell lung cancer (NSCLC). EGFR is therefore one of the main targets for the development of anticancer drugs.
Oxitetinib (Osimertinib, AZD 9291) is a third generation EGFR-TKI targeted drug, and patients develop resistance despite its higher response to drug resistance caused by the L858R/T790M mutation (Clinical Cancer Research [2015 ]],17:3924-3933). First report in 2015 (Nature Medicine [2015 ]]21:560-562) resistance analysis of 15 patients with AZD9291, wherein the third mutation, EGFR, was obtained C797S Mutations are one of the main mechanisms responsible for drug resistance of AZD9291, accounting for about 40%. Meanwhile, the drug resistance of AZD9291 is reported in each conference, wherein 2015WCLC,Oxnard GR reports drug resistance analysis of 67 patients, wherein C797S accounts for 22%;2017ASCO, piotrowska also reported 23 cases, C797S also accounting for approximately 22%;2022WCLC,Winship Cancer Institute, guardant Health and Blueprint Medicines cooperatively report that after 5 years of follow-up, 65273 adult patients with advanced NSCLC have been analyzed for resistance, and that C797X has amplified beyond MET as the most frequently occurring resistance mutation upon treatment with AZD 9291. EGFR in patients who may develop disease progression following administration of AZD9291 as a first line C797X The incidence of mutation was 12.5%1.25 times greater than MET amplification; EGFR when used as a second line therapy C797X The incidence of mutation was 2.4 times that of MET amplification. In addition to the first year of AZD9291 first-line treatment, MET amplification occurred at rates exceeding EGFR C797X The method comprises the steps of carrying out a first treatment on the surface of the In the next 2-5 years, EGFR C797X MET amplification was exceeded. Whereas the C797S mutation is the most common mutation type of C797X. Thus, overcoming AZD9291 resistance against C797S mutation provides safer and more effective EGFR for patients L858R/T790M/C797S Inhibitors have important research significance.
In 2016, a compound EAI045 was reported that was able to overcome AZD9291 resistance against the C797S mutation (Nature [2016 ]],534:129-132). EAI045 belongs to an allosteric inhibitor, and shows better tumor inhibition effect in a mouse in-vivo drug effect model aiming at L858R/T790M/C797S mutation after being combined with EGFR monoclonal antibody; but the compound failed to enter clinical studies. In 2017, it was reported that the combination of bujitinib (brigerinib, AP 26113) and EGFR mab can overcome AZD9291 resistance caused by C797S mutation (Nature Communications [2017]8:14768), in PC9 (EGFR) del19/T790M/C797S ) The results of the mouse drug effect model show that both AP26113 and panitumumab or cetuximab in combination show good anti-tumor drug effect.
Some of the current 2-anilinopyrimidine inhibitors reported (e.g., WO2012051587A1, CN113354685A, CN113166110 a) already have therapeutic potential or properties for cancers that have metastasized to the CNs, but still have the potential to further enhance brain barrier permeability, enhance metabolic stability, improve pharmacokinetic properties and patent drug potential.
Disclosure of Invention
Problems to be solved by the invention
In order to solve the above problems in the prior art, the present invention provides a novel substituted 2-arylamino pyrimidine compound or pharmaceutically acceptable salt thereof, which has enhanced metabolic stability, longer metabolic half-life, shows higher inhibitory activity to EGFR in an active or drug-resistant mutant form than wild type EGFR, and can effectively reduce side effects.
The invention also provides a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt thereof.
Furthermore, the present invention provides the use of the above compound or a pharmaceutically acceptable salt thereof.
Solution for solving the problem
The invention firstly provides a compound with a structure shown in a general formula (I) or pharmaceutically acceptable salt thereof,
wherein:
x is selected from C, N;
R 1 selected from H, C 1-6 Alkyl and C 3-6 Cycloalkyl; wherein the C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally substituted with 0, 1, 2 or 3R;
R 2 selected from H, halogen, CN, OH, NO 2 、NH 2 、C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-14 Cycloalkyl, C 3-6 Cycloalkenyl, C 4-6 Cycloalkynyl, phenyl and 3-14 membered heterocyclyl; wherein the NH is 2 、C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-14 Cycloalkyl, C 3-6 Cycloalkenyl, C 4-6 Cycloalkynyl, phenyl and 3-14 membered heterocyclyl optionally substituted with 0, 1, 2 or 3R';
R 3 selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl and a 5-to 6-membered heterocyclyl containing 1, 2 or 3N or O atoms; wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl and 5-to 6-membered heterocyclyl containing 1, 2 or 3N or O atoms, optionally substituted with 0, 1, 2 or 3R';
R 4 selected from H, halogen, CN, NH 2 、C 1-4 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl, phenyl and 5-6 membered heterocyclyl; wherein the NH is 2 、C 1-4 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl, phenyl and 5-to 6-membered heterocyclyl are optionally substituted with 0, 1, 2 or 3R' ";
R 5 and R is 6 Are respectively and independently selected from H, C 1-14 Alkyl, C 1-14 Alkoxy, C 3-6 Cycloalkyl and C 3-6 Cycloalkyl oxy; wherein the C 1-14 Alkyl, C 1-14 Alkoxy, C 3-6 Cycloalkyl and C 3-6 Cycloalkyl oxy is optionally substituted with 0, 1, 2 or 3R ";
r, R ', R' are each independently selected from H, halogen, CN, OH, NH 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, C 4-6 Cycloalkynyl radicals, C 1-6 Heteroalkyl, 3-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl;
"hetero" means a heteroatom or a heteroatom group, C 1-6 Heteroalkyl, 3-to 14-membered heterocyclyl, 5-to 6-membered heterocyclyl, C 1-4 "hetero" groups of heteroalkyl groups, 5-to 6-membered heterocyclic groups, 3-to 6-membered heterocyclic groups, 5-to 6-membered heteroaryl groups, each independently selected from-C (=O) N (R) a )-、-N(R b )-、-S(＝O) 2 N(R c )-、-NH-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-S(＝O) 2 -and-N (R) d )C(＝O)N(R e ) -; in either case, the number of heteroatoms or groups of heteroatoms is independently selected from 1, 2 or 3, R a 、R b 、R c 、R d 、R e Are respectively and independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, C 4-6 Cycloalkynyl groups.
In one embodiment of the invention, R, R ', R' are each independently selected from H, F, cl, br, I, -CN, -OH, -NH 2 、-N(CH 3 ) 2 、-CH 3 、CH 3 CH 2 -、-CH 3 CH 2 CH 2 、-CH(CH 3 ) 2 、CH 3 O-、 And->
In one embodiment of the invention, R 1 Selected from H, C 1-3 Alkyl, wherein, the C 1-3 Alkyl is optionally substituted with 0, 1, 2 or 3R.
In one embodiment of the invention, R 2 Selected from H, halogen, CN, OH, NO 2 、NH 2 、C 3-12 Cycloalkyl and 3-12 membered heterocyclyl; wherein the NH is 2 、C 3-12 Cycloalkyl and 3-to 12-membered heterocyclyl are optionally substituted with 0, 1, 2 or 3R'.
In one embodiment of the invention, R 2 Preferably 0, 1, 2 or 3R' substituted piperidine, piperazine or morpholine rings.
In one embodiment of the invention, R 3 Selected from H, F, cl, br, -CH 3 、CH 3 CH 2 -、(CH 3 ) 2 CH-。
In one embodiment of the invention, R 4 Select H, F, cl, br, I, CH 3 、CH 3 CH 2 、CH 3 CH 2 CH 2 、(CH 3 ) 2 CH. Phenyl group,Wherein the CH 3 、CH 3 CH 2 、CH 3 CH 2 CH 2 、(CH 3 ) 2 CH. Phenyl group,/->Optionally substituted with 0, 1, 2 or 3R' ".
In one embodiment of the invention, R 5 And R is 6 Are respectively and independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 Cycloalkyl, wherein, the C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 Cycloalkyl is optionally substituted with 1, 2 or 3R "".
In one embodiment of the invention, R 5 And R is 6 Are respectively and independently selected from H, C 2-3 An alkyl group; c (C) 2-3 The alkyl group is optionally substituted with 0, 1, 2 or 3R "".
In one embodiment of the invention, the compound is specifically selected from:
in one embodiment of the present invention, the pharmaceutically acceptable salt is an inorganic salt or an organic salt, and the inorganic salt includes hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, bisulfate, nitrate, phosphate, and acid phosphate; the organic salt is selected from formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, succinate, glutarate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, p-toluenesulfonate, ascorbate.
In one embodiment of the invention, the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, sulfate, succinate or mesylate salts.
The invention also provides a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, excipient or diluent.
The invention also provides the use of the compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease, particularly cancer, mediated by EGFR-activated or drug-resistant mutants in a mammal, particularly a human.
The invention also provides the use of the compound or a pharmaceutically acceptable salt thereof, wherein the cancer is non-small cell lung cancer.
The invention also provides the use of a combination of said compound or a pharmaceutically acceptable salt thereof and an antineoplastic agent selected from the group consisting of:
(i) Antitumor drugs acting on DNA structures;
(ii) Antitumor drugs that affect nucleic acid synthesis;
(iii) Antitumor agents that affect transcription of nucleic acids;
(iv) An antitumor drug synthesized by tubulin;
(v) Inhibitors of cell signaling pathways such as inhibitors of epidermal growth factor receptor;
(vi) Anti-tumor monoclonal antibody.
ADVANTAGEOUS EFFECTS OF INVENTION
The invention provides a novel 2-arylaminopyrimidine inhibitor of an activated mutant form of an EGFR, which has better pharmacodynamics performance and higher metabolic stability, shows higher inhibition activity to EGFR of an activated or drug-resistant mutant form than wild EGFR, and can effectively reduce side effects such as rash, diarrhea and the like.
Detailed Description
The technical scheme of the present invention will be described in detail with reference to examples.
In the present invention C 1-4 Alkyl, C 1-6 Alkyl, C 1-14 Alkyl groups refer to groups having 1 to 4 carbon atoms and 1 to 6 carbon atoms, respectivelyExamples of straight or branched saturated hydrocarbon groups of 1 to 14 carbon atoms include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, tert-butyl;
C 2-6 alkenyl refers to a straight or branched hydrocarbon group having one or more double bonds and 2 to 6 carbon atoms;
C 2-6 alkynyl refers to a straight or branched hydrocarbon radical having one or more triple bonds and from 2 to 6 carbon atoms;
C 3-6 cycloalkyl, C 3-14 Cycloalkyl refers to a saturated monocyclic or polycyclic hydrocarbon group having 3 to 6 ring carbon atoms, 3 to 14 ring carbon atoms, respectively, examples of which include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
C 3-6 Cycloalkenyl refers to a monocyclic or polycyclic hydrocarbon group having one or more double bonds and 3 to 6 ring carbon atoms;
C 4-6 cycloalkynyl refers to a monocyclic or polycyclic hydrocarbon group having one or more triple bonds and 4 to 6 ring carbon atoms;
C 1-4 heteroalkyl, C 1-6 Heteroalkyl refers to a straight or branched chain monovalent saturated alkyl group having 1 to 4 carbon atoms, 1 to 6 carbon atoms, respectively, wherein 1 to 3 hydrogen atoms are replaced by heteroatoms or groups of heteroatoms;
3-6 membered heterocyclyl, 5-6 membered heterocyclyl, 3-14 membered heterocyclyl refer to monocyclic or polycyclic hydrocarbon groups having 3 to 6 ring carbon atoms, 5 to 6 ring carbon atoms, 3 to 14 ring carbon atoms, respectively, wherein 1 to 3 hydrogen atoms are replaced by heteroatoms or heteroatom groups;
a 5-to 6-membered heteroaryl group refers to a monocyclic or polycyclic aryl group having 5 to 6 ring carbon atoms, wherein 1 to 3 hydrogen atoms are replaced by heteroatoms or groups of heteroatoms;
C 1-14 alkoxy refers to a straight or branched saturated hydrocarbon group having 1 to 14 carbon atoms connected by an oxygen bridge, examples of which include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy;
C 3-6 cycloalkyloxy means having 3 to 6 ringsMonocyclic or polycyclic hydrocarbon groups in which carbon atoms are linked through an oxygen bridge;
indicating the attachment of substituents therefrom.
The term "disease" as used herein refers to any condition or disorder that impairs or interferes with the normal function of cells, organs or tissues.
The term "inhibitor" as used herein refers to a compound or agent that has the ability to inhibit a biological function of a targeted protein or polypeptide, for example by inhibiting the activity or expression of the protein or polypeptide.
The term "antineoplastic agent" as used herein refers to any agent useful in the treatment of neoplastic disorders.
The term "pharmaceutically acceptable" as used herein refers to those compositions which are, within the scope of sound medicine, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio. By "pharmaceutically acceptable salt" is meant any non-toxic salt that, upon administration to a recipient, is capable of providing a compound or prodrug of a compound of the invention, either directly or indirectly.
The term "effective amount" or "therapeutically effective amount" as used herein means an amount of a compound or pharmaceutical composition described herein sufficient to achieve the intended use, including, but not limited to, treatment of a disease. In some embodiments, the amount is an amount effective to kill or inhibit cancer cell growth or spread; the size or number of tumors; or the severity level, stage and progression of cancer. The therapeutically effective amount may vary depending on the intended use, such as in vitro or in vivo, the condition and severity of the disease, the age, weight, or mode of administration of the subject, and the like. The term also applies to a particular response in which a dose will induce target cells, e.g., reduce cell migration. The specific dosage will depend, for example, upon the particular compound chosen, the subject species and their age/existing health or risk of health, the route of administration, the severity of the disease, the administration in combination with other agents, the time of administration, the tissue to which it is administered, and the means of administration, etc.
In the present invention, "administering" or "administering" a compound to an individual refers to providing a compound of the present invention to an individual in need of treatment.
The compounds of the present invention may contain one or more asymmetric centers and thus appear as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of these compounds are expressly included in the present invention. The compounds of the invention may also exhibit multiple tautomeric forms, in which case the invention expressly includes all tautomeric forms of the compounds described herein. All such isomeric forms of such compounds are included in the present invention. All crystalline forms of the compounds described herein are expressly included in the present invention.
< Compound or pharmaceutically acceptable salt thereof >
The invention provides a novel 2-arylamino pyrimidine compound of an activated mutant form of an epidermal growth factor receptor or pharmaceutically acceptable salt thereof, and the structural formula of the compound is shown as a general formula (I):
wherein:
x is selected from C, N;
R 1 selected from H, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein, the C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally substituted with 0, 1, 2 or 3R;
R 2 Selected from H, halogen, CN, OH, NO 2 、NH 2 、C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-14 Cycloalkyl, C 3-6 Cycloalkenyl, C 4-6 Cycloalkynyl, phenyl and 3-14 membered heterocyclyl, wherein the NH 2 、C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl groups、C 2-6 Alkynyl, C 3-14 Cycloalkyl, C 3-6 Cycloalkenyl, C 4-6 Cycloalkynyl, phenyl and 3-14 membered heterocyclyl optionally substituted with 0, 1, 2 or 3R';
R 3 selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl and a 5-to 6-membered heterocyclic group containing 1, 2 or 3N or O atoms, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl and 5-to 6-membered heterocyclyl containing 1, 2 or 3N or O atoms, optionally substituted with 0, 1, 2 or 3R';
R 4 selected from H, halogen, CN, NH 2 、C 1-4 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl, phenyl and 5-6 membered heterocyclyl, wherein the NH group 2 、C 1-4 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl, phenyl and 5-to 6-membered heterocyclyl are optionally substituted with 0, 1, 2 or 3R' ";
R 5 and R is 6 Are respectively and independently selected from H, C 1-14 Alkyl, C 1-14 Alkoxy, C 3-6 Cycloalkyl and C 3-6 Cycloalkyl oxy, wherein, the C 1-14 Alkyl, C 1-14 Alkoxy, C 3-6 Cycloalkyl and C 3-6 Cycloalkyl oxy is optionally substituted with 0, 1, 2 or 3R ";
r, R ', R' are each independently selected from H, halogen, CN, OH, NH 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, C 4-6 Cycloalkynyl radicals, C 1-6 Heteroalkyl, 3-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl;
"hetero" means a heteroatom or a heteroatom group, C 1-6 Heteroalkyl, 3-to 14-membered heterocyclyl, 5-to 6-membered heterocyclyl, C 1-4 "hetero" groups of heteroalkyl, 5-6 membered heterocycle, 3-6 membered heterocyclyl, 5-6 membered heteroaryl are each independently selected from-C (=O) N (Ra) -, -N (Rb) -, -S (=O) 2 N(Rc)-、-NH-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-S(＝O) 2 -and-N (Rd) C (=o) N (Re) -; any one of the aboveIn each case, the number of heteroatoms or hetero-radicals is independently selected from 1, 2 or 3, R a 、R b 、R c 、R d 、R e Are respectively and independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, C 4-6 Cycloalkynyl groups.
In certain embodiments of the invention, X is selected from C, N; further, X is preferably C.
In certain embodiments of the invention, R, R ', R', are each independently selected from H, halogen, CN, OH, NH 2 、-N(CH 3 ) 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, C 4-6 Cycloalkynyl radicals, C 1-6 Heteroalkyl, 3-to 6-membered heterocyclyl, phenyl, and 5-to 6-membered heteroaryl.
In certain embodiments of the invention, R 1 Selected from H, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein, the C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally substituted with 0, 1, 2 or 3R; further, R 1 Selected from C 1-6 Alkyl, R is selected from H or OH; further R 1 Selected from methyl, ethyl or 2-propyl, R is selected from H.
In certain embodiments of the invention, R 2 Selected from H, halogen, CN, OH, NO 2 、NH 2 、C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-14 Cycloalkyl, C 3-6 Cycloalkenyl, C 4-6 Cycloalkynyl, phenyl and 3-14 membered heterocyclyl, wherein the NH 2 、C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-14 Cycloalkyl, C 3-6 Cycloalkenyl, C 4-6 Cycloalkynyl, phenyl and 3-14 membered heterocyclyl optionally substituted with 0, 1, 2 or 3R'; further, R 2 Selected from C 1-6 Heteroalkyl or 3-14 membered heterocyclyl, R' is selected from H or OH; further R 2 Selected from the group consisting of morpholine, 1-isopropylpiperazine, 4-dimethylaminopiperidine or N-methylpiperazine, R' is selected from the group consisting of H.
In certain embodiments of the invention, R 3 Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl and a 5-to 6-membered heterocyclic group containing 1, 2 or 3N or O atoms, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl and 5-to 6-membered heterocyclyl containing 1, 2 or 3N or O atoms, optionally substituted with 0, 1, 2 or 3R'; further, R 3 Selected from C 1-6 Alkyl, R' is selected from H or OH; further R 3 Selected from methyl, R' is selected from H.
In certain embodiments of the invention, R 4 Selected from H, halogen, CN, NH 2 、C 1-4 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl, phenyl and 5-6 membered heterocyclyl, wherein the NH group 2 、C 1-4 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl, phenyl and 5-to 6-membered heterocyclyl are optionally substituted with 0, 1, 2 or 3R' "; further, R 4 Selected from H, R' "is selected from H.
In certain embodiments of the invention, R 5 And R is 6 Are respectively and independently selected from H, C 1-14 Alkyl, C 1-14 Alkoxy, C 3-6 Cycloalkyl and C 3-6 Cycloalkyl oxy, wherein, the C 1-14 Alkyl, C 1-14 Alkoxy, C 3-6 Cycloalkyl and C 3-6 Cycloalkyl oxy is optionally substituted with 0, 1, 2 or 3R "; further, R 5 Preferably H or C 1-14 Alkyl, R 6 Preferably C 1-14 Alkyl, C 1-14 Alkoxy, C 3-6 Cycloalkyl or C 3-6 Cycloalkyloxy, R "" is selected from H or OH; further, R 5 Selected from methyl, R 6 Selected from methyl or 1-propyl, R "" is selected from H; alternatively, R 5 Selected from H, R 6 Selected from 1-propyl, 2-methoxyethyl or 4-methoxycyclohexyl, R "" is selected from H; in addition, R 5 Selected from H, R 6 Selected from ethyl, 1-propyl, 1-butyl, 2-propyl, 2- (3-methyl) butyl, (S) -2-propylThe radical, (R) -2-propyl or 4-cyclohexyl, R "" is selected from OH.
The compounds of formula (I) include pharmaceutically acceptable salts thereof. The pharmaceutically acceptable salt is inorganic salt or organic salt, wherein the inorganic salt comprises hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, bisulfate, nitrate, phosphate and acid phosphate; the organic salt is selected from formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, succinate, glutarate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, p-toluenesulfonate, ascorbate. Preferably, from a pharmaceutical point of view, the salt according to the invention is a hydrochloride, a sulfate, a succinate or a mesylate salt.
It will be appreciated that certain compounds of formula (I) or pharmaceutically acceptable salts thereof may be in the form of solvent compounds as well as in the form of non-solvates, such as, for example, water and forms. It is to be understood that the present invention encompasses all such solvate forms possessing active mutant EGFR inhibiting activity.
The synthesis of the compounds of the general formula (I) according to the invention can be carried out by the skilled worker in synthetic chemistry. All documents mentioned in the background of the present text are incorporated herein by reference in their entirety. The preparation method is described in detail in examples.
< pharmaceutical composition >
The invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the invention and a pharmaceutically acceptable carrier, excipient or diluent.
The compounds of the present invention or pharmaceutically acceptable salts thereof may be formulated as solid formulations for oral administration, including, but not limited to, capsules, tablets, pills, powders, granules, and the like. In these solid dosage forms, the compounds of formula (I) according to the invention are mixed as active ingredient with at least one conventional inert excipient (or carrier), for example with sodium citrate or dicalcium phosphate. Or with the following components: (1) Fillers or solubilisers, for example starch, lactose, sucrose, glucose, mannitol, silicic acid and the like; (2) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, acacia, and the like; (3) humectants, for example, glycerin, etc.; (4) Disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, and the like; (5) a slow solvent such as paraffin wax or the like; (6) absorption accelerators such as quaternary ammonium compounds and the like; (7) Wetting agents such as cetyl alcohol and glycerol monostearate, and the like; (8) adsorbents such as kaolin and the like; (9) Lubricants, for example, talc, calcium stearate, solid polyethylene glycol, sodium lauryl sulfate, and the like, or mixtures thereof. Buffers may also be included in capsules, tablets, pills.
The solid dosage forms, such as tablets, dragees, capsules, pills and granules, may be provided with coatings and shell materials such as enteric coatings and other materials known in the art in the form of crystalline coatings or microencapsulations. They may contain opacifying agents and the release of the active ingredient in such a composition may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active ingredient may also be in the form of microcapsules with one or more of the above excipients, if desired.
The compounds of the present invention or pharmaceutically acceptable salts thereof may be formulated into liquid dosage forms for oral administration, including, but not limited to, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, tinctures, and the like. In addition to the compounds of formula (I) or pharmaceutically acceptable salts thereof as active ingredients, liquid dosage forms may contain inert diluents commonly used in the art such as water and other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular cottonseed, groundnut, corn, olive, castor, sesame oils and the like or mixtures of these substances and the like. In addition to these inert diluents, the liquid dosage forms of the present invention can also include conventional adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents and the like.
Such suspending agents include, for example, ethoxylated stearyl alcohol, polyoxyethylene sorbitol, and sorbitan, microcrystalline cellulose, agar-agar, and the like, or mixtures of these.
The compounds of the present invention and pharmaceutically acceptable salts thereof may be formulated in dosage forms for parenteral injection, including, but not limited to, physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions and dispersions. Suitable carriers, diluents, solvents, excipients include water, ethanol, polyols and suitable mixtures thereof.
The compounds of the present invention or pharmaceutically acceptable salts thereof may be formulated into dosage forms for topical administration, including, for example, ointments, powders, suppositories, drops, sprays, inhalants and the like. The compounds of the general formula (I) according to the invention or their pharmaceutically acceptable salts as active ingredients are mixed under sterile conditions with physiologically acceptable carriers and optionally with preservatives, buffers and, if appropriate, propellants.
The compound of formula (I) or a pharmaceutically acceptable salt thereof according to the invention will be administered to a mammal in a unit dose in the range of 0.01-2000mg/kg, in particular 2.5-1000mg/kg, in particular 5-500mg/kg, and this should provide an effective dose. However, the daily dose will necessarily vary depending on the host treated, the particular route of administration, and the severity of the condition being treated. Thus, the optimal dosage may be determined by the practitioner treating any particular patient.
< use >
The present invention provides the use of a compound of formula (I) as defined above, and pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment of diseases mediated by EGFR-activated or drug-resistant mutants, particularly cancer, in a mammal, particularly a human.
In the present invention, the EGFR in the form of an activatable mutant, EGFR in the form of a drug resistant mutant may be, for example, an L858R activating mutant, an Exon19 deletion activating mutant, a T790M resistant mutant and/or a C797S resistant mutant. Thus, the disease, disorder or condition mediated by an EGFR-activated or drug-resistant mutant may be, for example, a disease, disorder or condition mediated by an L858R-activated mutant, an Exon 19-deleted-activated mutant, a T790M-resistant mutant, and/or a C797S-resistant mutant, and the invention is particularly applicable to EGFR-resistant mutant-mediated diseases, disorders or conditions such as a T790M-resistant mutant, a C797S-resistant mutant. Types of cancers that may be susceptible to treatment affected by the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof include, but are not limited to: ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-hodgkin's lymphoma, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor, thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, anaplastic large cell lymphoma, acute myelogenous leukemia, multiple myeloma, melanoma, mesothelioma. Preferably, the cancer comprises non-small cell lung cancer, metastatic non-small cell lung cancer.
The treatment of cancer according to the present invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof, will be administered to a mammal, more particularly a human.
The EGFR activity treatment of the active mutant forms of EGFR, drug resistant mutant forms of the present invention may be used as a sole therapy or may involve conventional surgery or radiation therapy (e.g., WBRT of the present invention) in addition to the compounds of the present invention, may be administered in combination with other pharmaceutically acceptable therapeutic agents, and with other anti-tumor agents, by simultaneous, sequential or separate use of the various components of the treatment. Such therapeutic agents include, but are not limited to: antitumor drugs acting on the chemical structure of DNA, such as cisplatin, antitumor drugs affecting nucleotide synthesis, such as methotrexate, 5-fluorouracil, etc., antitumor drugs affecting nucleic acid transcription, such as doxorubicin, epirubicin, aclacinomycin, etc., antitumor drugs acting on tubulin synthesis, such as paclitaxel, vinorelbine, etc., aromatase inhibitors, such as aminoglutethimide, letrozole, ryanodine, etc., cell signaling pathway inhibitors, such as the epidermal growth factor receptor inhibitor imatinib, gefitinib, erlotinib, afatinib, oxatinib, etc., 6- (4-bromo-2-chloro-phenylamino) -7-fluoro-3-methyl-3H-benzimidazole-5-carboxylic acid (2-hydroxy-ethoxy) -amide or a pharmaceutically acceptable salt thereof, 1- [ (1S) -1- (imidazo [1,2-a ] pyridin-6-yl) ethyl ] -6- (1-methyl-1H-pyrazol-4-yl) -1H [1,2,3] triazolo [4,5-b ] pyrazine, or a pharmaceutically acceptable salt thereof. Anti-tumor monoclonal antibodies, e.g., anti-CTLA-4 antibodies, immunosuppressant PD-1, PD-L1, OX40 agonist antibodies, etc., each of the components to be combined may be administered simultaneously or sequentially, either in a single formulation or in different formulations. The combinations include not only combinations of one or more other active agents of the compounds of the present invention, but also combinations of two or more other active agents of the compounds of the present invention.
The following examples illustrate, but do not limit, the synthesis of compounds of formula (I). The temperatures are in degrees celsius. All the evaporation was carried out under reduced pressure, if not otherwise stated. Reagents were purchased from commercial suppliers and used without further purification, if not otherwise indicated. The structure of the end products, intermediates and starting materials is confirmed by standard analytical methods, such as elemental analysis, spectroscopic characterization, such as MS, NMR. Abbreviations used are conventional in the art.
Intermediate A
5-fluoro-4-methyl-2-nitrophenol
3-fluoro-4-methylphenol (10.00 g,79.31 mmol) and benzyltriethylammonium chloride (1.77 g,7.93 mmol) were dissolved in dichloromethane (80 mL) and 65% concentrated nitric acid (7.35 g,79.31 mmol) was slowly added dropwise at 0deg.C and stirring was continued for 0.5h after the addition was completed. Adding saturated sodium bicarbonate solution into the reaction solution in ice bath after the reaction is finished, regulating the pH value to 8.0-9.0, extracting the water phase with dichloromethane (40 mL multiplied by 2), merging organic phases, washing with water (40 mL) and saturated sodium chloride (40 mL multiplied by 2) in sequence, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain a crude product, and performing column chromatography [ PE: EA=200:1 (v/v) ]]Isolation and purification gave intermediate A (11.30 g) as a reddish brown oil in 83.2% yield. 1 H-NMR(400MHz,CDCl 3 -d)δ:10.63(s,1H),7.99(d,J＝7.8Hz,1H),6.80(d,J＝10.1Hz,1H),2.26(d,J＝1.9Hz,3H)。ESI-HRMS(m/z):170.1257[M+H] - 。
Intermediate B
1-fluoro-5-methoxy-2-methyl-4-nitrobenzene
Intermediate A (11.30 g,66.00 mmol) was dissolved in N, N-dimethylformamide (100 mL), anhydrous potassium carbonate (13.71 g,99.00 mmol) and methyl iodide (14.12 g,99.30 mmol) were added and stirred overnight at room temperature. Ice water (220 mL) is added after the reaction is finished, solids are separated out, the mixture is stirred at room temperature for 1h and then is kept stand for 20min, suction filtration is carried out, a filter cake is washed by water (50 mL) and is dried overnight in a vacuum drying oven at 50 ℃ to obtain an off-white solid intermediate B (11.61 g), the yield is 94.6%, and the off-white solid intermediate B can be directly used for the next reaction without post treatment. 1 H-NMR(400MHz,DMSO-d 6 )δ:7.94(d,J＝8.0Hz,1H),7.27(d,J＝11.7Hz,1H),3.91(s,3H),2.21(d,J＝2.0Hz,3H)。ESI-HRMS(m/z):186.0627[M+H] + 。
Intermediate C
1- (1- (5-methoxy-2-methyl-4-nitrophenyl) piperidin-4-yl) -4-methylpiperazine
Intermediate B (11.61 g,62.52 mmol) was dissolved in N, N-dimethylformamide (200 mL), anhydrous potassium carbonate (17.33 g,125.04 mmol) and 1-methyl-4- (piperidin-4-yl) piperazine (17.24 g,93.73 mmol) were added, stirred at 120℃for 4h, after the reaction was completed, cooled to room temperature, the reaction mixture was slowly added to ice water (400 mL) with solid precipitation, stirred at room temperature for 1.5h and allowed to stand for 30min, suction filtration, and the filter cake was washed with water (60 mL) and dried overnight in a vacuum oven at 50℃to give intermediate C (20.02 g) as a yellow solid in 92.1% yield, which was directly used for the next reaction without work-up. 1 H-NMR(400MHz,CDCl 3 -d)δ:7.81(s,1H),6.54(s,1H),3.93(s,3H),3.34(d,J＝11.9Hz,2H),2.96(s,4H),2.88(s,4H),2.73～2.59(m,5H),2.30(s,3H),2.23(s,3H),1.71(qd,J＝12.0,3.8Hz,2H)。ESI-HRMS(m/z):349.2045[M+H] + 。
Intermediate D
2-methoxy-5-methyl-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) aniline
Intermediate C (20.02 g,57.51 mmol) was added to a mixed solution of ethanol and water [210mL, etOH: H 2 O＝2:1(V/V)]Ammonium chloride (21.52 g,403.07 mmol) was added, stirred under reflux for 1h to dissolve it sufficiently, iron powder (16.13 g,288.05 mmol) was added, the reaction was continued at 80 ℃ for 4h, the hot reaction solution was filtered off with celite after the end of the reaction, the filter cake was washed with ethanol until no fluorescence was detected by TLC, the filtrate was collected and concentrated under reduced pressure, dried overnight in a vacuum oven at 50 ℃ to give black solid intermediate D (17.94 g) in 97.8% yield, which was used directly for the next reaction without work-up. 1 H-NMR(400MHz,CD 3 OD-d 4 )δ:6.62(s,1H),6.60(s,1H),3.80(s,3H),3.05(d,J＝11.6Hz,2H),2.81～2.44(m,10H),2.36(dt,J＝11.5,3.8Hz,1H),2.31(s,3H),2.14(s,3H),2.00～1.92(m,2H),1.66(qd,J＝12.0,3.9Hz,2H)。ESI-HRMS(m/z):319.2355[M+H] + 。
Intermediate E
N- (2-methoxy-5-methyl-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) carboxamide
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Acetic anhydride (1.51 g,14.70 mmol) and formic acid (0.76 g,16.51 mmol) were thoroughly mixed, stirred under reflux for 4h, then the reaction was cooled to room temperature and added to tetrahydrofuran (15 mL) dissolved intermediate D (1.50 g,4.71 mmol), stirred at room temperature for 2h, saturated sodium bicarbonate solution was added after the reaction was completed, the pH was adjusted to 8.0-9.0, and dichloromethane was used(25 mL. Times.4) extraction, combining the organic phases, washing with saturated sodium chloride (40 mL), drying over anhydrous sodium sulfate, suction filtration, and concentration of the filtrate under reduced pressure afforded intermediate E (1.48 g) as a pale yellow solid, which was 90.5% yield and used directly in the next reaction without work-up. ESI-HRMS (m/z): 347.2331[ M+H ] ] + 。
Intermediate F
1- (2- (methylthio) pyrimidin-4-yl) -3-phenyl-1H-pyrazole-4-carbaldehyde
2-methylsulfanyl-4-chloropyrimidine (5.11 g,32.02 mmol) was sufficiently dissolved in N, N-dimethylformamide (35 mL), anhydrous potassium carbonate (8.04 g,58.22 mmol) and 3-phenyl-1H-pyrazole-4-carbaldehyde (L-2, 5.00g,29.13 mmol) were added, stirred at 50℃for 12 hours, cooled to room temperature after the completion of the reaction, then the reaction solution was slowly added to ice water (80 mL), stirred for 3 hours, solid was precipitated, left stand for 20 minutes, the obtained solid was filtered, and the cake was washed with water (10 mL) and dried overnight in a vacuum oven at 50℃to give an off-white solid intermediate F (7.01 g) in a yield of 81.4% which was directly used for the next reaction without any post-treatment. ESI-HRMS (m/z): 297.0735[ M+H ]] + 。
Intermediate G
1- (2- (methylsulfonyl) pyrimidin-4-yl) -3-phenyl-1H-pyrazole-4-carbaldehyde
Intermediate F (7.01G, 23.72 mmol) and ammonium molybdate tetrahydrate (2.92G, 2.37 mmol) were fully dissolved in ethanol (50 mL), 30% hydrogen peroxide solution (26.82G, 236.53 mmol) was slowly added dropwise at room temperature, stirred for 2h after the addition, water (70 mL) was added after the reaction was completed, extracted with dichloromethane (70 mL. Times.3), the organic phases were combined, washed with 10% sodium sulfite solution (30 mL. Times.2), finally washed sequentially with water (70 mL), saturated sodium chloride (60 mL), dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure to give intermediate G (6.53G) as a white solid in 84.3% yield without post-treatment Can be directly used for the next reaction. ESI-HRMS (m/z): 328.1768[ M+H ]] + 。
Intermediate H
1- (2- ((2-methoxy-5-methyl-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -3-phenyl-1H-pyrazole-4-carbaldehyde
Intermediate E (1.48 g,4.27 mmol) was added to ultra-dry tetrahydrofuran (9 mL) under nitrogen, followed by addition of ultra-dry N, N-dimethylacetamide (6 mL) to allow complete dissolution. Subsequently, the temperature was lowered to 5℃and a solution of 1.0mol/L of sodium tert-butoxide (6 mL) dissolved in tetrahydrofuran was slowly added dropwise, followed by stirring for 2 hours after the completion of the addition. Then the reaction temperature is adjusted to room temperature, intermediate G (1.68G, 5.12 mmol) is added, stirring is continued for 1h, saturated sodium bicarbonate solution is added into the reaction solution after the reaction is finished, the pH value is adjusted to 8.0-9.0, dichloromethane (30 mL multiplied by 3) is used for extraction, the organic phases are combined, then saturated sodium chloride (40 mL) is used for washing, anhydrous sodium sulfate is used for drying, suction filtration and filtrate decompression concentration are carried out, thus obtaining crude products, and the crude products are subjected to column chromatography [ DCM: meOH=15:1 (v/v)]Intermediate H (1.06 g) was isolated and purified as a pale yellow solid in 43.9% yield. ESI-HRMS (m/z): 567.3224[ M+H ]] + 。
Example 1
4- (4- ((dimethylamino) methyl) -3-phenyl-1H-pyrazol-1-yl) -N- (2-methoxy-5-methyl-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) pyrimidin-2-amine
Intermediate H (1.00 g,1.80 mmol) was added to methanol (20 mL), followed by dimethylamine (0.24 g,5.31 mmol), glacial acetic acid (2 drops) and anhydrous magnesium sulfate (1.73 g,14.12 mmol) and stirred at 70℃for 2H. After the completion of the reaction, the temperature was adjusted to room temperature, and sodium cyanoborohydride (3.31 g,5.32 mmol) was added thereto and stirred overnight. After the completion of the reaction, water (30 mL) was added to the reaction mixture to quench the reaction, followed by extraction with methylene chloride (30 mL. Times.6)All organic phases were combined, washed with saturated sodium chloride (60 mL), dried over anhydrous sodium sulfate, suction filtered, and the filtrate concentrated under reduced pressure to give the crude product, which was purified by column chromatography [ DCM: meoh=10:1 (v/v)]The desired product example 1 (0.21 g) was isolated and purified in 19.5% yield. 1 H NMR(400MHz,DMSO-d 6 )δ:8.49(s,1H),8.30(s,1H),7.94(d,J＝7.7Hz,2H),7.74(s,1H),7.50(t,J＝7.5Hz,3H),7.44(d,J＝7.2Hz,1H),7.25(d,J＝5.4Hz,1H),6.73(s,1H),3.81(s,3H),3.42(s,2H),3.11(d,J＝11.1Hz,2H),2.62(dd,J＝24.5,12.7Hz,8H),2.33(dd,J＝6.9,3.6Hz,3H),2.23(s,6H),2.21(s,6H),1.87(d,J＝12.1Hz,2H),1.59(d,J＝13.8Hz,2H).ESI-HRMS(m/z):596.3786[M+H] + 。
Salt formation:
4- (4- ((dimethylamino) methyl) -3-phenyl-1H-pyrazol-1-yl) -N- (2-methoxy-5-methyl-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) pyrimidin-2-amine hydrochloride
Example 1 (0.21 g) was dissolved in acetonitrile (2 mL), 1N HCl (2 mL) was slowly added with stirring, and after a while stirring, the solvent was removed by freeze drying to give a yellow solid, i.e., hydrochloride salt of the compound of example 1 (0.26 g). 1 H-NMR(400MHz,D 2 O)δ:8.35(s,1H),8.21(s,1H),7.79(d,J＝7.7Hz,2H),7.64(s,1H),7.42(t,J＝7.5Hz,3H),7.33(d,J＝7.2Hz,1H),7.11(d,J＝5.4Hz,1H),6.58(s,1H),3.59(s,3H),3.31(s,2H),3.03(d,J＝11.1Hz,2H),2.52(dd,J＝24.5,12.7Hz,8H),2.22(dd,J＝6.9,3.6Hz,3H),2.12(s,6H),2.10(s,6H),1.67(d,J＝12.1Hz,2H),1.46(d,J＝13.8Hz,2H).ESI-HRMS(m/z):596.3786[M+H] + 。
Examples 2-20 (see Table 1) were synthesized in a similar manner to the basic operation of example 1, to give the desired products.
TABLE 1 Structure and Mass Spectrometry data for examples 2-20
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Note that: the procedure for the preparation of example 7: racemic DL-aminopropanol substrate was selected, intermediate H (1.00 g,1.80 mmol) was added to methanol (20 mL), and DL-aminopropanol (0.39 g,5.20 mmol), glacial acetic acid (2 drops) and anhydrous magnesium sulfate (1.73 g,14.12 mmol) were added and stirred at 70℃for 2H. After the completion of the reaction, the temperature was adjusted to room temperature, and sodium cyanoborohydride (3.31 g,5.32 mmol) was added thereto and stirred overnight. After the reaction, water (30 mL) was added to quench the reaction, dichloromethane (30 ml×6) was added to extract, all the organic phases were combined, washed with saturated sodium chloride (60 mL), dried over anhydrous sodium sulfate, suction-filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was separated and purified by column chromatography [ DCM: meoh=10:1 (v/v) ] to give the corresponding racemic product (0.15 g) in 13.54% yield.
Examples 9 and 10 preparation procedure referring to example 7, the corresponding chiral product was prepared by substituting the substrate D-aminopropanol and L-aminopropanol for DL-aminopropanol, respectively.
Example 20 Activity test
Measurement 1: lance screening assay for EGFR inhibitory Activity
Determination of IC by Lance Ultra assay assay 50 Values. The assay comprises two steps, an enzymatic reaction and a detection step. First, EGFR is treated L858R/T790M/C797S A mixture of test compounds, peptide substrates and Adenosine Triphosphate (ATP) at different concentrations is incubated in assay buffer. When EGFR phosphorylates peptide substrates, specific antibodies and TR-FRET assay techniques can be used to detect phosphorylation.
Detailed description: the Lance screening assay was performed as a TR-FRET based 384 well assay. In a first step EGFR is added L858R/T790M/C797S Incubation at 22℃in assay buffers containing different concentrations of test compound or without test compound (as negative control)Incubate for 15 minutes. Assay buffer containing 50mM HEPES pH 7.5,10mM MgCl 2 0.01% BSA,0.01% Tween-20 and 2mM Dithiothreitol (DTT). Echo 555 (labyte) was used to dispense the compound solution. Then, in the second step, purified ULight-labeled peptide substrate and ATP are added and the reaction mixture is incubated for 25 minutes at 22 ℃. The pharmacologically relevant assay volume was 5 μl. During incubation of the reaction mixture, the final concentration in the assay was 0.3nM EGFR L858R/T790M/C797S 50nM peptide substrate and 0.5. Mu.M ATP. The enzymatic reaction was stopped by the addition of EDTA. Phosphorylation by EGFR-mediated reactions in the presence of ATP can be detected using a fluorophore europium (Eu) -labeled specific antibody. To this end, 2 μl of an antibody-containing stop solution (12.5mM HEPES pH 7.5, 125mM EDTA,30mM sodium oxide, 300mM potassium fluoride, 0.006% Tween-20,0.21nM anti-tyrosine phosphorylation-LANCE-Eu antibody (PT 66), 15nM ULIGHT-peptide substrate was added to the reaction mixture, after 2 hours of signal development, the plate was analyzed in a EnVision (PerkinElmer) microplate reader using TRF mode and laser excitation, after excitation of donor europium at 340nM, fluorescence of ULIGHT at 665nM and fluorescence of ULIGHT at 615nM was measured, the ratio of the amount of phosphorylated peptide substrate to the amount of light emitted at 665nM and 615nM (i.e., the ratio of relative fluorescence units (rfu)), data were processed using Genedata Screener software, in particular, the IC was determined in a conventional manner by fitting a dose-response curve to the data points using nonlinear regression analysis 50 Values.
Reference compound (commercially available Lazertinib) has the structural formula:
the experimental results are shown in table 2.
TABLE 2 data for the determination of the activity of the examples according to the invention and of the reference compounds (commercially available Lazertinib)
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Measurement 2: evaluation of Compound stability Using human liver microsomes
Liver microsomal enzyme stability of the example compounds was compared to Lazertinib.
Measurement system: the metabolic stability of the compounds of the invention was tested with 1mM NADPH using liver microsomes mixed by men and women. The samples were analyzed using a mass spectrometer. HRMS was used to determine the peak area response ratio (peak area corresponding to test compound or control divided by peak area of the analytical internal standard) without running the standard curve. To detect all possible metabolites, HRMS scans were performed in the appropriate m/z range.
Measurement conditions: the assay was performed with one incubation (n=1). The test compound was incubated at 37℃in a buffer containing 0.5 mg/ml liver microsomal protein. The reaction was initiated by addition of cofactor and sampled at 0, 2, 4, 8, 16, 24, 36, 48 hours, and positive controls (5 μm testosterone) were incubated in parallel and sampled at 0, 2, 4, 8, 16, 24, 36, 48 hours.
And (3) measuring quality control: the control compound testosterone was run in parallel to confirm the enzymatic activity of the (liver) microsomes. After the final time point, NADPH addition to the reaction mixture was confirmed using fluorometry. T1/2 of the control met the acceptable internal standard.
The analysis method comprises the following steps:
liquid chromatographic column: thermo BDS Hypersil C18 30×2.0mm,3 μm with guard column m.p., buffer: 25mM formic acid buffer, pH 3.5; aqueous phase (a): 90% water, 10% buffer; organic phase (B): 90% acetonitrile, 10% buffer; flow rate: 300 microliter/min autosampler: the injection volume was 10 microliters. Gradient procedure is seen in table 3.
Table 3 gradient procedure
Time (minutes) ％A ％B
0.0 100 0
1.5 0 100
2.0 0 100
2.1 100 0
3.5 100 0
By using human liver microsomes, examples 4, 7, 9 and 10 as described in the present invention exhibited metabolic half-lives greater than 24 hours, examples 3, 5, 8 and 11 exhibited metabolic half-lives between 16 and 24 hours, significantly greater than 15 hours of Lazertinib. The relatively long metabolic half-life allows the present invention the potential to reduce medical doses and expand dosing intervals.
The above examples are not intended to limit the scope of the invention nor the order of execution of the steps described. The present invention is obviously modified by a person skilled in the art in combination with the prior common general knowledge, and falls within the scope of protection defined by the claims of the present invention.

Claims (10)

1. A 2-arylamino pyrimidine compound with a structure shown in a general formula (I) or pharmaceutically acceptable salt thereof,
wherein:
x is selected from C, N;
R 1 selected from H, C 1-6 Alkyl and C 3-6 Cycloalkyl; wherein the C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally substituted with 1, 2 or 3R;
R 2 selected from H, halogen, CN, OH, NO 2 、NH 2 、C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-14 Cycloalkyl, C 3-6 Cycloalkenyl, C 4-6 Cycloalkynyl, phenyl and 3-14 membered heterocyclyl; wherein the NH is 2 、C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-14 Cycloalkyl, C 3-6 Cycloalkenyl, C 4-6 Cycloalkynyl, phenyl and 3-14 membered heterocyclyl optionally substituted with 1, 2 or 3R';
R 3 selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl and a 5-to 6-membered heterocyclyl containing 1, 2 or 3N or O atoms; wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl and 5-to 6-membered heterocyclyl containing 1, 2 or 3N or O atoms, optionally substituted with 1, 2 or 3R';
R 4 selected from H, halogen, CN, NH 2 、C 1-4 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl, phenyl and 5-6 membered heterocyclyl; wherein the NH is 2 、C 1-4 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl, phenyl and 5-6 membered heterocyclyl are optionally substituted with 1, 2 or 3R' ";
R 5 and R is 6 Are respectively and independently selected from H, C 1-14 Alkyl, C 1-14 Alkoxy, C 3-6 Cycloalkyl and C 3-6 Cycloalkyl oxy; wherein the C 1-14 Alkyl, C 1-14 Alkoxy, C 3-6 Cycloalkyl and C 3-6 Cycloalkyl oxy is optionally substituted with 1, 2 or 3R ";
r, R ', R' are each independently selected from H, halogen, CN, OH, NH 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, C 4-6 Cycloalkynyl radicals, C 1-6 Heteroalkyl, 3-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl;
"hetero" means a heteroatom or a heteroatom group, C 1-6 Heteroalkyl, 3-to 14-membered heterocyclyl, 5-to 6-membered heterocyclyl, C 1-4 "hetero" groups of heteroalkyl groups, 5-to 6-membered heterocyclic groups, 3-to 6-membered heterocyclic groups, 5-to 6-membered heteroaryl groups, each independently selected from-C (=O) N (R) a )-、-N(R b )-、-S(＝O) 2 N(R c )-、-NH-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-S(＝O) 2 -and-N (R) d )C(＝O)N(R e ) -; in either case, the number of heteroatoms or groups of heteroatoms are each independently selected from 1, 2 or 3; r is R a 、R b 、R c 、R d 、R e Are respectively and independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, C 4-6 Cycloalkynyl groups.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R, R ', R ", R'", R "" are each independently selected from H, F, cl, br, I, -CN, -OH, -NH 2 、-N(CH 3 ) 2 、-CH 3 、CH 3 CH 2 -、-CH 3 CH 2 CH 2 、-CH(CH 3 ) 2 、CH 3 O-、
3. The 2-arylaminopyrimidine compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 Selected from H, C 1-3 Alkyl, wherein, the C 1-3 Alkyl is optionally substituted with 1, 2 or 3R.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from H, halogen, CN, OH, NO 2 、NH 2 、C 3-12 Cycloalkyl and 3-12 membered heterocyclyl; wherein the NH is 2 、C 3-12 Cycloalkyl and 3-to 12-membered heterocyclyl are optionally substituted with 0-3R'.
5. The 2-arylaminopyrimidine compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 Is a piperidine ring, piperazine ring, morpholine ring substituted with 0-3R'.
6. The 2-arylaminopyrimidine compound according to claim 1 or a pharmaceutically acceptable salt thereof, R 5 And R is 6 Are respectively and independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 Cycloalkyl, wherein, the C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 Cycloalkyl is optionally substituted with 0-3R'.
7. The 2-arylaminopyrimidine compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R 5 And R is 6 Are respectively and independently selected from H, C 2-3 An alkyl group; c (C) 2-3 The alkyl group is optionally substituted with 0-3R'.
8. The 2-arylaminopyrimidine compound or pharmaceutically acceptable salt thereof according to any one of claims 1-7, wherein said pharmaceutically acceptable salt is an inorganic salt or an organic salt, and wherein the inorganic salt comprises hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, bisulfate, nitrate, phosphate, acid phosphate; the organic salt is selected from formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, succinate, glutarate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, p-toluenesulfonate, ascorbate.
9. A pharmaceutical composition comprising a 2-arylaminopyrimidine compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.
10. Use of a 2-arylaminopyrimidine compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-8 in the manufacture of a medicament for treating cancer mediated by EGFR-activated or drug-resistant mutants in a mammal.
CN202310581835.XA 2023-05-23 2023-05-23 Substituted 2-arylamino pyrimidine compound, pharmaceutical composition and application thereof Pending CN116655600A (en)

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