WO2019015593A1 - Composé de pyrimidopyridone ou pyridopyridone et utilisation correspondante - Google Patents

Composé de pyrimidopyridone ou pyridopyridone et utilisation correspondante Download PDF

Info

Publication number
WO2019015593A1
WO2019015593A1 PCT/CN2018/096009 CN2018096009W WO2019015593A1 WO 2019015593 A1 WO2019015593 A1 WO 2019015593A1 CN 2018096009 W CN2018096009 W CN 2018096009W WO 2019015593 A1 WO2019015593 A1 WO 2019015593A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
amino
pyrimidin
phenyl
pyrido
Prior art date
Application number
PCT/CN2018/096009
Other languages
English (en)
Chinese (zh)
Inventor
丁克
丁健
申佳奕
耿美玉
陆小云
谢华
孙敏
宗在伟
Original Assignee
江苏奥赛康药业股份有限公司
暨南大学
中国科学院上海药物研究所
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 江苏奥赛康药业股份有限公司, 暨南大学, 中国科学院上海药物研究所 filed Critical 江苏奥赛康药业股份有限公司
Priority to CN201880047588.2A priority Critical patent/CN110914267B/zh
Publication of WO2019015593A1 publication Critical patent/WO2019015593A1/fr

Links

Images

Classifications

    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention relates to the field of chemical medicine, in particular to a pyrimidopyridone or pyridopyridone compound and application thereof.
  • Tumor molecular targeted therapy is a treatment based on the selective killing of tumor cells by chemical or biological means of key molecules closely related to tumor growth.
  • the characteristics of targeted therapy are: high specificity, strong selectivity, and mild side effects; when combined, it can enhance the efficacy of traditional chemotherapy and radiotherapy and reduce postoperative recurrence.
  • Imatinib mesylate (STI571) (Novartis, 2001), gefitinib (ZD1839) (AstraZeneca, 2003), erlotinib (OSI774) (Genentech and OSIP, 2004), sorafenib P-toluenesulfonate (Bay 43-9006) (Bayer and Onyx, 2005), sunitinib malate (SU11248) (Pfizer, 2006) and dasatinib (BMS-354825) (Bristol-Myers Squibb, The targeted drugs represented in 2006) have opened up a new era for cancer chemotherapy. Tumor-targeted therapy has developed rapidly in just a few years.
  • tumor-targeted therapy is a hot spot and development trend of cancer treatment.
  • EGFR Epidermal growth factor receptor
  • EGFR is over-activated or continuously activated in a variety of tumor cells, such as lung cancer, breast cancer, prostate cancer, and the like.
  • tumor cells such as lung cancer, breast cancer, prostate cancer, and the like.
  • EGFR small molecule inhibitors Gefitinib and Erlotinib which were marketed in 2003-2004, have been used in the treatment of advanced non-small cell lung cancer, further clarifying that EGFR is an effective target for the treatment of non-small cell lung cancer.
  • the first generation of EGFR small molecule inhibitors achieved significant clinical efficacy in patients with EGFR-sensitive mutations, prolonging their survival. However, most patients will develop resistance after 10 to 12 months of drug use. Among them, more than 50% of drug-resistant patients (carrying EGFR-sensitive mutations) are due to EGFR mutations in T790M. Compared with the L858R-sensitive mutant EGFR, the L858R/T790M secondary mutation of EGFR has a stronger affinity for ATP, and the first generation of drugs are ATP competitive inhibitors, thus leading to drug resistance.
  • Osimertinib The third generation of the irreversible inhibitor Osimertinib (AZD9291), which overcomes the resistance of EGFRT790M, was approved by the US FDA in November 2015 (Cancer discovery 2014, 4(9), 1046-1061), which is clinically effective.
  • EGFR Epidermal growth factor receptor
  • Osimertinib has achieved great success in the clinical treatment of EGFRT790M-mutant non-small cell lung cancer, some beneficiated patients have developed resistance after 9 to 14 months of treatment (Nature Medicine 2015, 21(6), 560-2).
  • the present invention provides a novel class of pyrimidopyridones or pyridopyridones which selectively inhibit the activity of mutant EGFR and overcome the resistance of existing EGFR tyrosine kinase inhibitors. Sexual problems.
  • X is selected from: CH or N;
  • W is selected from: H, D, CH 3 , CD 3 , CF 3 , CH 2 F, CHF 2 , F, Cl, Br, C 2 -C 5 alkyl, C 3 -C 6 cycloalkyl, substituted C 3 -C 6 cycloalkyl;
  • L is selected from:
  • n is selected from an integer between 1 and 8;
  • n is selected from 0, 1, 2, 3;
  • n is selected from 0, 1, 2, 3;
  • R 1 is selected from:
  • R 4 is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl;
  • Y is selected from the group consisting of halogen, hydroxy, amino, (N-methyl)amino, (N,N-dimethyl)amino;
  • R 2 is selected from:
  • n is selected from the group consisting of 0, 1 , 2;
  • a 1 , A 2 , A 3 , A 4 , and A 5 are independently selected from:
  • R 5 and R 6 are each independently selected from the group consisting of C 1 -C 5 alkyl, C 3 -C 6 cycloalkyl, substituted C 3 -C 6 cycloalkyl, and R 5 and R 6 are cyclized to contain 1 a 4-8-membered saturated heterocyclic ring of 3 hetero atoms, a 4-8-membered aromatic heterocyclic ring having 1-3 hetero atoms formed by cyclization of R 5 and R 6 ;
  • R 3 is selected from:
  • B 1 , B 2 , B 3 , B 4 , and B 5 are independently selected from:
  • R 5 and R 6 are each independently selected from substituted or unsubstituted C 1 -C 5 alkyl, C 3 -C 6 cycloalkyl, substituted C 3 -C 6 cycloalkyl, R 5 and R 6 ring a substituted or unsubstituted 4-8 membered saturated heterocyclic ring containing 1-3 heteroatoms, a substituted or unsubstituted 4-8 member having 1-3 heteroatoms formed by cyclization of R 5 with R 6 aromatic heterocycle, R 5 and R 6 together form a ring containing 1-3 heteroatoms substituted or unsubstituted 8-12 membered saturated spiro ring containing 1-3 heteroatoms R 5 and R 6 together form a ring a substituted or unsubstituted 8-12 membered saturated fused ring, a substituted or unsubstituted 8-12 membered saturated bridged ring containing 1-3 heteroatoms formed by cyclization of R 5 with R 6 ;
  • a 5-12-membered saturated carbocyclic or heterocyclic ring containing 0-3 heteroatoms is formed between two adjacent substituents of B 1 , B 2 , B 3 , B 4 , and B 5 .
  • the compound has the structure of formula (II):
  • a 1 , A 2 , A 3 , A 4 , and A 5 are each independently selected from the group consisting of: A 1 , A 2 , A 3 , A 4 , and A 5 are independently selected from the group consisting of hydrogen and halogen.
  • a 1 , A 2 , A 3 , A 4 , and A 5 are each independently selected from the group consisting of: hydrogen, halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 ⁇ C 4 alkoxy.
  • a 1 , A 2 , A 3 , A 4 , and A 5 are each independently selected from the group consisting of hydrogen, chlorine, fluorine, methyl, and methoxy.
  • W is selected from H, C 1 -C 5 alkyl.
  • L is selected from:
  • L is selected from:
  • L is selected from:
  • R 1 is selected from:
  • R 4 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, neopentyl, cyclopentyl, cyclohexyl .
  • R 1 is selected from:
  • R 4 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, neopentyl, cyclopentyl, cyclohexyl .
  • the compound has the structure of Formula III, Formula IV, Formula V, or VI:
  • R 3 is selected from:
  • B 1 , B 2 , B 3 , B 4 , B 5 are each independently selected from the group consisting of: H, substituted or unsubstituted C 1 -C 6 alkyl, halogen, C 1 -C 4 alkane An oxy group, a C 1 -C 3 fluoroalkyl group, a substituted ethoxy group, a substituted or unsubstituted C 4 -C 9 heterocyclic group, And esters, amides, sulfones, sulfoxides, ureas formed by the above groups;
  • R 5 and R 6 are each independently selected from a substituted or unsubstituted C 1 -C 5 alkyl group, and R 5 and R 6 are cyclized to form a substituted or unsubstituted 4-8 member having 1 to 3 hetero atoms.
  • R 5 and R 6 together form a ring
  • R 5 and R 6 together form a ring containing 1-3 heteroatoms substituted or unsubstituted 8-12 membered saturated spiro ring containing 1 to 3 heteroatoms substituted or unsubstituted fused 8-12 membered saturated ring
  • R 5 and R R 5 and R 6 together form a ring of 6 ring
  • B 1 , B 2 , B 3 , B 4 , B 5 are each independently selected from the group consisting of: H, C 1 -C 6 alkyl, halogen, C 1 -C 4 alkoxy, C 1 ⁇ C 3 fluoroalkyl, N,N-dimethylaminoethoxy, N,N-dimethylaminopropoxy, 2-(N-methylpiperazinyl)ethoxy, 2-( N-acetylpiperazinyl)ethoxy, 2-morphinolinylethoxy, 2-thiophinylethoxy, 2-piperidinylethoxy, 2-tetrahydropyrrolylethoxy, N-methylpiperazinyl, N-ethylpiperazinyl, piperazinyl, (R)-3,4-dimethylpiperazinyl, (S)-3,4-dimethylpiperazinyl, 4-isopropylpiperazin-1-yl, (3S,5R)-3
  • B 1 , B 2 , B 3 , B 4 , B 5 are each independently selected from the group consisting of: H, C 1 -C 3 alkyl, halogen, 4-methylpiperazin-1-yl, 4-isopropylpiperazin-1-yl, piperidinyl, 9-methyl-3,9-diazaspiro[5.5]undec-3-yl, 3-methyl-1,3-di Azepan-1-yl, (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl,(2-(dimethylamino)ethyl (M)amino, 4-(dimethylamino)piperidin-1-yl, 7-methyl-2,7-diazaspiro[3.5]decane-2-yl, (R)- 3,4-Dimethylpiperazin-1-yl, (3S,5R)-3,4,5-trimethylpiperazin-1-yl, (R)
  • B 1 , B 2 , B 4 , and B 5 are each independently selected from the group consisting of: H, C 1 -C 3 alkyl, halogen; and B 3 is selected from the group consisting of: 4-methylpiperazine-1- Base, 4-isopropylpiperazin-1-yl, piperidinyl, 9-methyl-3,9-diazaspiro[5.5]undec-3-yl, 3-methyl-1,3 -diazepan-1-yl, (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl, (2-(dimethylamino) Ethyl)(methyl)amino, 4-(dimethylamino)piperidin-1-yl, 7-methyl-2,7-diazaspiro[3.5]decane-2-yl, (R -3,4-Dimethylpiperazin-1-yl, (3S,5R)-3,4,5-trimethylpiperazin-1-yl
  • W is selected from the group consisting of: H, methyl; X is selected from N;
  • R 1 is selected from: Wherein R 4 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, neopentyl, cyclopentyl, and ring. Hexyl
  • R 2 is selected from: Wherein n is 0; A 1 , A 2 , A 3 , A 4 , and A 5 are independently selected from the group consisting of hydrogen, chlorine, and fluorine;
  • B 1 , B 2 , B 3 , B 4 , B 5 are independently selected from the group consisting of: H, methyl, halogen, 4-methylpiperazin-1-yl, piperidinyl, 9-methyl-3,9 -diazaspiro[5.5]undec-3-yl, 3-methyl-1,3-diazepan-1-yl, (1S,4S)-5-methyl-2,5 -diazabicyclo[2.2.1]heptan-2-yl, (2-(dimethylamino)ethyl)(methyl)amino, 4-(dimethylamino)piperidin-1-yl, 7 -methyl-2,7-diazaspiro[3.5]decane-2-yl, (R)-3,4-dimethylpiperazin-1-yl, (3S,5R)-3,4, 5-trimethylpiperazin-1-yl, (R)-3-methylpiperazin-1-yl, 4-(4-methylpiperazin-1-yl
  • L is selected from:
  • W is H;
  • R 4 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl;
  • a 1 is chlorine, A 2 , A 3 , A 4 , A 5 All are hydrogen;
  • B 2 is methyl,
  • B 3 is 4-methylpiperazin-1-yl,
  • B 1 , B 4 , B 5 are all H;
  • L is selected from:
  • W is methyl;
  • R 4 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl;
  • a 1 is chlorine,
  • a 2 , A 3 , A 4 , A 5 is hydrogen;
  • B 2 is methyl,
  • B 3 is 4-methylpiperazin-1-yl,
  • B 1 , B 4 , B 5 are H;
  • L is selected from:
  • the compound is selected from the group consisting of
  • the present invention also provides the use of the above pyridopyrimidinone or pyridopyridone compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof.
  • the tumor is a malignant tumor of a EGFR gene mutation.
  • the tumor comprises: non-small cell lung cancer, malignant melanoma, prostate cancer, kidney cancer, bladder cancer, ovarian cancer, colon cancer, rectal cancer, breast cancer, cervical cancer, lung cancer, laryngeal cancer, Nasopharyngeal carcinoma, pancreatic cancer, multiple myeloma, B lymphoma, leukemia.
  • the tumor is a non-small cell lung cancer of the EGFR L858R/T790MC797S mutation.
  • the invention also provides a pharmaceutical composition for preventing and treating tumors.
  • a pharmaceutical composition for controlling tumors which comprises the above-mentioned pyridopyrimidinone or pyridopyridone compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof.
  • the tumor is a malignant tumor of a EGFR gene mutation.
  • the tumor comprises: non-small cell lung cancer, malignant melanoma, prostate cancer, kidney cancer, bladder cancer, ovarian cancer, colon cancer, rectal cancer, breast cancer, cervical cancer, lung cancer, laryngeal cancer, Nasopharyngeal carcinoma, pancreatic cancer, multiple myeloma, B lymphoma, leukemia.
  • the tumor is a non-small cell lung cancer of the EGFR L858R/T790MC797S mutation.
  • the compound of the present invention can selectively inhibit the activity of mutant EGFR and inhibit the other proteases of EGFR and Her family, and is a novel type of novel and capable of overcoming the resistance of existing EGFR tyrosine kinase inhibitors and is selective and A protein kinase inhibitor of good pharmacokinetic properties.
  • the compounds of the present invention are effective for inhibiting the growth of a variety of tumor cells, particularly for selectively inhibiting EGFR L858R/T790MC797S lung cancer cells, and the selectivity of some preferred compounds is greater than 50-fold compared to wild-type cancer cells.
  • the compounds of the present invention are useful for the preparation of antitumor drugs, and can overcome the drug resistance problems induced by existing drugs (such as gefitinib, erlotinib, especially octetinib (AZD9291)), mainly for existing The third generation of EGFR small molecule inhibitors against non-small cell lung cancer drugs Osimertinib (AZD9291), Olmutinib (HM6171), Rociletinib (9, CO-1686) induced 797th cysteine mutation into serine (C797S) Resistance.
  • the compounds of the present invention are useful for preventing postoperative recurrence of various tumors, as well as further consolidating treatment, for the purpose of prolonging the survival of tumor patients, improving their quality of life, and inhibiting tumor deterioration.
  • Figure 1 is a graph showing the results of a test of the effect of compound 560082 of the present invention on phosphorylation of EGFR L858R/T790M/C797S and EGFR 19D/T790M/C797S in a tool cell;
  • Figure 2 is a graph showing the results of a test of the effect of Compound 580120 of the present invention on phosphorylation of EGFR L858R/T790M/C797S and EGFR 19D/T790M/C797S in a tool cell.
  • any variable e.g. R 1, R, etc.
  • any variable e.g. R 1, R, etc.
  • combinations of substituents and variables are allowed as long as such combinations stabilize the compound.
  • a line drawn from a substituent into the ring system means that the bond referred to can be attached to any ring atom that can be substituted. If the ring system is polycyclic, it means that such a bond is only attached to any suitable carbon atom of the adjacent ring. It will be appreciated that one of ordinary skill in the art can select substituents and substitution patterns for the compounds of the present invention to provide compounds which are chemically stable and which are readily synthesized from readily available starting materials by techniques in the art and the methods set forth below.
  • substituent itself is substituted by more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms as long as the structure is stabilized.
  • the phrase "optionally substituted with one or more substituents” is considered to be equivalent to the phrase “optionally substituted with at least one substituent” and in this case the preferred embodiment will have 0-3 substituents.
  • alkyl and alkylene as used herein are meant to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • the definition of “C 1 -C 5 " in “C 1 -C 5 alkyl” includes a group having 1, 2, 3, 4, or 5 carbon atoms arranged in a straight or branched chain.
  • “C 1 -C 5 alkyl” specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl.
  • cycloalkyl refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms.
  • cycloalkyl includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl and the like.
  • heteroaryl denotes a stable monocyclic ring of up to 6 atoms in the ring or a bicyclic carbon ring of up to 6 atoms in each ring, at least one of which is an aromatic ring and contains from 1 to 4 Heteroatoms from O, N and S.
  • Heteroaryl groups within the scope of this definition include, but are not limited to, imidazolyl, triazolyl, pyrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyridyl, Pyrimidinyl, pyrrolyl.
  • Heteroaryl is also understood to include any N-oxide derivative of a nitrogen-containing heteroaryl group for the definition of the following heteroaryl.
  • the heteroaryl substituent is bicyclic and contains a ring which is non-aromatic or contains no heteroatoms, it is understood that each is attached via an aromatic ring or via a heteroatom-containing ring.
  • heterocycle refers to a 5- to 6-membered aromatic or non-aromatic heterocyclic ring containing from 1 to 4 heteroatoms selected from O, N and S, and includes a bicyclic group. group.
  • heterocyclyl thus includes the heteroaryl groups mentioned above, as well as the dihydrogenated and tetrahydrogenated analogs thereof.
  • heterocyclyl include, but are not limited to, imidazolyl, indolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxetanyl, pyridyl Meryl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinoxalinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, l, 4-Dioxoalkyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydrogen Pyrazolyl, dihydropyridyl, di
  • heterocyclic substituent can be achieved by a carbon atom or by a hetero atom.
  • the heterocyclic ring is selected from the group consisting of imidazolyl, pyridyl, 1-pyrrolidone, 2-piperidone, 2-pyrimidinone, 2-pyrrolidone, thienyl, oxazolyl, triazolyl, isoxazole base.
  • halo or halogen as used herein is meant to include chloro, fluoro, bromo and iodo.
  • alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl substituents may be unsubstituted or substituted.
  • (C 1 -C 6 )alkyl may be substituted by one, two or three substituents selected from OH, halogen, alkoxy, dialkylamino or heterocyclic groups such as morpholinyl, piperidinyl and the like. Replace.
  • the invention includes the free forms of the compounds of Formulas I-VI, as well as the pharmaceutically acceptable salts and stereoisomers thereof.
  • Some specific exemplary compounds herein are protonated salts of amine compounds.
  • the term "free form" refers to an amine compound in a non-salt form.
  • Included pharmaceutically acceptable salts include not only the exemplary salts of the particular compounds described herein, but also all of the typical pharmaceutically acceptable salts of the free forms of the compounds of Formulas I-VI.
  • the free form of the particular salt of the compound can be isolated using techniques known in the art.
  • the free form can be regenerated by treating the salt with a suitable dilute aqueous base such as a dilute aqueous solution of NaOH, a dilute aqueous solution of potassium carbonate, dilute aqueous ammonia, and a dilute aqueous solution of sodium bicarbonate.
  • a suitable dilute aqueous base such as a dilute aqueous solution of NaOH, a dilute aqueous solution of potassium carbonate, dilute aqueous ammonia, and a dilute aqueous solution of sodium bicarbonate.
  • the free form differs somewhat from its respective salt form in solubility in certain physical properties, such as in polar solvents, but for purposes of the invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of the present invention containing a basic moiety or an acidic moiety by conventional chemical methods.
  • salts of basic compounds are prepared by ion exchange chromatography or by reaction of a free base with a stoichiometric or excess amount of an inorganic or organic acid in the desired salt form in a suitable solvent or combination of solvents.
  • a salt of an acidic compound is formed by reaction with a suitable inorganic or organic base.
  • pharmaceutically acceptable salts of the compounds of the invention include the conventional non-toxic salts of the compounds of the invention which are formed by the reaction of a basic compound of the invention with an inorganic or organic acid.
  • conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and also include organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, and hard.
  • Fatty acid lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetyl A salt prepared from oxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid or the like.
  • a suitable "pharmaceutically acceptable salt” refers to a salt prepared by pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganese salts, potassium salts, sodium salts, zinc salts and the like. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred.
  • a salt derived from a pharmaceutically acceptable organic non-toxic base comprising a salt of a primary, secondary and tertiary amine, the substituted amine comprising a naturally occurring substituted amine, a cyclic amine and a basic ion exchange resin such as a fine Amino acid, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, B Diamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine , piperidine, guanidine, polyamine resin, procaine, guanidine, theobromine, triethylamine, trimethylamine, tripropylamine, t
  • the acidic moiety such as a carboxyl group
  • a cationic moiety such as tetravalent
  • the compounds of the invention are potential internal salts or zwitterions.
  • the compounds of the invention can be prepared using the reactions as shown in the scheme below. Accordingly, the following illustrative schemes are for illustrative purposes and are not limited to the listed compounds or any particular substituents. The number of substituents shown in the schemes does not necessarily have to correspond to the number used in the claims, and for the sake of clarity, it is shown that the mono-substituents are attached to a compound which allows multiple substituents under the definition of formula I above.
  • the compounds of formula I-VI, and pharmaceutically acceptable salts thereof, provided herein, are useful for treating transitional proliferative diseases or conditions, such as tumors in humans or other mammals.
  • the compounds designed herein and pharmaceutically acceptable salts thereof can be used to treat or control non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer , liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, nasopharyngeal carcinoma and other transitional proliferative diseases.
  • Metabolites of the compounds and pharmaceutically acceptable salts thereof, and prodrugs which can be converted in vivo to the structures of the compounds and pharmaceutically acceptable salts thereof, are also included in the claims of the present application. in.
  • the compounds of formula I-VI can be combined with other agents known to treat or ameliorate similar conditions.
  • the mode of administration & dosage of the original drug remains unchanged, while the compound of formula I-IV is administered simultaneously or subsequently.
  • the compound of formula I-IV is administered concurrently with one or more other drugs, it is preferred to use a pharmaceutical composition comprising both one or several known drugs and a compound of formula I-IV.
  • Combination of drugs also includes the administration of a compound of formula I-IV with one or more other known drugs over an overlapping period of time.
  • the dose of the compound of formula I-IV or a known drug may be lower than when they are administered alone.
  • Drugs or active ingredients which may be combined with a compound of formula I-VI include, but are not limited to:
  • the pharmaceutical or active ingredient that can be administered in combination with a compound of Formulas I-VI includes, but is not limited to, leucine, alendronate, interferon, atraxine, allopurinol, Sodium decylate, palonosetron hydrochloride, hexamethylene melamine, aminoglutamine, amifostine, amrubicin, amsacrine, anastrozole, dolasetron, aranesp, arglabin, Arsenic trioxide, anoxin, 5-azacytidine, azathioprine, BCG or tici BCG, betahidine, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, bromine Gan, bortezomib, busulfan, calcitonin, alemzumab injection, capecitabine, carboplatin, constance, cefesone, simmein, daunorubicin,
  • Step 4 (S)-3-(6-(2-Chlorophenyl)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl) -pyrrolidine-1-carboxylic acid tert-butyl ester (5)
  • Step 7 (S)-6-(2-Chlorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8-(pyrrole) Alkan-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (8)
  • Step 8 (S)-8-(1-Acetylpyrrol-3-yl)-6-(2-chlorophenyl)-2-((3-methyl-4-(4-methylpiperazine)- 1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (560123)
  • Step 9 ((1R,4R)-4-((5-Bromo-2-chloropyrimidin-4-yl)amino)cyclohexyl)carbamic acid tert-butyl ester (10) tert-butyl((1R,4R)- 4-((5-bromo-2-chloropyrimidin-4-yl)amino)cyclohexyl)carbamate
  • Step 10 ((1R,4R)-4-(2-chloro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexyl)carbamic acid Butyl ester (11)
  • Step 11 ((1R,4R)-4-(6-Bromo-2-chloro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexyl ) tert-butyl carbamate (12)
  • Step 12 ((1R,4R)-4-(6-Bromo-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino) -7-oxopyrido[2,3-d]pyrimidine-8(7H)-yl)cyclohexyl)carbamic acid tert-butyl ester (13)
  • Step 13 ((1R,4R)-4-(6-(2-Chlorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl) Phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexyl)carbamic acid tert-butyl ester (14)
  • Step 14 8-((1R,4R)-4-Aminocyclohexyl)-6-(2-chlorophenyl)-5-methyl-2-((3-methyl-4-(4-methyl) Piperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (15)
  • Step 15 N-((1R,4R)-4-(6-(2-chlorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazine-1) -yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexyl)acetamide (560083)
  • the synthesis method was as in Example 18, and the yield was 85.4%.
  • the synthesis method was as in Example 18, and the yield was 60.6%.
  • the synthesis method was as in Example 18, and the yield was 75.9%.
  • the synthesis method was as in Example 18, and the yield was 85.4%.
  • the synthesis method was as in Example 18, and the yield was 81.6%.
  • the synthesis method was as in Example 18, and the yield was 80.9%.
  • the synthesis method was as in Example 18, and the yield was 70.3%.
  • the synthesis method was as in Example 18, and the yield was 85.4%.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne un composé de pyridopyrimidinone ou de pyridopyridone ayant une structure de formule (I) ou un sel pharmaceutiquement acceptable ou un stéréoisomère ou une molécule de promédicament de celui-ci. De tels composés peuvent inhiber l'activité de la 797ème mutation de cystéine en sérine mutante de l'EGFR (EGFR C797S), mais possèdent un faible impact sur l'activité de l'EGFR de type sauvage, peuvent ainsi inhiber efficacement la croissance de cellules tumorales du cancer du poumon non à petites cellules, et peuvent être utilisés pour préparer un médicament antitumoral, qui peut être principalement utilisé pour la résistance clinique de la 797ème mutation de cystéine en sérine (C797S) induite par le médicament de troisième génération existant contre le cancer du poumon non à petites cellules inhibiteur d'EGFR à petites molécules, tel que l'Osimertinib (AZD9291), Olmutinib(HM6171), Rociletinib(9,CO-1686) et analogues. Les composés sont sélectifs pour le cancer du poumon non à petites cellules de type sauvage. (I)
PCT/CN2018/096009 2017-07-19 2018-07-17 Composé de pyrimidopyridone ou pyridopyridone et utilisation correspondante WO2019015593A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201880047588.2A CN110914267B (zh) 2017-07-19 2018-07-17 嘧啶并吡啶酮或者吡啶并吡啶酮类化合物及其应用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710591644 2017-07-19
CN201710591644.6 2017-07-19

Publications (1)

Publication Number Publication Date
WO2019015593A1 true WO2019015593A1 (fr) 2019-01-24

Family

ID=65014945

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/096009 WO2019015593A1 (fr) 2017-07-19 2018-07-17 Composé de pyrimidopyridone ou pyridopyridone et utilisation correspondante

Country Status (2)

Country Link
CN (1) CN110914267B (fr)
WO (1) WO2019015593A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112010844A (zh) * 2019-05-31 2020-12-01 中国药科大学 N-(嘧啶-2-基)香豆素-7-胺衍生物作为蛋白激酶抑制剂的制法和应用
CN112759589A (zh) * 2019-11-01 2021-05-07 暨南大学 嘧啶并吡啶酮类化合物及其应用
WO2021139775A1 (fr) * 2020-01-10 2021-07-15 江苏先声药业有限公司 Composé de pyridone et son application
JP2022546375A (ja) * 2019-08-23 2022-11-04 北京泰徳製薬股▲フン▼有限公司 Ｅｇｆｒおよびａｌｋを阻害してそれらの分解を阻害する化合物
CN115353514A (zh) * 2022-08-31 2022-11-18 河南师范大学 氟代吡啶并嘧啶酮类化合物及其合成方法
JP2023509011A (ja) * 2019-12-31 2023-03-06 成都百裕制薬股▲ふん▼有限公司 プリン誘導体および医薬におけるその使用

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7098332B2 (en) * 2002-12-20 2006-08-29 Hoffmann-La Roche Inc. 5,8-Dihydro-6H-pyrido[2,3-d]pyrimidin-7-ones
WO2011063415A2 (fr) * 2009-11-23 2011-05-26 Afraxis, Inc. Méthodes de traitement de trouble cognitif léger
CN102648200A (zh) * 2009-10-09 2012-08-22 亚弗克希斯公司 用于治疗cns病症的8-乙基-6-(芳基)吡啶并[2，3-d]嘧啶-7(8h)-酮
WO2013086451A2 (fr) * 2011-12-09 2013-06-13 Afraxis, Inc. Inhibiteurs de pak destinés au traitement du cancer
CN103596951A (zh) * 2011-04-08 2014-02-19 阿弗拉克西斯控股股份有限公司 用于治疗神经系统障碍和癌症的8-乙基-6-(芳基)吡啶并[2,3-d]嘧啶-7(8h)-酮
CN105130986A (zh) * 2015-09-30 2015-12-09 广州科擎新药开发有限公司 嘧啶或吡啶并吡啶酮类化合物及其应用
CN105307657A (zh) * 2013-03-15 2016-02-03 西建阿维拉米斯研究公司 杂芳基化合物和其用途
CN106459034A (zh) * 2014-02-07 2017-02-22 普林斯匹亚生物制药公司 作为成纤维细胞生长因子受体抑制剂的喹诺酮衍生物

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104418860B (zh) * 2013-08-20 2016-09-07 中国科学院广州生物医药与健康研究院 嘧啶并杂环类化合物及其药用组合物和应用

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7098332B2 (en) * 2002-12-20 2006-08-29 Hoffmann-La Roche Inc. 5,8-Dihydro-6H-pyrido[2,3-d]pyrimidin-7-ones
CN102648200A (zh) * 2009-10-09 2012-08-22 亚弗克希斯公司 用于治疗cns病症的8-乙基-6-(芳基)吡啶并[2，3-d]嘧啶-7(8h)-酮
WO2011063415A2 (fr) * 2009-11-23 2011-05-26 Afraxis, Inc. Méthodes de traitement de trouble cognitif léger
CN103596951A (zh) * 2011-04-08 2014-02-19 阿弗拉克西斯控股股份有限公司 用于治疗神经系统障碍和癌症的8-乙基-6-(芳基)吡啶并[2,3-d]嘧啶-7(8h)-酮
WO2013086451A2 (fr) * 2011-12-09 2013-06-13 Afraxis, Inc. Inhibiteurs de pak destinés au traitement du cancer
CN105307657A (zh) * 2013-03-15 2016-02-03 西建阿维拉米斯研究公司 杂芳基化合物和其用途
CN106459034A (zh) * 2014-02-07 2017-02-22 普林斯匹亚生物制药公司 作为成纤维细胞生长因子受体抑制剂的喹诺酮衍生物
CN105130986A (zh) * 2015-09-30 2015-12-09 广州科擎新药开发有限公司 嘧啶或吡啶并吡啶酮类化合物及其应用

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112010844A (zh) * 2019-05-31 2020-12-01 中国药科大学 N-(嘧啶-2-基)香豆素-7-胺衍生物作为蛋白激酶抑制剂的制法和应用
CN112010844B (zh) * 2019-05-31 2023-07-25 中国药科大学 N-(嘧啶-2-基)香豆素-7-胺衍生物作为蛋白激酶抑制剂的制法和应用
JP2022546375A (ja) * 2019-08-23 2022-11-04 北京泰徳製薬股▲フン▼有限公司 Ｅｇｆｒおよびａｌｋを阻害してそれらの分解を阻害する化合物
CN112759589A (zh) * 2019-11-01 2021-05-07 暨南大学 嘧啶并吡啶酮类化合物及其应用
CN112759589B (zh) * 2019-11-01 2022-04-08 暨南大学 嘧啶并吡啶酮类化合物及其应用
JP2023509011A (ja) * 2019-12-31 2023-03-06 成都百裕制薬股▲ふん▼有限公司 プリン誘導体および医薬におけるその使用
JP7428806B2 (ja) 2019-12-31 2024-02-06 成都百裕制薬股▲ふん▼有限公司 プリン誘導体および医薬におけるその使用
WO2021139775A1 (fr) * 2020-01-10 2021-07-15 江苏先声药业有限公司 Composé de pyridone et son application
CN115353514A (zh) * 2022-08-31 2022-11-18 河南师范大学 氟代吡啶并嘧啶酮类化合物及其合成方法
CN115353514B (zh) * 2022-08-31 2023-07-25 河南师范大学 氟代吡啶并嘧啶酮类化合物及其合成方法

Also Published As

Publication number Publication date
CN110914267B (zh) 2022-07-12
CN110914267A (zh) 2020-03-24

Similar Documents

Publication Publication Date Title
WO2019015593A1 (fr) Composé de pyrimidopyridone ou pyridopyridone et utilisation correspondante
AU2016309833B2 (en) Pharmaceutical composition and application replacing quinolone derivative, pharmaceutical acceptable salt, or stereoisomer
AU2011274192B2 (en) Heterocyclic alkynyl benzene compounds and medical compositions and uses thereof
AU2015353210B2 (en) 2-aminopyrimidine compound and pharmaceutical composition and use thereof
EP2746283A1 (fr) Dérivés de pyrimidopyrimidone, compositions pharmaceutiques et leurs utilisations
WO2014079232A1 (fr) Dérivés de 7-oxo-pyrimidine, compositions pharmaceutiques et utilisations de celles-ci
WO2022253283A1 (fr) Agent de dégradation de protéine kinases et son utilisation
AU2019241374B2 (en) Quinoline or quinazoline compound and application thereof
CN103374000A (zh) 嘧啶并二氮杂卓类化合物及其药用组合物和应用
CN112851667B (zh) 含氮并杂环类化合物及其药用组合物和应用
CN114539263A (zh) 一类含氮并杂环化合物及其药用组合物和应用
WO2021180008A1 (fr) Composé cyclique tri-aromatique contenant une structure d'urée et utilisation associée
CN112313213B (zh) 3-氨基吡唑类化合物及其应用
CN103570731B (zh) 嘧啶并三环或嘧啶并四环类化合物及其药用组合物和应用
WO2022148317A1 (fr) Composé de 2-aminopyrimidine et composition pharmaceutique le comprenant et application associée
US20230348462A1 (en) Imidazo[4,5-c]quinoline compounds and their use as atm kinase inhibitors
CN118084902A (zh) 2-氨基噻唑嘧啶并吡啶酮类化合物或药学上可接受的盐或立体异构体及制备方法和应用
CN116063283A (zh) 3-氨基吲唑类化合物及其应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18834520

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18834520

Country of ref document: EP

Kind code of ref document: A1