WO2007126128A1 - ジヒドロピラゾロピリミジノン誘導体 - Google Patents
ジヒドロピラゾロピリミジノン誘導体 Download PDFInfo
- Publication number
- WO2007126128A1 WO2007126128A1 PCT/JP2007/059416 JP2007059416W WO2007126128A1 WO 2007126128 A1 WO2007126128 A1 WO 2007126128A1 JP 2007059416 W JP2007059416 W JP 2007059416W WO 2007126128 A1 WO2007126128 A1 WO 2007126128A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- lower alkyl
- alkyl group
- atom
- substituted
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
-
- 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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention is useful in the field of medicine. More specifically, the dihydropyrazo oral pyrimidinone derivative of the present invention is useful as a kinase inhibitor, particularly as a We 1 kinase inhibitor, in various cancer treatment fields. Background technology
- We e 1 kinase is a tyrosine kinase involved in the G2 checkpoint of the cell cycle.
- We el inactivates Cd c 2 by phosphorylating tyrosine 15 of C dc 2 (Cdkl), which is involved in the progression from the G 2 phase to the M phase of the cell cycle. Stop in Phase 2 [The EMBO Journal 1 (Vol. 12, pp. 75-85)]. Therefore, in cancer cells deficient in p53 function, the G2 checkpoint function by We e 1 is thought to be important in order to repair this and prevent cell death when DNA damage occurs.
- We e 1 inhibitors can increase the sensitivity to DNA-active anticancer drugs and radiation by inhibiting the G 2 checkpoint function of p53-deficient cancer cells. It is done.
- we 1 kinase inhibitors examples include US Patent Application US 2005/0250836, International Publication No. 2003/091255, Pancer, Cancer Research, Vol. 61, 8211. — The compounds described on page 8217 or Pio Organic and Medicinal Chemistry 'Letters (Bioo rg & Med. Chem. Lett.), Vol. 15, 1931—page 1935 are known. However, the compounds described in these documents are completely different in structure from the compounds of the present invention.
- An object of the present invention is to provide a novel anticancer agent having a kinase inhibitory action, particularly a We 1 kinase inhibitory action.
- a r 1 is a halogen atom, a lower alkyl group, a halo lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy group, a lower alkanoyl group, a hydroxy lower alkylamino group, a strong rubamoyl group, a hydroxy lower alkyl force rubamoyl group, or a lower alkyl group.
- An optionally substituted heteroaromatic group and a substituent selected from the group consisting of Q 1 — A 1 — Q 2 — A 2 (R la ) R lb Means an aryl group or a heteroaromatic ring group;
- a 1 represents a single bond, an oxygen atom or a sulfur atom, or an imino group optionally substituted by a lower alkyl group;
- a 2 represents a nitrogen atom, or a methine group or a 1-pinyl-2-ylidene group which may be substituted with a hydroxyl group, a lower alkyl group or a hydroxy lower alkyl group;
- Q 1 means a single bond, a strong sulfonyl group or a methylene group which may be substituted with a lower alkyl group;
- Q 2 means an ethylene group which may be substituted with a single bond or a lower alkyl group
- R 1 a and R 1 b are each independently a hydrogen atom, or means a lower alkyl group or a hydroxy lower ⁇ alkyl group, or means together such connexion lower alkylene group, here said lower alkylene group
- the constituting 1 or 2 or more methylene groups are each independently an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a pinylene group, or a group represented by —N (R lc ) 1. May be substituted, and may be substituted with, or with a hydroxyl or lower alkyl group;
- R lc means a hydrogen atom, a lower alkenyl group or a group represented by one Q 3 —A 3 (R ld ) R le ;
- a 3 represents a nitrogen atom, or a methine group or 1-pinyl-2-ylidene group which may be substituted with a hydroxyl group, a lower alkyl group or a hydroxy lower alkyl group;
- Q 3 represents a single bond or a lower alkylene group, wherein one or two or more methylene groups constituting the lower alkylene group are each independently an oxygen atom, a sulfur atom, a carbonyl group, a sulfenyl group. May be substituted with a group or a sulfonyl group, and may be substituted with Z or a halogen atom, a cyano group, a hydroxyl group or a lower alkyl group;
- R id and R le each independently represent a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, a lower alkyl group or a hydroxy lower alkyl group, or together, a lower alkylene group, 1 or 2 or more methylene groups constituting the lower alkylene group are each independently represented by an oxygen atom, a sulfur atom, a sulfiel group, a sulfonyl group, a carbonyl group, a pinylene group, or —N (R lf ) —. And / or may be substituted with a hydroxyl group or a lower alkyl group;
- R lf represents a hydrogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkenyl group or a lower alkyl group;
- R 1 represents a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a cyclo lower alkyl group which may be substituted with a halogen atom, or consists of a halogen atom, a cyano group, an amino group and a lower alkyl group Means an aryl group, an aralkyl group or a heteroaromatic group optionally having a substituent selected from the group;
- R 2 represents a hydrogen atom, a lower alkyl group, a lower alkenyl group or a lower alkynyl group, or a halogen atom, a cyano group, a nitro group, a carboxyl group, or —Q 4 —
- a 4 (R lg ) R lh Moto ⁇ Pi -Q 5 - a r a in may have a substituent group selected from the group consisting of groups represented means ⁇ rie group, a Ararukiru group or heteroaromatic ring group, wherein
- the lower alkyl group, lower alkenyl 1 or 2 or more methylene groups constituting a group or a lower alkynyl group are each independently an oxygen atom, a sulfur atom, a sulfiel group, a sulfonyl group, a carbonyl group, or a group represented by —N (R lj ) 1 And / or may be substituted with a
- a 4 represents a nitrogen atom or a methine group optionally substituted with a halogen atom, a hydroxyl group, a lower alkyl group or a hydroxy lower alkyl group;
- a ra may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a halo lower alkyl group, a hydroxy lower alkyl group and a lower alkoxy group, an aryl group or a heteroaromatic ring Means a group;
- Q 4 means a single bond or a lower alkylene group, wherein one or two or more methylene groups constituting the lower alkylene group are each independently replaced by an oxygen atom or a carbonyl group. , And / or optionally substituted with a lower alkyl group;
- Q 5 represents a single bond, an oxygen atom, a sulfur atom, a strong sulfonyl group or a lower alkylene group, wherein one or two or more methylene groups constituting the lower alkylene group are each independently an oxygen atom, sulfur May be substituted with an atom or force sulfonyl group, and may be substituted with a haguchi atom or a lower alkyl group;
- ⁇ is independently a hydrogen atom, a halogen atom, a cyan group, a hydroxyl group, a lower alkyl group, a lower alkoxy lower alkyl group, a lower alkanol group, a lower alkoxy group or a lower alkyl sulfone group.
- Group, or together means a lower alkylene group, wherein one or two or more methylene groups constituting the lower alkylene group are each independently an oxygen atom, a sulfur atom, a sulfier.
- R lj represents a hydrogen atom or a lower alkyl group
- R 3 represents a hydrogen atom or a lower alkyl group
- R 4 represents a hydrogen atom, a halogen atom, a 7K acid group, a lower alkyl group, or a group represented by —N (R lk ) R lm ;
- R l k and R lm each independently represent a hydrogen atom or a lower alkyl group
- T and U each independently represent a nitrogen atom or a methine group] (wherein R 1 is a methyl group and R 2 is an unsubstituted phenyl group)
- the present invention has been completed by finding that it has an excellent kinase inhibitory action, particularly a Wee 1 kinase inhibitory action.
- the compound (I) of the present invention has a kinase inhibitory action, in particular, Wee 1 kinase inhibitory action, for example, brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell cancer, non-small cell Cancer, Breast cancer, Lung cancer, Stomach cancer, Gallbladder 'Bile duct cancer, Liver cancer, Vaginal cancer, Colon cancer, Rectal cancer, Ovarian cancer, Chorioepithelial cancer, Endometrial cancer, Uterine cervix , Renal pelvic / ureteral cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, fetal cancer, Wilms cancer, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, It is useful as a therapeutic agent for various cancers such as Ewing's tumor, soft tissue sarcoma, acute leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and Hodg
- the compound (I) of the present invention is useful as a therapeutic agent for breast cancer, lung cancer, sputum cancer, colon cancer, ovarian cancer, acute leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin lymphoma and the like. is there.
- the present invention relates to a compound represented by the general formula (I), a salt or ester thereof, a production method and use thereof.
- Halogen atom means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
- “Lower alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group. Tert-butyl group, pentyl group, isopentyl group, hexyl group, isohexyl group and the like.
- Halo lower alkyl group means that any substitutable position is 1 or 2 or more, preferably 1 to 3 It means the lower alkyl group substituted with the same or different halogen atom, for example, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a 1,2-difluoroethyl group, a chloromethyl group, 2 Examples thereof include a chlorooctyl group, a 1,2-dichlorodiethyl group, a bromomethyl group, and a iodide methyl group.
- Haldroxy lower alkyl group means 1 or 2 or more, preferably 1 or
- hydroxyl group substituted with a hydroxyl group of 2 for example, hydroxymethyl group, 2-hydroxycetyl group, 1-hydroxy-11-methylethyl group, 1,2-dihydroxyethyl group, 3-hydroxypropyl group, etc. Is mentioned.
- “Lower alkoxy group” means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a sec-butoxy group, Examples thereof include an isobutoxy group, a tert-butoxy group, a pentyloxy group, an isopentyloxy group, a hexyloxy group, and an isohexyloxy group.
- the “lower alkanol group” means an alkanoyl group having the lower alkyl group, that is, an alkanoyl group having 2 to 7 carbon atoms.
- pivalol group means an alkanoyl group having the lower alkyl group, that is, an alkanoyl group having 2 to 7 carbon atoms.
- pivalol group pivalol group.
- “Hydroxy lower alkylamino group” means an amino group that is mono-substituted or di-substituted, preferably mono-substituted, to the hydroxy lower alkyl group.
- hydroxymethylamino group 2-hydroxychetylamino group
- 1-hydroxy examples thereof include 1-methylethylamino group, 1,2-dihydroxyethylamino group, and 3-hydroxypropylamino group.
- “Hydroxy-lower alkyl carbamoyl group” means a mono- or di-substituted, preferably mono-substituted, rubamoyl group, such as a hydroxymethyl carbamoyl group, 2-hydroxy group. Examples thereof include a tilcarbamoyl group, a 1-hydroxy-1-methylethylcarbamoyl group, a 1,2-dihydroxyethylcarbamoyl group, and a 3-hydroxypropyl rubamoyl group.
- aryl group examples include a phenyl group and a naphthyl group.
- Heteroaromatic group means a 5-membered or 6-membered member containing 1 or 2 or more, preferably 1 to 3 heteroatoms, which are the same or different from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom.
- an aromatic heterocyclic group such as pyraryl, furyl, chenyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, oxaziazol, 1, 2, 3—thiadiazolyl group, 1, 2, 4—thiadiazolyl group, 1, 3, 4-thiadiazolyl group, pyridyl group, pyrazinyl group, pyrimidinini Group, pyridazinyl group, 1, 2, 4 monotriazinyl group, 1, 3, 5_triazinyl group, indolyl group, benzofuranyl group, benzochelyl group., Benzoimidazolyl group, benzoxazolyl group, benzo Isoxazolyl, benzothiazolyl, benzoisothiazolyl, indazolyl, purinyl, quinolyl, is
- the “lower alkylene group” means a linear or branched alkylene group having 1 to 6 carbon atoms, such as a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, a hexamethylene group, etc. Is mentioned.
- “Lower alkenyl group” means a straight or branched alkenyl group having 2 to 6 carbon atoms, such as vinyl group, 1-propenyl group, allyl group, isopropenyl group, 3-butenyl group. , 2-butenyl group, 1-butenyl group, 1-methyl-2-propenyl group, 1-methyl-1-propenyl group, 1-ethenyl group, 1-ethenyl group, 2-methyl-2-propenyl group 2-methyl-1-propenyl group, 3-methyl-1,2-butenyl group, 4-pentenyl group and the like.
- “Lower alkynyl group” means a linear or branched alkynyl group having 2 to 6 carbon atoms, such as ethynyl group, 1-propynyl group, 2-propynyl group, 3-pentynyl group, 2-petitini group. Group, 1-butynyl group, 1-methyl-2-propynyl group, 1-ethyl-2-propynyl group, 1-methyl-2-butynyl group, 4-1-pentynyl group and the like.
- cyclo lower alkyl group means a cycloalkyl group having 3 to 6 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
- the “aralkyl group” means the lower alkyl group substituted with one or more, preferably 1, the aryl group at any substitutable position, such as a benzyl group, a 1-phenylethyl group, a phenyl group. Group, 1-naphthylmethyl group, 2-naphthylmethyl group and the like.
- “Lower alkoxy lower alkyl group” means the lower alkyl group substituted at one or more, preferably 1 or 2, the same or different lower alkoxy group at any substitutable position, for example, methoxymethyl Group, ethoxymethyl group, 2-methoxyethyl group, 2-ethoxyethyl group, 1-methoxy-1-methylethyl group, 1,2-dimethoxyethyl group, 3-methoxypropyl group and the like.
- “Lower alkoxycarbonyl group” means an alkoxy group having a lower alkoxy group.
- an alkoxycarbonyl group having 2 to 7 carbon atoms for example, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, a tert-butoxy group
- Examples include a carbonyl group and a pentyloxycarbonyl group.
- lower alkylsulfonyl group means a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms, such as a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, or an isopyl pyrsulfonyl group.
- salt of the compound of the present invention means a pharmaceutically acceptable conventional one.
- an acidic heterocyclic group such as a carboxyl group, a hydroxyl group, or a tetrazolyl group, the corresponding lpoxyl group, hydroxy acid And a base addition salt in a group or acidic heterocyclic group, or a salt of an acid addition salt in the amino group or basic heterocyclic group in the case of having an amino group or basic heterocyclic group.
- the base addition salt examples include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; such as ammonium salt; such as trimethylamine salt, triethylamine salt and dicyclohexylamine.
- alkali metal salts such as sodium salt and potassium salt
- alkaline earth metal salts such as calcium salt and magnesium salt
- ammonium salt such as trimethylamine salt, triethylamine salt and dicyclohexylamine.
- organic amine salts such as salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, pro-power-in salts, and N, N′-dibenzylethylenediamine salts.
- the acid addition salt examples include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, and perchlorate; for example, maleate, fumarate, tartrate, citrate, and ascorbine.
- Organic acid salts such as acid salts and trifluoroacetic acid salts; for example, sulfonic acid salts such as methanesulfonate, isethionate, benzenesulfonate, and p-toluenesulfonate.
- the “ester” of the compound of the present invention means, for example, a pharmaceutically acceptable conventional carboxylic group having a carboxyl group, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group.
- esters with rubamoyloxy lower alkyl groups esters with phthalidyl groups, (5-methyl-2-oxo-1,3-dioxo-4-yl) methyl groups (5-substituted-2-oxo 1 , 3-dioxol _ 4 yl) ester with methyl group.
- a r 1 is a halogen atom, a lower alkyl group, an eight-port lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy group, a lower alkanol group, a hydroxy lower alkyl amino group, a strong rubamoyl group, a hydroxy-lower alkyl group rubermoyl group, A heterocyclic group which may be substituted with a lower alkyl group and a substituent selected from the group consisting of —Q 1 — A 1 — Q 2 — A 2 (R la ) R lb; It means an aryl group or a heteroaromatic ring group which may be used.
- An optionally substituted heteroaromatic group and a substituent selected from the group consisting of a group represented by Q 1 — A 1 — Q 2 — A 2 (R la ) R lb , ⁇ Group or heteroaromatic ring group '' means the unsubstituted aryl group or heteroaromatic ring group, or the aryl group or heteroaromatic ring group having a substituent at any substitutable position;
- the substituent is a halogen atom, a lower alkyl group, a [Lambda] lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy group, a lower alkano
- One or two or more, preferably 1 or 2 can be selected from the group consisting of the groups represented.
- the halogen atom for the substituent is, for example, preferably a fluorine atom, a chlorine atom.
- the lower alkyl group for the substituent is, for example, preferably a methyl group, an ethyl group.
- the halo-lower alkyl group for the substituent is, for example, preferably a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group.
- the hydroxy lower alkyl group for the substituent is, for example, preferably a hydroxymethyl group, a 2-hydroxyethyl group.
- the lower alkoxy group for the substituent is, for example, preferably a methoxy group, an ethoxy group.
- the lower alkyl group of the substituent is, for example, preferably a acetyl group.
- the hydroxy-lower alkylamino group for the substituent is, for example, preferably a hydroxymethylamino group, a 2-hydroxyethylamino group.
- hydroxy lower alkyl strength ruberamoyl group of the substituent for example, hydroxymethylcarbamoyl group, 2-hydroxyethylcarbamoyl group and the like are preferable.
- heteroaromatic group optionally substituted with a lower alkyl group is the unsubstituted heteroaromatic group, or the same or different at any substitutable position, preferably 1 or more, preferably Means the above-mentioned heteroaromatic group having 1 or 2 lower alkyl groups, and for example, 4-methyl-1-imidazolyl group, 1-methyl-4-monopyrazolyl group and the like are preferable.
- a 1 represents a single bond, an oxygen atom or a sulfur atom, or a lower alkyl group
- a 2 represents a nitrogen atom, or a methine group or 1-bier-2 which may be substituted with a hydroxyl group, a lower alkyl group or a hydroxy lower alkyl group.
- Q 1 means a single bond, a carbonyl group or a methylene group optionally substituted with a lower alkyl group
- Q 2 represents an ethylene optionally substituted with a single bond or a lower alkyl group 1 1 3 and scale 1 13 each independently represent a hydrogen atom, a lower alkyl group or a hydroxy lower alkyl group, or together represent a lower alkylene group, wherein Lower alkylene group 1 or 2 or more methylene groups constituting each independently, an oxygen atom, a sulfur atom, Surufieru group, a sulfonyl group, Karuponiru group, Piniren group or - optionally replaced by N (R lc) groups represented in one Or Z and a hydroxyl group or a lower alkyl group may be substituted.
- the “imino group optionally substituted with a lower alkyl group” in A 1 means an unsubstituted imino group or an imino group substituted with the lower alkyl group, and the lower alkyl group of the substituent is For example, a methyl group, an ethyl group and the like are preferable.
- a methine group or 1-pinyl-2-ylidene group which may be substituted with a hydroxyl group, a lower alkyl group or a hydroxy lower alkyl group” in A 2 is an unsubstituted methine group or a 1-vinyl-2-ylidene group. Or a methine group or 1-vinyl-2-ylidene group having a substituent selected from the group consisting of a hydroxyl group, a lower alkyl group and a hydroxy lower alkyl group.
- the lower alkyl group for the substituent is, for example, preferably a methyl group, an ethyl group.
- the hydroxy lower alkyl group for the substituent is, for example, preferably a hydroxymethyl group, a 2-hydroxyethyl group.
- a hydroxyl group and the like are preferable.
- the “methylene group optionally substituted with a lower alkyl group” in Q 1 means an unsubstituted methylene group, or a methylene group substituted with the same or different 1 or 2 lower alkyl groups.
- the lower alkyl group for the substituent is preferably a methyl group or the like.
- the “ethylene group optionally substituted with a lower alkyl group” in Q 2 is an unsubstituted ethylene group, or 1 or 2 or more, preferably 1 or 2 of the above-mentioned An ethylene group substituted with a primary alkyl group is meant.
- the lower alkyl group for the substituent is preferably a methyl group or the like.
- the lower alkyl group for R 1 a or R lb for example a methyl group, Echiru group, propyl group, isopropyl group and the like.
- hydroxy lower alkyl groups for R 1 a or R lb such as hydroxymethyl group, and 2-hydroxy Shechiru groups are preferred.
- Preferred examples of the lower alkylene group formed when R la and Rlb are ⁇ are a trimethylene group, a tetramethylene group, a pentamethylene group, a hexamethylene group, and the like. These means that when “A 2 ” to be bonded is a nitrogen atom, together with the nitrogen atom, 1-azetidinyl group, 1-pyrrolidinyl group, piperidino group, perhydro-1H-azepine 1-yl group; When 2 ”is a methine group, it means a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group, respectively, together with the methine group; when“ A 2 ”is a 1-vinyl-2-ylidene group, 1-cyclopentenyl group, 1-cyclohexenyl group, 1-cycloheptenyl group, 1-cyclooctenyl group together with pin
- One or more methylene groups constituting the lower alkylene group are each independently represented by an oxygen atom, a sulfur atom, a sulfier group, a sulfonyl group, a carbonyl group, a pinylene group, or 1 N (R lc ) —. And / or a hydroxyl group or a lower alkyl group. Examples of such a substituted or substituted group include a group selected from the formula (aa 1): Is preferred.
- R lc is a hydrogen atom, a lower alkenyl group, or - means A 3 (R ld) the group represented by R le - Q 3.
- the lower alkenyl of R lc is, for example, preferably a vinyl group, a allyl group.
- a 3 means a nitrogen atom, or is substituted with a hydroxyl group, a lower alkyl group or a hydroxy lower alkyl group.
- Q 3 represents a single bond or a lower alkylene group, and one or more methylene groups constituting the lower alkylene group are Each independently may be substituted with an oxygen atom, a sulfur atom, a carbonyl group, a sulfiel group or a sulfonyl group, and may be substituted with a hydrogen atom, a halogen atom, a cyano group, an acid group or a lower alkyl group; R ld and R le are each independently a hydrogen atom, a halogen atom, Shiano group, a hydroxyl group, a force means a lower alkyl Motowaka properly hydroxy-lower alkyl group ,, or
- a lower alkylene group means that one or more methylene groups constituting the lower alkylene group are each independently an oxygen atom, a sulfur atom, a sulfinyl group,
- a 3 "Methine group or 1-vinyl-2-ylidene group optionally substituted with a hydroxyl group, lower alkyl group or hydroxy lower alkyl group” means an unsubstituted methine group or 1-pinyl1-2-ylidene. Or a methine group or 1-vinyl-2-ylidene group having a substituent selected from the group consisting of a hydroxyl group, a lower alkyl group and a hydroxy lower alkyl group.
- the lower alkyl group for the substituent is, for example, preferably a methyl group, an ethyl group.
- the hydroxy lower alkyl group for the substituent is, for example, preferably a hydroxymethyl group, a 2-hydroxyethyl group, a 2-hydroxypropyl group, a 2-methyl-1-hydroxypropyl group.
- a hydroxyl group, a lower alkyl group and the like are preferable.
- the lower alkylene group for Q 3 for example, a methylene group, an ethylene group, a trimethylene group and the like are preferable.
- 1 or 2 or more methylene groups constituting the lower alkylene group of Q 3 are each independently substituted with an oxygen atom, a sulfur atom, a carbonyl group, a sulfiel group or a sulfonyl group, and / or a halogen atom, It may be substituted with a cyano group, a hydroxyl group or a lower alkyl group.
- a substituted or substituted group for example, a group selected from the formula (aa 2) is preferable.
- halogen atom having a length of 1 £ 1 or 1 ⁇ for example, a fluorine atom, a chlorine atom and the like are preferable.
- the shaku or the lower alkyl group of the shaku is preferably, for example, a methyl group or an ethyl group.
- the hydroxy lower alkyl group for R ld or R le is, for example, preferably a hydroxymethyl group, a 2-hydroxychetyl group.
- R ld and R le for example, an ethylene group, a trimethylene group, a tetramethylene group and the like are preferable.
- These represent a 1-aziridinyl group, a 1-azetidinyl group, and a 1 pyrrolidinyl group together with the nitrogen atom when “A 3 ” to be bonded is a nitrogen atom; and when the “A 3 ” is a methine group, Together with a group, each means a cyclopropyl group, a cyclobutyl group, or a cyclopentyl group; and when “A 3 ” is a 1-vinyl_2-ylidene group, a 1-cyclobutenyl group, 1 -Cyclopentenyl group, 1-cyclo A xenyl group means a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and the like
- One or two or more methylene groups constituting the lower alkylene group are each independently represented by an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a vinylene group or —N (R lf ). Or a group selected from, for example, a group selected from the formula (aa 3). Is preferred.
- R lf is a hydrogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkenyl group or a lower Arukanoiru group.
- the lower alkyl group for R lf is, for example, preferably a methyl group, an ethyl group.
- Halo-lower alkyl as ri f for example Furuoromechiru group, Jifuruoromechiru group and the like.
- the lower alkenyl group for R 1 f is, for example, preferably an aryl group.
- an acetyl group is preferred.
- a 3 is a methine group optionally substituted with a hydroxyl group or a lower alkyl group, Q 3 is a single bond, and R ld and R le are each independently a hydrogen atom or a lower alkyl group.
- a 3 is a methine group, Q 3 is a single bond or a lower alkylene group, and R ld and R 1 e are ⁇ to mean a lower alkylene group, When one methylene group constituting the lower alkylene group is a group which may be replaced by a group represented by 1 N (R lf ) —;
- a 3 is a methine group which may be substituted with a hydroxyl group or a lower alkyl group
- Q 3 is a lower alkylene group, wherein 1 or 2 methylene groups constituting the lower alkylene group are Each independently an oxygen atom, a carbonyl group or a sulfonyl group, and / or a group optionally substituted with a hydroxyl group
- R ld and R le are each independently A hydrogen atom, a halogen atom, a cyano group or a lower alkyl group; or
- a 3 is a nitrogen atom
- Q 3 is a lower alkylene group, wherein one methylene group constituting the lower alkylene group is a group substituted with a carbonyl group
- R ld and R le Are each independently a hydrogen atom or a lower alkyl group; more preferably, the case of (i) above.
- R le is a group represented by, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a tert-butyl group, a hydroxymethyl group, 1- Hydroxy monomethylethyl, cyclopropyl, cycloptyl, cyclopropylmethyl, 1-acetyl, 31-azetidinyl, cyclopentyl, 2-hydroxycyclopentyl, 2-hydroxyethyl, 2-cyanoethyl, 2 —Methoxyethyl group, 2-ethoxyethyl group, 2-hydroxy-2-methylpropyl group, 3-fluoro-2-hydroxypropyl group, acetyl group, propionyl group, 2-methoxyacetyl group, tert-ptoxycarbonyl group, methylsulfonyl Group, 2- (methylsulfonyl) e
- R lc a hydrogen atom or one Q 3 - A 3 (R ld ) groups represented by R le, one more preferably Q 3 - groups represented by A 3 (R ld) R le preferable.
- Q 1 — A 1 — Q 2 — A 2 (R la ) R lb is, for example,
- a 1 , Q 1 and Q 2 are single bonds, A 2 is a nitrogen atom, and R 1 a and R 1 b are Wherein 1 or 2 methylene groups constituting the lower alkylene group are each independently represented by an oxygen atom, a sulfonyl group, a force sulfonyl group or 1 N (R lc ) —.
- a 2 may be substituted with a hydroxyl group, a methine group or a 1-piery-2-ylidene group, and R 1 a and R 1 b together represent a lower alkylene group, and when the 1 methylene group constituting the lower alkylene group is a group replaced by a group represented by 1 N (R lc ) — '
- a 1 is an oxygen atom
- a 2 is a methine group
- Q 1 and Q 2 are single bonds
- R la and R lb are preceded to mean a lower alkylene group
- the 1 alkylene group constituting the lower alkylene group is a group substituted by a group represented by 1 N (R lc ) 1;
- a 1 is an oxygen atom
- a 2 is a nitrogen atom
- Q 1 is a single bond
- Q 2 is an ethylene group
- R la and R lb are each independently lower When it is an alkyl group
- 1-piperazinyl group 4-methyl-1-piperazinyl group, 4-ethyl-1- 1-piperazinyl group, 4-propyl-1- 1-piperazinyl group, 4- ⁇ sopropyl-1-1-piperazinyl group, 4-- tert-butyl 1-1-piperazinyl group, 4- Hydroxymethyl 1-piperazinyl ⁇ , 4 1 (1-hydroxy-1- 1-methylethyl) 1 1-piperazinyl, 4-cyclopropyl 1-piperazinyl, 4-cyclobutyl _ 1-piperazinyl, 4-cyclopropylmethyl— 1— Piperazinyl group, 4-- (1-acetyl-1-3-zetidinyl) 1 1-piperazinyl group, 4-cyclopentyl 1-piperazinyl group, 4 — (2-hydroxycyclopentyl) 1 1-piperazinyl group, 4-- (2-hydroxyethyl) 1 1-piperazinyl group, 4- (2-Chanoethyl
- Examples of the substituent for A r 1 include a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy group, a lower alkanol group, and a heteroaromatic ring group which may be substituted with a lower alkyl group, — Q 1 — A 1 — Q A group represented by 2 — A 2 (R la ) R lb is preferred.
- aryl group of the aryl group optionally having the above-mentioned substituent for A r 1
- a phenyl group and the like are preferable.
- heteroaromatic ring group of the heteroaromatic ring group which may have the above-mentioned substituent for A r 1
- a pyrazolyl group, a pyridyl group and the like are preferable.
- Ar 1 for example, a phenyl group, a pyrazolyl group, a pyridyl group, or the like, a heteroalkyl group that may be substituted with a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy group, a lower alkanol group, or a lower alkyl group
- a group in which a group represented by a cyclic group or a group represented by Qi—A 1 —Q 2 —A 2 (R la ) R lb is substituted is preferable, and in particular, one —Q 1 —A 1 —Q 2 —A 2 (R la ) R lb is a substituted phenyl group, or one Q 1 — A 1 — Q 2 — A 2 (R la ) R lb in addition to the lower alkyl group A phenyl group substituted with a group or a hydroxy lower alkyl group is preferred.
- a r 1 for example,
- R 1 may be substituted with a halogen atom, a force meaning a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a cyclo-lower alkyl group, or a halogen atom, a cyano group, an amino group and It means an aryl group, an aralkyl group or a heteroaromatic ring group which may have a substituent selected from the group consisting of a lower alkyl group.
- a halogen atom a force meaning a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a cyclo-lower alkyl group, or a halogen atom, a cyano group, an amino group and It means an aryl group, an aralkyl group or a heteroaromatic ring group which may have a substituent selected from the group consisting of a lower alkyl group.
- the “lower alkyl group, lower alkenyl group, lower alkynyl group or cyclo-lower alkyl group optionally substituted with a halogen atom” of R i is the above-mentioned unsubstituted lower alkyl group, lower alkenyl group, lower alkynyl group.
- a cyclo-lower alkyl group, or the lower alkyl group, lower alkenyl group, lower alkynyl group or cyclo-lower alkyl group substituted by the halogen atom, and the halogen atom is an arbitrary substitutable atom of each group.
- the position may be the same or different, and 1 or 2 or more, preferably 1 to 3 may be substituted.
- the halogen atom for the substituent is, for example, preferably a fluorine atom, a chlorine atom.
- Examples of the “lower alkyl group optionally substituted with a halogen atom” for R 1 include, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a 2,2-difluoroethyl group, and a 2,2,2-trifluoroethyl group. More preferably, an ethyl group, an isopropyl group and the like are suitable.
- lower alkenyl group optionally substituted with a halogen atom for example, an aryl group, 2-methyl-2-propenyl group, 3-methyl-2-butenyl group and the like are preferable. Etc. are particularly preferred.
- the “lower alkynyl group optionally substituted with a halogen atom” for R i is, for example, preferably a 2-propynyl group.
- cyclo lower alkyl group optionally substituted with a halogen atom for R i, for example, a cyclopentyl group, a cyclobutyl group and the like are preferable.
- an aryl group, an aralkyl group or a heteroaromatic ring group optionally having a substituent selected from the group consisting of a halogen atom, a cyano group, an amino group and a lower alkyl group” of R 1 is an unsubstituted group.
- the aryl group, aralkyl group or heteroaromatic ring group, or the aryl group, aralkyl group or heteroaromatic ring group having a substituent at any substitutable position means a halogen atom, a cyano group, From the group consisting of an amino group and a lower alkyl group, one or more, preferably 1 or 2 can be selected, which are the same or different.
- the halogen atom for the substituent is, for example, preferably a fluorine atom, a chlorine atom.
- the lower alkyl group for the substituent is, for example, preferably a methyl group, an ethyl group.
- the substituent is preferably a halogen atom, a cyano group, an amino group or the like, more preferably a halogen atom.
- Examples of the aryl group that may have the above-mentioned substituent of R 1 include phenyl group, 1-naphthyl group, 2-chlorophenyl group, 2,6-dichlorophenyl group, 2-cyanophenyl group, 2- A chloro-6-cyanophenyl group and the like are preferable.
- heteroaromatic ring group which may have the substituent for R 1 , for example, 2-pyridyl group, 3-chloro 2-pyridyl group and the like are preferable.
- aralkyl group which may have the above substituent for R 1 , for example, a benzyl group, a trimethylbenzyl group and the like are preferable.
- R 1 a lower alkyl group which may be substituted with an atom atom is mentioned. More specifically, they are ethyl group, isopropyl group and the like.
- R 1 includes a lower alkenyl group which may be substituted with a halogen atom. More specifically, an aryl group, a 2-methyl-2-propenyl group, a 3-methyl-1-butenyl group, and the like, more preferably an aryl group.
- R 1 includes a lower alkynyl group optionally substituted with a halogen atom. More specifically, it is a 2-propynyl group.
- R 1 includes a phenyl group or a benzyl group which may have a substituent selected from the group consisting of a halogen atom, a cyan group, an amino group, and a lower alkyl group. More specifically, a 2-chlorophenyl group, a 2,6-dichlorophenyl group, a 2-cyanophenyl group, a 2-chloro-6-cyanophenyl group, a benzyl group, a monomethylbenzyl group, and the like, more preferably 2 —A chlorophenyl group and the like.
- R 1 is most preferably a lower alkenyl group such as an aryl group.
- R 2 represents a hydrogen atom, a lower alkyl group, a lower alkenyl group or a lower alkynyl group, Or halogen atom, Shiano group, a nitro group, a force Rupokishiru group, one Q 4 - A 4 (R ls ) groups represented by R lh and - Q 5 - is selected from the group consisting of groups represented by A r a An aryl group, an aralkyl group or a heteroaromatic ring group, which may have a substituent, wherein one or two or more methylene groups constituting the lower alkyl group, lower alkenyl group or lower alkynyl group Are independently substituted with an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group or a group represented by —N (R lj ) — and / or substituted with a halogen atom. May be.
- the lower alkyl group for R 2 is, for example, preferably a methyl group, an ethyl group.
- the lower alkenyl group for R 2 is preferably, for example, an aryl group.
- the lower alkynyl group for R 2 is, for example, preferably a 2-propynyl group.
- One or two or more methylene groups constituting the lower alkyl group, lower alkenyl group or lower alkynyl group of R 2 are each independently an oxygen atom, a sulfur atom, a sulfiel group, a sulfonyl group, a force sulfonyl group or a single group.
- N (R lj ) may be substituted with a group represented by 1 and may be substituted with a nitro or halogen atom. Examples of such a substituted or substituted group include a methoxymethyl group, methyl A sulfonylmethyl group, a acetyl group or a group represented by the formula (bbl) is preferred.
- R lj means a hydrogen atom or a lower alkyl group, and for example, a hydrogen atom, a methyl group and the like are preferable.
- Halogen atom R 2 Shiano group, a nitro group, a force Rupokishiru group, - consisting of groups represented by A r a - Q 4 - A 4 (R l E) groups represented by R lh and - Q 5
- An aryl group, an aralkyl group or a hetero-aromatic ring group optionally having a substituent selected from the group means an unsubstituted aryl group, aralkyl group or complex.
- An aromatic ring group, or the above-mentioned aryl group, aralkyl group or heteroaromatic ring group having a substituent at any substitutable position means a halogen atom, a cyano group, a nitro group, a strong lpoxyl group, one Q 4 - A 4 (R lg ) groups represented by R lh and one Q 5 - from the group consisting of groups represented by A r a, the same or different one or more, preferably 1 or 2 selected can do.
- the halogen atom for the substituent is, for example, preferably a fluorine atom, a chlorine atom, a bromine atom.
- a 4 represents a nitrogen atom, or substituted with a halogen atom, a hydroxyl group, a lower alkyl group or a hydroxy lower alkyl group
- Q 4 means a single bond or a lower alkylene group, wherein one or more methylene groups constituting the lower alkylene group are each independently an oxygen atom or be replaced by Karuponiru group, and / or may be substituted with a lower alkyl group; long ⁇ and scale 1 11 are each independently a hydrogen atom, a halogen atom, Shiano group, a hydroxyl group, a lower alkyl Group, lower alkoxy lower alkyl group, lower alkanoyl group, lower alkoxycarbonyl group or lower alkyl sul
- the “methine group optionally substituted with a halogen atom, hydroxyl group, lower alkyl group or hydroxy lower alkyl group” in A 4 means an unsubstituted methine group, or a halogen atom, hydroxyl group, lower alkyl group and hydroxy lower alkyl group. It means a methine group having a substituent selected from the group consisting of groups.
- the halogen atom for the substituent is, for example, preferably a fluorine atom, a chlorine atom.
- the lower alkyl group for the substituent is, for example, preferably a methyl group, an ethyl group.
- the hydroxy lower alkyl group for the substituent is, for example, preferably a hydroxymethyl group, a 2-hydroxyethyl group.
- a halogen atom for example, a hydroxyl group, a lower alkyl group and the like are preferable.
- the lower alkylene group of Q 4 for example, a methylene group, an ethylene group, a trimethylene group and the like are preferable.
- One or two or more methylene groups constituting the lower alkylene group of Q 4 may each independently be substituted with an oxygen atom or a force sulfonyl group and / or substituted with a lower alkyl group, As such a substituted or substituted group, for example, a group selected from the formula (bb 2) is preferable.
- halogen atom a fluorine atom, a chlorine atom or the like is preferred as the halogen atom.
- the lower alkyl group for example, a methyl group, an ethyl group, an isopropyl group and the like are preferable.
- R lg or R lh for example, a methoxymethyl group, a 2-methoxyetchyl group, a 3-methoxypropyl group, and the like are preferable.
- the lower alkanoyl group for R 1 g or R 1 h is, for example, preferably a acetyl group.
- R lg or R lh for example, a methoxycarbonyl group, a tert-butoxycarbonyl group and the like are preferable.
- the lower alkylsulfonyl group for R lg or R lh is, for example, preferably a methylsulfonyl group, an ethylsulfonyl group.
- the lower alkylene group formed by combining R lg and R lh together for example, an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group and the like are preferable.
- “A 4 ” to be bonded is a nitrogen atom, together with the nitrogen atom, 1-aziridinyl group, 1-azetidinyl group, 1-pyrrolidinyl group, piperidino group, and “A 4 ” of methine group
- methine group together with the methine group, it means a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group, respectively.
- One or two or more methylene groups constituting the lower alkylene group are each independently represented by an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a strong sulfonyl group, or —N (R 1 ′) 1 It may be substituted with a group, and / or may be substituted with a halogen atom or a lower alkyl group. As such a substituted or substituted group, for example, a group selected from the formula (bb 3) is preferable. It is. Among these, a group selected from the formula (bb 3 ′) is more preferable. R 1i (bb3 ')
- R 11 is a hydrogen atom, a lower alkyl group or a halo-lower alkyl group.
- the lower alkyl group for example, a methyl group, an ethyl group and the like are preferable.
- Preferred examples of the halo lower alkyl group for Rl i include a fluoromethyl group and a difluoromethyl group.
- a 4 is a nitrogen atom
- Q 4 is a single bond or a methylene group that may be substituted with a lower alkyl group
- R lg and R lh are each independently a hydrogen atom, lower When it is an alkyl group, a lower alkanol group, a lower alkoxy group, a sulfonyl group or a lower alkylsulfonyl group;
- a 4 is a nitrogen atom, or a methine group optionally substituted by a halogen atom, a hydroxyl group, a lower alkyl group or a hydroxy lower alkyl group, Q 4 is a carbonyl group, and R lg and R When 1 h is independently a hydrogen atom or a lower alkyl group;
- a 4 is a methine group optionally substituted with a halogen atom, a hydroxyl group, a lower alkyl group or a hydroxy lower alkyl group, and Q 4 is a methylene group optionally substituted with a single bond or an oxygen atom.
- R ig and R ih are each independently a hydrogen atom, a halogen atom, 7m, a lower alkyl group or a lower alkoxycarbonyl group;
- a 4 is a methine group which may be substituted with a halogen atom, a hydroxyl group, a lower alkyl group or a hydroxy lower alkyl group, and Q 4 is an ethylene group.
- the two methylene groups may be each independently replaced by an oxygen atom or a carbonyl group, and R lg and R lh are each independently a hydrogen atom, a hydroxyl group or a lower alkyl group. ;
- a 4 is a methine group optionally substituted with a halogen atom, a hydroxyl group, a lower alkyl group or a hydroxy lower alkyl group, Q 4 is a single bond, and R lg and R lh are Is a lower alkylene group, wherein one or more methylene groups constituting the lower alkylene group are each independently represented by an oxygen atom or —N (R 1! ) —. When it may be replaced by a group; or
- a 4 is a nitrogen atom
- Q 4 is a single bond
- R lg and R lh together represent a lower alkylene group, wherein 1 or 2 constituting the lower alkylene group
- the above methylene groups may be each independently replaced by a carbonyl group or a group represented by 1 N (R 1 ′) —, etc .; more preferably, in the case of (iii) above Is mentioned.
- Amino group methylaminomethyl group, dimethylaminomethyl group, isopropylmethylamino group, 1-amino-1-methylethyl group, methylsulfonylamino group, N-methyl_N-acetylaminomethyl group, N-methyl-N-methoxycarbonylaminoamino group, N-methyl-N-methylsulfonyl aminomethyl group, strong rubamoyl group, methylcarbamoyl group, dimethylcarbamoyl group, acetyl group, methyl group, trifluoromethyl group, 1 Fluoro-1-methylethyl group, hydroxymethyl group, 1-hydroxyethyl group, 1-hydroxy-1-methylethyl group, 2-hydroxy-1,1,1-dimethylethyl group, 2-hydroxy-2-methylpropyl group, 2-hydroxy-1 , 1-dimethylpropyl group, 1-methoxycarbonyl-1-methylethyl group, metho Xyl group
- Ariru group R 2 is a substituent of Ararukiru group or heteroaromatic ring group - Q 5 -
- a r a halogen atom, a lower alkyl group, a halo-lower alkyl group, hydroxy lower alk Q 5 represents a single bond, an oxygen atom, a sulfur atom, a carbonyl group or an aryl group or heteroaromatic ring group which may have a substituent selected from the group consisting of a kill group and a lower alkoxy group;
- Lower alkylene Wherein one or more methylene groups constituting the lower alkylene group are each independently replaced by an oxygen atom, a sulfur atom or a carbonyl group, and a Z or halogen atom. Alternatively, it may be substituted with a lower alkyl group.
- a R a may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a halo lower alkyl group, a hydroxy lower alkyl group and a lower alkoxy group, an aryl group or a hetero aromatic group.
- ring group means the unsubstituted aryl group or heteroaromatic ring group, or the aryl group or heteroaromatic ring group having a substituent at any substitutable position.
- the substituent is a halogen atom, lower From the group consisting of an alkyl group, a lower lower alkyl group, a hydroxy lower alkyl group, and a lower alkoxy group, one or two or more, preferably 1 or 2 can be selected.
- the halogen atom for the substituent is, for example, preferably a fluorine atom, a chlorine atom.
- the lower alkyl group for the substituent is, for example, preferably a methyl group, an ethyl group.
- the halo-lower alkyl group for the substituent is, for example, preferably a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group.
- the hydroxy lower alkyl group for the substituent is, for example, preferably a hydroxymethyl group, a 2-hydroxyethyl group.
- the lower alkoxy group for the substituent is, for example, preferably a methoxy group, an ethoxy group.
- substituent for example, a halogen atom, a lower alkyl group, a lower alkoxy group and the like are preferable.
- the "Ariru group” itself of A r a the may have a substituent group Ariru group, for example phenyl groups and the like.
- aromatic heterocyclic group itself of A r said substituent optionally heteroaromatic ring group which may have a a, for example, pyridyl group and the like.
- a r a may have the substituent of A r a, the preferred specific examples of Ariru group or heteroaromatic ring group, for example phenyl group, 4 Metokishifue group, 2 _ pyridyl, 6-methyl - 2 One pyridyl group and the like can be mentioned.
- the lower alkylene group for Q 5 is, for example, preferably a methylene group, an ethylene group.
- 1 or 2 or more methylene groups constituting the lower alkylene group of Q 5 may each independently be replaced by an oxygen atom, a sulfur atom or a carbonyl group, and / or a halogen atom or a lower alkyl group
- a substituted or substituted group for example, a group selected from (bb 4) is preferable. Therefore, -Q 5 - Examples of the group represented by A r a, specifically, for example, base Njiru group, Benzoiru group, phenoxy group, Benjiruokishi group, 4-methoxybenzyl O alkoxy group, a 2-pyridyl group and the like Is preferred.
- R 2 As the substituent for the “aryl group, aralkyl hetero group or aromatic ring group” of R 2 , for example, a group represented by —Q 4 —A 4 (R lg ) R lh is preferable.
- aryl group of the aryl group which may have the above substituent of R 2 , for example, a phenyl group and the like are preferable.
- aralkyl group of the aralkyl group which may have the substituent of R 2 , for example, a benzyl group and the like are preferable.
- heteroaromatic group of the heteroaromatic group optionally having the above-mentioned substituent for R 2 , for example, a chenyl group, a pyrazolyl group, a pyridyl group and the like are preferable.
- aryl group aralkyl group or heteroaromatic group which may have the substituent of R 2 , specifically, for example,
- R 2 is preferably a lower alkyl group or an aryl group or a heteroaromatic group which may have the above-described substituent.
- R 1 and R 2 in the general formula (I) may be a lower alkenyl group or a lower alkynyl group, more preferably a lower alkenyl group, which may be substituted with a halogen atom, and
- R 2 is a phenyl group or a pyridyl group having a group represented by —Q 4 —A 4 (R) R lh , more preferably a pyridyl group.
- R 3 means a hydrogen atom or a lower alkyl group, for example, a hydrogen atom, a methyl group, an ethyl group, etc., more preferably a hydrogen atom.
- R 4 represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, or a group represented by —N (R lk ) R lm .
- halogen atom for R 4 for example, a fluorine atom, a chlorine atom and the like are preferable.
- the lower alkyl group for R 4 is, for example, preferably a methyl group, an ethyl group, an isopropyl group.
- the scale and ⁇ each independently represent a hydrogen atom or a lower alkyl group.
- the lower alkyl group for R lk or R lm is, for example, preferably a methyl group, an ethyl group, an isopropyl group. .
- examples of the group represented by 1 N (R lk ) R lm include an amino group, a methylamino group, a dimethylamino group, and an isopropylmethylamino group.
- R 4 is preferably a hydrogen atom or the like.
- T and u each independently represent a nitrogen atom or a methine group, and it is preferable that both are nitrogen atoms.
- each of scales 5 and 6 is independently a hydrogen atom, an octalogen atom, a lower alkyl group, an eight-port lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy group, a lower alkanol group, or a hydroxy lower alkyl group.
- R 10 represents a lower alkyl group, a lower alkenyl group or a lower alkynyl group which may be substituted with a halogen atom
- R 2Q is a halogen atom
- a substituent selected from the group consisting of a cyano group, a nitro group, a strong lpoxyl group, a group represented by —Q 4 — A 4 (R ls ) R lh and a group represented by one Q 5 —A ra Means an aryl group or a heteroaromatic group which may have, A 1 , A 2 , A 4 , Ar a , Q 1 , Q 2 , Q 4 , Q 5 , R la , R lb , ⁇ And ⁇ have the above meanings]
- R 7a , R 7b , R 8a and R 8b each independently represents a hydrogen atom, a halogen atom or a cyan group; R 8 c represents a hydrogen atom or a lower alkyl group.
- AA 2 , Q 1 , Q 2 , R la , R lb , R 5 , R 6 and R 20 have the above-mentioned meanings], and a compound represented by the general formula (1-3)
- halogen atom for R 5 or R 6 for example, a fluorine atom, a chlorine atom and the like are preferable.
- the lower alkyl group for R 5 or R 6 is, for example, preferably a methyl group, an ethyl group.
- halo-lower alkyl group for R 5 or R 6 for example, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group and the like are preferable.
- the hydroxy lower alkyl group for R 5 or R 6 is, for example, preferably a hydroxymethyl group, a 2-hydroxyethyl group.
- the lower alkoxy group for R 5 or R 6 is, for example, preferably a methoxy group, an ethoxy group.
- hydroxy lower alkylamino group for R 5 or R 6 for example, a hydroxymethylamino group, a 2-hydroxyethylamino group and the like are preferable.
- hydroxy lower alkyl strength ruberamoyl group for R 5 or R 6 for example, hydroxymethylcarbamoyl group, 2-hydroxyethylcarbamoyl group and the like are preferable.
- R 5 and R 6 for example, when both are hydrogen atoms, either one is a hydrogen atom, and the other is a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy group or a lower alkanol group. Such as when.
- Preferred embodiment of the group represented by —Qi—A 1 —Q 2 —A 2 (R la ) R lb in the compound represented by the general formula (1-1), (1-2) or (1-3) Is the same as the group represented by —Q 1 —Ai—QS—A 2 (R la ) R lb in the general formula (I).
- the lower alkyl group which may be substituted with a halogen atom of R 10 for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a 2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group and the like are preferable. Among them, an ethyl group and an isopropyl group are more preferable. ⁇ '
- the lower alkenyl group optionally substituted with a halogen atom for R 10 for example, an aryl group, a 2-methyl-2-propenyl group, a 3-methyl-2-butenyl group, and the like are preferable. Is particularly preferred.
- the lower alkynyl group which may be substituted with a halogen atom of Rio, for example, 2-propynyl group and the like are preferable.
- R 10 includes a lower alkyl group which may be substituted with a halogen atom.
- R 10 includes a lower alkenyl group which may be substituted with a halogen atom. More specifically, it is an aryl group, a 2-methyl-2-propenyl group, a 3-methyl-2-butenyl group, and more preferably an aryl group.
- R 1G includes a lower alkynyl group which may be substituted with a halogen atom. More specifically, it is a 2-propynyl group.
- R 10 is particularly preferably a lower alkenyl group such as an aryl group.
- R2 Q "halogen atom, Shiano group, a nitro group, a carboxyl group, - Q 4 - A 4 ( R lg) groups are tables in R lh and - Q 5 - from the group consisting of groups represented by A r a
- a preferred embodiment of the aryl group or heteroaromatic ring group which may have a selected substituent ” is a“ halogen atom, cyan group, nitro group, carboxyl group of R 2 in the general formula (I) ” 1 Q 4 —A 4 (R lg ) R 1h and a group selected from the group consisting of Q 5 —Ar a may be substituted.
- Group or heteroaromatic ring group ”.
- R 2 () includes a phenyl group or a pyridyl group having a group represented by 1 Q 4 —A 4 (R ⁇ ) R lh , more preferably a pyridyl group.
- R 10 may be a lower alkenyl group or a lower alkynyl group, more preferably a lower alkenyl group, which may be substituted with a halogen atom
- R 2 () is a phenyl group or a pyridyl group, more preferably a pyridyl group having a group represented by —Q 4 —A 4 (R lg ) R lh .
- Preferred examples of the group represented by R 10 , R 20 and one Qi—A 1 —Q 2 —A 2 (R la ) R 1 b in the general formula (1-1) include, for example, R 1 Q a halogen atom may be substituted, a lower alkenyl group or lower alkynyl group, more preferably a lower alkenyl group, R 20 is - with the a 4 (R lB) groups represented by R lh, - Q 4 A phenyl group or a pyridyl group, more preferably a pyridyl group, and a group represented by — Q 1 — A 1 — Q 2 — A 2 (R la ) R lb is represented by the formula (a al ′) And a group selected from:
- Halo-Gen atoms R 7a, R 7b, 1 8 & or 1 813 preferably a fluorine atom, a chlorine atom
- R 8 c for example, a methyl group, an ethyl group, and the like are preferable.
- R 7 a and R 7 b for example one is when the force , either both hydrogen atoms with water atom and the other and the like when it is a halogen atom or a Shiano group.
- Preferable specific examples of the group represented by the formula (a-1) include, for example, a 2-chlorophenyl group, a 2,6-dichlorophenyl group, a 2-chloro-6-cyanophenyl group, and the like.
- R 8 a and R 8 b include, for example, when both are hydrogen atoms. Accordingly, preferred specific examples of the group represented by the formula (a-2) include a benzyl group and an ⁇ -methylpentyl group.
- a preferred embodiment of the group represented by the formula (a-1) of R 12 is the same as the preferred embodiment of the group represented by the formula (a-1) in the general formula (I-12).
- the lower alkyl group for R 21 is, for example, preferably a methyl group, an ethyl group.
- any substitutable position has a hydrogen atom that can be substituted on a carbon, nitrogen, oxygen and Z or sulfur atom, and the substitution of the hydrogen atom is allowed to It means a site that gives a stable compound.
- the replacement of the methylene group constituting the lower alkylene group with, for example, oxygen, sulfur, sulfinyl, sulfonyl, carbonyl, vinylene, and substituted or unsubstituted imine is chemically acceptable. The result is acceptable if it results in a stable compound.
- the compound of the present invention may have stereoisomers or tautomers such as optical isomers, diastereoisomers, and some isomers depending on the mode of the substituent or the salt form. Includes all these stereoisomers, tautomers and mixtures thereof.
- the present invention includes various crystals, amorphous, salts, hydrates and solvates of the compounds of the present invention.
- prodrugs of the compounds of the present invention are also within the scope of the present invention.
- such prodrugs are functional derivatives of the compounds of the present invention that can be readily converted to the compounds required in vivo. Therefore, in the method for treating various diseases according to the present invention, the term “administration” refers not only to the administration of the specified compound, but also to the compound converted into the specified compound in vivo after being administered to the patient. Including administration.
- Conventional means for the selection and production of suitable prodrug derivatives are described, for example, in “D esign of Prod rugs” ed. H. Bundga ard, Els ev ier, 1985, etc. The entire description is a part of this specification. Metabolites of these compounds include active compounds produced by placing the compounds of the invention in a biological environment and are within the scope of the invention.
- the compound (I) of the present invention can be produced, for example, by the following production method or the method shown in Example “Production Example”. However, the production method of the compound (I) of the present invention is not limited to these reaction examples. Manufacturing method 1
- R 2 P means a hydrogen atom, a lower alkyl group, a lower alkenyl group or a lower alkynyl group, or a halogen atom, a cyano group, a nitro group, — Q 4P — A 4P R A group represented by LHP and a group represented by one QSP and one A R , and optionally substituted substituents selected from the group consisting of optionally protected lupoxyl groups, an aryl group, an aralkyl group Or a heteroaromatic ring group, wherein one or two or more methylene groups constituting the lower alkyl group, lower alkenyl group or lower alkynyl group are each independently an oxygen atom, a sulfur atom, a sulfinyl group, A sulfonyl group, an optionally protected sulfonyl group, or a group represented by 1 N (R LJP ) —, and may be substituted with Z or a halogen
- a 4P represents a nitrogen atom, or a halogen atom, a hydroxyl group that may be protected, a lower alkyl group, or a methine group that may be substituted with a hydroxy lower alkyl group that may be protected.
- Ar ap may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group and an optionally protected hydroxy lower alkyl group, an aryl group or a hetero group Means an aromatic ring group;
- Q 4P means a single bond or a lower alkylene group, wherein 1 or 2 or more methylene groups constituting the lower alkylene group are each independently an oxygen atom or an optionally protected carbon atom. And / or may be substituted with a lower alkyl group;
- QSP means a single bond, an oxygen atom, a sulfur atom, an optionally protected carbonyl group or a lower alkylene group, wherein one or two or more methylene groups constituting the lower alkylene group are each independently And may be substituted with an oxygen atom, a sulfur atom or an optionally protected carbonyl group, and / or substituted with a halogen atom or a lower alkyl group;
- ⁇ > ⁇ And 1 11] 1) are independently a hydrogen atom, a halogen atom, a cyano group, an optionally protected hydroxyl group, a lower alkyl group, a lower alkoxy lower alkyl group, a lower alkanoyl group, or a lower alkoxy force.
- R 1 ip represents a protecting group for an imino group, a hydrogen atom, a lower alkyl group or a halo lower alkyl group
- R 1 jp represents a protecting group for an imino group, a hydrogen atom or a lower alkyl group
- R 4P means a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, a lower alkyl group or a group represented by —N ( RLKP ) RLMP ; And each independently represents an amino or imino protecting group, a hydrogen atom or a lower alkyl group, and T and U have the above-mentioned meanings] III)
- a r lp is a halogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group, a lower alkanol group, a strong rubamoyl group, a heteroaromatic group optionally substituted with a lower alkyl group, and a single Q lp
- R 1 bp is selected from the group consisting of 1 bp and optionally protected hydroxy lower alkyl group, hydroxy lower alkylamino group and hydroxy lower alkyl strength rubermoyl group
- A represents a single bond, an oxygen atom or a sulfur atom, or an imino group which may be substituted with an imino protecting group or a lower alkyl group;
- a 2 P is a force that means a nitrogen atom or a hydroxyl group that may be protected, a lower alkyl group, or a hydroxy lower alkyl group that may be protected, a methine group or 1-pinyl ⁇ 2— Means an iridene group;
- Q 1 P means a single bond, an optionally protected strong sulfonyl group or a methylene group optionally substituted with a lower alkyl group;
- R lap and R lbp each independently represent a hydrogen atom, a lower alkyl group, or an optionally protected hydroxy lower alkyl group, or together, a lower alkylene group, wherein One or two or more methylene groups constituting the lower alkylene group are each independently an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, an optionally protected carbonyl group, a vinylene group or —N (R lcp ) May be substituted with a group represented by —, and may be substituted with Z or an optionally protected hydroxyl group or lower alkyl group;
- R lcp means a hydrogen atom, a lower alkenyl group, or a group represented by one Q 3p — A 3p (R 1 ) R lep ;
- a 3 Represents a nitrogen atom, or a methine group or a 1-vinyl-1-ylidene group optionally substituted with a hydroxy group, a lower alkyl group, or a hydroxy lower alkyl group that may be protected Means;
- Q 3 p means a single bond or a lower alkylene group, wherein one or two or more methylene groups constituting the lower alkylene group are independently an oxygen atom, a sulfur atom, or a protected one. May be substituted with a good carbonyl group, sulfiel group or sulfonyl group, and / or may be substituted with a halogen atom, a cyano group, an optionally protected hydroxyl group or a lower alkyl group.
- R ldp and R lep each independently represent a hydrogen atom, a halogen atom, a cyano group, an optionally protected hydroxyl group, a lower alkyl group or an optionally protected hydroxy lower alkyl group, or Together, it means a lower alkylene group, wherein one or more methylene groups constituting the lower alkylene group are each independently an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, or a protected group. May be substituted with a carbonyl group, a pinylene group or a group represented by —N (R lfp ) 1, and may be substituted with a hydroxyl group or lower alkyl group which may be protected or protected;
- R 1 represents a protecting group for an imino group, a hydrogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkenyl group or a lower alkanol group, and Q 2 and R 3 have the above-mentioned compounds] Or the salt is reacted with general formula (IV)
- Examples of the leaving group represented by L 1 include a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, an organic sulfonyl group such as a methylsulfinyl group, a methylsulfonyl group, an ethylsulfonyl group, a phenylsulfonyl group, or a methyl group.
- Examples thereof include organic sulfonyloxy groups such as sulfonyloxy group, 1, trifluoromethylsulfonyloxy group, monotolylsulfonyloxy group, etc. Among them, chlorine atom, methyl sulfier group, methylsulfonyl group and the like are preferable. .
- This production method is a general production method of the compound represented by the general formula (I).
- the reaction when an amino group, imino group, hydroxyl group, carboxyl group, strong sulfonyl group, etc. that are not involved in the reaction are present in the reactant, the amino group, imino group, hydroxyl group, strong lpoxyl group, strong sulfonyl group is As appropriate, the reaction can be carried out after protecting with an amino- or imino-protecting group, a hydroxyl-protecting group, a strong l-poxyl-protecting group or a carbonyl-protecting group, and the protecting group can be removed after the reaction.
- the “amino group or imino group protecting group” is not particularly limited as long as it has the function.
- benzyl group, ⁇ -methoxybenzyl group, 3,4-dimethoxybenzyl group, Aralkyl groups such as benzyl, p-nitrobenzyl, benzhydryl, and trityl groups; for example, lower alkanoyl groups such as formyl, acetyl, propionyl, petityl, and bivaloyl groups; such as benzoyl groups; such as phenylacetyl groups
- Aryl alkanol groups such as phenoxyacetyl group
- lower alkoxycarbonyl groups such as methoxycarbonyl group, ethoxycarbonyl group, propyloxycarbonyl group, tert-butoxycarbonyl group
- Aralkyloxy groups such as
- Lower alkyl sulfonyl group such as a group; for example, arylsulfonyl group such as benzenesulfonyl group, toluenesulfonyl group and the like, in particular acetyl group, benzyl group, tert-ptoxycarbonyl group, trimethylsilylethoxy A methyl group, a methylsulfonyl group and the like are preferable.
- the “hydroxyl-protecting group” is not particularly limited as long as it has the function.
- a lower alkyl group such as a trimethylsilyl group or a tert-butyldimethylsilyl group; such as a methoxymethyl group or a 2-methoxyethoxymethyl group;
- Lower alkoxymethyl groups such as tetrahydrobiranyl group; for example trimethylsilylethoxymethyl group; for example, benzyl group, p-methoxybenzyl group, 2,3-dimethoxybenzyl group, 0-nitrobenzil group, p-nitromethane
- Aralkyl groups such as benzyl group and trityl group; for example, acyl groups such as formyl group and acetyl group, and the like, in particular, methyl group, methoxymethyl group, tetrahydrovillaryl group, trityl group, trimethylsilylethoxymethyl group, tert A butyldi
- the “protective group for the force loxyl group” is not particularly limited as long as it has the function, for example, a lower alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a tert-butyl group; Halo lower alkyl groups such as 2,2 trichloro-octyl groups; lower alkenyl groups such as allyl groups; benzyl groups, p-methoxybenzyl groups, p-nitrobenzyl groups, benzhydryl groups, trityl groups, etc.
- a lower alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a tert-butyl group
- Halo lower alkyl groups such as 2,2 trichloro-octyl groups
- lower alkenyl groups such as allyl groups
- An aralkyl group and the like, and a methyl group, an ethyl group, a tert-butyl group, a 'aryl group, a benzyl group, a p-methoxybenzyl group, a benzhydryl group and the like are particularly preferable.
- Carbonyl protecting group is not particularly limited as long as it has the function, and examples thereof include acetals such as ethylene ketal, trimethylene ketal and dimethyl ketal, ketals and the like.
- the reaction between the compound represented by the general formula (II) and the compound represented by the general formula (III) usually involves equimolar or excess molar amount of the compound (III) with respect to 1 mol of the compound (II). Preferably, it is carried out using equimolar or 1.5 molar. .
- the reaction is usually carried out in an inert solvent.
- the inert solvent include toluene, benzene, methylene chloride, black mouth form, tetrahydrofuran, dioxane, dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and the like.
- a mixed solvent or the like is preferable.
- the above reaction is preferably carried out in the presence of a base.
- a base examples include organic bases such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, sodium hydrogen carbonate, sodium carbonate.
- organic bases such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, sodium hydrogen carbonate, sodium carbonate.
- Inorganic bases such as potassium carbonate, cesium carbonate, sodium hydroxide and lithium hydroxide can be used.
- the amount of the base used is usually equimolar to excess molar, preferably 1 to 3 molar relative to 1 molar of the compound represented by the general formula (II).
- the reaction temperature is usually not 0 or 200 ° C, preferably 20 ° C to 150 ° C.
- the reaction time is usually 5 minutes to 7 days, preferably 30 minutes to 24 hours.
- the method for removing a protecting group differs depending on the type of protecting group and the stability of the target compound (I).
- the method described in the literature [Protective Group's Organic Synthesis sin Organic Synthesis), 3rd edition, written by TW Gleene, John Wiley & Sons (1999)] or similar methods, eg acid or Solvolysis using a base, that is, for example, 0.01 mol to a large excess of acid, preferably trifluoroacetic acid, formic acid, hydrochloric acid, or the like, or an equimolar to large excess of a base, preferably potassium hydroxide, calcium hydroxide, etc.
- the compound of general formula (I) can be easily isolated and purified by conventional separation means. Examples of such means include solvent extraction, recrystallization, column chromatography, preparative thin layer chromatography and the like. These compounds can be converted into pharmaceutically acceptable salts or esters by conventional methods. Conversely, conversion from a salt or ester to a free compound can also be carried out according to a conventional method.
- the “salt” of the compound represented by the general formula (III) is a conventional salt used in the field of organic chemistry. Meaning, for example, a base addition salt in the carboxyl group in the case of having a carboxidyl group or a salt of an acid addition salt in the amino group or basic heterocyclic group in the case of having an amino group or a basic heterocyclic group. it can.
- the base addition salt examples include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; for example ammonium salt; for example trimethylamine salt, triethylamine salt and dicyclohexane.
- Organic amine salts such as hexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, pro-power-in salt, N, N'-dibenzylethylenediamine salt, and the like.
- the acid addition salt examples include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, and perchlorate; for example, maleate, fumarate, tartrate, kenate, and ascorpinate.
- Organic acid salts such as trifluoroacetic acid salts; sulfonic acid salts such as methane sulfonate, isethionate, benzene sulfonate, and p-toluene sulfonate.
- Production method A is a compound represented by general formula (II) wherein L 1 is a methylsulfinyl group and T is a nitrogen atom, that is, general formula (I 1-1)
- the compound represented by the general formula (II-1) is obtained by reacting the compound represented by the formula (1) with the hydrazine derivative represented by the formula (2) in the presence of a base.
- a compound represented by the formula (3) The compound (3) can be produced by introducing a group represented by R lp into a compound (5), and finally oxidizing the methylthio group of the compound (5) to a methylsulfinyl group. it can.
- the step of reacting the compound represented by the formula (1) with the hydrazine derivative represented by the formula (2) in the presence of a base to produce the compound represented by the formula (3) ′ is usually a compound (1 )
- the hydrazine derivative (2) is used in an amount of 0.5 mol to excess mol, preferably equimolar to 3.0 mol with respect to 1 mol.
- the reaction is usually carried out in an inert solvent, and as the inert solvent, for example, methylene chloride, chloroform, tetrahydrofuran, ethyl ether, benzene, toluene, dimethylformamide, or a mixed solvent thereof is suitable.
- the above reaction is preferably carried out in the presence of a base.
- a base examples include organic bases such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, sodium hydroxide, hydroxy ⁇ Inorganic bases such as potassium, sodium carbonate, potassium carbonate, and sodium bicarbonate can be used.
- the base is preferably used in an equimolar to excess molar amount with respect to 1 mole of the compound (1).
- the base can be used as a solvent and base.
- the reaction temperature is usually —78 ° C. to 100 ° C., preferably 20 ° C. to 80 ° C.
- the reaction time is usually 5 minutes to 7 days, preferably 30 minutes to 24 hours.
- the step of producing the compound (5) by reacting the compound (3) with the compound (3) usually comprises 0.5 mole to excess mole, preferably 1 mole of the compound (4) with respect to 1 mole of the compound (3). It is carried out using 2.0 mol to 5.0 mol.
- a halogen atom such as a chlorine atom, a bromine atom, or an iodine atom is preferable.
- the reaction is usually carried out in an inert solvent such as tetrahydrofuran, benzene, toluene, acetonitrile, dimethylformamide, etc. in the presence of a base such as sodium hydride, sodium amide, sodium alkoxide, or methanol, for example. It is carried out in a solvent such as ethanol or acetonitrile in the presence of a base such as sodium hydroxide, potassium hydroxide or potassium carbonate.
- the reaction temperature is usually not 0 or preferably up to the boiling point of the solvent used for the reaction, and the reaction time is usually preferably 1 hour to 48 hours.
- the process of producing the compound (I 1-1) by oxidizing the methylthio group of the compound (5) is per se well-known in the field of organic chemistry, oxidizing the methylthio group to a methylsulfinyl group or a methylsulfonyl group.
- an inert solvent such as benzene, toluene, methylene chloride, black mouth form, tetrahydrofuran, acetonitrile, dimethylformamide
- an oxidizing agent such as methochloric peroxybenzoic acid, oxone, etc., or an excess mole, preferably equimolar to 1.5 moles.
- the reaction temperature is usually preferably from 0 ° C. to the boiling point of the solvent used for the reaction, and the reaction time is usually preferably from 30 minutes to 8 hours.
- the compound represented by the general formula (1) or (2) may be a commercially available product, or may be produced by appropriately combining known methods, methods described in Examples, or similar methods as necessary. wear.
- R 1 G () P represents a substituent selected from the group consisting of a halogen atom, a cyano group and a lower alkyl group, and an optionally protected amino group; Or an aryl group, an aralkyl group or a heteroaromatic ring group, and Me, R 2p , R 4 p and U have the above-mentioned meanings]
- the compounds represented by formula (II) are selected from the group group represented by R lp is a halogen atom, Shiano group and a lower alkyl group and an optionally protected amino group
- R lp is a halogen atom, Shiano group and a lower alkyl group and an optionally protected amino group
- the compound represented by the general formula (II-12) is produced by the compound represented by the formula (3) and the organometallic compound represented by the formula (6) produced in the production method A.
- a metal salt catalyst or a metal salt reagent to produce a compound represented by the formula (7), and then the methylthio group of the compound (7) is oxidized to a methylsulfinyl group. be able to.
- the step of producing compound (7) by reacting compound (3) and compound (6) usually involves compound (6) with respect to 1 mol of metal salt catalyst or metal salt reagent or compound (3). It is carried out using 0.5 mol to 5 mol, preferably 0.7 mol to 3 mol.
- metal salt catalyst or metal salt reagent used in the reaction examples include transition metals generally used in a cross coupling reaction such as copper, nickel, and palladium.
- transition metals generally used in a cross coupling reaction such as copper, nickel, and palladium.
- Copper sulfonate, copper iodide and the like are preferable.
- a general organometallic atom represented by M means an organometallic atom commonly used in cross-coupling reactions, such as lithium, boron, silicon, magnesium, aluminum, zinc, tin, etc.
- Preferred examples include boron, zinc, tin, and the like.
- Specific usage forms include, for example, boron for boric acid or borate ester, zinc for zinc chloride, zinc bromide or zinc iodide, and tin for tri And lower alkyl tin.
- the reaction is usually carried out in an inert solvent such as water, benzene, toluene, xylene, methylene chloride, black mouth form, dimethoxyethane, terahydrofuran, dioxane, dimethylformamide. Or a mixed solvent thereof is preferred.
- an inert solvent such as water, benzene, toluene, xylene, methylene chloride, black mouth form, dimethoxyethane, terahydrofuran, dioxane, dimethylformamide.
- a mixed solvent thereof is preferred.
- the reaction temperature is usually from room temperature to the boiling point of the solvent used for the reaction, preferably 20 ° C to 200 ° C.
- Reaction B Temple is usually 30 minutes to 7 days, preferably 24 hours to 3 days.
- the above reaction is preferably performed in the presence of a base.
- a base examples include potassium phosphate.
- inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate and cesium carbonate, and organic bases such as triethylamine and disopropylamine.
- the amount of the base used is usually 0.5 to 5 moles, preferably equimolar to 3 moles of the base with respect to 1 mole of the compound (3).
- the step of producing the compound (I 1-2) by oxidizing the methylthio group of the compound (7) comprises oxidizing the methylthio group of the compound (5) in production method A to produce the compound (II-1). It can be performed in the same manner as the manufacturing process.
- the compound represented by the general formula (6) can be produced by appropriately combining, as necessary, the ability to use a commercially available product, a known method, a method described in Examples, or a method analogous thereto. Manufacturing method C
- QP represents a protecting group for a hydrogen atom or an imino group
- R 2 T QP represents a halogen atom, a cyano group, a nitrite group, or a single Q 4p — A 4p (R lgp ) R lhp And a group represented by Q 5p — A I- ap and a substituent selected from the group consisting of an optionally protected carboxyl group, an aryl group, an aralkyl group or a heteroaromatic ring
- a 4p , Ar ap , Et , M, Me, Q 4p , Q 5p , R lgp , R lhp , R lp , R 4 p and U have the above-mentioned meanings
- protecting group for the imino group of R p for example, a benzyl group, a paramethoxybenzyl group, a tert-butoxycarbonyl group, a benzyloxycarbonyl group and the like are suitable.
- the group represented by R 2 P is represented by a halogen atom, a cyano group, a nitro group, and one Q 4p — A 4p (1 ⁇ ) R lhp. And a group represented by Q 5p — A r ap as well as an optionally protected substituent selected from the group consisting of a forceful loxyl group, an aryl group, an aralkyl group or a hetero group.
- This is a method for producing a compound which is an aromatic ring group, the leaving group of L 1 is a methylsulfinyl group and T is a nitrogen atom, that is, a compound represented by the general formula (I 1-3).
- the compound represented by the general formula (I 1-3) is obtained by reacting the compound represented by the formula (1) with the hydrazine derivative represented by the formula (8) in the presence of a base. After the hydrolysis, the compound is cyclized to obtain a compound represented by the formula (9), and then the organic metal compound represented by the formula (10) is added to the compound (9) in the presence of a catalyst.
- the compound (11) can be prepared by introducing a group represented by R 2 QQp by reaction, and finally the methylthio group of the compound (11) is oxidized to form a methylsulfonyl group.
- the step of reacting the compound represented by the formula (1) with the hydrazine derivative represented by the formula (8) in the presence of a base usually involves 0% of the hydrazine derivative (8) per 1 mol of the compound (1).
- the reaction is carried out using 5 mol to excess mol, preferably equimolar to 1.5 mol.
- the reaction is usually carried out in the presence of an organic base such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, or an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, carbonated potassium, sodium bicarbonate.
- an organic base such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine
- an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, carbonated potassium, sodium bicarbonate.
- an inert solvent such as methylene chloride, black mouth form, tetrahydrofuran, ethyl ether, benzene, toluene, dimethylformamide or a mixed solvent thereof.
- the base is preferably used in an equimolar to excess molar amount with respect to 1 mole of the compound (1).
- the base can be used as a solvent and base.
- the reaction temperature is usually from ⁇ 78 ° C. to 20 ° C., preferably from 20 ° C. to 100 ° C.
- the reaction time is usually 5 minutes to 7 days, preferably 8 hours to 24 hours.
- the step of hydrolyzing the compound obtained by the above reaction can apply a hydrolysis reaction method of a carboxylic acid ester, which is well known in the field of organic chemistry, and usually includes, for example, methanol, ethanol,
- the reaction can be carried out in a solvent such as tetrahydrofuran, dioxane, water, or a mixed solvent thereof using, for example, an acid such as hydrochloric acid or sulfuric acid, or a base such as sodium hydroxide, hydroxylated lithium or calcium hydroxide.
- the reaction temperature is usually preferably from 50 ° C. to the boiling point of the solvent used for the reaction, and the reaction time is usually preferably from 1 hour to 48 hours.
- the step of producing the compound (9) by cyclization of the obtained compound is carried out by allowing the reaction solution to acidify after the hydrolysis, so that the cyclization reaction proceeds as it is, or When the cyclization reaction does not proceed, the hydrolyzed compound is heated to reflux in the presence of acetic anhydride or by reacting thionyl chloride with the hydrolyzed compound. .
- the amount of acetic anhydride used is preferably an excess mole, and the reaction time is usually preferably 1 hour to 48 hours.
- the amount of salt thiothionyl used is preferably an excess mole, and the reaction time is usually preferably 1 hour to 48 hours.
- the step of producing compound (1 1) by reacting compound (9) with an organometallic compound represented by formula (10) in the presence of a catalyst and introducing a group represented by R 2 P is carried out by a production method. It can be carried out in the same manner as in the step of producing compound (6) from compound (3) in B.
- the above step can also be performed by using a halogenated compound having a group represented by R 2 QQ p in place of the organometallic compound represented by the formula (1 0).
- a halogenated compound having a group represented by R 2 QQ p in place of the organometallic compound represented by the formula (1 0).
- an iodine iodide (I) -diamine complex is suitable as the catalyst.
- the step of producing the compound (I 1-3) by oxidizing the methylthio group of the compound (11) produces the compound (II-1) by oxidizing the methylthio group of the compound (5) in production method A. It can be performed in the same manner as the step to be performed.
- the compound represented by the general formula (8) can be produced by using a commercially available product, or by appropriately combining known methods, methods described in Examples, or methods based thereon as necessary. Manufacturing method D Et0 2 C 1) R 100p NH 2 (13) 3) Cyclization
- compounds represented by formula (II) are selected from the group group represented by R lp is a halogen atom, Shiano group and a lower alkyl group and an optionally protected amino group
- a compound which may have a substituent, is an aryl group, an aralkyl group or a heteroaromatic ring group, the leaving group of L 1 is a methylsulfinyl group, and T is a methine group, that is, a compound represented by the general formula This is a method for producing a compound represented by I 1-4).
- the compound represented by the general formula (I 1-4) was hydrolyzed by reacting the compound represented by the formula (12) with the amino compound represented by the formula (13). Thereafter, the compound can be produced by cyclizing the compound to obtain a compound represented by the formula (14), and then oxidizing the methylthio group of the compound (14) to form a methylsulfinyl group.
- the reaction between the compound represented by the formula (12) and the amino compound represented by the formula (13) usually involves 0.5 mole or excess of the amino compound (13) with respect to 1 mole of the compound (12). Mole, preferably equimolar to 1.5 molar is used.
- the reaction is usually carried out in an inert solvent.
- the inert solvent include methanol, ethanol, methylene chloride, black mouth form, tetrahydrofuran, ethyl ether, benzene, toluene, dimethylformamide and the like.
- a mixed solvent or the like is preferable.
- the above reaction is preferably carried out in the presence of a base.
- a base examples include organic bases such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 2,6-lutidine, and water.
- organic bases such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 2,6-lutidine, and water.
- Inorganic bases such as sodium oxide, 7K potassium carbonate, sodium carbonate, potassium carbonate, sodium hydrogen carbonate can be used.
- the base is preferably used in an equimolar to excess molar amount with respect to 1 mole of the compound (12).
- the base can be used as a solvent and base.
- the reaction temperature is usually from 78 ° C to 200 ° C, preferably from 20 ° C to 120 ° C.
- the reaction time is usually 5 minutes to 7 days, preferably 30 minutes to 24 hours.
- a carboxylic acid ester hydrolysis reaction method well known in the field of organic chemistry can be applied, and the compound (1) in production method C can be applied. This can be carried out in the same manner as the hydrolysis step after the reaction of the hydrazine derivative (8).
- the step of producing the compound (14) by cyclizing the obtained compound is, for example, a salt methylene, butanol, black mouth form, tetrahydrofuran, dimethylformamide, pyridine, or a mixed solvent thereof.
- an inert solvent such as N, N'-dicyclohexyl carpositimide, N, N'-diisopropyl carposimide, 1- (3-dimethyl 1- (3-dimethylaminopropyl) 1- (3-dimethylaminopropyl) 1-ethylcarbopositimide hydrochloride, benzotriazol 1-loxysheet liquor (dimethylamino) phosphine hexafluorophosphate , Benzotriazole- 1-yloxy sheet bispyrroline dinophosphonium hexafluorophosphine, promotris (dimethylamino) phosphonium hexafluorophosphite, diphenyl phosphate azide, 1, 1 ' It can be carried out by allowing a condensing agent such as olponyldiimidazole to act.
- a condensing agent such as olponyldiimidazole to
- the condensing agent can be used in an amount of 1 mol to excess mol, preferably 1 mol or 1.5 mol, relative to 1 mol of the raw material compound.
- the reaction temperature is usually 50 ° C to 100 ° C, preferably -20 ° C to 50 ° C.
- the reaction time is usually 30 minutes to 7 days, preferably 1 hour to 24 hours.
- the step of producing the compound (II-14) by oxidizing the methylthio group of the compound (14) comprises the step of producing the compound (II-1) by oxidizing the methylthio group of the compound (5) in production method A. Can be done as well.
- the compound represented by the general formula (12) or (13) can be produced by appropriately combining, as necessary, the ability to use a commercially available product, a known method or a method described in Examples, or a method analogous thereto. .
- We e 1 kinase cDNA fused with daltathione-S-transferase (GST) at the amino terminal is incorporated into a baculovirus expression vector to produce a recombinant baculovirus, which is highly expressed by infecting insect cell line Sf9 I let you.
- GST-tagged We e 1 kinase protein is adsorbed onto the Daltathione column, eluted from the column with Daltathione, and the active fraction is desalted with a desalting column to obtain a purified enzyme. .
- the substrate is a synthetic peptide, P o 1 y (Lys, Tyr) Hydrbromide (Lys: Tyr (4: 1)) purchased from Sigma. Using. The reaction volume was 21.1 / XL, and the composition of the reaction buffer was 50 mM Tris-HCl buffer (pH 7.4) / 1 OmM magnesium chloride / ImM dithiothreitol.
- P] -labeled ATP (2500 CiZmmo 1 or more) was added and reacted at 30 ° C for 30 minutes. Thereafter, 10 L of 35 OmM phosphate buffer was added to the reaction system to stop the reaction. The substrate peptide was adsorbed on a P 81 paper filter 96 well plate, washed several times with 13 OmM phosphate buffer, and the radioactivity was measured with a liquid scintillation counter. [A- 33 P] label ATP was purchased from Amersham Biosciences.
- test compound was added to the reaction system by first preparing a dimethyl sulfoxide (DMS ⁇ ) dilution series of the compound and adding 1.1 L of the dilution series.
- a control system was prepared by adding 1. IL of DMSO to the reaction system.
- Pharmacological test 2 Drug effect assessment method using cells (C d c 2 (Cdk 1) tyrosine 15-phosphorylation inhibitory action))
- Ushi Fetal Serum is from Morgate
- RPMI 1640 and DMEM are from Invitrogen
- Camptothecin is from Sigma
- Gemushi Yupin is from Japan Lily
- Nocodazole and Proteaase Inhibitor Cocktail is from Sigma From Usagi anti-Cdc 2 antibody and mouse anti-Ccl c 2 antibody from Santa Cruz Biotechnology
- Usagi anti-tyrosine 15-phosphorylated Cdc 2 antibody and Western sapiperoxidase-labeled mouse IgG antibody are cell signaling From a technology company
- a Shuable Reservoir TMB peroxidase substrate was obtained from Kirkegard and Perry La Polaris, respectively.
- NC I—H 1299 Human non-small cell lung cancer cells
- WiD r human colon cancer cells
- the cells were suspended in RPMI 1640 medium supplemented with 10% FBS, and 2000 cells per well of Z100 microliter cell suspension was purchased from NUNK. Pour plates, 37 ° C, 5% C0 2 - and 1 ⁇ cultured at 95% air. Dissolve camptothecin in dimethyl sulfoxide (DMSO), dilute with RPMI 1640 medium supplemented with 10% FB S, and then add 50 microliters each so that the final concentration of camptothecin is 200 nM on the plate previously seeded with cells. Dispensing, 16 hours, 37 ° C, 5% C 0 2 — Incubated in 95% air.
- DMSO dimethyl sulfoxide
- Test compounds are serially diluted with DMSO and further diluted with 10% FBS-added RPM 1 1640 medium containing 4000 nM nocodazole, and then 50 microliters are dispensed onto a plate on which cells treated with camptothecin are plated. Noted. After incubation in air at 37 ° (: 5% C ⁇ 2 — 95% air for 8 hours, remove the culture solution, add 100 liters of lysis buffer, shake at 4 ° C for 2 hours, The cell lysate was frozen and thawed at 80 ° C. C dc 2 and tyrosine 15-phosphorylated C dc 2 in this cell lysate were measured by enzyme-linked immunoassay (EL ISA method).
- EL ISA method enzyme-linked immunoassay
- the ratio of tyrosine 15-phosphorylated Cd c 2 to dc 2 was calculated, and the 50 % phosphorylation inhibitory concentration (EC 50 , nM) of the test compound for the cells was determined.
- the reaction was stopped by dispensing 100 microliters at a time and measured by a colorimetric method.
- Measurement of tyrosine 15-phosphorylated Cdc 2 by ELISA was performed as follows. Disperse 50 microliters per well of Usagi anti-tyrosine 15-phosphorylated C dc 2 body solution diluted 100-fold with 50 fnM carbonate-bicarbonate buffer (pH 9.6) to 96-well maxisopym plate. The antibody was immobilized on the plate at 4 ° C for 1 hour.
- the cells are suspended in DMEM medium supplemented with 10% FBS, and 2 000 cells / well of Z100 microliters of cell suspension are dispensed into a 96-well Nunclon Delta-treated plastic plate. , 37 ° C, 5% C0 2 - and 1 ⁇ cultured at 95% air.
- Dissolve gemcitabine in PBS add 10% FBS, dilute in DMEM medium, and dispense 50 microliters at a time to give a final concentration of gemcibin bin of 100 nM on a plate previously seeded with cells. Incubate for 24 hours at 37, 5 C0 2 -95% in air.
- Test compounds are serially diluted with DMSO and further diluted with DMEM medium containing 10% FBS containing 1200 nM nocodazol, and then dispensed in 50-microliter aliquots onto a plate on which cells treated with gemcipin are plated. did. 8 hours, 37 ° C, 5% C0 2 - After culturing at 95% air to remove the culture medium, adding the cell lysis buffer by 100 micro rate torr, was shaken for 2 hours at 4 ° C, one 80 ° C A cell lysate was obtained by freezing and thawing the solution.
- C dc 2 and tyrosine 15-phosphorylated C dc 2 in this cell lysate were measured by ELISA, and the ratio of tyrosin 15-phosphorylated C dc 2 to C dc 2 was calculated. 50% phosphorylation inhibitory concentration (EC 50 , nM) was determined.
- Cdc2 measurement by EL ISA method was performed as follows. Dispose of 200 ⁇ L of Usagi anti-Cd c 2 antibody solution diluted 200-fold with 5 OmM carbonate-bicarbonate buffer (pH 9.6) to a 96-well maxi soap plastic plate in a volume of 50 microliters per well. The antibody was placed on a solid phase.
- the compounds according to the present invention have excellent C dc 2 -tyrosine 15 phosphorylation against human-derived cancer cells (NC I—H12 99 and Wi D r). Shows inhibitory action.
- FBS Fetal bovine serum
- DMEM medium from Invitrogene
- Geimushi Yupin from Nihon Iri Lily
- Nocodazol and 4 ' 6-diamidino-1 2-phenylindyl from Sigma
- the Usagi anti-phosphorylated histone H 3 body was obtained from Upstate
- the fluorescent label (A 1 ea Fluor 488) was obtained from Molecular Probe.
- test compound was serially diluted with dimethyl sulfoxide and further diluted with 10% FBS-added DMEM medium containing 1200 nM nocodazole, and then dispensed in 50 microliter aliquots onto the plate on which cells treated with gemcitabine were seeded. After incubation in air at 37 ° C, 5% C0 2 — 95% air for 8 hours, remove the culture medium, add 100 microliters of methanol that has been cooled to 20 ° C, and add the plate to 20 ° C. The cells were fixed by placing them for a while.
- the cells fixed with methanol were washed with PBS, 50 microliters of PBS containing 1% ushi serum albumin (1% BSA / PBS) was added and allowed to stand at room temperature for 30 minutes, and then 1% 83 Hachino? Usagibo phosphorylated histone H3 antibody diluted 250-fold with 33 was added in 50 microliter aliquots and allowed to stand at room temperature for 90 minutes.
- PBS containing 1% ushi serum albumin 1% BSA / PBS
- the compound according to the present invention exhibits an excellent checkpoint release action against human-derived cancer cells (Wi Dr).
- % T / C (tumor volume change of each test compound group in Day 3, 6, 10, 13) tumor volume change of control group in ZD ay 3, 6, 10, 13, X 100
- % T / C (tumor volume change of each test compound group at Day 3, 6, 10, 13) Tumor volume of each test compound group at ZD ay 0 X 100
- Table 5 shows the results of the tumor growth inhibitory effect.
- the tumor growth rate was reduced by gemcitabine administration
- the tumor growth rate was further reduced by administering the compound of the present invention in combination with gemcitabine, and tumor regression was observed in the high dose combination group.
- the compound of the present invention enhanced the action of other anticancer agents by using it in combination with other anticancer agents.
- FBS Fushi fetal serum
- RPMI 1640 medium and 0.25% trypsin EDTA from Invitrogen
- Cycle Test Plus DNA Regent Kit from Becton Dickinson
- Nylon Net Filter 1 from Millipore obtained.
- Chick non-small cell lung cancer cells (NC I—HI 299) were obtained from AT CC.
- NC I— HI 299 cells were suspended in RPMI 1640 medium supplemented with 10% FBS, and 100 000 cells per well were dispensed at 2 milliliters into 6-well Nunclon Delta-treated plastic plates purchased from Nunc. 37 ° (: 5% C0 2 1% in 95% air culture. After irradiating cells with 500 OR X-rays using Softex M-15 OWE, 16 hours, 37t: Incubated in 5% CO 2 -95% air After serial dilution of the test compound in DMSO, 2 microliters was added to each plate containing the cells treated with X-rays.
- the compound of the present invention exhibits an excellent DNA fragmentation-inducing action on human-derived cancer cells (NCI-H1299).
- the compound of the present invention enhanced the action of X-rays when used in combination with X-rays.
- the compound represented by the general formula (I) can be administered orally or parenterally, and can be used as a pharmaceutical composition or an anticancer agent by formulating it into a form suitable for such administration.
- Can do includes various sarcomas and carcinomas, including solid cancers and hematopoietic cancers.
- solid cancer is, for example, brain tumor, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, lung cancer, stomach cancer, gallbladder 'bile duct cancer, liver cancer, Vaginal cancer, colon cancer, rectal cancer, ovarian cancer, choriocarcinoma cancer, endometrial cancer, cervical cancer, renal pelvis / ureteral cancer, bladder cancer, prostate cancer, penile cancer, Testicular cancer, fetal cancer, viral tumor, skin cancer, melanoma, neuroblastoma, osteosarcoma, Ewing's tumor, soft tissue sarcoma, etc.
- examples of hematopoietic cancer include acute leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, polycythemia vera, malignant lymphoma, multiple myeloma, Hodgkin lymphoma, and non-Hodgkin lymphoma.
- cancer treatment means inhibiting the growth of cancer cells by administering an anticancer drug to a cancer patient.
- such treatment can reverse cancer growth, ie reduce measurable cancer size. More preferably, such treatment completely eliminates the cancer.
- Suitable cancers for which the compound of the present invention is expected to have a therapeutic effect include, for example, human solid cancers.
- human solid cancers include brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell cancer, non-small cell cancer, breast cancer, lung cancer, stomach cancer, and gallbladder cancer.
- the pharmaceutical composition or anticancer agent according to the present invention may contain a pharmaceutically acceptable carrier or diluent.
- a pharmaceutically acceptable carrier or diluent refers to an excipient [ For example, fat, beespox, semi-solid and liquid polyols, natural or hardened oils, etc.); water (eg, distilled water, especially distilled water for injection), physiological saline, alcohol (eg, ethanol) ), Glycerol, polyol, aqueous sugar solution, mannitol, vegetable oil, etc .; additives [eg, bulking agents, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, dispersants, preservatives] , Sweeteners, colorants, seasonings or fragrances, thickeners, diluents, buffer substances, solvents or solubilizers, drugs to achieve storage effect, salts to change osmotic pressure, coaty Grayed agent, or antioxidant], and
- the pharmaceutical composition or the pile cancer preparation of the present invention can be selected from various forms, for example, oral preparations such as tablets, capsules, powders, granules or liquids, or solutions or suspensions, for example.
- oral preparations such as tablets, capsules, powders, granules or liquids, or solutions or suspensions, for example.
- sterilized liquid parenteral preparations such as liquids, suppositories, and ointments.
- Solid preparations can also be produced using ifi, which can be produced as is in the form of tablets, capsules, granules or powders, and appropriate carriers (additives).
- carriers include, for example, sugars such as lactose or glucose; starches such as corn, wheat or rice; eg fatty acids such as stearic acid; eg magnesium aluminate metasilicate or anhydrous calcium phosphate.
- Inorganic salts such as synthetic polymers such as polyvinylpyrrolidone or polyalkylenedaricol; fatty acid salts such as calcium stearate or magnesium stearate; For example, alcohols such as stearyl alcohol or benzyl alcohol; synthetic cellulose derivatives such as methyl cellulose, carboxymethyl cellulose, ethyl cellulose or hydroxypropyl methyl cellulose; and other commonly used additives such as gelatin, talc, vegetable oil, gum arabic, etc. Is mentioned.
- solid preparations such as tablets, capsules, granules and powders are generally based on the weight of the whole preparation, for example, 0.1 to 100% by weight of the compound represented by the above formula (I), Preferably 5 to 98% by weight of active ingredient may be included.
- Liquid preparations use water, alcohols or appropriate additives usually used in liquid preparations such as plant-derived oils such as soybean oil, peanut oil, sesame oil, etc., suspensions, syrups, injections, Manufactured in the form of drops (intravenous infusion).
- plant-derived oils such as soybean oil, peanut oil, sesame oil, etc.
- suspensions, syrups, injections Manufactured in the form of drops (intravenous infusion).
- suitable solvents or diluents when administered parenterally by intramuscular injection, intravenous injection or subcutaneous injection include, for example, distilled water for injection, lidocaine hydrochloride aqueous solution (for intramuscular injection), physiological Saline, aqueous solution of bud sugar, ethanol, polyethylene glycol, propylene glycol, intravenous liquid (eg, aqueous solution of citrate and sodium citrate) or electrolyte solution (for intravenous infusion and intravenous injection), etc., or These mixed solutions are mentioned.
- injections may be dissolved in advance, or may be in powder form or added with an appropriate carrier (additive).
- additive can contain, for example, 0.1 to 10% by weight of an active ingredient based on the weight of the whole preparation.
- liquid preparations such as suspensions and syrups for oral administration can contain, for example, 0.1 to 10% by weight of an active ingredient based on the weight of the whole preparation.
- preparations can be easily produced by those skilled in the art according to conventional methods or conventional techniques.
- an oral preparation it can be produced, for example, by mixing an appropriate amount of the compound of the present invention and an appropriate amount of lactose and filling it into a hard gelatin capsule suitable for oral administration.
- the preparation containing the compound of the present invention is an injection, it can be produced, for example, by mixing an appropriate amount of the compound of the present invention with an appropriate amount of 0.9% physiological saline and filling the mixture into an injection vial. it can.
- the compound of the present invention can be used in combination with other agents useful for various cancer treatments or in combination with radiation therapy.
- the individual components of such a combination can be administered in divided or single formulations at different times or simultaneously during the treatment period.
- the present invention should be construed to include all simultaneous or different time administrations, and administration in the present invention should be construed as such.
- the range of combinations of the compound of the present invention with other agents useful for the treatment of the above-mentioned diseases includes, in principle, combinations with any pharmaceutical preparations useful for the treatment of the above-mentioned diseases.
- Radiation therapy itself refers to a common method in the field of cancer treatment. X-ray, a-ray, neutron beam, electron beam, proton beam, and other radiation types and radiation sources are used for the radiation therapy, but the most common radiation therapy is external radiation using a linear accelerator. Irradiate the line.
- the compound of the present invention can be combined with radiotherapy to enhance the therapeutic effect of the radiotherapy, and can be useful as a radiosensitizer in the field of cancer treatment.
- Another aspect of the compound of the present invention is that it is also useful as a sensitizer for other anticancer agents in the field of cancer treatment.
- the compound of the present invention can be used in combination with radiation therapy and / or in combination with other anticancer agents shown below.
- “sensitizer” of radiation or anticancer agent means that in the field of cancer treatment, it is used in combination with radiation therapy and / or chemotherapy using anticancer agent. Z or an agent that enhances the therapeutic effect of chemical therapy additively or synergistically.
- each preparation in the combination preparation according to the present invention can be selected from various forms, and each preparation can be produced in the same manner as the above preparation. Also, in the case of a combination containing the compound of the present invention and another anticancer agent, it can be easily produced by those skilled in the art according to ordinary methods or conventional techniques.
- composition of the present invention necessarily one other active substance but also a combination of two or more other active substances.
- combination of the composition of the present invention with one, two or more activators selected from the above therapeutic agents are many examples.
- sexually affected substances include plant-derived anticancer agents, anticancer platinum coordination compounds, anticancer camptothecin derivatives, anticancer typhocin kinase inhibitors, monoclonal antibodies, interferon, biological response
- examples thereof include preparations containing an anticancer agent selected from the group consisting of a regulator and other anticancer agents, or a pharmaceutically acceptable salt or ester thereof.
- anticancer alkylating agent refers to an alkylating agent having anticancer activity
- alkylating agent generally refers to an alkyl group that hydrogenates an organic compound. Alkylation substituted with a group In an alkylation reaction, an alkyl group is given.
- Anti-cancer alkylating agents include, for example, nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, mitopronil, force lumpocon, tiotepa, ranimustine, dimustine, temozolomide or carmustine Etc.
- an “anticancer antimetabolite” refers to an antimetabolite having anticancer activity
- “antimetabolite” in a broad sense is a metabolite important for living organisms ( Vitamin, coenzyme, amino acid, saccharide, etc.) are structurally or functionally similar to each other. Therefore, substances that prevent normal substance metabolism and high energy intermediates cannot be created by inhibiting the electron transport system. Including the substances to be made.
- Anti-antagonistic antimetabolites include, for example, methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorauracil, tegafur, doxyfluridine, carmofur, cytarapine, cyablabin phosphate, enositapine, S — 1, Gems evening bottle, fludarabine or pemetrex dosodymium, etc., preferably cytarabine, gemci evening bottle, etc.
- an “anticancer antibiotic” refers to an antibiotic having a bovine cancer activity.
- an “antibiotic” is produced by a microorganism, the growth of microorganisms and other biological cells, etc. Including substances that inhibit the function of.
- Anticancer antibiotics include, Or valrubicin, preferably doxolevicin or mitomycin C.
- the “plant-derived anticancer agent” used in the present specification includes a compound having anticancer activity found from a plant, or a compound obtained by adding chemical modification to the compound.
- the “plant-derived anticancer agent” is, for example, vincristine, pinblastine, vindesine, etoposide, sobuzoxane, docetaxel, paclitaxel, vinorelbine, and preferably etoposide.
- anticancer camptothecin derivative means a cancer cell growth inhibitory compound that includes camptothecin itself and is structurally related to force mptothecin.
- examples of the “bovine cancerous forceptothecin derivative” include, but are not limited to, camptothecin, 10-hydroxycamptothecin, topotecan, irinotecan, 9-aminocamptothecin, and preferably camptothecin.
- Irinotecan is metabolized in vivo and exhibits anticancer activity as S N-38.
- the camptothecin derivative is considered to have almost the same mechanism of action and activity as camptothecin (Nitta et al., Cancer and Chemotherapy, 14, 8 5 0-8 5 7 (1 9 8 7), etc.).
- anticancer platinum coordination compound refers to a platinum coordination compound having anticancer activity, where “platinum coordination compound” is platinum that provides platinum in the form of ions. It means a coordination compound.
- Preferred platinum compounds include: cisplatin; cis-diamminediacoplatinum (II) —ion; black mouth (diethylenetriamine) monoplatinum (II) chloride; dichloro (ethylenediamine) monoplatinum (II); diamine (1,1-cyclobutane) Dicarboxylato) Platinum (II) (Carpoplatin); Spiroplatin; Iprobratin; Diammine (2-Ethylmalonato) Monoplatinum (II); Ethylenediaminmalonatoplatinum (II); Aqua (1,2-Diaminodicyclohexane) Sulfatoplatinum (II); Aqua (1,2-Diaminodicyclohexane) Malonatoplatinum (II); (1
- an “anticancer tyrosine kinase inhibitor” refers to a tyrosine kinase having anticancer activity.
- tyrosine kinase inhibitor refers to a chemical substance that inhibits “tyrosine kinase”, which transfers the phosphate group of ATP to the hydroxyl group of a specific tyrosine of protein.
- examples of the “anticancer tyrosine kinase inhibitor” include gefitinib, imatinib, and L mouth tinib.
- monoclonal antibody is also referred to as a monoclonal antibody and refers to an antibody produced by a single clone of antibody-producing cells. Examples thereof include cetuximab, bevacizumab, rituximab, alemuduzumab, and trastuzumab.
- interferon refers to an interferon having anticancer activity, and is generally a sugar tongue having a molecular weight of about 20,000 that is produced and secreted by almost all animal cells upon viral infection. It is a protein that not only suppresses virus growth, but also has various immune effector effects such as suppression of cell growth (especially tumor cells) and enhancement of natural killer activity.
- the “Interferon” includes, for example, Inyu Feron ⁇ , Inter Feron 1 2a, Inter Feron ⁇ -2b, Inter Feron; 8, Inter Feron 1a, Inter Feron T—n 1 and so on.
- a “biological response modifier” is a so-called biological response modifier (BRM), which is generally a biological defense mechanism or the survival, proliferation or differentiation of tissue cells. It is a general term for substances and drugs that aim to bring the individual to the direction of tumors, infections, and other diseases by regulating biological responses.
- BRM biological response modifier
- Examples of the “biological response modifier” include krestin, lentinan, schizophyllan, pisipanil, ubenimex and the like.
- anticancer agents refers to anticancer agents that have anticancer activity and do not belong to any of the above.
- Other anticancer agents include mitoxantrone, L-asparaginase, procarpazine, dacarbazine, hydroxycarbamide, pentostatin, tretinoin, alfacept®, darbepoetin alfa, anastrozole, exemstan, bicalutamide, leuprorelin, Flutamide, fulvestrant, pegaptanibu kutasodium, denileukin difty tox, aldesleukin, thyrotropin alfa, arsenic trioxide, portezomip, force pesh evening pin, goserelin, etc.
- Anti-cancer alkylating agents Anti-cancer antimetabolites
- Pile cancer antibiotics Plant-derived cancer drugs
- Anti-cancer platinum coordination compounds Anti-cancer camptothecin derivatives
- anti-cancer tyrosin kinase inhibitors Monoclonal antibodies
- interferon anti-cancer tyrosin kinase inhibitors
- other anti-cancer agents These are both known and commercially available, or can be produced by those skilled in the art by a method known per se or a known / conventional method.
- a method for producing gefitinib is described in, for example, US Pat. No.
- nitrogen mustard N-oxide is from Mitsubishi Welpharma as Nitromine (trade name); cyclophosphamide is from Shionogi Pharmaceutical as Endoxan (trade name); , Ifomide (trade name) from Shionogi Yakuhin; Melphalan from Algaelan (trade name) from Daraxo Smith Kline; Busulfan from Mabulyn (trade name) from Takeda; Mitopronil!
- methotrexate is taken from Takeda as Methotrexate (trade name); 6-mercaptopurine riboside is taken from Aventis as Zeoino (trade name); Purin is from Takeda as Roykerin (trade name); 5-Fluorouracil is from Kyowa Hakko as 5-FU (trade name); Tegafur is from Taiho Pharmaceutical as ftrough (trade name); Doxyfluridine is from Fluturon (Product name) from Nippon Roche; Power Lumofol is from Yamanouchi Pharmaceutical as YAMAFU (Product name); Cytarabine is from Shiroside (Product name) from Nippon Shinyaku; Siyu Rabinokhosufart is from Straside (Product name) As from Niiyaku; Enocitabine, San Rabin (quotient Asahi Kasei as the product name; S-1 from TS-1 (product name) from Taiho Pharmaceutical; Gemushi Yubin from Gary as the
- anti-cancer antibiotics examples include, for example, actinomycin D from Cosmegen (trade name) from Manyu Pharmaceutical; doxorubicin from Kyowa Hakko as adriacin (trade name); ) From Meiji Seika; Neocartinostatin from Neocarchinos Yuchin (trade name) from Yamanouchi Pharmaceutical; Bleomycin from Breka (trade name) from Nippon Kayaku; Pepromycin from Pebro (trade name) From Nippon Kayaku; Mitomycin C from Kyowa Hakko as Mitomycin (trade name); Aclarubicin from Yamanouchi Pharmaceutical as Acracinone (trade name); Pilarpicin from Nippon Kayaku as Pinorbin (trade name); Shin is Falmorubicin (trade name) From Falmacia; Ginos Yuchin Stimalama is from Sumanox (trade name) from Yamanouchi Pharmaceutical; Idarubicin is from Idamycin (trade name) from Falmasia; and Sirolimus is from Weis
- pinklistin is from Shionogi Pharmaceutical as Oncopine (trade name); vinblastine is from Kyorin Pharmaceutical as vinblastine (trade name); vindesine is fildesine (trade name) ) From Shionogi & Co .; etoposide from Nippon Kayaku as Lastest (trade name); sobuzoxan from Zenyaku Kogyo as perazoline (trade name); docetaxel from Aventeis as taxotere (trade name); Paclitaxel can be obtained commercially from Bristol as taxol (trade name); and pinorelbine from Kyowa Hakko as navelvin (trade name).
- Examples of the above anti-cancer platinum coordination compounds include, for example, cisbratine from Nippon Kayaku as Randa (trade name); carpoplatin from Bristol as paraplatin (trade name); nedaplatin as akubra (trade name) Shionogi & Co., and oxalibratine are commercially available from Sanofi as Eloxatin (trade name).
- Examples of the above-mentioned anticancer camptothecin derivatives include, for example, irinotecan from Yakult as campto (trade name); topotecan from Darax Smith Kline as hicamtine (trade name); and camptothecin from Aldrich Chemical, USA Each can be obtained commercially.
- anti-cancer tyrosine kinase inhibitors examples include gefitinib from Astrazene as Iressa (trade name); imatinib from Novarteis as Darivek (trade name); Each product name is commercially available from OSI Pharmaceutical.
- cetuximap is from Bristol-Myers Squibb as Erbitux (trade name); bevacizumab is from Dienentech as Avastin (trade name); rituximab is from Biogen as Rituxan (trade name) Alemudzumab is from Berrex as Campus (trade name); and Trasduzumab is Herceptin (trade) Product name) can be obtained commercially from Chugai.
- Interferon is from Sumitomo Pharmaceuticals as Sumiferon (trade name); Interferon — 2 a is from Takeda as Kanferon 1 A (trade name); Interferon 1 2 b is , Intron A (trade name) from Schering Plow; Inyu Yui Ferron j3 from IFN i3 (trade name) Mochida Pharmaceutical; Inter 1 Ferron 1 a a Imunomax 1 r (trade name) Yoshishi Shiono And Yinyu Feroner n 1 can be obtained commercially from Otsuka as Ogamma (trade name).
- Krestin is a Krestin (trade name) from Sankyo
- Lentinan is a lentinan (trade name) from Aventis
- Sizophyllan is a sonifiran (trade name) from Kaken Pharmaceutical.
- Pisibanil can be obtained commercially from Chugai Pharmaceutical Co., Ltd. as Pishibanil (trade name); and Ubenimex can be obtained commercially from Nippon Kayaku Co., Ltd. as Bestatin (trade name).
- mitoxantrone is Nopantron (trade name) from Nippon Weissreary; L-susparaginase is leunase (trade name) from Kyowa Hakko; procarpadin is naturan (product) Name: from Japan Roche; dacarbazine from Dakarazine (trade name) from Kyowa Hakko; Hydroxycarbamide from Hydrea (trade name) from Pristor; Pentosyuchin as cofuolin (trade name) chemical and serum therapy From the Institute; and Tretinoin from Nippon Roche as Vesanoid (trade name); Alephacebut from Piogen as Amebib (trade name); Darbepoetin Alpha from Amgen as Alanesp (trade name); Anastro Zor is Arimi Dex (trade name) from AstraZene power; Exemestane from Afromachine (trade name) from Huaiza; Picaltamide from Casodex (trade name) from Astrazene power
- the invention also encompasses a method for treating cancer comprising administering a therapeutically effective amount of a compound of the invention, salt or ester thereof to a subject in need thereof.
- the preferred therapeutic unit is the dosage form of the compound of the present invention, the type of the compound of the present invention used, the dosage form of the compound of the present invention used; the types of other anticancer agents used together, It may vary depending on the dosage form, dosage form, etc .; and the cancer cells being treated, the patient's condition, etc.
- the optimal treatment for a given condition can be determined by one skilled in the art based on conventional treatment decision units and in view of Z or this specification.
- the therapeutic unit of the compound of the present invention is, specifically, the type of the compound used, the type of the formulated composition, the frequency of application and the specific site to be treated, the severity of the disease, the patient
- the dose per adult per day is, for example, 1 to 1 for oral administration.
- parenteral administration preferably intravenous administration, more preferably intravenous infusion, for example, within the range of 1 to 10 O mg Zm 2 (body surface area) per day.
- intravenous infusion for example, it may be administered continuously for 1 to 48 hours.
- the frequency of administration varies depending on the administration method and symptoms, but is, for example, 1 to 5 times a day. In addition, administration methods such as administration every other day, administration every other day, etc. can also be used.
- the treatment withdrawal period for parenteral administration is, for example, 1 to 6 weeks.
- the therapeutic unit of other anticancer agents used in combination with the compound of the present invention is not particularly limited, but can be determined by a person skilled in the art as necessary according to known literature. For example, as shown below.
- the therapeutic unit for 5-Fluorouracil (5-FU) is, for example, 200 to 30 Omg daily for 1 to 3 doses for oral administration, and 5 to 15 mg / day for injections. Intravenous or intravenous infusion of kg once a day for the first 5 consecutive days, and then 5 to 7.5 mg / kg intravenously or intravenously once a day every other day. May be increased or decreased).
- the treatment unit of S—1 (tegafur / gimestats / ostastkalyum) is, for example, the first dose (one dose) adjusted to the body surface area as the next reference amount, and one day after breakfast and dinner Administer twice daily for 28 days, followed by 14 days of withdrawal. Repeat this as a course.
- Initial reference amount per body surface area (equivalent to tegafur) is less than 1.25m2: 4 Omg / time, 1.25m2 or more to less than 1.5m2: 5Omg / time, 1.5m2 or more: 60mg / time
- the dose may be adjusted according to the patient's condition.
- the unit of treatment for Gemushi Yubin is, for example, 1 gZm 2 of Gemshi Yubin given as an intravenous infusion over 30 minutes, once a week for 3 consecutive weeks, and withdrawal from the fourth week. Repeat this as a course.
- the dose should be reduced according to age, symptoms or side effects.
- the therapeutic unit for doxorubicin (eg, doxorubicin hydrochloride) is, for example, 10 mg (0.2 mg / kg) (titer) once a day for 4 to 6 days, ⁇ 10 days off, taking this as 1 course and repeating 2-3 courses.
- the total dose is preferably 50 Omg (potency) / m2 (body surface area) or less, and may be appropriately increased or decreased within the range.
- the therapeutic unit of etoposide is, for example, 60 to 100 mg / m2 (body surface area) per day for 5 consecutive days and 3 weeks off (dose may be adjusted accordingly). Repeat this as one course.
- the therapeutic unit of etoposide for example, 60 to 100 mg / m2 (body surface area) per day for 5 consecutive days and 3 weeks off (dose may be adjusted accordingly). Repeat this as one course.
- 175-20 Omg per day is administered continuously for 5 days, and the drug is withdrawn for 3 weeks (the dose may be increased or decreased appropriately). Repeat this as one course.
- the therapeutic unit of docetaxel (docetaxel hydrate) is, for example, once a day, 60 mg / m2 (body surface area) of docetaxel is administered intravenously at intervals of 3 to 4 weeks over 1 hour. It can be increased or decreased as appropriate).
- the treatment unit for paclitaxel is, for example, 210 mg / m2 (body surface area) once a day, intravenously infused over 3 hours, and withdrawn for at least 3 weeks. Repeat this as a course.
- the dose can be increased or decreased as appropriate.
- the treatment unit for carpoplatin is, for example, once a day, 300-400 mg / m2 is administered by intravenous infusion over 30 minutes, and the drug is discontinued for at least 4 weeks (the dose may be adjusted accordingly). Repeat this as one course.
- the therapeutic unit for oxalibratine is 85 mg / m2 intravenously once a day, withdrawn for 2 weeks, and this is repeated as a course.
- the therapeutic unit for irinotecan (eg, irinotecan hydrochloride) is, for example, 100 mgZm2 once a day, 3 to 4 times at weekly intervals, and withdrawn for at least 2 weeks.
- the therapeutic unit for topotecan is, for example, once a day, 1.5 mg Zm 2 is infused intravenously for 5 days, and the drug is discontinued for at least 3 weeks.
- the therapeutic unit for cyclophosphamide may be intravenously injected, for example, once daily at 10 Omg daily, and if the patient can tolerate, the dose may be increased to 20 Omg daily, for a total of 3000-800 Omg Administration power ⁇ May be increased or decreased as appropriate. If necessary, it may be injected or injected into the muscle, thoracic cavity, or tumor. On the other hand, in the case of oral administration, for example, it is administered at a daily dose of 100-20 Omg.
- the unit of treatment for gefitinip is, for example, orally administered 25 Omg once a day.
- the therapeutic unit for cetuximab is, for example, 400 mgZm2 on the first day, followed by 250 mg / m2 every week.
- the therapeutic unit for bevacizumab is, for example, 3 mg / kg-intravenous weekly.
- the unit of treatment for trastuzumab is, for example, usually once a day for adults, 4 mg / kg (body weight) for the first dose of trastuzumab, and 2 mg / kg for the second and subsequent doses over a period of 90 minutes. Intravenously infused.
- the therapeutic unit for exemestane is, for example, usually 25 mg once a day after meals for adults.
- the therapeutic unit for leuprorelin (eg, leuprorelin acetate) is, for example, usually 11.25 mg subcutaneously once every 12 weeks for adults.
- the therapeutic unit for imatinib is, for example, usually 400 mg once daily after meals for adults with chronic myelogenous leukemia.
- the treatment unit for the combination of 5-FU and leucoporin is, for example, intravenous infusion of 5-FU 425 mg / m2 and leucovorin 200 mg / m2 from day 1 to day 5 at intervals of 4 weeks. Repeat with.
- the thin layer chromatography in the examples and production examples is Si 1 ica gel 6 as a plate.
- a UV detector was used as the detection method for F 254 (Me r ck).
- As the silica gel for the column Wakog e 1 TM C-300 or C-1200 (Wako Pure Chemical Industries) or NH (FU JISI LYS IA CHEM I CAL) was used.
- the MS spectrum was measured using JMS-SX 102 A (JEOL (JEOL)) or QU ATTRO II (Micromass).
- NMR spectra were measured using heavy dimethyl sulfoxide solution, using dimethyl sulfoxide as an internal standard, Gem ini-300 (3 O OMHz jVarian), VXR—300 (300 MHz; Varian), Measurement was carried out using a MERCURY 400 (400 MHz; Varian) or I nova400 (400 MHz; Varian) type spectrometer, and all ⁇ values were expressed in p pm.
- the compound obtained in 1 above was added to a solution of 13.8 g of methanol 10 OmL-tetrahydrofuran 10 OmL with 5 N sodium hydroxide aqueous solution 5 OmL and stirred at room temperature for 3 hours.
- the reaction system was concentrated under reduced pressure, and the residue was acidified with 5N aqueous hydrochloric acid solution, and extracted with 2-propanolulu chloroform (20/80) mixed solvent.
- the solvent was distilled off under reduced pressure to obtain crude 4- [2- (2-cyclophenyl) hydrazino] -1- (methylthio) pyrimidine-5-carboxylic acid as a white solid.
- Acetone 1.13 g and sodium cyanoborohydride 183 mg were added to an ethanol 2 OmL solution of the compound 50 Omg obtained in Production Example 9-1 and stirred at room temperature for 15 hours.
- the reaction solution was concentrated under reduced pressure, and 2N aqueous sodium hydroxide solution was added to the residue to make it basic.
- the organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off.
- the crude product was purified by silica gel column chromatography (hexane monoacetate) to give 12 Omg of the title compound as a yellow solid.
- Production Example 13-3 1- [2- (Methylsulfonyl) ethyl] 1-4- (4-12-tropenyl) N, N_dimethyl-2- (2-methyl-1-nitrophenoxy) instead of piperazine Except for using ethylamine, 542 mg of the title compound was obtained as a white solid in the same manner as in Production Example 13-3.
- Production Example 11 1-1 Production Example 11— 1 except that 3- (2-methyl-4-nitrophenoxy) azetidine hydrochloride was used instead of 1- (2-methyl-4-122 tropenyl) piperazine hydrochloride used in 1 In the same manner as described above, 142 mg of the title compound was obtained as a pale yellow solid.
- Epifluorhydrin 27 2 mg, 1- (4-nitrophenyl) piperazine 50 Omg of ethanol 15 mL was heated to reflux for 15 hours, and then the reaction mixture was concentrated under reduced pressure. The residue was solidified from ethyl acetate to give 30 Omg of the title compound as a yellow solid.
- Production Example 2 25 Omg of the title compound as a yellow solid in the same manner as in Production Example 23 1-1 except that 1,2-epoxy-2-methylpropan was used instead of the epifluorohydrin used in 3-1. Obtained.
- Example 1-1 instead of [3- (methoxycarbonyl)] phenylpolonic acid used in Example 1-1, 3-phenylpolonic acid was used, and 4- (4-methylbiperazine used in Example 1-13 was used. In this case, the title compound was converted to a yellow solid in the same manner as in Examples 1-1 to 1-3, except that [5-amino-2- (4-methylbiperazine)] was used instead of aniline. As a result, 17.5 mg was obtained. ! H-NMR (400 MHz, CDC 1 3 ) ⁇ : 8.82 (1H, s), 7.
- Example 1-11 [3- (methoxycarbonyl)] used in place of phenylboronic acid instead of 3-phenylboronic acid, and 4- (4-methylbiperazine used in Example 11-13) 1-yl) Instead of aniline (5-amino-2-morpholine 4-ylphenyl) Except for the use of methanol, the title compound as a yellow solid was obtained in the same manner as in Examples 1-1 to 1-3. Obtained.
- Example 1-1 instead of [3- (methoxycarbonyl)] phenylboronic acid used in Example 1-1, 3-cyanophenylboronic acid was used, and 4- (4-methylpiperazine used in Example 1-3)
- the title compound was converted into a yellow solid in the same manner as in Examples 1-1 to 1-3, except that 3-methyl-4- (4-methylbiperazine _1-yl) aniline was used instead of a dilin. 62 mg was obtained.
- Example 1-1 In place of [3- (methoxycarbonyl)] phenylboronic acid used in Example 1-1, 3-methoxyphenylboronic acid was used, and 4-methylpiperazine 1) The title compound was converted to a yellow solid in the same manner as in Example 1-1-1-3 except that 3-methyl-4-1- (4-methylpiperazine-1-yl) aniline was used instead of aniline. 52 mg was obtained.
- Example 1 1- 3 instead of 4- (4-methylbiperazine 1-l) aniline used in Example 3 ⁇ 3-methyl-4-l (4-methylbiperazine-1 1-il)
- Example 1 except that aniline was used :
- the title compound was obtained as a yellow solid in the same manner as in —4.
- Example 1 1 1 4 3 (4-methylbiperazine 1 1 yl) 4 1 (4-cyclopropylpiperazine 1 1 yl) instead of aniline Examples except using aniline
- the title compound was obtained as a yellow solid in the same manner as in 1-1-1-4.
- Example 4-4 (4-methylbiperazine 1-yl) used in Example 1-3 [5-amino-2- (4-cyclopropylpiperazine-11-yl) phenyl] methanol instead of aniline
- Example 2 1 24.3 mg of the title compound was obtained as a yellow solid in the same manner as in Example 1-1 1-1 1-4.
- Example 1 Example 1 except for using N, N-jetylamine instead of N, N-dimethylamine used in 4: 1! 58.5 mg of the title compound was obtained as a yellow solid in the same manner as in 1-4.
- Examples 1-14 The title compound was converted to a yellow amorphous compound in the same manner as in Examples 1-1 to 1-4 except that N-Edile N-methylamine was used instead of N, N-dimethylamine used in 4-6. Obtained.
- Examples 1-14 The title compound was prepared in the same manner as in Examples 1-1 to 1-4 except that N- (2-hydroxyethyl) — N-methylamine was used instead of N, N-dimethylamine used in 4. As a yellow amorphous, 76. lmg was obtained.
- Example 1-1 In place of [3- (methoxycarbonyl)] phenylboronic acid used in Example 1-1, 3-nitrophenylboronic acid was used, and 4- (4-methylbiperazine-one) used in Example 1-3. 3-methyl-4-1 (4-methylpiperazine-1-yl) instead of aniline Except for using aniline Example 1-1 1-1 1-3 Obtain 32 mg of the title compound as a yellow solid in the same manner It was.
- Example 1-11 The title was prepared in the same manner as in Examples 1-1 to 1-3 except that [3- (methoxycarbonyl)] phenylpolonic acid used above was used instead of the poronic acid obtained above. 35.2 mg of the compound was obtained as a yellow solid.
- Example 1-1 instead of [3- (methoxycarbonyl)] phenylpolonic acid used in Example 1-1, pyridine-4-ylboronic acid was used, and 4-1- (4-methylpiperazine- 1 1-
- the title compound is white in the same manner as in Examples 1-1 to 1-3 except that 3-methylolene 4- (4-methylbiperazine 1-l) is used in place of dilin. 5.4 mg was obtained as a solid.
- Example 1-11 [3- (methoxycarbonyl)] used in 1 instead of phenylboronic acid
- Example 1-11 26.5 mg of the title compound was obtained as a white solid in the same manner as in 1-1 to 3.
- Example 1-11 The title was prepared in the same manner as in Examples 1-1 to 1-3 except that the boronic acid obtained in 5 above was used in place of [3- (methoxycarbonyl)] phenylboronic acid. 48 mg of the compound was obtained as a yellow solid.
- Example 1 1-1 Same as Example 1-1 1 to 1-3 except that [3- (methoxycarbonyl)] phenylboronic acid used in [3- (methoxycarbonyl)] phenylboronic acid was used. The method yielded 42 mg of the title compound as a yellow solid.
- Example 1 1-1 Same as Example 1 1-1 1-3 except that [3- (methylsulfonyl) phenyl] boronic acid was used instead of [3- (methoxycarbonyl)] phenylpolonic acid used in 1 75 mg of the title compound was obtained as a yellow solid
- Example 191-1 the boronic acid obtained in Example 191-1 was used, and 4- (4 1-methylpiperazine 1- 1yl) 4- (1-methylbiperidine 4-yl) Instead of aniline, except that aniline was used, the title compound was prepared in the same manner as in Examples 1-11-1-3. 26.3 mg was obtained as a white solid.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (16)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ES07742851.4T ES2609087T3 (es) | 2006-04-27 | 2007-04-25 | Derivado de dihidropirazolopirimidinona |
PL07742851T PL2017278T3 (pl) | 2006-04-27 | 2007-04-25 | Pochodne dihydropirazolopirymidynonu |
AU2007244185A AU2007244185B2 (en) | 2006-04-27 | 2007-04-25 | Dihydropyrazolopyrimidinone derivative |
CA2650119A CA2650119C (en) | 2006-04-27 | 2007-04-25 | Dihydropyrazolopyrimidinone derivatives |
EP07742851.4A EP2017278B1 (en) | 2006-04-27 | 2007-04-25 | Dihydropyrazolopyrimidinone derivative |
SI200731875A SI2017278T1 (sl) | 2006-04-27 | 2007-04-25 | Derivat dihidropirazolopirimidinona |
DK07742851.4T DK2017278T3 (en) | 2006-04-27 | 2007-04-25 | DIHYDROPYRAZOLOPYRIMIDINON DERIVATIVES |
US12/226,707 US7935708B2 (en) | 2006-04-27 | 2007-04-25 | Dihydropyrazolopyrimidinone derivatives |
LTEP07742851.4T LT2017278T (lt) | 2006-04-27 | 2007-04-25 | Dihidropirazolopirimidinono darinys |
JP2008513330A JP4513919B2 (ja) | 2006-04-27 | 2007-04-25 | ジヒドロピラゾロピリミジノン誘導体 |
CN2007800150647A CN101432284B (zh) | 2006-04-27 | 2007-04-25 | 二氢吡唑并嘧啶酮衍生物 |
HK09110110.5A HK1132498A1 (en) | 2006-04-27 | 2009-10-29 | Dihydropyrazolopyrimidinone derivative |
US13/053,798 US8791125B2 (en) | 2006-04-27 | 2011-03-22 | Dihydropyrazolopyrimidinone derivatives |
US14/312,982 US20140303178A1 (en) | 2006-04-27 | 2014-06-24 | Dihydropyrazolopyrimidinone derivatives |
HRP20161763TT HRP20161763T1 (hr) | 2006-04-27 | 2016-12-21 | Derivati dihidropirazolopirimidinona |
CY20171100129T CY1118526T1 (el) | 2006-04-27 | 2017-01-27 | Παραγωγα διϋδροπυραζολοπυριμιδινονης |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2006124208 | 2006-04-27 | ||
JP2006-124208 | 2006-04-27 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/226,707 A-371-Of-International US7935708B2 (en) | 2006-04-27 | 2007-04-25 | Dihydropyrazolopyrimidinone derivatives |
US13/053,798 Division US8791125B2 (en) | 2006-04-27 | 2011-03-22 | Dihydropyrazolopyrimidinone derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2007126128A1 true WO2007126128A1 (ja) | 2007-11-08 |
Family
ID=38655640
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2007/059416 WO2007126128A1 (ja) | 2006-04-27 | 2007-04-25 | ジヒドロピラゾロピリミジノン誘導体 |
PCT/JP2007/059408 WO2007126122A1 (en) | 2006-04-27 | 2007-04-25 | Dihydropyrazolopyrimidinone derivatives |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2007/059408 WO2007126122A1 (en) | 2006-04-27 | 2007-04-25 | Dihydropyrazolopyrimidinone derivatives |
Country Status (39)
Country | Link |
---|---|
US (4) | US7935708B2 (ja) |
EP (2) | EP2017278B1 (ja) |
JP (2) | JP4513919B2 (ja) |
KR (1) | KR101409161B1 (ja) |
CN (1) | CN101432284B (ja) |
AR (1) | AR060635A1 (ja) |
AT (1) | ATE475662T1 (ja) |
AU (1) | AU2007244185B2 (ja) |
BR (1) | BRPI0710081A2 (ja) |
CA (1) | CA2650119C (ja) |
CR (1) | CR10359A (ja) |
CY (2) | CY1111069T1 (ja) |
DE (1) | DE602007008085D1 (ja) |
DK (2) | DK2017278T3 (ja) |
DO (1) | DOP2007000084A (ja) |
EC (1) | ECSP088812A (ja) |
ES (2) | ES2348751T3 (ja) |
GT (1) | GT200800211A (ja) |
HK (1) | HK1132498A1 (ja) |
HN (1) | HN2008001532A (ja) |
HR (2) | HRP20100563T1 (ja) |
HU (1) | HUE032987T2 (ja) |
IL (1) | IL194367A (ja) |
LT (1) | LT2017278T (ja) |
MA (1) | MA30428B1 (ja) |
MX (1) | MX2008013063A (ja) |
MY (1) | MY145408A (ja) |
NO (1) | NO341617B1 (ja) |
NZ (1) | NZ571196A (ja) |
PE (1) | PE20080695A1 (ja) |
PL (2) | PL2017278T3 (ja) |
PT (2) | PT2016080E (ja) |
RU (1) | RU2437885C2 (ja) |
SI (2) | SI2017278T1 (ja) |
SV (1) | SV2009003060A (ja) |
TW (1) | TWI409262B (ja) |
UA (1) | UA96152C2 (ja) |
WO (2) | WO2007126128A1 (ja) |
ZA (1) | ZA200807748B (ja) |
Cited By (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009054332A1 (ja) * | 2007-10-23 | 2009-04-30 | Banyu Pharmaceutical Co., Ltd. | ピリドン置換ジヒドロピラゾロピリミジノン誘導体 |
WO2010076887A1 (en) * | 2009-01-05 | 2010-07-08 | Banyu Pharmaceutical Co.,Ltd. | Predictive biomarkers useful for cancer therapy mediated by a wee1 inhibitor |
JP2010525057A (ja) * | 2007-04-25 | 2010-07-22 | 萬有製薬株式会社 | Weelキナーゼインヒビターとしてのジヒドロピラゾロピリミジノン誘導体の多形 |
WO2010098367A1 (en) * | 2009-02-25 | 2010-09-02 | Banyu Pharmaceutical Co.,Ltd. | Pyrimidopyrimidoindazole derivative |
WO2011027800A1 (en) * | 2009-09-02 | 2011-03-10 | Banyu Pharmaceutical Co.,Ltd. | Use of biomarker(s) to identify a wee1 inhibitor responsive patient and methods of treating cancer mediated by dysfunctional or aberrant p53 via administration of a wee1 inhibitor |
WO2012074754A1 (en) | 2010-11-16 | 2012-06-07 | Array Biopharma Inc. | Combination of checkpoint kinase 1 inhibitors and wee 1 kinase inhibitors |
WO2013039854A1 (en) | 2011-09-15 | 2013-03-21 | Merck Sharp & Dohme Corp. | Compositions and methods for treating cancer |
US8703779B2 (en) | 2009-09-15 | 2014-04-22 | Merck Sharp & Dohme Corp. | Preparation of crystalline forms of dihydropyrazolopyrimidinone |
WO2014085216A1 (en) | 2012-11-28 | 2014-06-05 | Merck Sharp & Dohme Corp. | Compositions and methods for treating cancer |
JP2016516763A (ja) * | 2013-04-11 | 2016-06-09 | アルマック・ディスカバリー・リミテッドAlmac Discovery Limited | 2−アミノピリド[4,3−D]ピリミジン−5−オン誘導体及びWee−1阻害薬としてのそれらの使用 |
US9856253B2 (en) | 2015-04-17 | 2018-01-02 | Abbvie, Inc. | Tricyclic modulators of TNF signaling |
US9879016B2 (en) | 2015-04-17 | 2018-01-30 | Abbvie Inc. | Indazolones as modulators of TNF signaling |
JP2018536651A (ja) * | 2015-11-01 | 2018-12-13 | ザ リージェンツ オブ ザ ユニヴァーシティ オブ コロラド,ア ボディ コーポレイト | Wee1キナーゼ阻害剤、並びにそれを作製及び使用する方法 |
US10160748B2 (en) | 2015-04-17 | 2018-12-25 | Abbvie Inc. | Indazolones as modulators of tnf signaling |
JP2020510630A (ja) * | 2017-01-23 | 2020-04-09 | シージャーズォアン サガシティ ニュー ドラッグ デベロップメント カンパニー リミテッド | Wee1阻害剤としての1,2−ジヒドロ−3H−ピラゾロ[3,4−d]ピリミジン−3−オン誘導体 |
JP2020511520A (ja) * | 2017-03-23 | 2020-04-16 | シャンハイ ドーァ ノボ ファーマテック カンパニー,リミティド | ピラゾロ[3,4−d]ピリミジン−3−オンの大環状誘導体、その医薬組成物及び応用 |
WO2020259724A2 (zh) | 2019-06-28 | 2020-12-30 | 上海医药集团股份有限公司 | 一种吡唑酮并嘧啶类化合物、其制备方法及应用 |
WO2020259703A1 (zh) | 2019-06-28 | 2020-12-30 | 上海医药集团股份有限公司 | 一种吡唑酮并嘧啶类化合物、其制备方法及应用 |
JP2021501191A (ja) * | 2017-11-01 | 2021-01-14 | シージャーズォアン サガシティ ニュー ドラッグ デベロップメント カンパニー リミテッド | Wee1阻害剤としての大環状化合物及びその使用 |
JP2021516231A (ja) * | 2018-02-28 | 2021-07-01 | ザ リージェンツ オブ ザ ユニバーシティ オブ コロラド,ア ボディー コーポレイトTHE REGENTS OF THE UNIVERSITY OF COLORADO,a body corporate | Wee1キナーゼ阻害物質およびそれを使用してがんを処置する方法 |
WO2022247641A1 (zh) | 2021-05-28 | 2022-12-01 | 江苏天士力帝益药业有限公司 | Wee1抑制剂及其用途 |
JP7481336B2 (ja) | 2018-10-26 | 2024-05-10 | ウーシー・バイオシティ・バイオファーマシューティクス・カンパニー・リミテッド | Wee1阻害剤としてのピリミドピラゾロン類誘導体及びその使用 |
Families Citing this family (52)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PE20080695A1 (es) * | 2006-04-27 | 2008-06-28 | Banyu Pharma Co Ltd | Derivados de dihidropirazolopirimidinona como inhibidores de quinasa weel |
WO2008141385A1 (en) * | 2007-05-21 | 2008-11-27 | Biota Scientific Management Pty Ltd | Viral polymerase inhibitors |
US8507504B2 (en) | 2008-06-12 | 2013-08-13 | Merck Sharp & Dohme Corp. | Process for producing bicycloaniline derivatives |
US8575179B2 (en) | 2008-12-12 | 2013-11-05 | Msd K.K. | Dihydropyrazolopyrimidinone derivatives |
EP2703385B1 (en) * | 2011-04-27 | 2017-09-20 | Zeon Corporation | Polymerizable compound, polymerizable composition, polymer, and optically anisotropic material |
US8796289B2 (en) | 2011-07-19 | 2014-08-05 | Abbvie Inc. | Pyridazino[4,5-D]pyrimidin-5(6H)-one inhibitors of kinases |
CN104011049A (zh) | 2011-10-20 | 2014-08-27 | 艾伯维公司 | 激酶的吡啶并嘧啶酮抑制剂 |
CN104271576A (zh) * | 2012-02-23 | 2015-01-07 | 艾伯维公司 | 激酶的吡啶并嘧啶酮抑制剂 |
WO2014062454A1 (en) * | 2012-10-15 | 2014-04-24 | Merck Sharp & Dohme Corp. | Compositions and methods for treating cancer |
JP2016516772A (ja) | 2013-04-09 | 2016-06-09 | リクスト・バイオテクノロジー,インコーポレイテッド | オキサシクロヘプタン及びオキサビシクロヘプテンの配合物 |
GB201322602D0 (en) | 2013-12-19 | 2014-02-05 | Almac Discovery Ltd | Pharmaceutical compounds |
WO2016098546A1 (ja) * | 2014-12-17 | 2016-06-23 | Delta-Fly Pharma株式会社 | 高齢又は末期の癌患者を治療又は寛解するための医薬組成物 |
CA2997051C (en) * | 2015-09-01 | 2020-03-24 | Taiho Pharmaceutical Co., Ltd. | Novel pyrazolo[3,4-d]pyrimidine compound or salt thereof |
CN105130986B (zh) * | 2015-09-30 | 2017-07-18 | 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 |
CN106271589B (zh) * | 2016-06-23 | 2018-12-28 | 中山市美捷时包装制品有限公司 | 一种用于预装阀杆、弹簧、垫片的组装设备 |
GB201612092D0 (en) * | 2016-07-12 | 2016-08-24 | Almac Discovery Ltd | Pharmaceutical compounds |
JP6733050B2 (ja) | 2016-09-15 | 2020-07-29 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Ripk2の阻害剤としてのヘテロアリールカルボキサミド化合物 |
CN106719769A (zh) * | 2016-11-28 | 2017-05-31 | 山东农业大学 | 一种含香菇多糖、苯醚甲环唑和噻虫啉的病虫兼治农药组合物 |
GB201703881D0 (en) * | 2017-03-10 | 2017-04-26 | Almac Discovery Ltd | Pharmaceutical compounds |
JP2020512977A (ja) | 2017-03-31 | 2020-04-30 | シアトル ジェネティックス, インコーポレイテッド | Chk1阻害剤とwee1阻害剤との組み合わせ |
SG11202000789WA (en) * | 2017-08-01 | 2020-02-27 | Recurium Ip Holdings Llc | 1, 2 - dihydro- 3h- pyrazolo [3, 4 - d] pyrimidin -3 - one analogs |
WO2019037678A1 (zh) * | 2017-08-24 | 2019-02-28 | 上海迪诺医药科技有限公司 | 吡唑并[3,4-d]嘧啶-3-酮衍生物、其药物组合物及应用 |
WO2019074979A1 (en) * | 2017-10-09 | 2019-04-18 | Girafpharma, Llc | HETEROCYCLIC COMPOUNDS AND USES THEREOF |
CA3078945A1 (en) | 2017-10-09 | 2019-04-18 | Nuvation Bo Inc. | Heterocyclic compounds and uses thereof |
CN109810111B (zh) * | 2017-11-20 | 2023-10-27 | 上海医药集团股份有限公司 | 一种吡唑酮并嘧啶类化合物、其制备方法及应用 |
CN111315747B (zh) * | 2018-01-05 | 2023-05-02 | 四川科伦博泰生物医药股份有限公司 | 二氢吡唑酮并嘧啶类化合物及其制备方法和用途 |
WO2019165204A1 (en) | 2018-02-23 | 2019-08-29 | Newave Pharmaceutical Inc. | 1,2-dihydro-3h-pyrazolo[3,4-d]pyrimidine-3-one compounds as inhibitors of wee-1 kinase |
CN117720541A (zh) * | 2018-03-09 | 2024-03-19 | 里科瑞尔姆Ip控股有限责任公司 | 取代的1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮 |
CN108653282B (zh) * | 2018-06-28 | 2020-08-14 | 中国科学院昆明植物研究所 | 苯并噻唑类及苯并吡咯类化合物在制备抗肿瘤药物中的应用 |
CN111662283B (zh) * | 2019-03-07 | 2021-11-16 | 湖南化工研究院有限公司 | 咪唑并吡啶类化合物及其中间体、制备方法与应用 |
US20220194960A1 (en) * | 2019-03-22 | 2022-06-23 | Shouyao Holdings (beijing) Co., Ltd. | Wee1 inhibitor and preparation and use thereof |
CN113939296A (zh) | 2019-04-09 | 2022-01-14 | 诺维逊生物股份有限公司 | 杂环化合物及其用途 |
WO2020210320A1 (en) * | 2019-04-11 | 2020-10-15 | Recurium Ip Holdings, Llc | Substituted l,2-dihydro-3h-pyrazolo[3,4-d]pyrimidin-3-ones |
CA3138240A1 (en) | 2019-04-30 | 2020-11-05 | Shijiazhuang Sagacity New Drug Development Co., Ltd. | Crystal forms of wee1 inhibitor coumpound and use thereof |
MX2022004934A (es) | 2019-10-25 | 2022-05-16 | Astrazeneca Ab | Metodos para tratar un cancer. |
CN113387962A (zh) * | 2020-03-12 | 2021-09-14 | 上海迪诺医药科技有限公司 | 吡唑并[3,4-d]嘧啶-3-酮衍生物、其药物组合物及应用 |
WO2021254389A1 (zh) * | 2020-06-17 | 2021-12-23 | 微境生物医药科技(上海)有限公司 | 作为Wee-1抑制剂的吡唑并[3,4-d]嘧啶-3-酮衍生物 |
KR102549484B1 (ko) * | 2020-12-08 | 2023-06-29 | 한국화학연구원 | 피라졸로피리미딘 설폰아마이드 유도체 및 이를 유효성분으로 포함하는 암 관련 질환의 예방 또는 치료용 약학적 조성물 |
WO2022171128A1 (zh) * | 2021-02-09 | 2022-08-18 | 微境生物医药科技(上海)有限公司 | 作为Wee-1抑制剂的吡唑并[3,4-d]嘧啶-3-酮衍生物 |
WO2022171088A1 (zh) * | 2021-02-09 | 2022-08-18 | 微境生物医药科技(上海)有限公司 | 吡唑并[3,4-d]嘧啶-3-酮衍生物 |
CN116848117A (zh) * | 2021-02-09 | 2023-10-03 | 微境生物医药科技(上海)有限公司 | 作为Wee-1抑制剂的稠环化合物 |
CN115197221B (zh) * | 2021-04-02 | 2024-05-24 | 轩竹(北京)医药科技有限公司 | 二氢吡唑并嘧啶酮类大环衍生物及其用途 |
EP4329815A1 (en) | 2021-04-29 | 2024-03-06 | Novartis AG | Deubiquitinase-targeting chimeras and related methods |
CA3214894A1 (en) | 2021-04-30 | 2022-11-03 | Yuli Xie | Fused ring compound as wee-1 inhibitor, and preparation method therefor and use thereof |
CN115838375A (zh) * | 2021-09-18 | 2023-03-24 | 优领医药科技(香港)有限公司 | 含嘧啶并二氢吡唑啉酮类衍生物、其药学上可接受的盐及其制备方法和应用 |
CN113735863A (zh) * | 2021-09-29 | 2021-12-03 | 武汉九州钰民医药科技有限公司 | Wee1抑制剂adavosertib的制备工艺 |
CN113880844B (zh) * | 2021-09-29 | 2023-02-14 | 武汉九州钰民医药科技有限公司 | Wee1蛋白激酶抑制剂adavosertib的化学合成方法 |
CN118176195A (zh) * | 2021-11-01 | 2024-06-11 | 正大天晴药业集团股份有限公司 | 吡唑[3,4-d]嘧啶-3-酮类化合物及其医药用途 |
CN116462687A (zh) | 2022-01-18 | 2023-07-21 | 江苏天士力帝益药业有限公司 | Wee1抑制剂及其制备和用途 |
CN116836184A (zh) * | 2022-03-25 | 2023-10-03 | 药雅科技(上海)有限公司 | Wee1激酶抑制剂的制备及其应用 |
CN115073460B (zh) * | 2022-07-13 | 2023-07-25 | 苏州施安鼎泰生物医药技术有限公司 | 一种嘧啶并[5,4-c][2,6]萘啶衍生物及其制备方法以及药物组合物和应用 |
TW202404977A (zh) * | 2022-07-15 | 2024-02-01 | 大陸商映恩生物製藥(蘇州)有限公司 | 一種嘧啶并五員雜環化合物、其製備方法和用途 |
Citations (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4604463A (en) | 1983-07-14 | 1986-08-05 | Kabushiki Kaisha Yakult Honsha | Camptothecin derivatives and process for preparing same |
JPH01139572A (ja) * | 1987-08-26 | 1989-06-01 | Mitsui Pharmaceut Inc | ピリミジン類及びその薬学的に許容される塩類 |
JPH02503143A (ja) | 1987-01-08 | 1990-10-04 | インターナショナル、ジェネティック、エンジニアリング、インコーポレーテッド | ヒトb細胞表面抗原に対して特異性のあるキメラ抗体 |
JPH045029B2 (ja) | 1981-08-24 | 1992-01-30 | ||
US5162532A (en) | 1990-12-20 | 1992-11-10 | North Carolina State University | Intermediates and method of making camptothecin and camptothecin analogs |
US5191082A (en) | 1990-12-20 | 1993-03-02 | North Carolina State University | Camptothecin intermediate and method of making camptothecin intermediates |
US5200524A (en) | 1990-12-20 | 1993-04-06 | North Carolina State University | Camptothecin intermediates and method of making same |
US5223608A (en) | 1987-08-28 | 1993-06-29 | Eli Lilly And Company | Process for and intermediates of 2',2'-difluoronucleosides |
US5243050A (en) | 1990-12-20 | 1993-09-07 | North Carolina State University | Alkylpyridone DE ring intermediates useful for the manufacture of camptothecin and camptothecin analogs |
US5247089A (en) | 1990-12-20 | 1993-09-21 | North Carolina State University | Method of making intermediates useful for the manufacture of camptothecin and camptothecin analogs |
WO1994010202A1 (en) | 1992-10-28 | 1994-05-11 | Genentech, Inc. | Vascular endothelial cell growth factor antagonists |
US5420319A (en) | 1993-05-21 | 1995-05-30 | Tanaka Kikinzoku Kogyo K.K. | Cis-oxalato(trans-1-1,2-cyclohexanediamine) Pt(II) complex having high optical purity and process of preparing same |
WO1996040210A1 (en) | 1995-06-07 | 1996-12-19 | Imclone Systems Incorporated | Antibody and antibody fragments for inhibiting the growth of tumors |
US5734056A (en) | 1990-09-28 | 1998-03-31 | Smithkline Beecham Corporation | Process for the preparation of certain 9-substituted camptothecins |
US5770599A (en) | 1995-04-27 | 1998-06-23 | Zeneca Limited | Quinazoline derivatives |
US5959133A (en) | 1996-07-04 | 1999-09-28 | Tanaka Kikinzoku Kogyo K.K. | Process for the preparation of platinum compounds |
WO2003037872A1 (en) | 2001-11-01 | 2003-05-08 | Astrazeneca Ab | Therapeutic quinoline compounds with 5-ht-antagonistic properties |
WO2003091255A1 (en) | 2002-04-26 | 2003-11-06 | Warner-Lambert Company Llc | Inhibitors of checkpoint kinases (wee1 and chk1) |
WO2004056786A2 (en) | 2002-12-20 | 2004-07-08 | Pfizer Products Inc. | Pyrimidine derivates for the treatment of abnormal cell growth |
WO2004065378A1 (en) * | 2003-01-17 | 2004-08-05 | Warner-Lambert Company Llc | 2-aminopyridine substituted heterocycles as inhibitors of cellular proliferation |
WO2005021532A1 (en) | 2003-08-25 | 2005-03-10 | Amgen Inc | Substituted 2,3-dihydro-1h-isoindol-1-one derivatives and methods of use |
US20050250836A1 (en) | 2004-05-03 | 2005-11-10 | Pfizer Inc | Inhibitors of checkpoint kinases (Wee1 and Chk1) |
WO2006004040A1 (ja) | 2004-07-01 | 2006-01-12 | Daiichi Asubio Pharma Co., Ltd. | Pde7阻害作用を有するチエノピラゾール誘導体 |
WO2006091737A1 (en) | 2005-02-24 | 2006-08-31 | Kemia, Inc. | Modulators of gsk-3 activity |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CZ27399A3 (cs) | 1999-01-26 | 2000-08-16 | Ústav Experimentální Botaniky Av Čr | Substituované dusíkaté heterocyklické deriváty, způsob jejich přípravy, tyto deriváty pro použití jako léčiva, farmaceutická kompozice a kombinovaný farmaceutický přípravek tyto deriváty obsahující a použití těchto derivátů pro výrobu léčiv |
EP1611125A1 (en) * | 2003-02-07 | 2006-01-04 | Vertex Pharmaceuticals Incorporated | Heteroaryl substituted pyrolls useful as inhibitors of protein kinases |
AU2006205851A1 (en) * | 2005-01-14 | 2006-07-20 | Janssen Pharmaceutica N.V. | 5-membered annelated heterocyclic pyrimidines as kinase inhibitors |
PE20080695A1 (es) | 2006-04-27 | 2008-06-28 | Banyu Pharma Co Ltd | Derivados de dihidropirazolopirimidinona como inhibidores de quinasa weel |
-
2007
- 2007-04-24 PE PE2007000511A patent/PE20080695A1/es active IP Right Grant
- 2007-04-24 AR ARP070101763A patent/AR060635A1/es active IP Right Grant
- 2007-04-25 EP EP07742851.4A patent/EP2017278B1/en active Active
- 2007-04-25 AT AT07742843T patent/ATE475662T1/de active
- 2007-04-25 PT PT07742843T patent/PT2016080E/pt unknown
- 2007-04-25 HU HUE07742851A patent/HUE032987T2/en unknown
- 2007-04-25 RU RU2008146759/04A patent/RU2437885C2/ru active
- 2007-04-25 BR BRPI0710081-7A patent/BRPI0710081A2/pt not_active Application Discontinuation
- 2007-04-25 CA CA2650119A patent/CA2650119C/en active Active
- 2007-04-25 DE DE602007008085T patent/DE602007008085D1/de active Active
- 2007-04-25 EP EP07742843A patent/EP2016080B1/en active Active
- 2007-04-25 WO PCT/JP2007/059416 patent/WO2007126128A1/ja active Application Filing
- 2007-04-25 PL PL07742851T patent/PL2017278T3/pl unknown
- 2007-04-25 AU AU2007244185A patent/AU2007244185B2/en active Active
- 2007-04-25 ES ES07742843T patent/ES2348751T3/es active Active
- 2007-04-25 CN CN2007800150647A patent/CN101432284B/zh active Active
- 2007-04-25 ES ES07742851.4T patent/ES2609087T3/es active Active
- 2007-04-25 US US12/226,707 patent/US7935708B2/en active Active
- 2007-04-25 US US11/789,548 patent/US7834019B2/en active Active
- 2007-04-25 SI SI200731875A patent/SI2017278T1/sl unknown
- 2007-04-25 JP JP2008513330A patent/JP4513919B2/ja active Active
- 2007-04-25 PT PT77428514T patent/PT2017278T/pt unknown
- 2007-04-25 UA UAA200813667A patent/UA96152C2/ru unknown
- 2007-04-25 LT LTEP07742851.4T patent/LT2017278T/lt unknown
- 2007-04-25 WO PCT/JP2007/059408 patent/WO2007126122A1/en active Application Filing
- 2007-04-25 DK DK07742851.4T patent/DK2017278T3/en active
- 2007-04-25 SI SI200730373T patent/SI2016080T1/sl unknown
- 2007-04-25 NZ NZ571196A patent/NZ571196A/en unknown
- 2007-04-25 MX MX2008013063A patent/MX2008013063A/es active IP Right Grant
- 2007-04-25 KR KR1020087026239A patent/KR101409161B1/ko active IP Right Grant
- 2007-04-25 PL PL07742843T patent/PL2016080T3/pl unknown
- 2007-04-25 DK DK07742843.1T patent/DK2016080T3/da active
- 2007-04-27 DO DO2007000084A patent/DOP2007000084A/es unknown
- 2007-04-27 TW TW096114902A patent/TWI409262B/zh active
-
2008
- 2008-09-09 ZA ZA200807748A patent/ZA200807748B/xx unknown
- 2008-09-18 MY MYPI20083651A patent/MY145408A/en unknown
- 2008-09-25 IL IL194367A patent/IL194367A/en active IP Right Grant
- 2008-10-09 EC EC2008008812A patent/ECSP088812A/es unknown
- 2008-10-10 GT GT200800211A patent/GT200800211A/es unknown
- 2008-10-10 SV SV2008003060A patent/SV2009003060A/es unknown
- 2008-10-10 CR CR10359A patent/CR10359A/es unknown
- 2008-10-10 HN HN2008001532A patent/HN2008001532A/es unknown
- 2008-11-24 MA MA31411A patent/MA30428B1/fr unknown
- 2008-11-26 NO NO20084968A patent/NO341617B1/no unknown
-
2009
- 2009-10-29 HK HK09110110.5A patent/HK1132498A1/xx unknown
-
2010
- 2010-02-08 JP JP2010025458A patent/JP5167291B2/ja active Active
- 2010-10-18 HR HR20100563T patent/HRP20100563T1/hr unknown
- 2010-10-27 CY CY20101100973T patent/CY1111069T1/el unknown
-
2011
- 2011-03-22 US US13/053,798 patent/US8791125B2/en active Active
-
2014
- 2014-06-24 US US14/312,982 patent/US20140303178A1/en not_active Abandoned
-
2016
- 2016-12-21 HR HRP20161763TT patent/HRP20161763T1/hr unknown
-
2017
- 2017-01-27 CY CY20171100129T patent/CY1118526T1/el unknown
Patent Citations (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH045029B2 (ja) | 1981-08-24 | 1992-01-30 | ||
US4604463A (en) | 1983-07-14 | 1986-08-05 | Kabushiki Kaisha Yakult Honsha | Camptothecin derivatives and process for preparing same |
JPH02503143A (ja) | 1987-01-08 | 1990-10-04 | インターナショナル、ジェネティック、エンジニアリング、インコーポレーテッド | ヒトb細胞表面抗原に対して特異性のあるキメラ抗体 |
JPH01139572A (ja) * | 1987-08-26 | 1989-06-01 | Mitsui Pharmaceut Inc | ピリミジン類及びその薬学的に許容される塩類 |
US5223608A (en) | 1987-08-28 | 1993-06-29 | Eli Lilly And Company | Process for and intermediates of 2',2'-difluoronucleosides |
US5434254A (en) | 1987-08-28 | 1995-07-18 | Eli Lilly And Company | Process for preparing 2',2'-difluoronucleosides |
US5734056A (en) | 1990-09-28 | 1998-03-31 | Smithkline Beecham Corporation | Process for the preparation of certain 9-substituted camptothecins |
US5200524A (en) | 1990-12-20 | 1993-04-06 | North Carolina State University | Camptothecin intermediates and method of making same |
US5243050A (en) | 1990-12-20 | 1993-09-07 | North Carolina State University | Alkylpyridone DE ring intermediates useful for the manufacture of camptothecin and camptothecin analogs |
US5247089A (en) | 1990-12-20 | 1993-09-21 | North Carolina State University | Method of making intermediates useful for the manufacture of camptothecin and camptothecin analogs |
US5321140A (en) | 1990-12-20 | 1994-06-14 | North Carolina State University | Pyridinecarboxaldehyde D-ring intermediates useful for the synthesis of camptothecin and camptothecin analogs |
US5191082A (en) | 1990-12-20 | 1993-03-02 | North Carolina State University | Camptothecin intermediate and method of making camptothecin intermediates |
US5162532A (en) | 1990-12-20 | 1992-11-10 | North Carolina State University | Intermediates and method of making camptothecin and camptothecin analogs |
WO1994010202A1 (en) | 1992-10-28 | 1994-05-11 | Genentech, Inc. | Vascular endothelial cell growth factor antagonists |
US5420319A (en) | 1993-05-21 | 1995-05-30 | Tanaka Kikinzoku Kogyo K.K. | Cis-oxalato(trans-1-1,2-cyclohexanediamine) Pt(II) complex having high optical purity and process of preparing same |
US5770599A (en) | 1995-04-27 | 1998-06-23 | Zeneca Limited | Quinazoline derivatives |
WO1996040210A1 (en) | 1995-06-07 | 1996-12-19 | Imclone Systems Incorporated | Antibody and antibody fragments for inhibiting the growth of tumors |
US5959133A (en) | 1996-07-04 | 1999-09-28 | Tanaka Kikinzoku Kogyo K.K. | Process for the preparation of platinum compounds |
WO2003037872A1 (en) | 2001-11-01 | 2003-05-08 | Astrazeneca Ab | Therapeutic quinoline compounds with 5-ht-antagonistic properties |
WO2003091255A1 (en) | 2002-04-26 | 2003-11-06 | Warner-Lambert Company Llc | Inhibitors of checkpoint kinases (wee1 and chk1) |
WO2004056786A2 (en) | 2002-12-20 | 2004-07-08 | Pfizer Products Inc. | Pyrimidine derivates for the treatment of abnormal cell growth |
WO2004065378A1 (en) * | 2003-01-17 | 2004-08-05 | Warner-Lambert Company Llc | 2-aminopyridine substituted heterocycles as inhibitors of cellular proliferation |
WO2005021532A1 (en) | 2003-08-25 | 2005-03-10 | Amgen Inc | Substituted 2,3-dihydro-1h-isoindol-1-one derivatives and methods of use |
US20050250836A1 (en) | 2004-05-03 | 2005-11-10 | Pfizer Inc | Inhibitors of checkpoint kinases (Wee1 and Chk1) |
WO2006004040A1 (ja) | 2004-07-01 | 2006-01-12 | Daiichi Asubio Pharma Co., Ltd. | Pde7阻害作用を有するチエノピラゾール誘導体 |
WO2006091737A1 (en) | 2005-02-24 | 2006-08-31 | Kemia, Inc. | Modulators of gsk-3 activity |
Non-Patent Citations (13)
Title |
---|
BIOORG & MED. CHEM. LETT., vol. 15, pages 1931 - 1935 |
BIOORG. & MED. CHEM. LETT., vol. 14, pages 5793 - 5797 |
CANCER BIOLOGY & THERAPY, vol. 3, pages 305 - 313 |
CANCER RESEARCH, vol. 61, pages 8211 - 8217 |
CELL PROLIFERATION, vol. 33, pages 261 - 274 |
JOURNAL OF MEDICINAL CHEMISTRY, vol. 48, pages 2371 - 2387 |
JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTION II, vol. 3, pages 843 |
MACHON Z. ET AL.: "Derivatives of 2-hydrogxy-4-mercapto-6-methylpyrimidine -5-carboxylic acid", POLISH JOURNAL OF PHARMACOLOGY AND PHARMACY, vol. 28, no. 5, 1976, pages 511 - 520, XP003019120 * |
NITTA ET AL., GAN TO KAGAKU RYOHO, vol. 14, 1987, pages 850 - 857 |
PALMER B.D. ET AL.: "Structure-activity relationships for 2-anilino-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-ones as inhibitors of the cellular checkpoint kinase Weel", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 15, 2005, pages 1931 - 1935, XP004789411 * |
T. W. GREENE: "Protective Groups in Organic Synthesis", 1999, JOHN WILEY & SONS |
THE EMBO JOURNAL, vol. 12, pages 75 - 85 |
WANG Y. ET AL.: "Radiosensitization of p53 mutant cells by PD0166285, a novel G2 checkpoint abrogator", CANCER RESEARCH, vol. 61, 2001, pages 8211 - 8217, XP002280759 * |
Cited By (35)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2010525057A (ja) * | 2007-04-25 | 2010-07-22 | 萬有製薬株式会社 | Weelキナーゼインヒビターとしてのジヒドロピラゾロピリミジノン誘導体の多形 |
WO2009054332A1 (ja) * | 2007-10-23 | 2009-04-30 | Banyu Pharmaceutical Co., Ltd. | ピリドン置換ジヒドロピラゾロピリミジノン誘導体 |
WO2010076887A1 (en) * | 2009-01-05 | 2010-07-08 | Banyu Pharmaceutical Co.,Ltd. | Predictive biomarkers useful for cancer therapy mediated by a wee1 inhibitor |
WO2010098367A1 (en) * | 2009-02-25 | 2010-09-02 | Banyu Pharmaceutical Co.,Ltd. | Pyrimidopyrimidoindazole derivative |
JP2012518598A (ja) * | 2009-02-25 | 2012-08-16 | Msd株式会社 | ピリミドピリミドインダゾール誘導体 |
US8288396B2 (en) | 2009-02-25 | 2012-10-16 | Msdkk | Pyrimidopyrimidoindazole derivative |
WO2011027800A1 (en) * | 2009-09-02 | 2011-03-10 | Banyu Pharmaceutical Co.,Ltd. | Use of biomarker(s) to identify a wee1 inhibitor responsive patient and methods of treating cancer mediated by dysfunctional or aberrant p53 via administration of a wee1 inhibitor |
US8703779B2 (en) | 2009-09-15 | 2014-04-22 | Merck Sharp & Dohme Corp. | Preparation of crystalline forms of dihydropyrazolopyrimidinone |
US9388186B2 (en) | 2009-09-15 | 2016-07-12 | Merck Sharp & Dohme Corp. | Preparation of crystalline forms of dihydropyrazolopyrimidinone |
US9370567B2 (en) | 2010-11-16 | 2016-06-21 | Array Biopharma Inc. | Combination of checkpoint kinase 1 inhibitors and WEE 1 kinase inhibitors |
WO2012074754A1 (en) | 2010-11-16 | 2012-06-07 | Array Biopharma Inc. | Combination of checkpoint kinase 1 inhibitors and wee 1 kinase inhibitors |
US10434094B2 (en) | 2010-11-16 | 2019-10-08 | Array Biopharma Inc. | Combination of checkpoint kinase 1 inhibitors and wee 1 kinase inhibitors |
WO2013039854A1 (en) | 2011-09-15 | 2013-03-21 | Merck Sharp & Dohme Corp. | Compositions and methods for treating cancer |
JP2016500110A (ja) * | 2012-11-28 | 2016-01-07 | メルク・シャープ・アンド・ドーム・コーポレーションMerck Sharp & Dohme Corp. | 癌を処置するための組成物および方法 |
WO2014085216A1 (en) | 2012-11-28 | 2014-06-05 | Merck Sharp & Dohme Corp. | Compositions and methods for treating cancer |
JP2016516763A (ja) * | 2013-04-11 | 2016-06-09 | アルマック・ディスカバリー・リミテッドAlmac Discovery Limited | 2−アミノピリド[4,3−D]ピリミジン−5−オン誘導体及びWee−1阻害薬としてのそれらの使用 |
US9879016B2 (en) | 2015-04-17 | 2018-01-30 | Abbvie Inc. | Indazolones as modulators of TNF signaling |
US10160748B2 (en) | 2015-04-17 | 2018-12-25 | Abbvie Inc. | Indazolones as modulators of tnf signaling |
US10266532B2 (en) | 2015-04-17 | 2019-04-23 | Abbvie Inc. | Tricyclic modulators of TNF signaling |
US10273238B2 (en) | 2015-04-17 | 2019-04-30 | Abbvie Inc. | Indazolones as modulators of TNF signaling |
US9856253B2 (en) | 2015-04-17 | 2018-01-02 | Abbvie, Inc. | Tricyclic modulators of TNF signaling |
JP2018536651A (ja) * | 2015-11-01 | 2018-12-13 | ザ リージェンツ オブ ザ ユニヴァーシティ オブ コロラド,ア ボディ コーポレイト | Wee1キナーゼ阻害剤、並びにそれを作製及び使用する方法 |
US10954253B2 (en) | 2017-01-23 | 2021-03-23 | Shijiazhuang Sagacity New Drug Development Co., Ltd. | 1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one derivative as Wee1 inhibitor |
JP2020510630A (ja) * | 2017-01-23 | 2020-04-09 | シージャーズォアン サガシティ ニュー ドラッグ デベロップメント カンパニー リミテッド | Wee1阻害剤としての1,2−ジヒドロ−3H−ピラゾロ[3,4−d]ピリミジン−3−オン誘導体 |
JP7140337B2 (ja) | 2017-03-23 | 2022-09-21 | シャンハイ ドーァ ノボ ファーマテック カンパニー,リミティド | ピラゾロ[3,4-d]ピリミジン-3-オンの大環状誘導体、その医薬組成物及び応用 |
JP2020511520A (ja) * | 2017-03-23 | 2020-04-16 | シャンハイ ドーァ ノボ ファーマテック カンパニー,リミティド | ピラゾロ[3,4−d]ピリミジン−3−オンの大環状誘導体、その医薬組成物及び応用 |
JP2021501191A (ja) * | 2017-11-01 | 2021-01-14 | シージャーズォアン サガシティ ニュー ドラッグ デベロップメント カンパニー リミテッド | Wee1阻害剤としての大環状化合物及びその使用 |
US11613545B2 (en) | 2017-11-01 | 2023-03-28 | Wuxi Biocity Biopharmaceutics Co., Ltd. | Macrocyclic compound serving as Wee1 inhibitor and applications thereof |
JP7290638B2 (ja) | 2017-11-01 | 2023-06-13 | ウーシー・バイオシティ・バイオファーマシューティクス・カンパニー・リミテッド | Wee1阻害剤としての大環状化合物及びその使用 |
JP2021516231A (ja) * | 2018-02-28 | 2021-07-01 | ザ リージェンツ オブ ザ ユニバーシティ オブ コロラド,ア ボディー コーポレイトTHE REGENTS OF THE UNIVERSITY OF COLORADO,a body corporate | Wee1キナーゼ阻害物質およびそれを使用してがんを処置する方法 |
JP7483620B2 (ja) | 2018-02-28 | 2024-05-15 | ザ リージェンツ オブ ザ ユニバーシティ オブ コロラド,ア ボディー コーポレイト | Wee1キナーゼ阻害物質およびそれを使用してがんを処置する方法 |
JP7481336B2 (ja) | 2018-10-26 | 2024-05-10 | ウーシー・バイオシティ・バイオファーマシューティクス・カンパニー・リミテッド | Wee1阻害剤としてのピリミドピラゾロン類誘導体及びその使用 |
WO2020259703A1 (zh) | 2019-06-28 | 2020-12-30 | 上海医药集团股份有限公司 | 一种吡唑酮并嘧啶类化合物、其制备方法及应用 |
WO2020259724A2 (zh) | 2019-06-28 | 2020-12-30 | 上海医药集团股份有限公司 | 一种吡唑酮并嘧啶类化合物、其制备方法及应用 |
WO2022247641A1 (zh) | 2021-05-28 | 2022-12-01 | 江苏天士力帝益药业有限公司 | Wee1抑制剂及其用途 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2007126128A1 (ja) | ジヒドロピラゾロピリミジノン誘導体 | |
US10780073B2 (en) | N4-phenyl-quinazoline-4-amine derivatives and related compounds as ErbB type I receptor tyrosine kinase inhibitors for the treatment of hyperproliferative diseases | |
JP6496376B2 (ja) | 阻害剤化合物 | |
EP4291176A1 (en) | Cdk inhibitors and methods of use thereof | |
KR101661405B1 (ko) | 사이클린 의존성 키나제 억제제로서의 신규 피라졸로피리미딘 유도체 | |
JP2019510043A (ja) | Tam阻害剤としてのピロロトリアジン化合物 | |
CN111212839A (zh) | 吡唑并嘧啶酮化合物及其用途 | |
AU2012295802A1 (en) | Tricyclic heterocyclic compounds and JAK inhibitors | |
JP2008505084A (ja) | フラノピリミジン | |
TW200300350A (en) | C-5 modified indazolylpyrrolotriazines | |
JP2012511502A (ja) | ジヒドロピリミドピリミジン誘導体 | |
US8288396B2 (en) | Pyrimidopyrimidoindazole derivative | |
KR20160013188A (ko) | 헤지호그 신호전달 경로 억제제로서의 헤테로사이클릭 화합물 | |
JP7071383B2 (ja) | cdc7阻害剤としてのピリミジノン誘導体 | |
JP2022532145A (ja) | 置換ベンズイミダゾロン化合物 | |
JP2023052069A (ja) | ベンズイミダゾロン由来のbcl6阻害剤 |
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: 07742851 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2008513330 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2007244185 Country of ref document: AU |
|
ENP | Entry into the national phase |
Ref document number: 2007244185 Country of ref document: AU Date of ref document: 20070425 Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2650119 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12226707 Country of ref document: US |
|
WWE | Wipo information: entry into national phase |
Ref document number: 200780015064.7 Country of ref document: CN |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 9391/DELNP/2008 Country of ref document: IN |
|
REEP | Request for entry into the european phase |
Ref document number: 2007742851 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2007742851 Country of ref document: EP |