WO2011145718A1 - Nouveau composé de pyrrolo[2,3-d]pyrimidine - Google Patents

Nouveau composé de pyrrolo[2,3-d]pyrimidine Download PDF

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WO2011145718A1
WO2011145718A1 PCT/JP2011/061625 JP2011061625W WO2011145718A1 WO 2011145718 A1 WO2011145718 A1 WO 2011145718A1 JP 2011061625 W JP2011061625 W JP 2011061625W WO 2011145718 A1 WO2011145718 A1 WO 2011145718A1
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group
fluoro
compound
pyrrolo
pyrimidin
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PCT/JP2011/061625
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Japanese (ja)
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康範 坪井
公博 白井
崇 本城
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田辺三菱製薬株式会社
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Priority claimed from JP2010117021A external-priority patent/JP2013177315A/ja
Priority claimed from JP2010160697A external-priority patent/JP2013177319A/ja
Application filed by 田辺三菱製薬株式会社 filed Critical 田辺三菱製薬株式会社
Publication of WO2011145718A1 publication Critical patent/WO2011145718A1/fr

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    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a novel pyrrolo [2,3-d] pyrimidine compound or a pharmacologically acceptable salt thereof which has an excellent GPR119 receptor agonistic activity and is useful as a medicine.
  • GPR119 a G protein-coupled receptor (GPCR)
  • GPCR G protein-coupled receptor
  • OAA oil ethanolamide
  • PSN632408 low molecular weight synthetic ligand
  • Non-Patent Document 2 a recent study on the physiological role of GPR119 using a selective small molecule agonist (AR231453) represented by the following formula revealed that pancreatic pancreatic pancreatic pancreatic pancreas was mediated by increased cAMP (adenylate cyclase activation) by activation of the receptor. It has been clarified that glucose-dependent insulin release in ⁇ -cells is enhanced, and that glucose homeostasis can be improved (Non-Patent Document 2).
  • cAMP adenylate cyclase activation
  • this receptor regulates glucose homeostasis through enhanced release of incretins (glucagon-like peptide-1 / GLP-1 and glucose-dependent insulin peptide / GIP), which may be referred to as endogenous antidiabetic hormones.
  • incretins glucagon-like peptide-1 / GLP-1 and glucose-dependent insulin peptide / GIP
  • endogenous antidiabetic hormones glucagon-like peptide-1 / GLP-1 and glucose-dependent insulin peptide / GIP
  • the low molecular weight GPR119 agonist can be expected to have an effect of directly and / or indirectly protecting the pancreas via an incretin hormone (an anti-apoptotic action and / or a proliferation promoting action on islet cells). From the above findings, GPR119 has attracted attention as an attractive therapeutic target in metabolic related diseases including diabetes and obesity.
  • An object of the present invention is to provide a novel pyrrolo [2,3-d] pyrimidine compound having an excellent GPR119 receptor agonistic activity and useful as a medicine.
  • Ring A has the following formula:
  • a substituted benzene ring, a substituted pyridine ring or a substituted piperidine ring represented by R 01A and R 01B are the same or different and are a hydrogen atom, a halogen atom, an alkyl group or a trihalogenoalkyl group
  • R 02 is A) an alkylthio group
  • D) a saturated or unsaturated nitrogen-containing 5-membered heterocyclic group which may be substituted with 1 to 2 groups selected from an alkyl group, an alkoxycarbonyl group, a hydroxyalkyl group, an amino group, an oxo group and a carbamoyl group
  • the heterocyclic group may contain an oxygen atom as a hetero atom other than a nitrogen atom
  • G is a group represented by the formula: —C ( ⁇ O) — or —CH 2 —, and ring B further contains a heteroatom selected from a nitrogen atom, a sulfur atom and an oxygen atom.
  • a 4- to 6-membered hetero ring wherein R A1 and R A2 are the same or different and are a hydrogen atom or a halogen atom, R A3 and R A4 are the same or different and are a) a hydrogen atom, b) a halogen atom, c) Cyano group, d) hydroxyl group, e) oxo group, f) alkyl group, g) hydroxyalkyl group, h) alkoxyalkyl group, i) alkoxycarbonyl group, j) carboxyl group, k) 1-2 alkyl groups An optionally substituted amino group or l) a carbamoyl group optionally substituted by 1 to 2 alkyl groups), R 03 is a hydrogen atom
  • R 001 is a 6-membered heteroaryl group or alkoxycarbonyl group optionally substituted with an alkyl group, R k represents a hydrogen atom or an alkyl group),
  • R 1 is a) an acyl group represented by R 11 OCO— (where R 11 represents an alkyl group which may be substituted with 1 to 3 halogen atoms), or b) a nitrogen atom, an oxygen atom and 5- to 6-membered heteroaryl group containing the same or different 1 to 4 heteroatoms selected from the group consisting of sulfur atoms (the heteroaryl group is substituted with 1 to 3 halogen atoms).
  • R 2 is a halogen atom
  • R 3 represents a hydrogen atom, a hydroxyl group, a halogen atom or an alkyl group.
  • Ring A is a substituted benzene ring represented by the formula (Ai)
  • Q is a single bond
  • R 0 is a group represented by the formula (R-iii)
  • R 3 is a hydrogen atom
  • R 02 is a group represented by the formula (B-iii)
  • G is a group represented by the formula: —C ( ⁇ O) —
  • R A1 , R A2 , R A3 and R A4 are all hydrogen atoms.
  • R 02 when R 02 is a group represented by the formula: —CONR a R b and R b is an alkyl group or a monohydroxyalkyl group; or (c) R 02 is an alkylsulfonyl group If there is; (D) R 02 is an unsubstituted nitrogen-containing 5-membered heterocyclic group; or (E) When R 02 is a group represented by the formula (B-iii), G is a group represented by the formula: —C ( ⁇ O) —, and R A3 and / or R A4 is a hydroxyl group Represents the group R 01A on the substituted benzene ring ( Ai ) is an alkyl group). ] Or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to a pharmaceutical composition comprising the compound [I] or a pharmacologically acceptable salt thereof as an active ingredient. Furthermore, the present invention relates to a GPR119 modulator, particularly a GPR119 agonist (agonist) comprising the above compound [I] or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a GPR119 modulator particularly a GPR119 agonist (agonist) comprising the above compound [I] or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound of the present invention is a compound that exerts an excellent regulatory action (agonist action, etc.) on GPR119 activity, has few side effects, and has high medicinal safety.
  • the compound of the present invention was useful as a GPR119 agonist because it exhibited an excellent cAMP production enhancing action against the same cells in an assay system using human GPR119-expressing CHO cells. is there.
  • the compound of the present invention which is a low molecular weight GPR119 agonist can be expected to have a pancreatic protective action (anti-apoptotic action and / or proliferation promoting action on islet cells) directly and / or indirectly through incretin hormone. .
  • Ring A is represented by the following formula (Aia):
  • Ring A is the following formula:
  • Ring A is represented by the following formula (Aib):
  • the substituent (R 02 ) on ring A may be substituted with 1 to 2 groups selected from an alkyl group, an alkoxycarbonyl group, a hydroxyalkyl group, an amino group, and a carbamoyl group.
  • the nitrogen-containing 5-membered heterocyclic group examples include an oxazolyl group, a dihydrooxazolyl group, an oxadiazolyl group, a triazolyl group, and a tetrazolyl group.
  • Preferred examples of the optionally substituted nitrogen-containing 5-membered heterocyclic group (R 02 ) include the following formula:
  • R X represents a hydroxyalkyl group, an alkoxycarbonyl group or a carbamoyl group
  • R Y represents an alkyl group
  • R Z represents a hydroxyalkyl group
  • R W represents an amino group
  • a dotted line represents the presence or absence of a bond.
  • the substituent (R 02 ) on the ring A is represented by the formula (B-iii):
  • R A20 represents a hydrogen atom or a halogen atom
  • R A30 is a hydrogen atom, a halogen atom or a hydroxyl group
  • R A40 represents a hydrogen atom, a halogen atom, a cyano group, an amino group, a hydroxyl group, a hydroxyalkyl group, an alkoxyalkyl group, a carboxyl group, an alkoxycarbonyl group, or a carbamoyl group (the amino moiety of the carbamoyl group is 1 to 2 alkyl groups).
  • R A11 , R A21 , R A32 and R A42 are the same or different halogen atoms
  • R A33 is a hydrogen atom or a hydroxyl group
  • R A43 represents an alkyl group, a hydroxyalkyl group, an alkoxycarbonyl group or a carbamoyl group
  • Z is an oxygen atom or a sulfur atom
  • R A44 represents a hydrogen atom or a hydroxyalkyl group
  • R A35 and R A45 are the same or different halogen atoms
  • R A36 represents a hydrogen atom, an alkyl group or a hydroxyalkyl group (provided that when the above substituents R A20 , R A30 and R A40 are both hydrogen atoms, they are on the substituted benzene ring represented by the formula (Ai)).
  • the group R 01A is an alkyl group).
  • G is a group represented by the formula: —C ( ⁇ O) —.
  • R 02 when the substituent (R 02 ) on ring A is a group represented by the formula: —CONR a R b and R b is a 5- to 6-membered aliphatic sulfur-containing heterocyclic group
  • the 5- to 6-membered aliphatic sulfur-containing heterocyclic group include a tetrahydrothienyl group and a tetrahydrothiopyranyl group.
  • the 5- to 6-membered aliphatic sulfur-containing heterocyclic group may be substituted with the same or different 1 to 3 groups selected from a hydroxyl group, an oxo group and a hydroxyalkyl group.
  • substituted 5- to 6-membered aliphatic sulfur-containing heterocyclic group include a tetrahydrothienyl group substituted with 1 or 2 oxo groups (this group may be further substituted with a hydroxyl group). And a dioxotetrahydrothiopyranyl group substituted with one or two oxo groups, a tetrahydrothiopyranyl group substituted with a hydroxyalkyl group, and the like.
  • Preferred examples of the substituted 5- to 6-membered aliphatic sulfur-containing heterocyclic group include 1,1-dioxotetrahydrothienyl group, 3-hydroxy-1,1-dioxotetrahydrothienyl group, 1,1-dioxotetrahydro group.
  • Examples thereof include a thiopyranyl group and a 4-hydroxymethyltetrahydrothiopyranyl group.
  • R 1 is a 5- to 6-membered heteroaryl group containing the same or different 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom
  • the heteroaryl group As, for example, pyrrolyl group, imidazolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, isothiazolyl group, isoxazolyl group, thiazolyl group, oxadiazolyl group, furazanyl group, thiadiazolyl group, thienyl group, furyl group, pyridyl group, pyrimidinyl group, A pyrazinyl group, a pyridazinyl group, a triazinyl group, etc.
  • a 5- or 6-membered heteroaryl group (such as an oxadiazolyl group, a pyridyl group, or a pyrimidinyl group) containing 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom is preferable.
  • the heteroaryl group may be substituted with 1 to 3 groups selected from a halogen atom, an alkyl group optionally substituted with 1 to 3 halogen atoms, a cycloalkyl group and an alkoxy group.
  • Preferred examples of the substituted 5- to 6-membered heteroaryl group include (1) a pyrimidinyl group substituted with a halogen atom, an alkyl group, a cycloalkyl group, or a trihalogenoalkyl group, or (2) an alkyl group or And an oxadiazolyl group substituted with a trihalogenoalkyl group.
  • Ring A is a substituted benzene ring represented by the above formula (Ai), R 01A is a hydrogen atom or a halogen atom, R 01B is a hydrogen atom or a halogen atom
  • R 02 is (a) an alkylsulfinyl group; (B) an alkylsulfonyl group; (C) a group represented by the formula: —CONR a R b , wherein R a is a hydrogen atom or an alkyl group, R b is an alkyl group, a monohydroxyalkyl group, a dihydroxyalkyl group, an aminoalkyl group, or a carbamoylalkyl group; (D) The following formula:
  • R A20 is a hydrogen atom or a halogen atom
  • R A30 is a hydrogen atom, a hydroxyl group or a halogen atom
  • R A40 is a hydrogen atom, a halogen atom, a cyano group, a hydroxyalkyl group or a carbamoyl group
  • R A11 , R A21 , R A32 and R A42 are the same or different halogen atoms
  • R A35 and R A45 are the same or different halogen atoms; or (e) 5-membered unsaturation containing 1 to 4 nitrogen atoms as heteroatoms A heterocyclic group
  • Examples thereof include compounds in which R 2 is a halogen atom, and R 3 is a hydrogen atom or an alkyl group (provided that R A20 , R A30 and R A40 are all hydrogen atoms and Q is a single bond, R 0 is a group represented by the formula (R-vii)).
  • Ring A is a substituted benzene ring represented by the formula (Aia), and R 1 is a) an alkoxycarbonyl group or b) 1 to 3 selected from a nitrogen atom and an oxygen atom
  • R 1 is a) an alkoxycarbonyl group or b) 1 to 3 selected from a nitrogen atom and an oxygen atom
  • ring A is represented by formula (A-ii)
  • R 03 is an alkyl group
  • R 04 is an alkylsulfonyl group
  • Q is an alkylene group
  • R 0 is the following formula:
  • R 1 is a nitrogen-containing 6-membered heteroaryl group substituted with a trihalogenoalkyl group.
  • more preferred compounds include, for example, the following formula [I-AA]:
  • R A represents 2- (hydroxyC 1-4 alkyl) -1-pyrrolidinyl group, 2-cyano-1-pyrrolidinyl group, 2-carbamoyl-1-pyrrolidinyl group, 4-hydroxy-2- (hydroxyC 1-4 alkyl) -1-pyrrolidinyl group, 3-halogeno-1-pyrrolidinyl group, 1,1-dioxothiomorpholino group, N- (dihydroxy C 1-4 alkyl) amino group, N—C 1-4 alkyl -N- (dihydroxy C 1-4 alkyl) amino group, N- (amino C 1-4 alkyl) amino group or N-C 1-4 alkyl-N- (carbamoyl-C 1-4 alkyl) amino group, R 01C is a halogen atom, R 01D is hydrogen atom or halogen atom, R 10 is C 1-4 alkoxycarbonyl group, 5-halogeno-2-yl group, 5-C 1-4 A Kill
  • particularly preferred compounds include, for example, [4- [7- [1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] -5-fluoro-7H-pyrrolo [2,3-d] pyrimidin-4-ylamino] -3-fluoro Phenyl] ((R) -2-hydroxymethylpyrrolidin-1-yl) methanone; [4- [7- [1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] -5-fluoro-7H-pyrrolo [2,3-d] pyrimidin-4-ylamino] -3-fluoro Phenyl] (1,1-dioxo-1 ⁇ 6 -thiomorpholin-4-yl) methanone; [4- [7- [1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] -5-fluoro-7H-pyrrolo [2,3-d]
  • the compound [I] of the present invention When the compound [I] of the present invention has an asymmetric carbon atom in the molecule, it can exist as a plurality of stereoisomers (diastereoisomers, optical isomers) based on the asymmetric carbon atom.
  • the invention includes any one of these stereoisomers or mixtures thereof.
  • the compound [I] of the present invention has an excellent agonistic effect on the GPR119 receptor, various diseases or conditions that can be expected to be improved by regulating the receptor activity, such as obesity, hyperglycemia, diabetes (Including insulin-dependent diabetes, non-insulin-dependent type 2 diabetes, or their intermediate type diabetes) and complications thereof, metabolic syndrome, impaired glucose tolerance, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, It is useful for the prevention and treatment of metabolic diseases including diseases such as hypertriglyceridemia and abnormal lipid metabolism, or cardiovascular diseases such as arteriosclerosis, hypertension, coronary disease, and myocardial infarction.
  • metabolic diseases including diseases such as hypertriglyceridemia and abnormal lipid metabolism, or cardiovascular diseases such as arteriosclerosis, hypertension, coronary disease, and myocardial infarction.
  • the compound [I] of the present invention or a pharmacologically acceptable salt thereof has a feature of low toxicity and high safety as a medicine.
  • the compound [I] of the present invention can be used for pharmaceutical use either in a free form or in the form of a pharmacologically acceptable salt thereof.
  • pharmaceutically acceptable salts include inorganic acid salts such as hydrochloride, sulfate, phosphate or hydrobromide, acetate, trifluoroacetate, fumarate, oxalate, citric acid, and the like.
  • organic acid salts such as acid salts, methanesulfonate, benzenesulfonate, tosylate, and maleate.
  • the compound [I] of the present invention or a pharmacologically acceptable salt thereof includes any of its intramolecular salts and adducts, solvates or hydrates thereof.
  • the compound [I] of the present invention or a pharmacologically acceptable salt thereof can be administered orally or parenterally, and tablets, granules, capsules, powders, injections, inhalants, etc. It can be used as a conventional pharmaceutical preparation.
  • the dose of the compound [I] of the present invention or a pharmacologically acceptable salt thereof varies depending on the administration method, the age, body weight and condition of the patient. 100 mg / kg, especially about 0.01 to 10 mg / kg, and in the case of an oral preparation, it is usually preferably about 0.01 to 1000 mg / kg, especially about 0.1 to 100 mg / kg per day.
  • the compound [I] of the present invention or a pharmacologically acceptable salt thereof can be used alone or in combination with one or more other drugs depending on the disease to be treated.
  • examples of such drugs include the following.
  • Antihypertensive drugs angiotensin converting enzyme inhibitors (enalapril maleate, imidapril hydrochloride, etc.), angiotensin II receptor antagonists (losartan potassium, candesartan cilexetil, etc.), ⁇ -blockers (atenolol, bisoprolol fumarate, etc.), ⁇ / ⁇ blockers (such as carvedilol and labetalol hydrochloride), calcium antagonists (such as amlodipine besylate and diltiazem hydrochloride), ⁇ 1 blockers (such as doxazosin mesylate and prazosin hydrochloride), central ⁇ 2 agonists, and other central effects Drugs (clonidine hydrochloride, reserpine, etc.), vasodilators (hydralazine hydrochloride, minoxidil, etc.), etc .; (B) Diuretics: thiazide di
  • Chemotherapeutic agents antimetabolites (5-fluorouracil, methotrexate, etc.), anticancer drugs (vincristine, taxol, cisplatin, etc.);
  • Immunomodulators immunosuppressants (cyclosporine, tacrolimus, etc.), immune enhancers (crestin, lentinan, etc.), cytokines (interleukin 1, interferon, etc.), cyclooxygenase inhibitors (indomethacin, celecoxib, etc.), anti-TNF ⁇ Antibodies (such as infliximab).
  • the administration form includes (1) administration of a single preparation (mixture) containing the compound [I] and another drug, and (2) The combined administration of a preparation containing compound [I] and a preparation containing other drugs can be mentioned. In the case of the combined administration of (2), the administration route and administration time of each preparation may be different. (Synthesis method 1) Among the compounds [I] of the present invention, the following general formula [Ia]:
  • the reaction between the compound [II-a] and the amine compound [III-a] can be carried out in a solvent in the presence of a palladium catalyst and a base, and if necessary, in the presence of a ligand.
  • the solvent may be any inert solvent that does not interfere with the reaction. Examples of such solvents include ethers such as dioxane and dimethoxyethane, aromatic hydrocarbons such as toluene, and N, N-dimethylformamide. Such amides, water and the like.
  • Examples of the palladium catalyst include palladium acetate, tris (dibenzylideneacetone) dipalladium, dichlorobis (triphenylphosphine) palladium, tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium dichloride.
  • Examples of the ligand include 2- (ditert-butylphosphino) biphenyl, triphenylphosphine, 2- (ditert-butylphosphino) -1,1′-binaphthyl, and 2-dicyclohexylphosphino-2 ′.
  • the amount of the palladium catalyst to be used is 0.01 to 0.3 equivalent, preferably 0.01 to 0.1 equivalent, relative to compound [II-a] or compound [III-a].
  • the amount of the base used is 1.0 to 5.0 equivalents, preferably 2.0 to 3.0 equivalents, relative to compound [II-a] or compound [III-a].
  • the amount of the ligand used is 0.01 to 0.3 equivalent, preferably 0.01 to 0.1 equivalent, relative to compound [II-a] or compound [III-a]. This reaction can be carried out at 0 to 200 ° C., preferably 60 to 150 ° C.
  • reaction of the compound [II-a] and the amine compound [III-a] can also be carried out by reacting in a solvent (alcohol such as isopropanol) in the presence of an acid catalyst (hydrochloric acid or the like).
  • a solvent such as isopropanol
  • an acid catalyst hydroochloric acid or the like.
  • the amount of the acid catalyst used can be 0.01 to 1.0 equivalent relative to compound [II-a].
  • reaction between the compound [II-a] and the amine compound [III-a] is carried out by using a base (an alkali metal alkoxide such as sodium tert-butoxide) in a solvent (an ether such as dioxane, an alcohol such as ethanol),
  • a base an alkali metal alkoxide such as sodium tert-butoxide
  • a solvent an ether such as dioxane, an alcohol such as ethanol
  • the reaction can also be carried out in the presence of a tertiary amine such as diisopropylethylamine.
  • the amount of the base used can be 1.0 to 3.0 equivalents relative to compound [II-a].
  • W 1 represents a halogen atom, and other symbols have the same meaning as described above.
  • It can also manufacture by making the compound shown by react.
  • the reaction of compound [II-a] and compound [III-c] can be carried out in a solvent in the presence of a base.
  • the solvent may be any inert solvent that does not interfere with the reaction. Examples of such solvents include ethers such as dimethyl sulfoxide and tetrahydrofuran, amides such as N, N-dimethylformamide, and ketones such as acetone. Etc. Examples of the base include potassium carbonate, cesium carbonate, sodium carbonate, sodium hydride and the like.
  • the amount of compound [III-c] to be used is 0.9 to 3.0 equivalents, preferably 1.0 to 1.5 equivalents, relative to compound [II-a].
  • the amount of the base to be used is 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, relative to compound [II-a] or compound [III-c].
  • This reaction can be carried out at 0 ° C. to 200 ° C., preferably 60 ° C. to 100 ° C. (Synthesis Method 4)
  • R 1 is an acyl group represented by the formula: R 11 OCO—, that is, the following general formula [Ie]:
  • the reaction of compound [II-c] or a salt thereof (such as a mineral salt such as hydrochloride) and compound [III-e] can be carried out in a solvent in the presence of a base.
  • the solvent may be any inert solvent that does not interfere with the reaction.
  • solvents include halogenated aliphatic hydrocarbons such as dichloromethane, ethers such as tetrahydrofuran, and aromatic hydrocarbons such as toluene. And the like.
  • the base include triethylamine, diisopropylethylamine, pyridine and the like.
  • the amount of compound [III-e] to be used is 0.9 to 3.0 equivalents, preferably 1.0 to 1.5 equivalents, relative to compound [II-c].
  • the amount of the base used is 1.0 to 5.0 equivalents, preferably 1.5 to 2.0 equivalents, relative to compound [II-c] or compound [III-e].
  • This reaction can be carried out at 0 ° C. to 100 ° C., preferably 0 ° C. to room temperature.
  • R 31 is a protected hydroxyl group
  • the protecting group can be removed in the same manner as described in Synthesis Method 1.
  • R 1 is represented by the following formula:
  • ring B 1 represents a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms which are the same or different and are selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom
  • the heteroaryl group may be substituted with 1 to 3 groups selected from a halogen atom, an alkyl group optionally substituted with 1 to 3 halogen atoms, and an alkoxy group)
  • X 4 represents a halogen atom or a methanesulfonyl group, and other symbols have the same meaning as described above. ] It can manufacture by making the compound shown by react.
  • the reaction of compound [II-c] or a salt thereof (mineral salt such as hydrochloride) and compound [III-g] can be carried out in a solvent in the presence or absence of a base.
  • the solvent may be any inert solvent that does not interfere with the reaction.
  • the solvent include amides such as dimethylformamide, ethers such as tetrahydrofuran, and the like.
  • the base include diisopropylethylamine, triethylamine, pyridine, potassium carbonate and the like.
  • the amount of compound [III-g] to be used is 1.0 to 10 equivalents, preferably 1.5 to 3.0 equivalents, relative to compound [II-c].
  • the amount of the base to be used is 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, relative to compound [II-c] or compound [III-g]. This reaction can be carried out at 0 ° C. to 150 ° C., preferably at room temperature to 80 ° C.
  • reaction of compound [II-c] or a salt thereof and compound [III-g] can also be carried out in a solvent in the presence of a palladium catalyst and a base and in the presence or absence of an activator.
  • a palladium catalyst and base those exemplified in Synthesis Scheme 1 (reaction of compound [II-a] with amine compound [III-a]) can be used.
  • the activator include 1,3-bis (2,6-diisopropylphenyl) -4,5-dihydroimidazolium tetrafluoroboric acid.
  • the amount of compound [III-g] to be used is 1.0 to 3.0 equivalents, preferably 1.0 to 1.5 equivalents, relative to compound [II-c].
  • the amount of the palladium catalyst to be used is 0.01 to 0.3 equivalent, preferably 0.01 to 0.1 equivalent, relative to compound [II-c] or compound [III-g].
  • the amount of the base used is 1.0 to 5.0 equivalents, preferably 2.0 to 4.0 equivalents, relative to compound [II-c] or compound [III-g]. This reaction can be carried out at 0 to 200 ° C., preferably 100 to 150 ° C. (Synthesis Method 6)
  • ring A is represented by the following formula:
  • the 6-membered aromatic ring A 1 is one or two groups selected from a halogen atom, an alkyl group and a cyano group in addition to the group represented by the formula: —CONR a R b
  • the reaction of compound [II-d] or a salt thereof (such as a mineral salt such as hydrochloride) and amine compound [III-i] or a salt thereof (such as a mineral salt such as hydrochloride) It can be carried out in the presence, in the presence or absence of a base and an activator.
  • the solvent may be an inert solvent that does not interfere with the reaction. Examples of such a solvent include halogenated aliphatic hydrocarbons such as dichloromethane.
  • Examples of the condensing agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC ⁇ HCl).
  • the activator include N-hydroxybenzotriazole monohydrate.
  • Examples of the base include triethylamine, diisopropylethylamine and the like.
  • the amount of compound [III-i] to be used is 1.0 to 5.0 equivalents, preferably 1.0 to 1.5 equivalents, relative to compound [II-d].
  • the amount of the condensing agent to be used is 1.0 to 5.0 equivalents, preferably 1.0 to 1.5 equivalents, relative to compound [II-d] or compound [III-i].
  • the amount of the activator used is 1.0 to 5.0 equivalents, preferably 1.0 to 1.5 equivalents, relative to compound [II-d] or compound [III-i].
  • the amount of the base used is 1.0 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, relative to compound [II-d] or compound [III-i]. This reaction can be carried out at 0 to 100 ° C., preferably 0 to 40 ° C. (Synthesis Method 7) Among the compounds [I] of the present invention, the following formula [Il]:
  • R a1 represents an alkyl group or a trihalogenoalkyl group, and other symbols have the same meaning as described above.
  • an appropriate protecting group may be introduced into the hydroxyl group prior to carrying out the above reactions.
  • the hydroxyl-protecting group include a benzoyl group.
  • the removal of the protecting group can be carried out according to a conventional method.
  • the removal of the protecting group can be carried out by a base treatment such as sodium tert-butoxide.
  • ring A in the intermediate compounds in the above synthesis methods 1 to 7 is a benzene ring substituted with a group containing a hydroxyl group (for example, a hydroxyalkyl group)
  • the hydroxyl group is converted to an appropriate protecting group (for example, tert- It may be protected with a butyldimethylsilyl group or the like, and the protecting group can be removed by a conventional method (tetrabutylammonium fluoride treatment or the like).
  • an appropriate protecting group for example, tert- It may be protected with a butyldimethylsilyl group or the like, and the protecting group can be removed by a conventional method (tetrabutylammonium fluoride treatment or the like).
  • R m represents an alkyl group or a cycloalkyl group which may be substituted with 1 to 3 halogen atoms, and other symbols have the same meaning as described above.
  • R m represents an alkyl group or a cycloalkyl group which may be substituted with 1 to 3 halogen atoms, and other symbols have the same meaning as described above.
  • an acid catalyst a protonic acid such as p-toluenesulfonic acid, Lewis such as zinc chloride
  • the amount of the acid catalyst to be used can be 0.001 to 1.0 equivalent relative to compound [II-r].
  • a compound having a substituent containing a formula: alkylsulfinyl group on ring A is a solvent (such as dichloromethane) having a corresponding compound having a substituent containing formula: alkylthio group on ring A.
  • a solvent such as dichloromethane
  • an oxidizing agent m-chloroperbenzoic acid, etc.
  • acid methanesulfonic acid, trifluoroacetic acid, etc.
  • halogenated aliphatic hydrocarbons alcohols such as methanol, etc.
  • the compound (R a R b NC ( ⁇ O) —) on the ring A is a group containing a carboxyalkyl group, the corresponding substituent is an alkoxycarbonylalkyl group. It can be prepared by treating the compound as the containing group with a base (such as sodium hydroxide) or an acid (such as hydrochloric acid-dioxane) in a solvent (such as ethers such as tetrahydrofuran).
  • a base such as sodium hydroxide
  • an acid such as hydrochloric acid-dioxane
  • solvent such as ethers such as tetrahydrofuran
  • a compound in which the substituent on ring A is an amino group or a group containing an amino group is an amino group in which the corresponding substituent is substituted with an alkoxycarbonyl group (protecting group) or It can also be prepared by treating a compound which is a group containing a substituted amino group with hydrochloric acid or the like to remove the protecting group.
  • R 1 is a group containing a group represented by the formula: —CONR c R d , and both R c and R d are bonded to each other to form 1 to 2 halogen atoms
  • the compound which forms a 3- to 7-membered nitrogen-containing aliphatic heterocyclic group which may be substituted with a corresponding compound in which R 1 is a group containing —COOH and the following formula: HNR c R d [b] [Wherein the symbols have the same meaning as described above.
  • the compound in which the substituent on the ring A is a hydroxymethyl group or a group containing a hydroxymethyl group is, for example, a group in which the substituent on A contains an alkoxycarbonyl group or an alkoxycarbonyl group.
  • ring A is represented by the following formula:
  • R 02 is formula (iii):
  • R n represents an alkyl group, an alkoxycarbonyl group, a hydroxyalkyl group, or a carbamoyl group, and other symbols have the same meaning as described above.
  • a dehydrating agent such as N, N-diethylaminosulfur trifluoride (DAST)
  • DAST N, N-diethylaminosulfur trifluoride
  • solvent such as halogenated aliphatic hydrocarbons such as dichloromethane
  • the compound in which the substituent on the ring A is a group containing a carbamoyl group includes, for example, a corresponding compound in which the substituent on A is a group containing an alkoxycarbonyl group in a solvent (tetrahydrofuran In such ethers), the reaction product and ammonia can be treated in the same manner as in Synthesis Method 6 after treatment with a base (sodium hydroxide, etc.).
  • a base sodium hydroxide, etc.
  • Compound [II-a], compound [II-b], compound [II-c] and compound [II-d], which are synthetic intermediates in the present invention, can be produced, for example, according to the following synthesis method.
  • R 21 represents a halogen atom
  • X 1 represents a halogen atom
  • other symbols have the same meaning as described above.
  • the reaction of compound [1a] and a halogenating agent can be carried out in a solvent in the presence or absence of an acid.
  • the solvent may be any inert solvent that does not interfere with the reaction. Examples of such a solvent include nitriles such as acetonitrile, halogenated aliphatic hydrocarbons such as dichloromethane, and the like.
  • halogenating agent examples include N-fluoro-N ′-(chloromethyl) triethylenediamine bis (tetrafluoroborate), N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide and the like.
  • acid examples include acetic acid and the like.
  • the reaction of compound [2a] and compound [3a] can be carried out in a solvent in the presence of a trisubstituted phosphine such as triphenylphosphine and an additive such as diethyl azodicarboxylate.
  • the solvent may be any inert solvent that does not interfere with the reaction. Examples of such a solvent include ethers such as tetrahydrofuran, aromatic hydrocarbons such as toluene, and the like.
  • Compound [II-b] can be produced, for example, according to the following reaction synthesis method 19.
  • reaction of compound [1b] or a salt thereof (hydrochloride, etc.) and compound [2b] can be carried out in a solvent such as dichloromethane in the presence of a base such as triethylamine.
  • reaction of compound [3b] and aminoacetaldehyde diethyl acetal can be carried out in a solvent such as dichloromethane in the presence of an acid catalyst such as acetic acid, a base such as triethylamine and a borohydride compound such as sodium triacetoxyborohydride. .
  • reaction of compound [4b] and malononitrile can be carried out in a solvent such as dichloromethane in the presence of an additive such as p-toluenesulfonic acid.
  • reaction of compound [5b] and triethyl orthoformate can be carried out in a solvent such as acetonitrile in the presence of an acid catalyst such as acetic acid.
  • Conversion of compound [6b] to compound [7b] can be carried out by treating compound [6b] with ammonia in a solvent such as methanol.
  • the reaction of compound [7b] and the halogenating agent can be carried out in a solvent such as acetonitrile.
  • a solvent such as acetonitrile.
  • the halogenating agent include N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, bromine and the like.
  • Compound [II-c] can be produced, for example, according to the following reaction synthesis method 20.
  • the deacylation reaction of compound [Ie] can be carried out according to a conventional method depending on the kind of acyl group.
  • the removal of the acyl group from the compound [Ie] in which R 11 is a tert-butoxycarbonyl group can be carried out by treating the compound with hydrochloric acid / dioxane.
  • Compound [II-d] can be produced, for example, according to Synthesis Method 21 below.
  • Z 1 represents a protecting group for a carboxyl group, and other symbols have the same meaning as described above.
  • Examples of Z 1 in the compound [II-y] include an alkyl group such as a tert-butyl group and an aralkyl group such as a benzyl group.
  • Removal of the protecting group from compound [II-y] can be carried out by a conventional method.
  • removal of the protecting group from the compound [II-y] having a tert-butyl group as Z 1 can be carried out by treating the compound with hydrochloric acid / dioxane or the like in a solvent or without a solvent.
  • the compound is treated with osmium tetroxide and N-methylmorpholine oxide in a solvent (such as a mixture of nitriles such as acetonitrile and water) in the following formula [II-v]:
  • a protective group (Z 2 ) is further introduced into the hydroxyl group at the 3-position of the compound according to a conventional method.
  • halogen atom means a fluorine atom, chlorine atom, iodine atom or bromine atom
  • alkyl or alkoxy means 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. It means straight-chain or branched alkyl or alkoxy
  • cycloalkyl means cycloalkyl having 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms.
  • Alkylene means linear or branched alkylene having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms
  • alkanoyl means 2 to 8 carbon atoms, preferably 2 carbon atoms. Means up to 6 linear or branched alkanoyl.
  • Example 138 [4- [7- [1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] -5-fluoro-7H-pyrrolo [2,3-d] pyrimidin-4-ylamino] -3-fluoro Phenyl]-((R) -2-hydroxymethylpiperidin-1-yl) methanone (Compound 138A) and [(R) -1- [4- [7- [1- (5-ethylpyrimidin-2-yl) Preparation of piperidin-4-yl] -5-fluoro-7H-pyrrolo [2,3-d] pyrimidin-4-ylamino] -3-fluorobenzyl] piperidin-2-yl] methanol (Compound 138B)
  • Examples 203-215 The corresponding starting materials were treated in the same manner as in Example 173, to give compounds as shown in Tables 27 to 28 below.
  • Example 283 The corresponding starting compounds were treated in the same manner as in Example 146 to give the compounds as shown in Table 39 below.
  • Example 291 4- [7-[(3S, 4R) -1- (5-ethylpyrimidin-2-yl) -3-methylpiperidin-4-yl] -5-fluoro-7H-pyrrolo [2,3-d] pyrimidine -4-ylamino] -3-fluoro-N, N-dimethylbenzamide and 4- [7-[(3R, 4S) -1- (5-ethylpyrimidin-2-yl) -3-methylpiperidin-4-yl ] -5-Fluoro-7H-pyrrolo [2,3-d] pyrimidin-4-ylamino] -3-fluoro-N, N-dimethylbenzamide
  • Example 258 138 mg of the compound obtained in Example 258 was dissolved in 6 mL of ethanol, and optical resolution (x6 times) was performed using a chiral column under the following conditions, whereby the title compounds Compound A: 56 mg and Compound B: 55 mg were respectively white powder. (Yield 41%, 41%).
  • the reaction mixture was concentrated under reduced pressure, 3.5 mL of toluene, 184 ⁇ L of diisopropylethylamine, and 95 mg of 2-fluoro-2-methyl-propionic acid ethyl ester were added, and the mixture was stirred at 100 ° C. for 6 hours.
  • the reaction mixture was cooled to room temperature, 2 mL of tetrahydrofuran and 28 mg of sodium hydride were added, and the mixture was stirred at 70 ° C. for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform.
  • Example 294 4- [7-[(R) -1- [5- (1,1-difluoroethyl)-[1,2,4] oxadiazol-3-yl] pyrrolidin-3-ylmethyl] -5-fluoro- Preparation of 7H-pyrrolo [2,3-d] pyrimidin-4-ylamino] -3-fluoro-N, N-dimethylbenzamide
  • reaction solution was concentrated under reduced pressure, and O- (7-azabenzotriazol-1-yl) -N ′, N ′, N ′, N′-tetramethyluronium hexafluorophosphate (HATU) 608 mg, 2,2-difluoro 106 mg of propionic acid, 8 mL of dimethylformamide and 557 ⁇ L of diisopropylethylamine were added, and the mixture was stirred at 100 ° C. for 6 hours.
  • the reaction mixture was cooled to room temperature, tetrahydrofuran (2 mL) and sodium hydride (28 mg) were added, and the mixture was stirred at room temperature for 24 hours.
  • Benzoic acid cis-1- (5-ethylpyrimidin-2-yl) -4-hydroxypiperidin-3-yl ester 1.08 g, 4-chloro-5-fluoro-7H-pyrrolo [2,3-d] pyrimidine 0
  • a solution of diethyl azodicarboxylate-toluene (2.2 mol / L, 2.25 mL) was added dropwise to a solution of .62 g and 1.30 g of triphenylphosphine in 50 mL of tetrahydrofuran under ice-cooling, and the mixture was stirred overnight at room temperature.
  • the reaction mixture was poured into water and extracted with ethyl acetate.
  • Example 183 The compound obtained in Example 183 was treated in the same manner as in Reference Example 4, and then the obtained compound was treated with a saturated aqueous sodium hydrogen carbonate solution to obtain the title compound.
  • Experimental example 1 The purpose of this experiment is to evaluate the GPR119 agonist activity (in vitro) of these compounds by adding a sample compound to human GPR119-expressing CHO cells and measuring the amount of cAMP produced by the cells.
  • CHO cells expressing human GPR119 (L8-18) are luciferase expression vector pLG3-CRE6-CRE-VIP (in accordance with a known method (The Journal of Biological Chemistry Vol. 274 (34), pp. 23940-23947)). It was prepared by introducing the expression vector pMSF1-GPR119 (Geneticin resistance) carrying the human GPR119 gene into CHO cells (LM-3; Mock cells) into which Hygromycin B resistance) was introduced.
  • the cryopreserved L8-18 cells were thawed, suspended in 9 times the assay buffer, and centrifuged (1000 rpm, 5 minutes) at room temperature. After removing the supernatant, the precipitated cells were resuspended in 4 mL of assay buffer, and IBMX (Sigma, # 17018-1G) -containing assay buffer was added thereto to add 7.5 ⁇ 10 4 cells / mL. Cell suspension was prepared.
  • the cell suspension was allowed to stand at room temperature for 15 minutes, and then 20 ⁇ L of the cell suspension and 5 ⁇ L of the sample compound solution or AR231453 solution (25 ⁇ L / total) were added to each well of a 96 half well white plate (Corning, # 3693). well) (final concentration: 1500 cells / mL, 500 ⁇ M IBMX, 1% dimethyl sulfoxide). After incubating the mixture at 37 ° C. for 30 minutes, 20-fold dilutions (12.5 ⁇ L / well each) of cAMP-d2 and Anti cAMP-Cryptate from the HTRF cAMP kit (Cisbio, # 62AM4PEC) were added to each well. did.
  • Blood collection from the test mice is performed immediately before drug administration ( ⁇ 60 min), immediately before glucose load (0 min), 30 minutes after glucose load (30 min), 60 minutes (60 min), and 120 minutes (120 min). It was.
  • the blood glucose level at each time point was measured using Glucose CII-Test Wako (manufactured by Wako Pure Chemical Industries), and AUC (0-120 min) in each administration group was calculated based on the measured value, and SAS 9.1. Tested with Student's t-Test using 3 (SAS Institute, Inc.).
  • Table 48 shows the blood glucose elevation-inhibiting action of each sample compound (value of the ratio of AUC (0-120 min) in the sample administration group when the AUC (0-120 min) in the control group is 100).
  • “*” and “**” have the following meanings. *: P ⁇ 0.05 **: P ⁇ 0.01
  • Blood collection from the test mice is performed immediately before drug administration ( ⁇ 60 min), immediately before glucose load (0 min), 30 minutes after glucose load (30 min), 60 minutes (60 min), and 120 minutes (120 min). It was.
  • the blood glucose level at each time point was measured using Glucose CII-Test Wako (manufactured by Wako Pure Chemical Industries), AUC (0-120 min) in each administration group was calculated based on the measured value, and SAS 9.1. 3 (SAS Institute, Inc.) was used for Student's t-test.
  • the compound [I] of the present invention or a pharmacologically acceptable salt thereof has an agonistic action on the GPR119 receptor
  • various diseases or conditions that can be expected to be improved by regulating the receptor activity such as obesity Metabolic diseases including diseases such as hyperglycemia, diabetes and its complications, metabolic syndrome, impaired glucose tolerance, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia and lipid metabolism disorders, or It is useful as a medicament for the prevention and treatment of cardiovascular diseases such as arteriosclerosis, hypertension, coronary disease, myocardial infarction.

Abstract

La présente invention concerne un nouveau composé de pyrrolo[2,3-d]pyrimidine qui possède une activité agoniste du récepteur GPR119 et qui est utile en tant que médicament. L'invention concerne spécifiquement un composé représenté par la formule [I] ou l'un de ses sels pharmacologiquement acceptables. Dans la formule [I], E représente -NH- ou analogues; A représente un cycle benzène substitué représenté par la formule (A-i), ou analogues; R01A et R01B peuvent être identiques ou différents et représentent chacun un atome d'hydrogène, d'halogène, ou analogues; R02 représente un groupe alkylthio ou analogues; R03 représente un atome d'hydrogène ou un groupe alkyle; R04 représente un groupe alkyle ou analogues; R05 représente un groupe alkylsulfonyle; Q représente une liaison simple ou un groupe alkylène; R0 représente un groupe cyclique représenté par la formule (R-iii), ou analogues; R1 représente un groupe acyle représenté par la formule : R11OCO- [où R11 représente un groupe alkyle qui peut être substitué par un à trois atomes d'halogène], ou analogues; R2 représente un atome d'halogène; et R3 représente un atome d'hydrogène ou analogues.
PCT/JP2011/061625 2010-05-21 2011-05-20 Nouveau composé de pyrrolo[2,3-d]pyrimidine WO2011145718A1 (fr)

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WO2012170867A1 (fr) 2011-06-09 2012-12-13 Rhizen Pharmaceuticals Sa Nouveaux composes utilises comme modulateurs de gpr-119
WO2013130890A1 (fr) * 2012-02-29 2013-09-06 Amgen Inc. Composés hétérobicycliques et leur utilisation en tant qu'inhibiteurs de la phosphodiestérase
WO2014011926A1 (fr) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comportant des statines, des biguanides et d'autres agents pour réduire un risque cardiométabolique
US20160002252A1 (en) * 2013-03-15 2016-01-07 Northwestern University SUBSTITUTED PYRROLO[2,3-d]PYRIMIDINES FOR THE TREATMENT OF CANCER AND PROLIFERATIVE DISORDERS
JP2016538296A (ja) * 2013-11-26 2016-12-08 チョン クン ダン ファーマシューティカル コーポレーション Ｇｐｒ１１９アゴニストとしてのアミド誘導体
US9944600B2 (en) 2012-06-12 2018-04-17 Chong Kun Dang Pharmaceutical Corp. Piperidine derivatives for GPR119 agonist
CN115677704A (zh) * 2021-07-30 2023-02-03 山东大学 含有7H-吡咯并[2,3-d]嘧啶结构的组蛋白去乙酰化酶6抑制剂及制备方法和应用

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WO2010009207A1 (fr) * 2008-07-16 2010-01-21 Schering Corporation Dérivés hétérocycliques bicycliques et leur utilisation comme modulateurs de gpcr
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WO2012170867A1 (fr) 2011-06-09 2012-12-13 Rhizen Pharmaceuticals Sa Nouveaux composes utilises comme modulateurs de gpr-119
WO2013130890A1 (fr) * 2012-02-29 2013-09-06 Amgen Inc. Composés hétérobicycliques et leur utilisation en tant qu'inhibiteurs de la phosphodiestérase
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WO2014011926A1 (fr) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comportant des statines, des biguanides et d'autres agents pour réduire un risque cardiométabolique
US20160002252A1 (en) * 2013-03-15 2016-01-07 Northwestern University SUBSTITUTED PYRROLO[2,3-d]PYRIMIDINES FOR THE TREATMENT OF CANCER AND PROLIFERATIVE DISORDERS
US9981968B2 (en) * 2013-03-15 2018-05-29 Northwestern University Substituted pyrrolo[2,3-d]pyrimidines for the treatment of cancer and proliferative disorders
JP2016538296A (ja) * 2013-11-26 2016-12-08 チョン クン ダン ファーマシューティカル コーポレーション Ｇｐｒ１１９アゴニストとしてのアミド誘導体
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CN115677704A (zh) * 2021-07-30 2023-02-03 山东大学 含有7H-吡咯并[2,3-d]嘧啶结构的组蛋白去乙酰化酶6抑制剂及制备方法和应用
CN115677704B (zh) * 2021-07-30 2023-12-05 山东大学 含有7H-吡咯并[2,3-d]嘧啶结构的组蛋白去乙酰化酶6抑制剂及制备方法和应用

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