WO2012115479A2 - Dérivés de diaminopyrimidine et leurs procédés de préparation - Google Patents

Dérivés de diaminopyrimidine et leurs procédés de préparation Download PDF

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Publication number
WO2012115479A2
WO2012115479A2 PCT/KR2012/001425 KR2012001425W WO2012115479A2 WO 2012115479 A2 WO2012115479 A2 WO 2012115479A2 KR 2012001425 W KR2012001425 W KR 2012001425W WO 2012115479 A2 WO2012115479 A2 WO 2012115479A2
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Prior art keywords
diamine
diethyl
propylpyrimidine
diethylamino
ylamino
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PCT/KR2012/001425
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WO2012115479A3 (fr
Inventor
Jae-Young Sim
Myung-Hun Cha
Tae-Kyun Kim
Hyun-Joo Lee
Young-Ae Yoon
Dong-Hoon Kim
Hee-Jeong AHN
Tai-Au Lee
Kyoung-Kyu AHN
Kwan-Hoon HYUN
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Yuhan Corp
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Yuhan Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms

Definitions

  • the present invention relates to a novel 5-HT 4 receptor agonist, more specifically a novel diaminopyrimidine derivative or its pharmaceutically acceptable salt having an activity as a 5-HT 4 receptor agonist, a process for the preparation thereof, a pharmaceutical composition comprising the same, and a use thereof.
  • Serotonin (5-hydroxytryptamine, 5-HT), one of the neurotransmitters, is broadly distributed throughout human body including both the central nervous system and the peripheral nervous system. Approximately 95% of the human body's total serotonin is found in the gastrointestinal tract, while about 5% thereof is found in the brain. Serotonin receptors are located in intestinal nerves, enterochromaffin cells, intestinal smooth muscle, immune tissues, etc. Serotonin receptor subtypes include 5-HT 1 , 5-HT 2 , 5-HT 3 , 5-HT 4 , 5-HT 5 , 5-HT 6 , and 5-HT 7 . Interactions between these various receptors and serotonin are linked to various physiological functions.
  • 5-HT 4 receptor agonists are useful for treating an abnormal gastrointestinal motility, i.e., dysfunction in gastrointestinal motility.
  • the abnormal gastrointestinal motility may result in various disorders, for example irritable bowel syndrome (IBS), constipation, dyspepsia, delayed gastric emptying, gastroesophageal reflux disease (GERD), gastroparesis, post-operative ileus, intestinal pseudo-obstruction, drug-induced delayed transit, etc.
  • 5-HT 4 receptor agonists disclosed in prior arts include tegaserod (an aminoguanidine derivative, US5,510,353), prucalopride (a benzofuran carboxamide derivative, EP0445862), cisapride (a benzamide derivative, US4,962,115), mosapride (EP0243959), etc. These compounds are known as an agent stimulating gastrointestinal motility.
  • the present inventors found that a certain diaminopyrimidine derivative functions as a 5-HT 4 receptor agonist, and therefore can be usefully applied for preventing or treating dysfunction in gastrointestinal motility.
  • the present invention provides the above diaminopyrimidine derivative or its pharmaceutically acceptable salt, a process for the preparation thereof, a pharmaceutical composition comprising the same, and a use thereof.
  • a diaminopyrimidine derivative or its pharmaceutically acceptable salt for the manufacture of a medicament for preventing or treating a dysfunction in gastrointestinal motility
  • a pharmaceutical composition for preventing or treating a dysfunction in gastrointestinal motility comprising a diaminopyrimidine derivative or its pharmaceutically acceptable salt as an active ingredient.
  • the compound of the present invention i.e., the diaminopyrimidine derivative or its pharmaceutically acceptable salt, functions as a 5-HT 4 receptor agonist, and therefore can be usefully applied for preventing or treating dysfunction in gastrointestinal motility, one of the gastrointestinal diseases, such as gastroesophageal reflux disease (GERD), constipation, irritable bowel syndrome (IBS), dyspepsia, post-operative ileus, delayed gastric emptying, gastroparesis, intestinal pseudo-obstruction, drug-induced delayed transit, or diabetic gastric atony.
  • gastroesophageal reflux disease GUD
  • constipation constipation
  • IBS irritable bowel syndrome
  • dyspepsia post-operative ileus
  • delayed gastric emptying gastroparesis
  • intestinal pseudo-obstruction drug-induced delayed transit
  • alkyl refers to a straight or branched aliphatic hydrocarbon radical.
  • C 1 -C 6 alkyl means a straight or branched aliphatic hydrocarbon having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, n -butyl, n -pentyl, n -hexyl, isopropyl, isobutyl, sec -butyl, tert -butyl, neopentyl, and isopentyl.
  • alkoxy or alkyloxy refers to a radical formed by substituting the hydrogen atom of a hydroxyl group with an alkyl.
  • C 1 -C 6 alkoxy includes methoxy, ethoxy, propoxy, n -butoxy, n -pentyloxy, isopropoxy, sec -butoxy, tert -butoxy, neopentyloxy, and isopentyloxy.
  • alkenyl refers to a straight or branched aliphatic hydrocarbon radical having one or more double bond(s).
  • C 2 -C 6 alkenyl includes ethenyl, propenyl, butenyl, pentenyl, and hexenyl.
  • alkynyl refers to a straight or branched aliphatic hydrocarbon radical having one or more triple bond(s).
  • C 2 -C 6 alkynyl includes ethynyl, propynyl, butynyl, pentynyl, and hexynyl.
  • the present invention provides a use of a compound of Formula 1 or its pharmaceutically acceptable salt for the manufacture of a medicament for preventing or treating a dysfunction in gastrointestinal motility:
  • R 1 is a phenyl group substituted with one or more substituents selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, hydroxycarbonyl, C 1-5 alkyl (where the C 1-5 alkyl is optionally substituted with one or more halogens), C 2-6 alkenyl, C 2-6 alkynyl, C 1-5 alkoxy (where the C 1-5 alkoxy is optionally substituted with one or more halogens), C 1-5 alkylthio, mono or di-C 1-5 alkylamino, C 1-5 alkylsulfonylamino, C 1-5 alkylcarbonylamino, C 1-5 alkoxycarbonyl, aminosulfonyl, aminocarbonyl, and benzyloxycarbonylamino; or
  • heteroaryl group selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, thiophenyl, naphthyl, indanyl, quinolinyl, quinolinonyl, chromenonyl, dihydroindolonyl, isoindoline-1,3-dionyl, dihydrobenzoimidazolonyl, benzoxazolonyl, benzofuranyl, benzothiophenyl, benzo[ d ][1,3]dioxolyl, dihydrobenzo[1,4]dioxinyl, indolyl, indolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, and indazolyl, wherein the heteroary
  • R 2 and R 3 are, independently of each other, a C 1-5 alkyl group optionally substituted with hydroxy or C 1-5 alkoxy, and
  • R 4 is a C 1-5 alkyl group optionally substituted with phenyl; or a C 2-6 alkenyl group optionally substituted with phenyl or C 3-6 cycloalkyl.
  • the dysfunction in gastrointestinal motility includes gastrointestinal diseases, such as gastroesophageal reflux disease (GERD), constipation, irritable bowel syndrome (IBS), dyspepsia, post-operative ileus, delayed gastric emptying, gastroparesis, intestinal pseudo-obstruction, drug-induced delayed transit, or diabetic gastric atony.
  • the constipation includes chronic constipation, chronic idiopathic constipation (CIC), opioid-induced constipation (OIC), etc.
  • the dyspepsia includes functional dyspepsia.
  • the compound or its salt may be the compound of Formula 1 or its pharmaceutically acceptable salt, wherein R 2 and R 3 is an ethyl group.
  • the present invention also provides a pharmaceutical composition for preventing or treating a dysfunction in gastrointestinal motility comprising a therapeutically effective amount of a compound of Formula 1 or its pharmaceutically acceptable salt; and a pharmaceutically acceptable carrier:
  • R 1 is a phenyl group substituted with one or more substituents selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, hydroxycarbonyl, C 1-5 alkyl (where the C 1-5 alkyl is optionally substituted with one or more halogens), C 2-6 alkenyl, C 2-6 alkynyl, C 1-5 alkoxy (where the C 1-5 alkoxy is optionally substituted with one or more halogens), C 1-5 alkylthio, mono or di-C 1-5 alkylamino, C 1-5 alkylsulfonylamino, C 1-5 alkylcarbonylamino, C 1-5 alkoxycarbonyl, aminosulfonyl, aminocarbonyl, and benzyloxycarbonylamino; or
  • heteroaryl group selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, thiophenyl, naphthyl, indanyl, quinolinyl, quinolinonyl, chromenonyl, dihydroindolonyl, isoindoline-1,3-dionyl, dihydrobenzoimidazolonyl, benzoxazolonyl, benzofuranyl, benzothiophenyl, benzo[ d ][1,3]dioxolyl, dihydrobenzo[1,4]dioxinyl, indolyl, indolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, and indazolyl, wherein the heteroary
  • R 2 and R 3 are, independently of each other, a C 1-5 alkyl group optionally substituted with hydroxy or C 1-5 alkoxy, and
  • R 4 is a C 1-5 alkyl group optionally substituted with phenyl; or a C 2-6 alkenyl group optionally substituted with phenyl or C 3-6 cycloalkyl.
  • the dysfunction in gastrointestinal motility includes gastrointestinal diseases, such as gastroesophageal reflux disease (GERD), constipation, irritable bowel syndrome (IBS), dyspepsia, post-operative ileus, delayed gastric emptying, gastroparesis, intestinal pseudo-obstruction, drug-induced delayed transit, or diabetic gastric atony.
  • the constipation includes chronic constipation, chronic idiopathic constipation (CIC), opioid-induced constipation (OIC), etc.
  • the dyspepsia includes functional dyspepsia.
  • the compound or its salt may be the compound of Formula 1 or its pharmaceutically acceptable salt, wherein R 2 and R 3 is an ethyl group.
  • the pharmaceutical composition of the present invention may comprise a pharmaceutically acceptable carrier, such as diluents, disintegrants, sweeteners, lubricants, or flavoring agents.
  • a pharmaceutically acceptable carrier such as diluents, disintegrants, sweeteners, lubricants, or flavoring agents.
  • the pharmaceutical composition may be formulated to an oral dosage form such as tablets, capsules, powders, granules, suspensions, emulsions, or syrups; or a parenteral dosage form such as injection.
  • the dosage form may be various forms, e.g., dosage forms for single administration or for multiple administrations.
  • the pharmaceutical composition of the present invention may comprise, for example, a diluent (e.g., lactose, corn starch, etc); a lubricant (e.g., magnesium stearate); an emulsifying agent; a suspending agent; a stabilizer; and/or an isotonic agent. If necessary, the composition further comprises sweeteners and/or flavoring agents.
  • composition of the present invention may be administered orally or parenterally, including intravenous, intraperitoneal, subcutaneous, rectal and topical routes of administration. Therefore, the composition of the present invention may be formulated into various forms such as tablets, capsules, aqueous solutions or suspensions.
  • carriers such as lactose, corn starch, and lubricating agents, e.g. magnesium stearate, are conventionally used.
  • lactose and/or dried corn starch can be used as a diluent.
  • the active ingredient may be combined with emulsifying and/or suspending agents.
  • composition of the present invention may be in the form of an aqueous solution containing pharmaceutically acceptable carriers, e.g., saline having a pH level of 7.4.
  • pharmaceutically acceptable carriers e.g., saline having a pH level of 7.4.
  • the solutions may be introduced into a patient's intramuscular blood-stream by local bolus injection.
  • the compound of Formula 1 or its pharmaceutically acceptable salt may be administered in a therapeutically effective amount ranging from about 0.001 mg/kg to about 10 mg/kg per day to a subject patient.
  • the dosage may be changed according to the patient's age, weight, susceptibility, symptom, or activity of the compound.
  • the present invention also provides a method for treating a dysfunction in gastrointestinal motility, such as gastroesophageal reflux disease (GERD), constipation, irritable bowel syndrome (IBS), dyspepsia, post-operative ileus, delayed gastric emptying, gastroparesis, intestinal pseudo-obstruction, drug-induced delayed transit, or diabetic gastric atony, in a patient, which comprises administering a therapeutically effective amount of the compound of Formula 1 or its pharmaceutically acceptable salt to the patient in need thereof.
  • the constipation includes chronic constipation, chronic idiopathic constipation (CIC), opioid-induced constipation (OIC), etc.
  • the dyspepsia includes functional dyspepsia.
  • the present invention also provides a compound of Formula 1 or its pharmaceutically acceptable salt:
  • R 1 is a phenyl group substituted with one or more substituents selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, hydroxycarbonyl, C 1-5 alkyl (where the C 1-5 alkyl is optionally substituted with one or more halogens), C 2-6 alkenyl, C 2-6 alkynyl, C 1-5 alkoxy (where the C 1-5 alkoxy is optionally substituted with one or more halogens), C 1-5 alkylthio, mono or di-C 1-5 alkylamino, C 1-5 alkylsulfonylamino, C 1-5 alkylcarbonylamino, C 1-5 alkoxycarbonyl, aminosulfonyl, aminocarbonyl, and benzyloxycarbonylamino; or
  • heteroaryl group selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, thiophenyl, naphthyl, indanyl, quinolinyl, quinolinonyl, chromenonyl, dihydroindolonyl, isoindoline-1,3-dionyl, dihydrobenzoimidazolonyl, benzoxazolonyl, benzofuranyl, benzothiophenyl, benzo[ d ][1,3]dioxolyl, dihydrobenzo[1,4]dioxinyl, indolyl, indolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, and indazolyl, wherein the heteroary
  • R 2 and R 3 are, independently of each other, a C 2-5 alkyl group optionally substituted with hydroxy or C 1-5 alkoxy, and
  • R 4 is a C 2-5 alkyl group optionally substituted with phenyl; or a C 2-6 alkenyl group optionally substituted with phenyl or C 3-6 cycloalkyl.
  • the compound or its salt may be the compound of Formula 1 or its pharmaceutically acceptable salt, wherein R 2 and R 3 is an ethyl group.
  • the compound of Formula 1 or its pharmaceutically acceptable salt may have substituents containing asymmetric carbon and therefore be in the form of racemic mixture (RS) or in forms of optical isomers, such as (R) or (S) isomer.
  • the compound of Formula 1 or its pharmaceutically acceptable salt comprises both racemic mixture (RS) and optical isomers such as (R) or (S) isomer.
  • the compound of Formula 1 or its pharmaceutically acceptable salt may be in the form of cis- or trans- geometrical isomer, according to substituents having e.g., the double bond therein.
  • the compound of Formula 1 or its pharmaceutically acceptable salt comprises both cis- and trans- geometrical isomers.
  • the compound of Formula 1 or its pharmaceutically acceptable salt may be in the form of one or more diastereomic isomer(s) or a mixture thereof.
  • the compound of Formula 1 or its pharmaceutically acceptable salt comprises both diastereomic isomer(s) and a mixture thereof.
  • the compound of Formula 1 of the present invention may be in a pharmaceutically acceptable salt form.
  • the salt may be an acid addition salt form, which includes e.g., salts derived from an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfonic acid, sulfamic acid, phosphoric acid, or nitric acid; and salts derived from an organic acid such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, citric acid, maleic acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, benzenesulfonic acid, oxalic acid or trifluoroacetic acid.
  • the salt may be prepared by reacting
  • more preferable compounds include a compound (or its pharmaceutically acceptable salt) selected from the group consisting of:
  • the pharmaceutical composition, the treatment method, and the compound according to the present invention still more preferable compounds in terms of pharmacological activity include the compound (or its pharmaceutically acceptable salt) described in Table 2.
  • the present invention includes, within its scope, a process for preparing a compound of Formula 1 or its pharmaceutically acceptable salt, which comprises reacting a compound of Formula 2 with a compound of Formula 3 to obtain a compound of Formula 4; performing a methylation of the compound of Formula 4 to obtain a compound of Formula 5; reacting the compound of Formula 5 with R 1 -NH 2 to obtain a compound of Formula 6; performing a halogenation of the compound of Formula 6 to obtain a compound of Formula 7; and reacting the compound of Formula 7 with R 2 R 3 -NH to obtain a compound of Formula 1:
  • R 1 , R 2 , R 3 , and R 4 are the same as defined in the above; and X is halogen.
  • the compounds of Formula 2 and 3 are commercially available.
  • the reaction between the compound of Formula 2 and the compound of Formula 3 may be performed in the presence of a base and a solvent.
  • the base may be potassium carbonate, sodium carbonate, etc.
  • the solvent may be an aqueous solvent such as water. Typically, the reaction may be carried out under heating.
  • the methylation of the compound of Formula 4 may be carried out using a methylating agent such as iodomethane.
  • the methylation may be performed in the presence of a base and a solvent.
  • the base may be sodium hydroxide, potassium hydroxide, etc and the solvent may be an aqueous solvent such as water.
  • the methylation may be carried out at room temperature or under heating.
  • the reaction between the compound of Formula 5 and R 1 -NH 2 may be performed in the absence of a solvent or in the presence of a solvent such as diglyme.
  • the reaction may be carried out at a temperature ranging from 140°C to 180°C.
  • the halogenation of the compound of Formula 6 may be carried out using a halogenating agent such as phosphorus oxychloride.
  • the halogenation may be performed preferably at a temperature of about 100°C or higher.
  • the halogenation may be performed in the presence of N,N -dimethylaniline or N,N -dimethylformamide in a catalytic amount.
  • the reaction between the compound of Formula 7 and R 2 R 3 -NH may be performed in the presence of an organic solvent, such as anhydrous tetrahydrofuran, and alcohol. Typically, the reaction may be carried out under heating. And also, for improving reaction rate and/or yield, the reaction may be performed in the presence of a base such as triethylamine and diisopropylethylamine; or performed under microwave ranging from 300W to 600W.
  • an organic solvent such as anhydrous tetrahydrofuran, and alcohol.
  • the reaction may be carried out under heating.
  • a base such as triethylamine and diisopropylethylamine; or performed under microwave ranging from 300W to 600W.
  • the compound of Formula 6 may be also prepared by reacting a compound of Formula 2 with a compound of Formula 8:
  • R 1 and R 4 are the same as defined in the above.
  • the compound of Formula 8 may be easily prepared by using known methods, e.g., EP0560726.
  • the reaction between the compound of Formula 2 and the compound of Formula 8 may be performed in the presence of a base and a solvent.
  • the base may be sodium methoxide, sodium ethoxide, etc and the solvent may be an alcohol. Typically, the reaction may be carried out under heating.
  • the present invention also provides a process for preparing a compound of Formula 1 or its pharmaceutically acceptable salt, which comprises performing a halogenation of a compound of Formula 4 to obtain a compound of Formula 9; reacting the compound of Formula 9 with R 2 R 3 -NH to obtain a compound of Formula 10; and reacting the compound of Formula 10 with R 1 -NH 2 to obtain a compound of Formula 1:
  • R 1 , R 2 , R 3 , and R 4 are the same as defined in the above; and X is halogen.
  • the halogenation of the compound of Formula 4 may be carried out using a halogenating agent such as phosphorus oxychloride.
  • the halogenation may be performed preferably at a temperature of about 100°C or higher.
  • the halogenations may be performed in the presence of N,N -dimethylaniline or N,N -dimethylformamide in a catalytic amount.
  • the reaction between the compound of Formula 9 and R 2 R 3 -NH may be performed in the presence of an organic solvent, such as anhydrous tetrahydrofuran, alcohol, chloroform, dichloromethane or N,N -dimethylformamide.
  • an organic solvent such as anhydrous tetrahydrofuran, alcohol, chloroform, dichloromethane or N,N -dimethylformamide.
  • the reaction may be carried out at room temperature or under heating.
  • the reaction may be performed in the presence of a base such as triethylamine and diisopropylethylamine.
  • the reaction between the compound of Formula 10 and R 1 -NH 2 may be performed in the presence of an organic solvent such as alcohol, toluene, 1,4-dioxane, and N,N -dimethylformamide.
  • the reaction may be carried out under heating.
  • the reaction may be performed in the presence of a metallic catalyst (e.g., palladium), a ligand, and a base (e.g., cesium carbonate); or performed under microwave ranging from 300W to 600W.
  • the compound of Formula 9 may be also prepared by reacting a compound of Formula 11 with R 4 -Q:
  • R 4 and X are the same as defined in the above; and Q is MgX, boronic acid (B(OH) 2 ) or boronic acid pinacol ester.
  • the compound of Formula 11 is commercially available.
  • the reaction between the compound of Formula 11 and R 4 -Q may be performed in the presence of an organic solvent such as anhydrous tetrahydrofuran, N -methylpyrrolidine, and 1,4-dioxane.
  • the reaction may be carried out at room temperature or under heating.
  • the reaction may be performed preferably in the presence of a metallic catalyst (e.g., palladium, iron, etc), a ligand, and a base (e.g., potassium phosphate).
  • a metallic catalyst e.g., palladium, iron, etc
  • a ligand e.g., potassium phosphate
  • the present invention provides a process for preparing a compound of Formula 1 or its pharmaceutically acceptable salt, which comprises reacting a compound of Formula 12 with R 2 R 3 -NH to obtain a compound of Formula 13; performing a oxidation of the compound of Formula 13 to obtain a compound of Formula 14; reacting the compound of Formula 14 with R 1 -NH 2 to obtain a compound of Formula 15; and reacting the compound of Formula 15 with R 4 -Q to obtain a compound of Formula 1:
  • R 1 , R 2 , R 3 , and R 4 are the same as defined in the above;
  • X is halogen; and
  • Q is MgX, boronic acid (B(OH) 2 ), or boronic acid pinacol ester.
  • the compound of Formula 12 is commercially available.
  • the reaction between the compound of Formula 12 and R 2 R 3 -NH may be performed in the presence of an organic solvent, such as anhydrous tetrahydrofuran. Typically, the reaction may be carried out at room temperature or under heating.
  • the oxidation of the compound of Formula 13 may be carried out using an organic or inorganic oxidizing agent, such as oxone.
  • the oxidation may be performed in an organic solvent (e.g., alcohol) at low temperature.
  • the reaction between the compound of Formula 14 and R 1 -NH 2 may be performed in the presence of a solvent such as anhydrous toluene and alcohol. Typically, the reaction may be carried out under heating. And also, for improving reaction rate and/or yield, the reaction may be performed under microwave ranging from 300W to 600W.
  • a solvent such as anhydrous toluene and alcohol.
  • the reaction may be carried out under heating.
  • the reaction between the compound of Formula 15 and R 4 -Q may be performed in the presence of an organic solvent (e.g., anhydrous 1,4-dioxane) at room temperature or under heating. And also, the reaction may be performed preferably in the presence of a metallic catalyst (e.g., palladium, etc), a ligand, and a base (e.g., potassium phosphate). And also, for improving reaction rate and/or yield, the reaction may be performed under microwave ranging from 300W to 600W.
  • an organic solvent e.g., anhydrous 1,4-dioxane
  • a metallic catalyst e.g., palladium, etc
  • a ligand e.g., potassium phosphate
  • a base e.g., potassium phosphate
  • 6-Nitroindole 200 mg, 1.23 mmol was dissolved in anhydrous N,N -dimethylformamide (2 ml), and then 60% sodium hydride (71 mg, 1.85 mmol) and iodomethane (92 ⁇ l, 1.48mmol) were added thereto at 0°C.
  • the titled compound (150 mg) was prepared in accordance with the same procedures as in Preparation 2, using 6-nitroindole and iodoethane. The product was used in the subsequent reaction without further purification.
  • the titled compound (150 mg) in the form of pale yellow solid was prepared in accordance with the same procedures as in Preparation 4, using 5-nitro-1 H -benzo[ d ]imidazole. The product was used in the subsequent reaction without further purification.
  • the titled compound (1.5 g) in the form of pale yellow solid was prepared in accordance with the same procedures as in Preparation 4, using 2,3-dimethyl-5-nitrobenzofuran prepared in Step 2. The product was used in the subsequent reaction without further purification.
  • the titled compound in the form of yellow oil was prepared in accordance with the same procedures as in Preparation 10, using N,N -dimethyl-3-nitroaniline (Yield: 81 %).
  • the titled compound in the form of yellow solid was prepared in accordance with the same procedures as in Preparation 10, using 5-nitroanthranilonitrile (Yield: 98 %).
  • reaction mixture was cooled to room temperature, added to a 1N hydrochloric acid solution, and then extracted with ethyl acetate.
  • the organic layer was washed with water and brine, dried on anhydrous sodium sulfate, and then concentrated under reduced pressure.
  • the titled compound (8.2 g) was prepared in accordance with the same procedures as in Step 1 of Preparation 9, using ethyl acetoacetate (10 g, 76.8 mmol), N -(4-fluorophenyl)guanidine (10.7 g, 69.8 mmol) and sodium methoxide (4.2 g, 7.18 mmol). The product was used in the subsequent step.
  • the titled compound (4.5 g) in the form of white solid was prepared in accordance with the same procedures as in Step 2 of Preparation 9, using 2-(4-fluorophenylamino)-6-methylpyrimidin-4-ol (8.2 g, 37.4 mmol) prepared in Step 1 and phosphorus oxychloride (15.9 ml, 172.0 mmol).
  • the titled compound was prepared in accordance with the same procedures as in Step 1 of Preparation 15, using 2,4,6-trichloropyrimidine and allyl boronic acid pinacol ester. The product was used in the subsequent reaction without further purification.
  • the titled compound was prepared in accordance with the same procedures as in Step 2 of Preparation 15, using 4-allyl-2,6-dichloropyrimidine prepared in Step 1 and diethylamine. The product was used in the subsequent reaction without further purification.
  • the titled compound was prepared in accordance with the same procedures as in Step 1 of Preparation 17, using 2,4,6-trichloropyrimidine and 2.0M solution of phenethylmagnesium bromide in diethyl ether. The product was used in the subsequent reaction without further purification.
  • the titled compound (110 mg) in the form of colorless oil was prepared in accordance with the same procedures as in Step 2 of Preparation 17, using 2,4-dichloro-6-phenethylpyrimidine prepared in Step 1 and diethylamine.
  • the titled compound was prepared in accordance with the same procedures as in Step 1 of Preparation 17, using 2,4,6-trichloropyrimidine and 1.0M solution of ethylmagnesium bromide in tetrahydrofuran. The product was used in the subsequent reaction without further purification.
  • the titled compound (145 mg) in the form of colorless oil was prepared in accordance with the same procedures as in Step 2 of Preparation 17, using 2,4-dichloro-6-ethylpyrimidine prepared in Step 1 and diethylamine.
  • the titled compound was prepared in accordance with the same procedures as in Step 1 of Preparation 17, using 2,4,6-trichloropyrimidine and 2.0M solution of isopropylmagnesium chloride in tetrahydrofuran. The product was used in the subsequent reaction without further purification.
  • the titled compound (75 mg) in the form of colorless oil was prepared in accordance with the same procedures as in Step 2 of Preparation 17, using 2,4-dichloro-6-isopropylpyrimidine prepared in Step 1 and diethylamine.
  • the titled compound was prepared in accordance with the same procedures as in Step 1 of Preparation 17, using 2,4,6-trichloropyrimidine and 2.0M solution of butylmagnesium chloride in tetrahydrofuran. The product was used in the subsequent reaction without further purification.
  • the titled compound (42 mg) in the form of colorless oil was prepared in accordance with the same procedures as in Step 2 of Preparation 17, using 4-butyl-2,6-dichloropyrimidine prepared in Step 1 and diethylamine.
  • the titled compound was prepared in accordance with the same procedures as in Step 1 of Preparation 17, using 2,4,6-trichloropyrimidine and 1.0M solution of benzylmagnesium bromide in diethyl ether. The product was used in the subsequent reaction without further purification.
  • the titled compound (90 mg) in the form of colorless oil was prepared in accordance with the same procedures as in Step 2 of Preparation 17, using 4-benzyl-2,6-dichloropyrimidine prepared in Step 1 and diethylamine.
  • the titled compound was prepared in accordance with the same procedures as in Step 1 of Preparation 17, using 2,4,6-trichloropyrimidine and 2.0M solution of pentylmagnesium chloride in tetrahydrofuran. The product was used in the subsequent reaction without further purification.
  • the titled compound was prepared in accordance with the same procedures as in Step 2 of Preparation 17, using 2,4-dichloro-6-pentylpyrimidine prepared in Step 1 and diethylamine. The product was used in the subsequent reaction without further purification.
  • Examples 2 to 34 were prepared in accordance with the same procedures as in Example 1, using 2-chloro- N,N -diethyl-6-propylpyrimidine-4-amine prepared in Preparation 1; and 4-aminobenzonitrile, 3-fluoroaniline, 3-(methylthio)aniline, 3-chloroaniline, 2,5-dichloro-1,4-phenylenediamine, o -anisidine, 3-methoxyaniline, 3-aminobenzonitrile, 4-chloroaniline, p -nitroaniline, 2-fluoro-5-methylaniline, 2-fluoro-4-methylaniline, 5-fluoro-2-methylaniline, 3-fluoro-4-methylaniline, 4-chloro-3-nitroaniline, 3-methoxy-5-(trifluoromethyl)aniline, 5-methoxy-2-methylaniline, 6-chloro-3-methoxyaniline hydrochloride, 3-chloro-2-methylaniline, 2-amino-3-nitrophenol, 5-
  • 2-Aminopyridine (17 mg, 0.18 mmol) was added to a solution of 2-chloro- N,N -diethyl-6-propylpyrimidine-4-amine (40 mg, 0.18 mmol) prepared in Preparation 1, palladium(II) acetate(0.8 mg, 2 mol%), 4,5-bis(diphenylphosphino)-9,9-dimethyl-xanthene (3.1 mg, 3 mol%), and cesium carbonate (117 mg, 0.36 mmol) in anhydrous 1,4-dioxane (1 ml), which was then stirred at microwave (600 W) for 1 hour.
  • Examples 36 to 70 were prepared in accordance with the same procedures as in Example 35, using 2-chloro- N,N -diethyl-6-propylpyrimidine-4-amine prepared in Preparation 1; and 3-aminopyridine, 4-aminopyridine, 2-aminopyrazine, 3-aminoquinoline, 4-aminopyrimidine, 2,3,4-trifluoroaniline, 2,6-difluoroaniline, 4-chloro-2-fluoroaniline, 2-amino-4-methylbenzonitrile, 2-aminobenzonitrile, 4-fluoro-2-methylaniline, 2-methyl-3-nitroaniline, 2-amino-3-picoline, 4-(methylthio)aniline, 2,5-difluoroaniline, 4-bromoaniline, 2-amino-5-methylthiazole, 2-amino-5-chloropyridine, 6-aminoindole, 5-amino-2-methoxypyridine, 2-amino-4-chlorobenz
  • the titled compound (254 mg) in the form of pale yellow solid was prepared in accordance with the same procedures as in Example 35, using 2-chloro- N,N -diethyl-6-propylpyrimidine-4-amine prepared in Preparation 1 and 3-aminobenzonitrile.
  • the product (77 mg) in the form of pale yellow solid was prepared in accordance with the same procedures as in Example 71, using 2-chloro- N,N -diethyl-6-propylpyrimidine-4-amine prepared in Preparation 1 and 4-chloro-3-nitroaniline.
  • Examples 74 to 95 were prepared in accordance with the same procedures as in Example 73, using 2-chloro- N,N -diethyl-6-propylpyrimidine-4-amine prepared in Preparation 1; and 6-aminoindazole, 5-amino-2-(trifluoromethyl)benzimidazole, 5-aminoindole, 6-aminobenzothiazole, 7-amino-2-methyl-4 H -chromen-4-one, 5-amino-2-methylbenzothiazole dihydrochloride, 7-amino-4-methylcoumarin, 4-aminoindole, 2-methoxy-5-nitroaniline, 2,5-dimethoxyaniline, 4-amino-2-nitrophenol, 3-nitro-1,2-phenylenediamine, 2-nitro-1,4-phenylenediamine, 4-nitro-3-(trifluoromethyl)aniline, (5-amino-2-methoxyphenyl)-carbamic acid benzyl ester, m -toluid
  • the product (25.8 mg) in the form of pale yellow oil was prepared in accordance with the same procedures as in Example 73, using 2-chloro- N,N -diethyl-6-propylpyrimidine-4-amine prepared in Preparation 1 and 2,3-dimethylbenzofuran-5-amine prepared in Preparation 6.
  • the titled compound (300 mg) in the form of pale yellow solid was prepared in accordance with the same procedures as in Example 73, using 2-chloro- N,N -diethyl-6-propylpyrimidine-4-amine prepared in Preparation 1 and 6-aminoindole.
  • the titled compound (295 mg) in the form of pale yellow solid was prepared in accordance with the same procedures as in Step 2 of Example 71, using N 4 , N 4 -diethyl- N 2 -(1 H -indol-6-yl)-6-propylpyrimidine-2,4-diamine in Step 1.
  • N 4 , N 4 -Diethyl- N 2 -(1 H -indol-6-yl)-6-propylpyrimidine-2,4-diamine (30 mg, 0.09 mmol) prepared in Example 54 was dissolved in anhydrous N,N -dimethylformamide (1 ml).
  • 60 wt% Sodium hydride (5.4 mg, 0.14 mmol) and 1-iodo-2-methylpropane (16 ⁇ l, 0.14 mmol) were added at 0°C to the reaction mixture, which was then stirred at room temperature overnight. Water was added to the reaction mixture and then extracted with ethyl acetate.
  • N 4 , N 4 -Diethyl- N 2 -(4-fluoro-3-nitrophenyl)-6-propylpyrimidine-2,4-diamine (20 mg, 0.06 mmol) prepared in Example 62 was dissolved in methanol (2 ml) and then palladium/charcoal (25 mg, 10 wt%) was added thereto.
  • the reaction mixture was stirred at room temperature under hydrogen atmosphere (30 bar) for 3 hours and then filtered through a celite pad. The resulting filtrate was concentrated under reduced pressure.
  • the product (8.0 mg) in the form of pale yellow oil was prepared in accordance with the same procedures as in Example 104, using N 4 , N 4 -diethyl- N 2 -(4-methyl-3-nitrophenyl)-6-propylpyrimidine-2,4-diamine prepared in Example 65.
  • Examples 110 to 115 were prepared in accordance with the same procedures as in Example 109, using 4-chloro- N -(4-fluorophenyl)-6-propylpyrimidine-2-amine prepared in Preparation 7; and dimethylamine, dipropylamine, N -ethylbutylamine, 2-(methylamino)ethanol, bis(2-methoxyethyl)amine, or N -(2-methoxyethyl)ethylamine.
  • the product in the form of pale yellow oil was prepared in accordance with the same procedures as in Example 109, using 4-butyl-6-chloro- N -(4-fluorophenyl)pyrimidine-2-amine prepared in Preparation 8 and diethylamine.
  • N 4 , N 4 -Diethyl- N 2 -(4-fluorophenyl)-6-propylpyrimidine-2,4-diamine (20 mg, 0.08 mmol) prepared in Example 109 was dissolved in ethyl acetate (1 ml) and then hydrogen chloride gas was added thereto. The reaction mixture was stirred at room temperature for 1 hour and then filtered to give 10 mg of the product as a white solid.
  • Examples 120 to 137 were prepared in accordance with the same procedures as in Example 73, using 2-chloro- N,N -diethyl-6-propylpyrimidine-4-amine prepared in Preparation 1; and 4-aminophthalonitrile, 5-amino-2-fluorobenzonitrile, 3'-aminoacetanilide, 5-amino-2-methylbenzonitrile, 3'-amino-4'-methoxyacetanilide, 4-amino- N -methylphthalimide, N -(3-aminophenyl)methanesulfonamide, 7-amino-4-(trifluoromethyl)coumarin, 7-amino-4-methylquinolin-2(1 H )-one, 3-(difluoromethoxy)aniline, 3-(trifluoromethoxy)aniline, p -toluidine, 4-aminophenol hydrochloride, 2-(trifluoromethyl)-1,4-phenylenedi
  • the product in the form of pale yellow oil was prepared in accordance with the same procedures as in Example 73, using 2-chloro- N,N -diethyl-6-propylpyrimidine-4-amine prepared in Preparation 1 and 5-amino-1 H -benzo[ d ]imidazol-2(3 H )-one prepared in Preparation 10.
  • the product in the form of pale yellow oil was prepared in accordance with the same procedures as in Example 73, using 2-chloro- N,N -diethyl-6-propylpyrimidine-4-amine prepared in Preparation 1 and N 1 ,N 1 - dimethylbenzene-1,3-diamine prepared in Preparation 11.
  • the product in the form of pale yellow oil was prepared in accordance with the same procedures as in Example 73, using 2-chloro- N,N -diethyl-6-propylpyrimidine-4-amine prepared in Preparation 1 and 2,5-diaminobenzonitrile prepared in Preparation 12.
  • the titled compound (150 mg) in the form of red oil was prepared in accordance with the same procedures as in Example 73, using 2-chloro- N,N -diethyl-6-propylpyrimidine-4-amine prepared in Preparation 1 and 6-aminoindolin-2-one prepared in Preparation 13. The product was used in the subsequent step without further purification.
  • 6-(4-Diethylamino-6-propylpyrimidin-2-ylamino)indolin-2-one (20 mg, 0.05 mmol) prepared in Step 1 was dissolved in ethyl acetate (1 ml) and hydrogen chloride gas was added thereto to give 5 mg of the titled compound as a pale red solid.
  • Example 147 The product in the form of yellow oil was prepared in accordance with the same procedures as in Example 146, using N 2 -(4-dimethylamino-3-nitrophenyl)- N 4 ,N 4 - diethyl-6-propylpyrimidine-2,4-diamine prepared in Example 147.
  • Examples 150 to 152 were prepared in accordance with the same procedures as in Example 149, using 4-chloro- N -(4-fluorophenyl)-6-methylpyrimidine-2-amine prepared in Preparation 14; and a 2.0M solution of dimethylamine in tetrahydrofuran, N -methylbutylamine, or diisobutylamine.
  • Examples 154 and 155 were prepared in accordance with the same procedures as in Example 153, using 4-chloro- N -(4-fluorophenyl)-6-methylpyrimidine-2-amine prepared in Preparation 14; and dipropylamine or diisopropylamine.
  • Examples 157 to 159 were prepared in accordance with the same procedures as in Example 156, using ( E )-2-chloro- N,N -diethyl-6-styrylpyrimidine-4-amine prepared in Preparation 15; and 3-nitroaniline, 4-chloro-3-nitroaniline, or 3-aminobenzonitrile.
  • Examples 160 and 161 were prepared in accordance with the same procedures as in Example 156, using 6-allyl-2-chloro- N,N -diethylpyrimidine-4-amine prepared in Preparation 16; and 4-fluoroaniline or 3-aminobenzonitrile.
  • Examples 162 to 164 were prepared in accordance with the same procedures as in Example 156, using 2-chloro- N,N -diethyl-6-isobutylpyrimidine-4-amine prepared in Preparation 17; and 4-fluoroaniline, 4-fluoro-3-nitroaniline, or 3-aminobenzonitrile.
  • Examples 165 to 168 were prepared in accordance with the same procedures as in Example 156, using 2-chloro- N,N -diethyl-6-phenethylpyrimidine-4-amine prepared in Preparation 18; and 3-nitroaniline, 4-chloro-3-nitroaniline, 4-fluoro-3-nitroaniline, or 2-chloro-4-aminotoluene.
  • Examples 169 to 171 were prepared in accordance with the same procedures as in Example 156, using 2-chloro- N,N ,6-triethylpyrimidine-4-amine prepared in Preparation 19; and 3-aminobenzonitrile, 3-nitroaniline, or 4-chloro-3-nitroaniline.
  • Examples 172 to 175 were prepared in accordance with the same procedures as in Example 156, using 2-chloro- N,N -diethyl-6-isopropylpyrimidine-4-amine prepared in Preparation 20; and 3-aminobenzonitrile, 3-nitroaniline, 4-chloro-3-nitroaniline, or 4-fluoroaniline.
  • Examples 176 to 178 were prepared in accordance with the same procedures as in Example 156, using 6-butyl-2-chloro- N,N -diethylpyrimidine-4-amine prepared in Preparation 21; and 3-aminobenzonitrile, 3-nitroaniline, or 4-chloro-3-nitroaniline.
  • Examples 179 to 182 were prepared in accordance with the same procedures as in Example 156, using 6-benzyl-2-chloro -N,N- diethylpyrimidine-4-amine prepared in Preparation 22; and 3-aminobenzonitrile, 3-nitroaniline, 4-chloro-3-nitroaniline, or 4-fluoroaniline.
  • the product was prepared in accordance with the same procedures as in Example 156, using 2-chloro- N,N -diethyl-6-pentylpyrimidine-4-amine prepared in Preparation 23 and 4-fluoroaniline.
  • Example 157 The product was prepared in accordance with the same procedures as in Example 184, using ( E )- N 4 ,N 4 -diethyl- N 2 -(3-nitrophenyl)-6-styrylpyrimidine-2,4-diamine prepared in Example 157.
  • Example 158 The product was prepared in accordance with the same procedures as in Example 184, using ( E )- N 2 -(4-chloro-3-nitrophenyl)- N 4 ,N 4 -diethyl-6-styrylpyrimidine-2,4-diamine prepared in Example 158.
  • Example 167 The product was prepared in accordance with the same procedures as in Example 184, using N 4 , N 4 -diethyl- N 2 -(4-fluoro-3-nitrophenyl)-6-phenethylpyrimidine-2,4-diamine prepared in Example 167.
  • Example 184 The product was prepared in accordance with the same procedures as in Example 184, using N 4 , N 4 ,6-triethyl- N 2 -(3-nitrophenyl)pyrimidine-2,4-diamine prepared in Example 170.
  • Example 171 The product was prepared in accordance with the same procedures as in Example 184, using N 2 -(4-chloro-3-nitrophenyl)- N 4 , N 4 ,6-triethylpyrimidine-2,4-diamine prepared in Example 171.
  • Example 173 The product was prepared in accordance with the same procedures as in Example 184, using N 4 , N 4 -diethyl-6-isopropyl- N 2 -(3-nitrophenyl)pyrimidine-2,4-diamine prepared in Example 173.
  • Example 177 The product was prepared in accordance with the same procedures as in Example 184, using 6-butyl- N 4 , N 4 -diethyl- N 2 -(3-nitrophenyl)pyrimidine-2,4-diamine prepared in Example 177.
  • Example 178 The product was prepared in accordance with the same procedures as in Example 184, using 6-butyl- N 2 -(4-chloro-3-nitrophenyl)- N 4 , N 4 -diethylpyrimidine-2,4-diamine prepared in Example 178.
  • Example 180 The product was prepared in accordance with the same procedures as in Example 184, using 6-benzyl- N 4 , N 4 -diethyl- N 2 -(3-nitrophenyl)pyrimidine-2,4-diamine prepared in Example 180.
  • Example 181 The product was prepared in accordance with the same procedures as in Example 184, using 6-benzyl- N 2 -(4-chloro-3-nitrophenyl)- N 4 , N 4 -diethylpyrimidine-2,4-diamine prepared in Example 181.
  • the product was prepared in accordance with the same procedures as in Example 196, using 6-chloro- N 4 , N 4 -diethyl- N 2 -(4-fluorophenyl)pyrimidine-2,4-diamine prepared in Preparation 24 and trans-2-cyclopropylvinyl boronic acid.
  • Test Example 1 Evaluation of agonistic activity in CHO-K1 cells expressing human 5-HT 4(a)
  • CHO-K1 cells stably expressing human 5-HT 4(a) we used the GeneBlAzer HTR4-CRE-bla CHO-K1 cells (Invitrogen Corp.). The cells were cultured, under the condition of 37 °C and 5 % CO 2 , in a DMEM supplemented with 10 % fetal bovine serum (FBS), 25 mM HEPES (pH7.4), 600 ⁇ g/ml hygromycin B, 0.1 mM non-essential amino acids, 100 unit/ml penicillin and 100 ⁇ g/ml streptomycin. Subcultures were performed three times per one week, each being at less than 80% confluence.
  • FBS fetal bovine serum
  • HEPES 25 mM HEPES
  • 0.1 mM non-essential amino acids 100 unit/ml penicillin and 100 ⁇ g/ml streptomycin.
  • the cells were collected using 0.5% trypsin/EDTA and then diluted with a DMEM supplemented with 1 % FBS, 25 mM HEPES, and 0.1 mM non-essential amino acids into 3.125 x 10 5 cells/ml. 32 ⁇ l of the diluted cells were added into 384-well plate (10 4 cells per well) and then incubated overnight. After the overnight culture, 8 ⁇ l of the medium having 1% of DMSO was added into the cell-free control well and the non-stimulating control well, respectively.
  • Example EC 50 (nM) Example EC 50 (nM) 9 0.24 147 0.22 16 0.31 161 0.35 54 0.04 163 0.4 65 0.11 164 0.43 72 0.34 169 0.45 86 0.029 171 0.48 99 0.11 176 0.12 101 0.071 178 0.32 104 0.039 179 0.16 105 0.19 180 0.3 107 0.38 181 0.38 121 0.136 190 0.031 123 0.076 193 0.03 133 0.2 194 0.22 140 0.076 195 0.092 142 0.22
  • the compounds of the present invention have excellent activities as a 5-HT 4 receptor agonist, and therefore they can be usefully applied for preventing or treating the dysfunction in gastrointestinal motility.

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Abstract

La présente invention concerne un dérivé de diaminopyrimidine ou son sel pharmaceutiquement acceptable, son procédé de préparation, une composition pharmaceutique le comprenant, et son utilisation. Ledit dérivé de diaminopyrimidine ou son sel pharmaceutiquement acceptable fonctionne en tant qu'agoniste du récepteur 5-HT4, et peut donc être appliqué utilement dans la prévention ou le traitement d'un dysfonctionnement de la motilité gastrointestinale, l'une des maladies gastrointestinales, telles que le reflux gastro-œsophagien pathologique (GERD), la constipation, le syndrome du côlon irritable (IBS), la dyspepsie, l'occlusion intestinale postopératoire, la vidange gastrique retardée, la gastroparésie, la pseudo-occlusion intestinale, le transit retardé d'origine médicamenteuse, ou l'atonie gastrique diabétique.
PCT/KR2012/001425 2011-02-25 2012-02-24 Dérivés de diaminopyrimidine et leurs procédés de préparation Ceased WO2012115479A2 (fr)

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WO2014174745A1 (fr) * 2013-04-26 2014-10-30 国立大学法人京都大学 INHIBITEUR D'Eg5
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WO2008104472A1 (fr) * 2007-02-28 2008-09-04 F. Hoffmann-La Roche Ag Dérivés de 2, 4 -diaminopyrimidine et utilisation de ces derniers comme antagonistes p2x ou comme promédicaments de ceux-ci

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JP2016520098A (ja) * 2013-05-24 2016-07-11 ユーハン・コーポレイションＹＵＨＡＮ Ｃｏｒｐｏｒａｔｉｏｎ ピリミジン環を含む二環式誘導体及びその製造方法
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JP2022081606A (ja) * 2016-04-15 2022-05-31 エピザイム，インコーポレイティド Ｅｈｍｔ１およびｅｈｍｔ２阻害剤としてのアミン置換アリールまたはヘテロアリール化合物
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US11672800B2 (en) 2017-04-21 2023-06-13 Epizyme, Inc. Combination therapies with EHMT2 inhibitors
US20200317642A1 (en) * 2017-10-17 2020-10-08 Epizyme, Inc. Amine-substituted heterocyclic compounds as ehmt2 inhibitors and derivatives thereof
EP3697419A4 (fr) * 2017-10-17 2021-08-18 Epizyme, Inc. Composés hétérocycliques à substitution amine utilisés comme inhibiteurs de l'ehmt2 et dérivés de ces derniers
JP2021534256A (ja) * 2018-08-27 2021-12-09 デウン ファーマシューティカル カンパニー リミテッドDaewoong Pharmaceutical Co., Ltd 新規なヘテロサイクリックアミン誘導体およびこれを含む薬学組成物
JP7162741B2 (ja) 2018-08-27 2022-10-28 デウン ファーマシューティカル カンパニー リミテッド 新規なヘテロサイクリックアミン誘導体およびこれを含む薬学組成物
US12227498B2 (en) 2018-08-27 2025-02-18 Daewoong Pharmaceutical Co., Ltd. Heterocyclic amine derivative and pharmaceutical composition comprising same

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