WO2010058858A1 - ５－ｈｔ２ｂ受容体拮抗活性を有する新規ピラゾール－３－カルボキサミド誘導体 - Google Patents

５－ｈｔ２ｂ受容体拮抗活性を有する新規ピラゾール－３－カルボキサミド誘導体 Download PDF

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WO2010058858A1
WO2010058858A1 PCT/JP2009/069816 JP2009069816W WO2010058858A1 WO 2010058858 A1 WO2010058858 A1 WO 2010058858A1 JP 2009069816 W JP2009069816 W JP 2009069816W WO 2010058858 A1 WO2010058858 A1 WO 2010058858A1
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methyl
ethyl
carboxamide
pyrazole
morpholin
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PCT/JP2009/069816
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English (en)
French (fr)
Japanese (ja)
Inventor
竜也 山岸
清 川村
義 井上
宍戸　祐二
啓晶 伊藤
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ラクオリア創薬株式会社
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Application filed by ラクオリア創薬株式会社 filed Critical ラクオリア創薬株式会社
Priority to ES09827639.7T priority Critical patent/ES2549005T3/es
Priority to RU2011125314/04A priority patent/RU2528406C2/ru
Priority to CN200980146558.8A priority patent/CN102224142B/zh
Priority to EP09827639.7A priority patent/EP2386546B1/en
Priority to US13/129,916 priority patent/US8252790B2/en
Priority to BRPI0921097A priority patent/BRPI0921097B8/pt
Priority to CA2741511A priority patent/CA2741511C/en
Priority to MX2011005221A priority patent/MX2011005221A/es
Priority to JP2010539267A priority patent/JP5621148B2/ja
Publication of WO2010058858A1 publication Critical patent/WO2010058858A1/ja
Priority to HK12103083.8A priority patent/HK1163063A1/xx

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Definitions

  • the present invention relates to a novel pyrazole-3-carboxamide derivative having 5-HT 2B receptor antagonistic activity.
  • the compound of the present invention is a compound useful as a selective antagonist of 5-HT 2B receptor, and is useful for prevention or treatment of various diseases in which this receptor is involved.
  • the present invention also relates to a pharmaceutical composition comprising the compound.
  • Serotonin (5-hydroxytryptamine) is a type of neurotransmitter that was first discovered in 1948 and is a type of tryptamine derivative that is distributed at high concentrations in the hypothalamus, basal ganglia, medullary raphe nucleus, and the like. Serotonin is a chemical substance generally contained in animals and plants including humans, and is biosynthesized from tryptophan. There are about 10 milligrams of serotonin in the human body, most of which is in chromaffin cells in the mucous membrane of the small intestine. The serotonin synthesized here acts on muscles such as the intestine and is greatly related to the movement of the digestive tract.
  • Serotonin is also present in the central nervous system and greatly affects human mental activity. The effects of serotonin are attracting attention from daily life to mental disorders such as depression and neurosis. In recent years, therapeutic agents for these diseases have been developed by using drugs that act on serotonin.
  • the serotonin receptor is a kind of G protein coupled receptor mainly in the central nervous system.
  • Serotonin (5-HT) receptors are classified into seven families, 5-HT 1 to 5-HT 7 , with a total of 14 subtypes recognized. Pharmacological research is underway for each subtype (Non-Patent Document 1).
  • the 5-HT 2 family includes three types of 5-HT 2A , 5-HT 2B and 5-HT 2C . It is known that subtypes exist.
  • the 5-HT 2B receptor various pharmacological actions have been reported, and it has been reported to be useful for treating or preventing various diseases.
  • 5-HT 2B receptor antagonist compounds are migraine, inflammatory pain, nociceptive pain, fibromyalgia, chronic low back pain, visceral pain, gastroesophageal reflux disease (GERD), constipation, diarrhea, functional gastrointestinal Diseases, irritable bowel syndrome (hereinafter abbreviated as IBS, definition and criteria are defined in Rome III, Non-Patent Document 2), asthma, osteoarthritis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, glomerulus Nephritis, nephritis, dermatitis, hepatitis, vasculitis, renal ischemia, stroke, myocardial infarction, cerebral ischemia, Alzheimer's disease, reversible airway obstruction, adult respiratory system syndrome, chronic obstructive pulmonary disease (COPD), pulmonary hypertension Useful for the treatment or prevention of various diseases, including symptom (PH), idiopathic interstitial pneumonia, bronchitis, liver fibrosis, liver
  • 5-HT 2B receptor As for the 5-HT 2B receptor, the relationship between the receptor and the digestive organs and pulmonary artery blood vessels is known from experiments using 5-HT 2B selective antagonist compounds. Regarding the role in the digestive system, it has been shown that 5-HT 2B antagonistic compounds are useful for irritable bowel syndrome since the contraction of human intestinal tissue by electrical stimulation was suppressed (Patent Document 1). There is a description that 5-HT 2B antagonistic compounds are effective in treating functional bowel disorders because the contraction of rat intestinal tissue induced by serotonin stimulation was suppressed (Patent Document 2).
  • TNBS 2,4,6-trinitrobenzenesulfonic acid
  • 5-HT 2B receptor is involved in the improvement of chronic hypoxic mouse model of pulmonary hypertension, and 5-HT 2B antagonistic compounds are effective in treating pulmonary hypertension.
  • Non-Patent Document 9 5-HT 2B selective antagonist compounds have a significant blood pressure lowering effect in a placebo-controlled double-blind initial phase 2 study in patients with pulmonary hypertension associated with chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • An object of the present invention is to provide a pharmaceutical or pharmaceutical composition containing, as an active ingredient, a compound having a 5-HT 2B receptor antagonistic action useful for the treatment or prevention of a disease state mediated by 5-HT 2B receptor stimulation. Is to provide. In addition, it exhibits high selective affinity for the 5-HT 2B receptor, and further reduces its involvement in other receptors as an antagonist compound, thereby reducing various undesirable effects involving the receptor. This is also an issue.
  • the inventors of the present invention have made extensive studies to solve the above-mentioned problems, and a novel 5-substituted-1H-pyrazole-3-carboxamide derivative having a specific unique chemical structure is a serotonin receptor subtype. It was found that the 5-HT 2B receptor has selective and strong antagonism. In addition, it was confirmed that the novel 5-substituted-1H-pyrazole-3-carboxamide derivatives of the present invention significantly improve the visceral pain threshold in the rat TNBS-induced IBS model.
  • the novel 5-substituted-1H-pyrazole-3-carboxamide derivatives of the present invention have migraine, inflammatory pain, nociceptive pain, fibromyalgia mediated by the aforementioned 5-HT 2B receptor stimulation, Chronic low back pain, visceral pain, gastroesophageal reflux disease (GERD), constipation, diarrhea, functional gastrointestinal disease, irritable bowel syndrome (IBS), asthma, osteoarthritis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, Glomerulonephritis, nephritis, dermatitis, hepatitis, vasculitis, renal ischemia, stroke, myocardial infarction, cerebral ischemia, Alzheimer's disease, reversible airway obstruction, adult respiratory system syndrome, chronic obstructive pulmonary disease (COPD), It is useful for the treatment or prevention of disease states such as pulmonary hypertension (PH), idiopathic interstitial pneumonia and bronchitis, liver fibro
  • 5-HT 2B comprising the following compound, or a pharmaceutically acceptable salt thereof, or the compound or a pharmacologically acceptable salt thereof as an active ingredient.
  • a compound represented by the following general formula (I 0 ) or a pharmaceutically acceptable salt thereof is as follows.
  • R 1 is a linear, branched, or cyclic lower alkyl group having 1 to 6 carbon atoms, or a linear, branched, or cyclic haloalkyl group having 1 to 6 carbon atoms
  • R 2 is a (hetero) aryl ring group represented by the following general formula (Ar)
  • R 3 is a hydrogen atom or a halogen atom
  • R 4 is a linear, branched or cyclic lower alkyl group having 1 to 6 carbon atoms, a linear, branched or cyclic haloalkyl group having 1 to 6 carbon atoms, OH, OR 1A , halogen,- (CH 2 ) aOH, CO 2 H, CONH 2 , CONHR 1A , CONR 1A R 1A , CN, COR 1A , NH 2 ,
  • R 4 when R 4 has two R 1A s , they may be the same or different, and in some cases, a bond between R 1A and another R 1A is possible;
  • R 5 is a linear, branched, or cyclic lower alkyl group having 1 to 6 carbon atoms, — (CH 2 ) aOH, — (CH 2 ) aOR 1B , halogen, CONH 2 , CONR 1B R 1B , COR 1B , SO 2 R 1B , —OCH 2 CH 2 NR 1B R 1B, or a linear, branched, or cyclic haloalkyl group having 1 to 6 carbon atoms, and when p is plural, R 5 is the same or different A bond between R 5 and another R 5 is also possible;
  • R 1A and R 1B are each independently a linear, branched, or cyclic lower alkyl group having 1 to 6 carbon atoms, or a linear, branched, or cyclic halo
  • W is an oxygen atom, (H, H), (H, R 5 ), or (R 5 , R when X is CH 2 , NH, O, CHR 5 , CR 5 R 5 , or NR 5. 5 ), and when X is S, SO, SO 2 , it represents (H, H), (H, R 5 ), or (R 5 , R 5 ).
  • W represents two monovalent groups, and the two monovalent groups are H, H, and H Means R 5 , or R 5 and R 5 ;
  • Y is NH, NR 1 , O, or S;
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 are each independently N, C, CH, or CR 4 (R 4 is the same as defined above, and 1 from Z 1 to Z 6 2 or 3 may represent a nitrogen atom).
  • Ring A is a 3- to 8-membered ring and may contain 0 to 4 heteroatoms selected from O, S, N;
  • R 1 is a C 1 -C 6 alkyl group, or a C 1 -C 6 haloalkyl group;
  • R 2 is a saturated or mono- or bicyclic aryl ring group that is partially or fully unsaturated, and may be substituted with the substituent R 4 ;
  • R 3 is a hydrogen atom or a halogen atom;
  • R 4 is a C 1 -C 6 alkyl group, a C 1 -C 6 haloalkyl group, OH, OR 1A , halogen, — (CH 2 ) aOH, CO 2 H, CONH 2 , CONHR 1A , CONR 1A R 1A , CN, COR 1A , NH 2 , NHR 1A , NR 1A R 1A , NHCOR 1A , SR 1A , SOR
  • R 4 when R 4 has two R 1A s , they may be the same or different, and in some cases, a bond between R 1A and another R 1A is possible;
  • R 5 is a C 1 -C 6 alkyl group, — (CH 2 ) aOH, — (CH 2 ) aOR 1B , halogen, CONH 2 , CONR 1B R 1B , COR 1B , SO 2 R 1B , —OCH 2 CH 2 NR 1B R 1B or a C 1 -C 6 haloalkyl group, and when p is plural, R 5 may be the same or different, and a bond between R 5 and another R 5 is also possible;
  • R 1A and R 1B are each independently a C 1 -C 6 alkyl group or a C 1 -C 6 haloalkyl group; a is 0, 1, or 2; n is 1 or 2; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, or 3.
  • R 2 is represented by the following general formula Ar 1 , Ar 2 , Ar 3 , or Ar 4 .
  • R 4 and q are as defined in the above [2];
  • Y is NH, NR 6 , O, or S;
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 are each independently N, C, CH, or CR 4 ( 1, 2 or 3 of Z 1 to Z 6 are nitrogen atoms) May be represented);
  • R 6 is hydrogen, C 1 -C 6 alkyl group, C 1 -C 6 haloalkyl group, C 1 -C 6 alkoxy C 1 -C 6 alkyl group, hydroxy C 1 -C 6 alkyl group, halo C 1 -C 6 An alkoxy C 1 -C 6 alkyl group, a di C 1 -C 6 alkylamino C 1 -C 6 alkyl group, a mono C 1
  • Ring A is N-linked morpholine, piperidine, pyrrolidine, or azetidine; n is 1; p is 0, 1, or 2; q is 0, 1, or 2; The compound according to [2] above, or a pharmaceutically acceptable salt thereof.
  • the compound represented by the general formula (I) is: 1-methyl-N- [2- (morpholin-4-yl) ethyl] -5- (quinolin-3-yl) -1H-pyrazole-3-carboxamide; 1-methyl-5- ⁇ 5-methyl-1H-pyrrolo [3,2-b] pyridin-2-yl ⁇ -N- [2- (morpholin-4-yl) ethyl] -1H-pyrazole-3-carboxamide ; 1-methyl-N- [2- (morpholin-4-yl) ethyl] -5- ⁇ 1H-pyrrolo [2,3-b] pyridin-2-yl ⁇ -1H-pyrazole-3-carboxamide; 1-methyl-N- [2- (morpholin-4-yl) ethyl] -5- ⁇ 7H-pyrrolo [2,3-d] pyrimidin-6-yl ⁇ -1H-pyrazole-3-carboxamide; 1-methyl-N- [2- (morpholin-4-y
  • a pharmaceutical composition comprising the compound according to any one of [2] to [6] above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a combination of the compound according to any one of [2] to [6] above and another pharmacologically active agent.
  • An effective amount of a pharmaceutical composition comprising the compound according to any one of [2] to [6] above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, Migraine, inflammatory pain, nociceptive pain, fibromyalgia, chronic low back pain, visceral pain, gastroesophageal reflux disease (GERD), constipation, diarrhea, functional gastrointestinal disease characterized by administration to mammals Irritable bowel syndrome (IBS), asthma, osteoarthritis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, glomerulonephritis, nephritis, dermatitis, hepatitis, vasculitis, renal ischemia, stroke, myocardial infarction, Cerebral ischemia, Alzheimer's disease, reversible airway obstruction, adult respiratory system syndrome, chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH), idiopathic interstitial pneumonia, bronchitis,
  • the pyrazole-3-carboxamide derivative which is an active ingredient of the medicament of the present invention, has a novel skeleton and potently and selectively inhibits the function of 5-HT 2B receptor.
  • the strong 5-HT 2B receptor antagonistic action of the medicament of the present invention exhibits a therapeutic effect based on an excellent pharmacological effect.
  • the high selectivity of the medicament of the present invention is useful as a highly safe therapeutic or prophylactic agent because it reduces a wide range of side effects caused by the action on other receptors other than the 5-HT 2B receptor. is there.
  • FIG. 4 is a graph showing the results of a colon extension stimulation test using a TNBS-induced rat IBS model for Example Compound 24.
  • the compounds of the present invention are characterized by having specific binding activity to the 5-HT 2B receptor.
  • the compound of the present invention selectively inhibits the activity of the 5-HT 2B receptor as an antagonist of 5-HT 2B by binding to the 5-HT 2B receptor in an antagonistic manner, and a mammal in which the receptor is involved It is useful for the treatment or prevention of other diseases.
  • the ability of these antagonists and agonists to bind to part of the receptor is called binding affinity, and this evaluation of binding affinity can be performed in vitro on the receptor as in the examples below. This is done by comparing the Ki value calculated by the binding test, optionally the IC 50 value in the binding test to the receptor performed under the same conditions. Incidentally, in the binding test to the receptor, if it can not calculate an IC 50 value not exhibit sufficient inhibitory effect at a certain concentration may be regarded an IC 50 value of the compound with the density higher.
  • the compounds of the present invention has a binding affinity for the 5-HT 2B receptor binding, IC 50 values representing the activity (inhibiting activity) of inhibiting the action of serotonin binding to 5-HT 2B receptors , Preferably 1000 nM or less, more preferably 100 nM or less, even more preferably 10 nM or less, most preferably 1 nM or less.
  • the compound of the present invention or a pharmacologically acceptable salt thereof preferably has “selective” inhibitory activity on the receptor as compared with other receptors.
  • “Selective” means that the inhibitory activity on the receptor is higher than the inhibitory activity on “other receptors”.
  • “selective” means that when the IC 50 value indicating the inhibitory activity to the receptor is 1/10 or less compared to the IC 50 value of “other receptors”, preferably It means that the value is 1/100 or less, more preferably 1/1000 or less.
  • the “other receptors” are other receptors reported in existing non-selective serotonin antagonists, and particularly receptors that are involved in undesirable actions.
  • selectivity for 5-HT 2A and 5-HT 2C as 5-HT 2B selective antagonist compounds it is possible to evaluate the influence of existing compounds on existing receptors and enzymes. preferable.
  • the receptor inhibitory activity or receptor antagonism of the 5-HT 2B selective antagonist compound in the present invention can be easily evaluated by known techniques described below.
  • C 1 -C 6 means a straight, branched, or cyclic carbon chain having 1 to 6 carbon atoms unless otherwise specified.
  • the “C 1 -C 6 alkyl group” is an alkyl group having 1 to 6 carbon atoms (sometimes referred to as Alk), and in particular, a methyl group (sometimes represented as Me), an ethyl group (Et and A propyl group, an isopropyl group, a butyl group, an isobutyl group, or a tert-butyl group.
  • Halogen means a Group 17 element in the periodic table, among which fluorine, chlorine, bromine or iodine is preferred.
  • Haloalkyl group means a C 1 -C 6 alkyl group substituted with 1 to 5 halogen atoms.
  • the “aryl ring” refers to a monocyclic or bicyclic ring that is saturated or partially or completely unsaturated.
  • the aryl ring group means a substituent bonded from the site where one hydrogen is removed from the aryl ring, and those represented by the general formulas Ar 1 , Ar 2 , Ar 3 and Ar 4 are preferable.
  • unsaturated monocyclic groups include phenyl, pyrazolyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrrolyl, thiophenyl, A pyrazinyl group, a pyridazinyl group, an isoxazolyl group, an isothiazolyl group, a triazolyl group, a furazanyl group, and the like can be given.
  • unsaturated bicyclic groups include naphthyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indolyl, isoindolyl, benzoxazolyl, benzothiazolyl, indazolyl, benzimidazolyl, A quinolyl group, an isoquinolyl group, a cinnolinyl group, a phthalazinyl group, a quinazolinyl group, a quinoxalinyl group, and the like can be given.
  • saturated ring group include a ring group in which a part or all of the unsaturated portion of the unsaturated monocyclic or unsaturated bicyclic ring is saturated.
  • the bonding mode is not limited to the following formula. “A bond between R 1B and another R 1B is also possible” has the same meaning as above, and R 1A is read as R 1B .
  • the detachable substituent include, but are not limited to, ethoxy, phenoxy, halogen, alkoxycarbonyloxy, allyloxycarbonyloxy, imidazol-1-yl, 4-nitrophenoxy group and the like.
  • the salt of the compound represented by the general formula (I) is a pharmaceutically acceptable salt, and includes acid addition salts and base addition salts thereof (including dioxidation addition salts and dibasic addition salts).
  • acid addition salts are formed from acids that form non-toxic salts.
  • Specific examples of acid addition salts include acetate, aspartate, benzoate, besylate, bicarbonate or carbonate, bisulfate or sulfate, borate, cansylate, and citrate.
  • Edicylate esylate, formate, fumarate, glycoheptonate, gluconate, hexafluorophosphate, hibenzic acid, hydrochloride, hydrobromide, hydroiodide, isethionate, Lactic acid, malate, maleate, malonate, mesylate, methyl sulfate, naphthylate, 2-naphthylate, nicotinate, nitrate, orotate, oxalate, palmitate, Examples include pamoate, phosphate, hydrogen phosphate or dihydrogen phosphate, saccharide salt, stearate, succinate, tartrate, tosylate, trifluoroacetate and the like.
  • Base addition salts are also formed from bases that form non-toxic salts.
  • Specific examples of the base addition salt include aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, zinc salt, etc.
  • the base addition salt include aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, zinc salt, etc.
  • a pharmaceutically acceptable salt of the compound of general formula (I) can be easily prepared by mixing the compound of general formula (I) and a desired acid or base solution suitable for each.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionization in the salt can vary from fully ionized to nearly non-ionized.
  • solvate is used to describe a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules, such as methanol.
  • solvent molecules such as methanol.
  • hydrate is used when the solvent is water.
  • solvates according to the invention include solvates in which the solvent for crystallization is isotopically substituted, for example D 2 O, d 6 -acetone, d 6 -dimethyl sulfoxide .
  • complexes such as clathrates, drug-host inclusion complexes, etc., in which the drug and host are present in stoichiometric or non-stoichiometric amounts are included within the scope of the present invention. It is. Also included are complexes of drugs containing two or more organic and / or inorganic components that may be in stoichiometric or non-stoichiometric amounts. The resulting complex may be ionized, partially ionized, or non-ionized (see J Pharm Sci, 64 (8), 1269-1288 (August 1975) by Halebrian, if necessary).
  • references to compounds of general formula (I) include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.
  • the compounds of the present invention include compounds of general formula (I), polymorphs, prodrugs as defined hereinbefore, as well as their isomers (optical isomers, as defined later herein). Geometrical isomers and tautomers) and isotopically labeled compounds of general formula (I).
  • prodrugs of the compounds of general formula (I) or salts thereof are also within the scope of the invention. That is, certain derivatives of compounds of general formula (I) that themselves have little or no pharmacological activity, when administered in the body or on the body surface, such as with enzymes, gastric acid, etc. under physiological conditions. May be converted to a compound of the general formula (I) having a desired activity or a salt thereof. Such derivatives are called “prodrugs”. Further information regarding the use of prodrugs can be found in Pro-drugs as Novell Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. EB Roche, America Pace.
  • Prodrugs according to the present invention can be prepared, for example, from suitable functional groups present in compounds of general formula (I), for example H.P. It can be produced by replacing with a specific part known to the person skilled in the art as “pro-moieties” as described in “Design of Prodrugs” by Bundgaard (Elsevier, 1985).
  • prodrugs according to the present invention include esterified, amidated compounds (eg, ethyl esters) where the compound of general formula (I) or salt thereof contains a carboxylic acid functional group (—COOH) , Phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3- Dioxolen-4-yl) methyl esterification, 1- (cyclohexyloxycarbonyloxy) ethyl esterification, methylamidated compound) and the like; the compound of general formula (I) or a salt thereof contains an alcohol functional group (—OH) If the hydroxyl group is acylated, alkylated, phosphorylated, borated Products (for example, acetylated, palmitoylated, propanoylated,
  • N-oxides may be formed, and these N-oxides are also included.
  • substituents according to the above examples and other prodrug type examples can be found in the above references.
  • certain compounds of general formula (I) may be able to serve as prodrugs of other compounds of general formula (I) by themselves, although their pharmacological effects are attenuated.
  • Compounds of general formula (I) containing one or more asymmetric carbon atoms may exist as two or more stereoisomers. Where a compound of general formula (I) contains an alkenyl or alkenylene group, geometric cis / trans (ie Z / E) isomers are possible. Where a compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerization ("tautomerism”) may exist. As a result, a single compound may exhibit more than one type of isomerism. All stereoisomers, geometric isomers and tautomers of compounds of general formula (I), including compounds exhibiting two or more types of isomerism, and mixtures of one or more thereof are within the scope of the present invention.
  • Acid addition salts or base salts in which the counterion is optically active for example D-lactate or L-lysine, or racemic, for example DL-tartrate or DL-arginine, are also included in the present invention. include.
  • Cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.
  • Conventional techniques for preparing / separating individual enantiomers include chiral synthesis from appropriate optically pure precursors or racemates (or salts using, for example, chiral high performance liquid chromatography (HPLC)). Or resolution of racemic derivatives).
  • the racemic compound (or racemic precursor) is converted to a suitable optically active compound, such as an alcohol, or, if the compound of general formula (I) contains an acidic or basic moiety, such as tartaric acid or 1-phenylethylamine It can be reacted with an acid or a base.
  • the resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization, wherein one or both of the diastereoisomers is purified by the corresponding pure one or more by means well known to those skilled in the art. Can be converted to the enantiomers of
  • the chiral compounds of the present invention (and their chiral precursors) contain 0-50 (w / w)% isopropanol, usually 2-20 (w / w)%, and 0-5 (w / w)% alkyl.
  • Stereoisomeric aggregates can be separated by conventional techniques known to those skilled in the art (see, if necessary, “Stereochemistry of Organic Compounds” by Wiley, New York, 1994.). .
  • the present invention includes a pharmaceutically acceptable general formula in which one or more atoms are replaced by an atom having the same atomic number but having an atomic weight or mass number different from the atomic weight or mass number normally found in nature. All isotope-labeled compounds of (I) are included. Examples of suitable isotopes for inclusion in the compounds of the present invention include hydrogen such as 2 H and 3 H, carbon such as 11 C, 13 C and 14 C, chlorine such as 36 Cl, fluorine such as 18 F , Iodine such as 123 I and 125 I, nitrogen such as 13 N and 15 N, oxygen such as 15 O, 17 O and 18 O, phosphorus such as 32 P, and sulfur isotopes such as 35 S.
  • Substitution with positron emitting isotopes such as 11 C, 18 F, 15 O and 13 N is useful in positron emission tomography (PET) studies to examine substrate receptor occupancy.
  • Certain isotopically-labelled compounds of general formula (I) for example, those that incorporate a radioactive isotope, are useful in drug and / or substrate tissue distribution studies.
  • the radioactive isotopes tritium, ie 3 H, and carbon-14, ie 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • the compound represented by the general formula (I) should be prepared by the means described in the following general methods, the specific means described in the Examples, etc., and the usual, conventional, or predetermined improvements relating thereto. Can do.
  • the invention further encompasses one or more processes for the preparation of not only compounds of general formula (I) but also novel intermediates used in connection therewith.
  • the compound of the general formula (I) of the present invention can be prepared according to a preparation method known per se, or a general procedure or preparation method illustrated in the following reaction scheme. Unless otherwise indicated, R 1 -R 5 and X, Y, and Z in the subsequent reaction schemes and discussion are as defined above.
  • the term “protecting group” used below refers to T.I. W.
  • each compound described in the general reaction formula may form a salt as long as it does not inhibit the reaction.
  • examples of such a salt include the same salts as the salt of compound (I).
  • the prodrug of this invention compound can be prepared by introduce
  • R ′ represents OH, O-lower alkyl, lower alkyl and fluorine
  • s represents 2 or 3
  • B represents a boron atom.
  • substituents include (OH) 2 B, (O-lower alkyl) 2 B, (lower alkyl) 2 B, and potassium salt of trifluoroborate (BF 3 ⁇ ) (BF 3 K).
  • the lower alkyl may be cyclic.
  • the iodine compound of formula III is prepared in one pot via the diazonium salt intermediate or after the formation of the diazonium salt in the presence of a suitable iodinating agent from formula II, with the addition of a suitable iodinating agent.
  • a suitable iodinating agent from formula II
  • a suitable iodinating agent from formula II
  • Diazonium salt formation can be performed by a conventionally known procedure. As a typical procedure, diazoniumation is carried out with sodium nitrite in an acidic solution. Suitable acid solutions include, for example, aqueous solutions of acetic acid, hydrochloric acid, formic acid or sulfuric acid, with acetic acid being preferred. This reaction time may be about 10 minutes to 12 hours, and generally about 30 minutes to 6 hours.
  • the reaction temperature may be about ⁇ 20 ° C. to 30 ° C., and is generally about ⁇ 10 ° C. to 5 ° C.
  • suitable iodinating agents include potassium iodide, sodium iodide, or iodine, with potassium iodide being preferred.
  • Me means a methyl group (the same applies hereinafter).
  • the compound of formula VI can be prepared using an aryl cross-coupling reaction with the compound prepared in step A-1 above (formula III).
  • Coupling of Formula III with an aryl metal reagent (IV) in a water-organic mixed solution or in an organic solvent under coupling conditions in the presence of an appropriate transition metal catalyst and a base (or in the absence of a base) Can be prepared.
  • Suitable R ′ s B substituents in aryl metal reagents include, for example, (OH) 2 B, (O-lower alkyl) 2 B, (lower alkyl) 2 B, potassium of trifluoroborate (BF 3 ⁇ ) Examples thereof include a salt (BF 3 K).
  • transition metal catalysts include, for example, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) chloride, copper (0), copper (I) acetate, copper (I) bromide, copper chloride (I), copper (I) iodide, copper (I) oxide, copper (I) trifluoromethanesulfonate, copper (II) acetate, copper (II) bromide, copper (II) chloride, copper iodide (II) ), Copper (II) oxide, copper (II) trifluoromethanesulfonate, palladium (II) acetate, palladium (II) chloride, bis (acetonitrile) dichloropalladium (II), bis (dibenzylideneacetone) palla
  • tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) chloride, palladium (II) acetate, bis (acetonitrile) dichloropalladium (II), tris (dibenzylideneacetone) dipalladium (0), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride is preferred.
  • aryl metal reagents include, but are not limited to, boronic acid reagents such as 2-indoylboronic acid derivatives and boronic acid ester reagents such as 2-indoylboronic acid ester derivatives. .
  • suitable organic solvents as the water-organic mixed solution include, for example, tetrahydrofuran in the presence or absence of a water-soluble base such as potassium hydroxide, sodium hydroxide, lithium hydroxide or potassium carbonate aqueous solution, , 4-dioxane, N, N-dimethylformamide (DMF), acetonitrile, alcohols such as methanol and ethanol; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride; or diethyl ether It is done. This reaction can be carried out in the presence of a suitable additional factor.
  • a water-soluble base such as potassium hydroxide, sodium hydroxide, lithium hydroxide or potassium carbonate aqueous solution, , 4-dioxane, N, N-dimethylformamide (DMF), acetonitrile, alcohols such as methanol and ethanol; halogenated hydrocarbons such as dich
  • additional factors include, for example, triphenylphosphine, tri-tert-butylphosphine, 1,1′-bis (diphenylphosphino) ferrocene, tri-2-furylphosphine, 2- (dichlorohexylphosphine Fino) biphenyl, triphenylarsine, tetrabutylammonium chloride, tetrabutylammonium fluoride, lithium acetate, lithium chloride, triethylamine, potassium (or sodium) methoxide, sodium hydroxide, sodium carbonate, potassium phosphate, cesium carbonate, bicarbonate Sodium (bicarbonate) or sodium iodide may be mentioned.
  • This reaction is about 0 ° C to 200 ° C, and generally about 20 ° C to 120 ° C.
  • the reaction time is about 5 minutes to 96 hours, and generally about 30 minutes to 24 hours.
  • the reaction can also be performed using a microwave reaction apparatus.
  • Y is NH
  • a reaction is carried out in which the nitrogen atom is protected with a lower alkoxycarbonyl group (eg Boc group) or (p-alkyl) benzenesulfonyl group (eg benzenesulfonyl or p-toluenesulfonyl group). You can also.
  • Process A-3 the preparation of the heterocyclic compound (formula VI) having a [5 + 6] ring corresponding to the general formula R 2 is prepared in the presence of a suitable transition metal catalyst (such as iridium) and an added adduct.
  • a suitable transition metal catalyst such as iridium
  • Is used for the carbon-hydrogen boration reaction of pinacol borane (HBpin) or bis (pinacolato) diborane (B 2 pin 2 , pin Me 4 C 2 O 2 ) with the [5 + 6] cyclic heterocyclic compound (V).
  • the derived aryl boronic acid ester is subjected to Suzuki-Miyaura reaction with Formula III to prepare the coupling compound, Formula (VI). These reactions can be carried out by a one-pot reaction or a two-stage operation.
  • the transition metal catalyst include [Ir (OMe) (COD)] 2 (COD is 1,5-cyclooctadiene), Cp * Rh ( ⁇ 4 -C 6 Me 6 ) (Cp * is C 5 Me 5). ), Ir ( ⁇ 5 -C 9 H 7 ) (COD), [IrCl (COD)] 2, [IrCl (COE) 2 ] 2, or RhCl ⁇ P (i-Pr) 3 ⁇ (N 2 ), etc. Is mentioned.
  • Examples of the additional substance to be added include 1,2-bis (dimethylphosphino) ethane (dmpe), 2,2′-bipyridine (dpy), 4,4′-di-tert-butyl-2,2′-bipyridine. (Dtbpy) or dppe.
  • Suitable organic solvents include, for example, hydrocarbons such as n-hexane or cyclohexane.
  • pinacol borane was prepared by using a combination of 1/2 [IrCl (COD)] 2 and 4,4′-di-tert-butyl-2,2′-bipyridine (dtbpy) in a hexane solvent as a catalyst.
  • step A-2 bis (pinacolato) diborane is reacted with an aryl compound. Subsequently, it is converted to Formula VI by the Suzuki-Miyaura reaction of the prepared aryl boronic acid ester and Formula III.
  • This reaction is essentially the same as in step A-2, and can be performed using the same reagents and reaction conditions as in step A-2 as in step A-2 described above.
  • N, N-dimethylformamide (DMF) or 1,4-dioxane as a solvent
  • solid potassium phosphate (K 3 PO 4 ) as a base
  • the direct bicyclic heteroaryl group (formula V) introduction reaction into the aryl halide (formula III) similar to the carbon-hydrogen boration described above, followed by the Suzuki-Miyaura reaction is palladium (Non-patent Document 10).
  • Non-Patent Document 11 a direct arylation reaction mediated by rhodium (Non-Patent Document 11) or copper (Non-Patent Document 12) can be used instead.
  • Non-Patent Document 12 a direct arylation reaction mediated by rhodium (Non-Patent Document 11) or copper (Non-Patent Document 12) can be used instead.
  • the carboxylic acid compound of formula VII can be prepared by hydrolysis of the ester compound of formula VI in the reaction solvent.
  • Hydrolysis can be performed by a conventionally known procedure. In a typical procedure, the hydrolysis can be carried out under basic conditions, for example in the presence of sodium hydroxide, potassium hydroxide or lithium hydroxide.
  • Suitable solvents include, for example, methanol, ethanol, propanol, butanol, 2-methoxymethanol, alcohols such as ethylene glycol; tetrahydrofuran (THF), 1,2-dimethoxyethane (DME), 1,4-dioxane, and the like.
  • Ethers such as N, N-dimethylformamide (DMF) or hexamethylphosphoric triamide; and sulfoxides such as dimethyl sulfoxide (DMSO), or water.
  • the reaction time is about 30 minutes to 48 hours, and generally about 60 minutes to 30 hours.
  • the reaction temperature is about ⁇ 20 ° C. to 100 ° C., and generally about 20 ° C. to 75 ° C.
  • Hydrolysis also occurs under acidic conditions, eg, hydrogen halides such as hydrogen chloride or hydrogen bromide; sulfonic acids such as p-toluenesulfonic acid or benzenesulfonic acid; pyrididium P-toluenesulfonate; and acetic acid or trifluoro
  • Suitable solvents include, for example, methanol, ethanol, propanol, butanol, 2-methoxymethanol, alcohols such as ethylene glycol; tetrahydrofuran (THF), 1,2-dimethoxyethane (DME), 1,4-dioxane, and the like.
  • the reaction time is about 30 minutes to 24 hours, and generally about 60 minutes to 10 hours.
  • the reaction temperature is about ⁇ 20 ° C. to 100 ° C., and generally about 0 ° C. to 65 ° C.
  • Process A-5 Prepared in this step, an amide compound of formula I A in an inert solvent, by a coupling reaction in the presence or an amine compound in the absence of a coupling agent (formula VIII) carboxylic acid compound (formula VII) can do.
  • This reaction can also be performed in the presence or absence of additives such as 1-hydroxybenzotriazole (HOBt) or 1-hydroxyazabenzotriazole.
  • Suitable solvents include acetone, nitromethane, N, N-dimethylformamide (DMF), sulfolane, dimethyl sulfoxide (DMSO), 1-methyl-2-pyrrolidinone (NMP), 2-butanone, acetonitrile; dichloromethane, And halogenated hydrocarbons such as 1,2-dichloroethane and chloroform; and ethers such as tetrahydrofuran and 1,4-dioxane.
  • the reaction time is about 5 minutes to 1 week, and generally about 30 minutes to 24 hours.
  • the reaction temperature is about ⁇ 20 ° C. to 100 ° C., and generally about 0 ° C. to 60 ° C.
  • a suitable coupling reagent is not limited as long as it is a reagent usually used in peptide synthesis.
  • diimide eg, dicyclohexylcarbodiimide (DCC), water-soluble carbodiimide (WSC), hexafluorophosphoric acid O-benzotriazole.
  • amide compounds of formula I a is oxalyl chloride, halogen such as phosphorus oxychloride or thionyl chloride It can also be prepared via an acyl halide that can be obtained by reaction with an agent, treating the amine compound of formula VIII with the resulting acyl halide without using the condensing agent reagent described in this step. The corresponding amide compound To the product (formula I A ).
  • Process B-1 the compound of formula IX can be prepared by hydrolysis of the ester compound of formula III.
  • This reaction is essentially the same as the above-described step A-4, and can be performed using the same reagents and reaction conditions as in step A-4, as in step A-4.
  • the compound of formula X can be prepared by an amidation reaction of a carboxylic acid compound of formula IX and an amine compound (formula VIII). This reaction is essentially the same as the aforementioned step A-5, and can be performed using the same reagents and reaction conditions as in step A-5, as in step A-5.
  • Process B-3 the compound of formula XI is reacted in a suitable reaction solution containing a base or in the presence of only a base in the presence of a catalytic amount of a palladium reagent and a copper (I) salt or a catalytic amount of a palladium reagent and a phosphine ligand. It can be prepared using a cross-coupling reaction between Formula X and acetylene protected with a trialkylsilyl group such as a trimethylsilyl group under the conditions used as solvent.
  • the palladium reagent include tetrakis (triphenylphosphine) palladium and bis (triphenylphosphine) palladium (II) chloride.
  • Preferred examples of the copper (I) salt include copper (I) iodide and copper (I) bromide.
  • Preferred examples of the phosphine ligand include bis (diphenylphosphino) butane (DPPB).
  • the base include, for example, diethylamine, triethylamine, diisopropylethylamine, dicyclohexylamine, potassium carbonate or sodium carbonate.
  • reaction solvent examples include tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide (DMF), acetonitrile, ethyl acetate, n-hexane, cyclohexane, benzene, toluene and other hydrocarbons, diethyl ether, and the like. Can be mentioned.
  • the reaction time is about 5 minutes to 96 hours, and generally about 30 minutes to 24 hours.
  • the reaction temperature is about ⁇ 78 ° C. to 200 ° C., and generally about ⁇ 20 ° C. to 80 ° C. In some cases, the reaction is performed using a microwave reaction apparatus.
  • the compound of formula XII can be removed from the trialkylsilyl group using conventional methods commonly known, such as those described in Protection Groups in Organic Synthesis (1999) by John Wiley & Sons. It can be prepared by protecting. As a usual method, deprotection can be performed in an alcohol solvent such as methyl alcohol or ethyl alcohol in the presence of a base such as potassium carbonate or sodium carbonate.
  • Process B-5 This reaction is essentially the same as the above-mentioned step B-3, and the acetylene compound (formula XII) and aryl halide are used in the same manner as in step B-3, using the same reagents and reaction conditions as in step B-3. It can be prepared by Sonogashira coupling reaction with a compound (formula XIII) (wherein P 1 represents a hydrogen atom or an amino protecting group such as tert-butoxycarbonyl group or trifluoroacetyl group).
  • a compound of formula I B are prepared by intramolecular cycloaddition reaction of the acetylene compound (Formula XIV) with a suitable base.
  • suitable bases include tert-butoxy potassium, tert-butoxy sodium, tert-butoxy cesium, cesium hydroxide, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,1,3, 3-Tetramethylguanidine, triethylamine or the like is used, and the reaction is performed in a suitable solvent.
  • Suitable solvents include N, N-dimethylformamide (DMF), N-methylpyrrolidinone (NMP), toluene, 1,4-dioxane, alcohols such as methanol and ethanol.
  • the reaction time is about 5 minutes to 96 hours, and generally about 30 minutes to 24 hours.
  • the reaction temperature is about ⁇ 78 ° C. to 250 ° C., and generally about ⁇ 20 ° C. to 150 ° C.
  • the reaction is performed at room temperature to 80 ° C. using potassium tert-butoxy in a DMF solvent.
  • intramolecular cyclization is performed by using a palladium catalyst (dichlorobis (triphenylphosphine) palladium (II), copper (I) iodide, triethylamine, DMF as a typical combination).
  • a palladium catalyst dichlorobis (triphenylphosphine) palladium (II), copper (I) iodide, triethylamine, DMF as a typical combination.
  • various metal catalysts and metal composites containing copper, gold, iridium, mercury, molybdenum, platinum and rhodium are also used.
  • the NHP 1 substituent is a phenol group or a thiol group
  • intramolecular cyclization proceeds under the above conditions, and it is possible to prepare a corresponding benzothiophene or benzofuran derivative.
  • the protecting group (P 1 ) remains after completion of the cyclization reaction, it can be deprotected using appropriate reaction conditions.
  • the compound of formula XVI is prepared by an N-alkylation reaction of formula XV which can be readily prepared from known literature using a suitable base and a suitable alkyl halide.
  • suitable bases include, for example, sodium ethoxide, tert-butoxy potassium, potassium hydride, sodium hydride, sodium bis (trimethylsilyl) amide, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide and the like. It is not limited to these.
  • suitable organic solvents include tetrahydrofuran, N, N-dimethylformamide (DMF), diethyl ether, acetonitrile and the like.
  • the reaction time is about 5 minutes to 96 hours, and generally about 30 minutes to 24 hours.
  • the reaction temperature is about ⁇ 78 ° C. to 250 ° C., and generally about ⁇ 20 ° C. to 150 ° C.
  • suitable halogen agent reagents include, for example, bromine, chlorine, sulfuryl chloride, hydrogen bromide, N-bromosuccinimide (NBS), 5,5-dibromo-2,2-dimethyl-4,6-dioxo-1, Examples include 3-dioxane and phenyltrimethylammonium tribromide.
  • Suitable organic solvents include halogenated hydrocarbons such as acetic acid, carbon disulfide, ether, tetrahydrofuran, N, N-dimethylformamide (DMF), dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride. .
  • the reaction time is about 5 minutes to 96 hours, and generally about 30 minutes to 24 hours.
  • the reaction temperature is about ⁇ 78 ° C. to 250 ° C., and generally about ⁇ 20 ° C. to 150 ° C.
  • Step C-3 a compound of formula XIX is prepared by a ring condensation reaction of a suitable amine compound (formula XVIII) and an ⁇ -haloketone compound (formula XVII) with heating in the presence of a suitable solvent.
  • suitable solvents include tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide (DMF), acetonitrile, alcohols such as methanol and ethanol, and the like.
  • the reaction time is about 5 minutes to 96 hours, and generally about 30 minutes to 24 hours.
  • the reaction temperature is about 0 ° C. to 250 ° C., and generally about 30 ° C. to 150 ° C.
  • Step C-4 the compound of formula XX can be prepared by hydrolysis of the ester compound of formula XIX.
  • This reaction is essentially the same as the above-described step A-4, and can be performed using the same reagents and reaction conditions as in step A-4, as in step A-4.
  • a compound of formula I C may be prepared by amidation reaction of a carboxylic acid compound and the amine compound of Formula XX (wherein VIII). This reaction is essentially the same as the aforementioned step A-5, and can be performed using the same reagents and reaction conditions as in step A-5, as in step A-5.
  • a compound of formula XXII can be prepared by an amidation reaction of a carboxylic acid compound of formula VII and an amine compound (formula XXI).
  • This reaction is essentially the same as the aforementioned step A-5, and can be performed using the same reagents and reaction conditions as in step A-5, as in step A-5.
  • Process D-2 the compound of formula XXIII deprotects the acetal group using commonly known conventional methods, such as the method described in Protection Groups in Organic Synthesis (1999) by John Wiley & Sons. Can be prepared. As a usual method, deprotection can be performed in a general organic solvent in the presence of an acid catalyst such as dilute hydrochloric acid or p-toluenesulfonic acid or under acidic conditions.
  • an acid catalyst such as dilute hydrochloric acid or p-toluenesulfonic acid or under acidic conditions.
  • a compound of formula ID can be prepared by a reductive amination reaction of an aldehyde compound of formula XXIII and an amine compound (formula XXIV) using a suitable reducing agent.
  • suitable reducing agents include sodium borohydride (NaBH4), sodium cyanoborohydride (NaBH 3 CN), sodium triacetoxyborohydride [NaBH (OAc) 3 ] and the like.
  • Suitable solvents include, for example, acetic acid, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, chloroform, halogenated hydrocarbons such as carbon tetrachloride, and if necessary, catalytic amounts of acetic acid, titanium tetrachloride, tetraisopropoxy titanium [
  • a Lewis acid such as Ti (O—iPr) 4
  • cyanoborohydride NaBH 3 CN
  • the reaction temperature is about 0 ° C. to 250 ° C., and generally about 30 ° C. to 100 ° C.
  • a compound of formula IE can be prepared by a coupling reaction between a halogen compound of formula X and an aryl boronic acid (or ester) derivative.
  • This reaction is essentially the same as step A-2 described above, and can be performed using the same reagents and reaction conditions as in step A-2, as in step A-2.
  • P 2 represents a protecting group and is selected from a lower alkoxycarbonyl group, a benzyloxycarbonyl group, a benzenesulfonyl and a 4-alkylbenzenesulfonyl group.
  • Process F-1 the compound of formula XXVI is protected with a halogen compound of formula X and a nitrogen atom of formula XXV optionally as protecting group P 2 , for example with a tert-butoxycarbonyl group, benzenesulfonyl or 4-alkylbenzenesulfonyl group. It can be prepared by a coupling reaction with a heteroaryl boronic acid (or ester) derivative. This reaction is essentially the same as step A-2 described above, and can be performed using the same reagents and reaction conditions as in step A-2, as in step A-2.
  • Step F-2 In this step, a compound of formula I F, such as the method described in John Wiley & Sons al Protecting Groups in Organic Synthesis of (1999), using conventional methods that are generally known, tert- butoxycarbonyl group And an arylsulfonyl group can be prepared by deprotection.
  • deprotection of the tert-butoxycarbonyl group can be performed in a general organic solvent in the presence of an acid catalyst such as dilute hydrochloric acid or p-toluenesulfonic acid or under acidic conditions.
  • the benzenesulfonyl or 4-alkylbenzenesulfonyl group can be deprotected in combination with a common organic solvent in the presence of an alkaline reagent such as potassium carbonate, sodium carbonate, cesium carbonate or sodium hydroxide.
  • an alkaline reagent such as potassium carbonate, sodium carbonate, cesium carbonate or sodium hydroxide.
  • a compound of formula I 'F is nitrogen lies on the heteroaryl ring of formula I F - prepared by converting the hydrogen bond site by using the R 6 -X reagent, nitrogen -R 6 bond be able to.
  • the R 6 -X reagent is an alkyl halide, it is essentially the same as the preceding step C-1 and is carried out under the same conditions as in the step C-1, as in the usual N-alkylation. Further, O-tosylate, O-mesylate, O-triflate, etc. having a leaving group at the hydroxyl group (—OH) can be substituted for the halide.
  • R 6 is an alkylsulfonyl group
  • alkylsulfonyl chloride is used, which is essentially the same as the previous step C-1, and is carried out under the same conditions as in step C-1.
  • the intermediate represented by the general formula (IA) is useful for producing the compound of the present invention.
  • it is an intermediate represented by X in the general synthesis step B, and is effectively used for producing the compound of the present invention.
  • the intermediate represented by the general formula (IB) is useful for producing the compound of the present invention.
  • it is an intermediate represented by VI and VII in general synthesis step A, XIX and XX in synthesis step C, and XXI in synthesis step D, and is effectively used for producing the compound of the present invention.
  • the pharmacological effect of the compound of the present invention as a 5-HT 2B antagonist can be evaluated by measuring the ameliorating effect on pulmonary blood pressure increase using an animal model (rat / mouse) exposed to chronic hypoxia.
  • an existing therapeutic agent for pulmonary hypertension (sildenafil, prostaglandin preparation, etc.) or RS-127445 known as a 5-HT 2B selective antagonist can be used.
  • other pharmacological effects of the compound of the present invention as a 5-HT 2B antagonist can be evaluated by measuring the ameliorating effect on diarrhea using a drug or a stress-treated animal (rat / mouse) model.
  • RS-127445 which is a known antidiarrheal drug (loperamide, berberine, etc.) 5-HT 2B selective antagonist, can be used.
  • the compound thus produced can be isolated or purified as a salt by leaving it free or subjecting it to a salt formation treatment by a conventional method.
  • the isolation or purification method is not particularly limited, and examples thereof include usual chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, or various chromatography.
  • Various isomers of the produced compound can be isolated by a conventional method using the difference in physicochemical properties between the isomers.
  • optical isomers can be obtained by a method of fractional recrystallization after introducing a racemate into a diastereomeric salt with an optically active organic acid such as tartaric acid, or a column chromatography using a chiral filler. Each can be separated or purified.
  • the optically active compound can also be produced by using an appropriate optically active compound as a raw material.
  • the mixture of diastereomers can be separated into each isomer by fractional recrystallization or chromatography.
  • Oral administration means that the compound is swallowed to enter the gastrointestinal tract, and when using buccal or sublingual administration, the compound enters the bloodstream directly from the mouth.
  • Preparations suitable for oral administration include tablets, capsules containing fine particles, liquids, powders, troches (including liquids), chews, multiparticulates, nanoparticles, gels, solid solutions, liposomes And solid preparations such as films (including mucoadhesive agents), vaginal suppositories, and sprays, as well as liquid preparations. Examples of liquid preparations include suspensions, solutions, syrups and elixirs.
  • Such formulations can be used as fillers in soft or hard capsules and are generally used as carriers, for example, water, methanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, as well as one Alternatively, a plurality of emulsifiers and / or suspending agents are used.
  • a liquid preparation can also be prepared by dissolving a solid drug, for example, a packaged drug in water or the like.
  • the compounds of the present invention can also be used in fast dissolving or fast disintegrating dosage forms, such as the dosage forms described by Liang and Chen in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 (2001).
  • the content of the drug as an active ingredient varies depending on the age, sex, and symptom level of the administration subject, but is preferably about 1% to 80% by weight, preferably 5% to 60%, based on the whole tablet. A weight percentage is more preferred.
  • Tablets can contain a disintegrant in addition to the drug as an active ingredient.
  • Disintegrants include, for example, sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch And sodium alginate.
  • the content of the disintegrant is preferably about 1% to 25% by weight and more preferably about 5% to 20% by weight with respect to the whole tablet.
  • Tablets can contain a binder in addition to the drug as an active ingredient.
  • the binder include microcrystalline cellulose, gelatin, lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, glucose, sucrose, sorbitol, polyethylene glycol, natural or synthetic rubber, Examples thereof include polyvinyl pyrrolidone, starch, pregelatinized starch, hydroxypropyl cellulose, dicalcium phosphate dihydrate, and hydroxypropylmethylcellulose.
  • Tablets may also contain surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
  • the surfactant content is preferably about 0.2 to 5% by weight based on the whole tablet, and the glidant content is about 0.2 to 1% by weight based on the whole tablet.
  • Tablets may also contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate.
  • the content of the lubricant is preferably about 0.25 to 10% by weight, more preferably about 0.5 to 3% by weight, based on the whole tablet.
  • Examples of other components that can be blended include an antioxidant, a colorant, a corrigent, a preservative, and a taste masking agent.
  • Exemplary tablets include up to about 80% by weight drug as the active ingredient, about 10% to about 90% by weight binder, about 0% to about 85% diluent, about 2% to about disintegrant. Tablets containing 10% by weight, and about 0.25% to about 10% by weight of a lubricant.
  • limit especially as a manufacturing method of a tablet It can manufacture using a general tablet manufacturing method suitably.
  • the tablet blend can be compressed directly or by roller to produce a tablet.
  • tablet blends or parts of blends can be produced by wet, dry, or melt granulation, melt congealing or extrusion prior to tableting.
  • the final formulation comprises one or more layers and may or may not be coated or encapsulated.
  • Solid formulations for oral administration can be formulated to be immediate and / or improved controlled release.
  • Modified release formulations include, for example, delayed release, sustained release, pulsed release, controlled release, target release or programmed release.
  • a modified release formulation suitable for the purposes of the present invention is described in US Pat. No. 6,106,864. Details of other suitable release techniques such as high energy dispersion and osmotic pressure and coated particles are described in Verma et al., Pharmaceutical Technology On-line, 25 (2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.
  • parenteral Administration The compounds of the present invention can also be administered directly into the bloodstream, muscle, or viscera.
  • Suitable means for parenteral administration include, for example, intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular or subcutaneous administration.
  • Devices suitable for parenteral administration include, for example, needle (including microneedle) syringes, needleless syringes or infusion techniques.
  • the parenteral preparation may contain additives such as salts, carbohydrates or buffers (preferably pH 3-9).
  • a parenteral preparation may be an aqueous solution prepared by dissolving a drug or the like in an appropriate solvent such as physiological saline.
  • parenteral administration can be readily prepared using standard pharmaceutical techniques well known to those skilled in the art, such as lyophilization under aseptic conditions.
  • the solubility of the compounds of general formula (I) used in the preparation of parenteral solutions can be increased by the use of appropriate formulation techniques such as the incorporation of solubility enhancers.
  • Parenteral formulations can be formulated to be immediate release and / or improved controlled release. Modified release formulations include, for example, delayed release, sustained release, pulsed release, controlled release, target release or programmed release.
  • the compounds of the present invention can also be formulated as solid, semi-solid, or thixotropic liquids for administration as implantable depots that provide improved release of the active compound.
  • Such formulations include, for example, drug-coated stents or PGLA microspheres.
  • Topical Administration The compounds of the present invention can also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • topical preparations include gels, hydrogels, lotions, liquids, creams, ointments, sprays, bandages, foams, films, skin patches, wafers, implants, sponges Agents, fiber agents, bandages, microemulsions and the like, and liposomes can also be used.
  • the carrier include alcohol, water, mineral oil, fluid petrolatum, white petrolatum, glycerin, polyethylene glycol, propylene glycol, or water.
  • Topically-administered formulations include, for example, those described by Finnin and Morgan J. Pharm. Sci.
  • Means used for local administration include, for example, delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (eg Powderject TM, Bioject TM etc.) injection, etc. Is mentioned.
  • Formulations for topical administration can be formulated to be immediate release and / or improved controlled release. Modified release formulations include, for example, delayed release, sustained release, pulsed release, controlled double release, target release and programmed release.
  • the compounds of the present invention are mixed with soluble polymers such as cyclodextrin and appropriate derivatives thereof or polyethylene glycol-containing polymers and used in the aforementioned administration methods, etc., so that their solubility, dissolution rate, taste Masking, bioavailability and / or stability can be improved.
  • drug-cyclodextrin complexes have been found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes can be used.
  • cyclodextrin can be used as an auxiliary additive, ie, a carrier, diluent, or solubilizer.
  • ⁇ -, ⁇ - and ⁇ -cyclodextrins are most commonly used for these purposes, examples of which are WO 91/11172, WO 94/02518, and WO 98 / No. 55148.
  • kits comprising a plurality of components
  • Two or more pharmaceutical compositions containing a compound according to the present invention may be combined in the form of a kit suitable for administration in combination, for example for simultaneous administration of the composition, It is included in the scope of the present invention. That is, the kit according to the present invention comprises two or more separate pharmaceutical compositions and containers, separate bottles, or separate foil packets, at least one containing the compound of general formula (I) according to the present invention. Means for holding the objects separately. Examples of such a kit include a blister pack used for packaging tablets and capsules.
  • the kit of the present invention can be used to administer different dosage forms, e.g., oral and parenteral, to administer separate compositions at various dosing intervals, or to separate compositions with respect to each other. Particularly suitable for increasing the amount.
  • the kit typically includes instructions for administration and a so-called memory aid is provided.
  • the total daily dose of the compound of the present invention is preferably about 0.05 mg to 1000 mg when an average human subject having a body weight of about 65 to 70 kg is used, About 0.1 mg to 100 mg is more preferable, and about 0.5 mg to 20 mg is more preferable. Needless to say, it depends on the administration method. For example, in the case of oral administration, the total daily dose is preferably about 1 mg to 500 mg, and in the case of intravenous administration, about 0.5 mg to 250 mg is preferred.
  • the total dose per day may be a single dose or divided doses. These doses can be appropriately changed depending on the sex and age of the human subject or the degree of symptoms.
  • the compounds of the present invention exhibit 5-HT 2B antagonistic activity.
  • the 5-HT 2B antagonist compound of the present invention is a kind particularly in cancer, inflammatory diseases, immunoregulatory diseases and gastrointestinal disorders (for example, motility abnormalities and hypersensitivity in the gastrointestinal tract, blood pressure adjustment in the pulmonary artery, and arterial repair).
  • it can be used in combination with two or more pharmacologically active agents.
  • a 5-HT 2B antagonist, in particular a compound of general formula (I), or a pharmaceutically acceptable salt as defined above is combined with one or more agents selected from the following list 1 And can be administered simultaneously, sequentially or separately.
  • Relaxants Regulan (registered trademark), Celevac (registered trademark) and the like.
  • Anticonvulsant factors mebeberin, pinaverium, otilionium bromide, trimebutine having a smooth muscle relaxing action; dicycloberine having an antimuscarinic action, hyoscyamine, cimetropium and the like.
  • Opioids / central agonists MOR agonists loperamide, naltrexone, methylnaltrexone, modulon®, albimopan; KOR agonists fedotozine, asimadoline; low-dose tricyclic antidepressant imipramine, amitrip Chinclomipramine, desipramine, lofepramine; selective serotonin reabsorption inhibitors sertraline, paroxetine, fluoxetine, citalopram, escitalopram; serotonin-noradrenaline reabsorption inhibitors venlafaxine, duloxetine; reversible monoamine oxidase inhibitor Moclobemide; benzodiazepine agonists diazepam, prazepam, clonazepam, dextofisopam; centrally acting analgesic oxymorphone R, Toramazoru; isocarboxazid a monoamine oxidase inhibitor,
  • Serotonergic receptor modulators 5-HT3 antagonists alosetron, ondansetron, tropisetron, palonosetron, ramosetron, mirtazapine, indisetron, silane setron, granisetron, dolasetron; 5-HT4 agonist tegaserod, mosapride; 5 -HT3 agonist MKC-733; 5-HT4 agonist / 5-HT3 antagonist renzapride; 5-HT3 / 5-HT4 antagonist indisetron; 5-HT7 antagonist DR-4004, SB-269970, SB-258719, SB-258741; 5-HT1A agonist or antagonist buspirone, gepirone; 5-HT1A / 1B / D agonist buspirone; migraine drug ergotamine Sumatriptan, such as rizatriptan, and the like.
  • Gastrointestinal motility factors NK1 antagonists malopitant, aprepitant, ezropitant; NK2 antagonists nepadutant, saredutant; NK3 antagonist talnetant; CRF1 receptor antagonists CP-154526, NBI-35965, CRA-1000; CCK-A Receptor antagonists dexioxilumide, dexroxyglumide; motilin agonist Minamcinal, PF-4548043; chloride channel agonist (type 2) lubiprostone; guanylate cyclase agonist linaclotide; glucagon-like peptide-1 GTP-010 which is an agonist, ibutmoren and capromorelin which are ghrelin receptor agonists .
  • Antibiotics sulfacetamide, erythromycin, rifaximin, tobramycin, ciprofloxacin and the like.
  • Probiotic bacteria Bifidobacterium, Nonpathogenic, infantis 35624, E. coli. coli and the like.
  • Anti-analgesic factor ⁇ 2-adrenergic agonists clonidine, medetomidine, lofexidine, dexmedetomidine, AGN-2-3818; ⁇ 3-adrenergic agonist sorbegron; cannabinoid 1 or 2 agonists GRC-10622, GW842166, S Selective COX-2 inhibitors celecoxib, rofecoxib, valdecoxib, ettricoxib, lumiracoxib; non-steroidal anti-inflammatory drugs (NSAIDs) piroxicam, naproxen, ibuprofen, diclofenac, indomethacin; NMDA antagonist dizocilpine; TRPs resiniferatoxin, capsazepine, which is a modulars (V1, V3, V4, M8, A1 subtypes); ⁇ Gabapentin is a 2-[delta] ligand, pregabalin, 3-methyl gabapentin; G
  • Anti-inflammatory factors Dexamethasone, prezonidolone, ciclesonide, budesonide, which are synthetic corticosteroids; anakinra, atrizumab, mepolizumab, etc., which are interleukin-derived therapeutic agents.
  • Antiallergic factors leukotriene antagonists montelukast, zafirlukast, pranlukast; ⁇ 2-agonists albuterol, levalbuterol, salmeterol, formoterol, alformoterol 1; asflux and / or chronic obstructive pulmonary disease roflumilast, tiotropium , Israpafant and so on.
  • drugs include: Polyflu (registered trademark), Metamucil (registered trademark), crofelemer, psyllium-husk and the like.
  • test compounds of the present invention is illustrated in the following non-limiting examples. Unless otherwise stated, all operations are carried out at room temperature or ambient temperature, ie in the range of 18-25 ° C., solvent evaporation is carried out using a rotary evaporator under reduced pressure at a bath temperature up to 60 ° C., and the reaction is Monitored by thin layer chromatography (TLC), the melting point (mp) shown is uncorrected (crystal polymorphs may give different melting points) and the structure of all isolated test compounds And purity can be determined by the following techniques: TLC (Merck silica gel 60F 254 pre-coated TLC plate or Merck NH 2 pre-coated HTLC plate), mass spectrometry, nuclear magnetic resonance spectrum (NMR), infrared absorption spectrum (IR), or trace Guaranteed by at least one of the analyses.
  • TLC Merck silica gel 60F 254 pre-coated TLC plate or Merck NH 2 pre-coated HTLC plate
  • mass spectrometry nuclear
  • Flash column chromatography was performed using Wako Silica Gel 300HG (40-60 ⁇ m, Fuji Silysia Chromatorex®: DU3050 (amine type, 30-50 ⁇ m), Biotage silica gel (32-63 mm, KP-Sil) or Biotage amino bound silica (amine). On silica gel, 35-75 ⁇ m, KP-NH).
  • the microwave apparatus used in the reaction is Emrys optimze from Personal chemistry or Initiator (registered trademark): Sixty from Biotage.
  • the ultrasonic device used in the reaction is an Ultra Sonic Cleaner SINGLE Frequency manufactured by AS ONE. Abbreviations relating to the reaction solvent are as follows.
  • Tetrahydrofuran THF
  • dimethyl sulfoxide DMSO
  • dimethylformamide DMF
  • An abbreviation for amidating condensing agent reagent is hexafluorophosphoric acid O-benzotriazol-1-yl-N, N, N ′, N′-tetramethyluronium (HBTU).
  • HBTU hexafluorophosphoric acid O-benzotriazol-1-yl-N, N, N ′, N′-tetramethyluronium
  • Apparatus Waters MS-trigger AutoPurification TM system (hereinafter abbreviated as purification apparatus A)
  • Method A Methanol or acetonitrile / 0.05% (v / v) aqueous formic acid
  • Method B Methanol or acetonitrile / 0.01% (v / v) aqueous ammonia
  • the purity was confirmed using the following equipment and conditions.
  • Apparatus Waters Acquity Ultra Performance LC on TUV Detector and ZQ mass spectrometer Column: Waters ACQUITY C18, 2.1 ⁇ 50 mm, 1.7 ⁇ m particle Column temperature: 60 ° C., flow rate: 1.0 mL / min, UV detection: 210 nm MS detection: ESI posi mode, method name: QC_neutral_full_1pt5min Eluent: acetonitrile / 10 mM ammonium acetate aqueous solution gradient: 5% (0-0.1 min), 5-95% (0.1-0.8 min), 95% (0.8-1 min), analysis time : 1.5 minutes Purification using HPLC can also be performed with the following equipment and conditions.
  • UV-trigger preparative HPLC system manufactured by Waters
  • purification apparatus B Column: XTerra MS C 18.5 ⁇ m, 19 ⁇ 50 mm or 30 ⁇ 50 mm
  • Detector UV 254nm
  • Low-resolution mass spectrum data (EI) was obtained by Integrity mass spectrum (Waters), Automass 120 mass spectrum (JEOL), or 6890GC / 5793MSD (GC-MS Agilent Technologies).
  • ppm parts per million
  • TMS tetramethylsilane
  • the IR spectrum was measured with an infrared spectrometer (IR-470: manufactured by Shimadzu Corporation).
  • the optical rotation was measured using a JASCO DIP-370 digital polarimeter (manufactured by JASCO Corporation).
  • the chemical symbol has the usual meaning, i.e. b. p. (Boiling point), m. p.
  • the protecting group Ts is a p-toluenesulfonyl group.
  • Example Compound 1 Synthesis intermediate compound 7 of 5- (1H-indol-2-yl) -1-methyl-N- [2- (piperidin-1-yl) ethyl] -1H-pyrazole-3-carboxamide 15 mg), amine form (1.1 equivalent) (14 mg as 2- (piperidin-1-yl) ethane-1-amine), triethylamine (0.026 mL, 3 equivalents) in DMF solution (0.5 mL) At room temperature, a DMF solution (0.5 mL) of hexafluorophosphoric acid O-benzotriazol-1-yl-N, N, N ′, N′-tetramethyluronium (36 mg, 1.5 equivalents) was added. .
  • the reaction solution was stirred at 50 ° C. for 2 hours.
  • the reaction solution was concentrated under reduced pressure, 1M aqueous sodium hydroxide solution (0.5 mL) was added to the residue, and the mixture was extracted twice with ethyl acetate (1 mL).
  • the combined organic layer residue was dissolved in a small amount of methanol, filled into an SCX cartridge (strong cation exchange cartridge), washed with methanol (10 mL), and finally eluted with 1 M ammonia-methanol solution (8 mL).
  • the crude product obtained by concentration was purified using preparative HPLC (purification apparatus A described in the introduction of [Example]).
  • Example compound 2 5- (1H-indol-2-yl) -N- [2- (4-methoxypiperidin-1-yl) ethyl] -1-methyl-1H-pyrazole-3-carboxamide
  • Example compound 3 N- [2- (4-Hydroxypiperidin-1-yl) ethyl] -5- (1H-indol-2-yl) -1-methyl-1H-pyrazole-3-carboxamide
  • Example Compound 4 N- [ 2- (4-Ethylpiperidin-1-yl) ethyl] -5- (1H-indol-2-yl) -1-methyl-1H-pyrazole-3-carboxamide
  • Example Compound 5 N- [2- (3 -Hydroxypiperidin-1-yl) ethyl] -5- (1H-indol-2-yl) -1-methyl-1H-pyrazole-3-carboxamide
  • Example Compound 5 N- [2- (3 -Hyd
  • Example Compound 17 Synthesis destination of 1-methyl-N- [2- (morpholin-1-yl) ethyl] -5- (quinolin-3-yl) -1H-pyrazole-3-carboxamide According to a method similar to the synthesis of Example Compound 1, Example Compound 17 (628 mg, 228 mg, 2.00 mg) was obtained as white crystals from Intermediate 12 (506 mg, 2.00 mmol) and 4- (2-aminoethyl) morpholine (286 mg, 2.20 mmol). 86% yield).
  • Example compound 18 1-methyl-N- [2- (piperidin-1-yl) ethyl] -5- (quinolin-3-yl) -1H-pyrazole-3-carboxamide
  • Example compound 19 1-methyl- N- [2- (Pyrrolidin-1-yl) ethyl] -5- (quinolin-3-yl) -1H-pyrazole-3-carboxamide
  • Example compound 20 1-methyl-N- [2- (pyrrolidin-1-yl) ethyl] -5- ⁇ 1H-pyrrolo [3,2-b] pyridin-2-yl ⁇ -1H-pyrazole-3- Synthesis of carboxamide
  • Example compound 20 1-methyl-N- [2- (pyrrolidin-1-yl) ethyl] -5- ⁇ 1H-pyrrolo [3,2-b] pyridin-2-yl ⁇ -1H-pyrazole-3-
  • Carboxamide synthesis intermediate 15 120 mg, 0.5 mmol
  • N- (2-aminoethyl) pyrrolidine 59 mg, 0.5 mmol
  • DMF 4 mL
  • Example Compound 21 N- [2- (3-hydroxypiperidin-1-yl) ethyl] -1-methyl-5- ⁇ 1H-pyrrolo [3,2-b] pyridin-2-yl ⁇ -1H-pyrazole- Synthesis of 3-carboxamide Example compound 21 (16 mg) from intermediate 15 (30 mg, 0.12 mmol) and 1- (2-aminoethyl) piperidin-3-ol (27 mg, 0.19 mmol) according to the method of Example compound 20 Yield 34%). MS (ESI) m / z: [M + H] + 369. For further purification, the preparative HPLC system (purification apparatus A) used in the purification of Example Compound 1 was used.
  • Example compound 22 1-methyl-5- ⁇ 5-methyl-1H-pyrrolo [3,2-b] pyridin-2-yl ⁇ -N- [2- (morpholin-4-yl) ethyl] -1H- Synthesis of pyrazole-3-carboxamide
  • Example compound 22 1-methyl-5- ⁇ 5-methyl-1H-pyrrolo [3,2-b] pyridin-2-yl ⁇ -N- [2- (morpholin-4-yl) ethyl] -1H-
  • pyrazole-3-carboxamide synthesis intermediate 20 36.9 mg, 0.1 mmol
  • DMF dimethyl methyl
  • potassium tert-butoxy 56 mg, 0.5 mmol
  • the reaction mixture was heated with stirring at 35 ° C. for 2 hours. After completion of the reaction, it was treated with water (0.5 mL), and the solvent was removed by concentration under reduced pressure.
  • Example Compound 22 (31.3 mg) as pale yellow crystals. Yield 84%).
  • Example compound 23 5- ⁇ 5,7-dimethyl-1H-pyrrolo [3,2-b] pyridin-2-yl ⁇ -1-methyl-N- [2- (morpholin-4-yl) ethyl]- Synthesis of 1H-pyrazole-3-carboxamide
  • Example compound 23 5- ⁇ 5,7-dimethyl-1H-pyrrolo [3,2-b] pyridin-2-yl ⁇ -1-methyl-N- [2- (morpholin-4-yl) ethyl]- Synthesis of 1H-pyrazole-3-carboxamide
  • Example Compound 23 (31.3 mg, 84% yield) as pale yellow crystals was obtained from Intermediate 21 (46.8 mg, 0.122 mmol) according to the same method as in the synthesis process of Example Compound 22.
  • 1 H-NMR 300 MHz, CDCl 3 ) ⁇ 9.75 (br s, 1H), 7.40-7.35 (m, 1H), 7.18 (s, 1H), 6.88 (s, 1H) , 6.82 (s, 1H), 4.09 (s, 3H), 3.80-3.67 (m, 4H), 3.57-3.44 (m, 2H), 2.62 (s , 3H), 2.60-2.40 (m, 6H), 2.54 (s, 3H).
  • MS (ESI) m / z: [M + H] + 383, [M ⁇ H] ⁇ 381.
  • Example compound 24 1-methyl-N- [2- (morpholin-4-yl) ethyl] -5- ⁇ 1H-pyrrolo [2,3-b] pyridin-2-yl ⁇ -1H-pyrazole-3- Synthesis of carboxamide
  • Example compound 24 1-methyl-N- [2- (morpholin-4-yl) ethyl] -5- ⁇ 1H-pyrrolo [2,3-b] pyridin-2-yl ⁇ -1H-pyrazole-3- Carboxamide Synthesis
  • Example Compound 24 (51.5 mg, 26% yield) as yellow crystals was obtained from Intermediate 22 (200 mg, 0.56 mmol) in the same manner as in Example Compound 22.
  • Example compound 25 1-methyl-N- [2- (morpholin-4-yl) ethyl] -5- ⁇ 5H-pyrrolo [3,2-d] pyrimidin-6-yl ⁇ -1H-pyrazole-3- Synthesis of carboxamide
  • Example compound 25 1-methyl-N- [2- (morpholin-4-yl) ethyl] -5- ⁇ 5H-pyrrolo [3,2-d] pyrimidin-6-yl ⁇ -1H-pyrazole-3- Carboxamide Synthesis
  • Example Compound 25 was prepared in the same manner as Example Compound 22 in the same manner as in Example Compound 22. Crude Example Compound 25 (41 mg, 37% yield), which was a pale brown solid from Intermediate 23 (112 mg, 0.315 mmol). ) was obtained.
  • Example compound 26 1-methyl-N- [2- (morpholin-4-yl) ethyl] -5- ⁇ 7H-pyrrolo [2,3-d] pyrimidin-6-yl ⁇ -1H-pyrazole-3- Synthesis of carboxamide
  • Example compound 26 1-methyl-N- [2- (morpholin-4-yl) ethyl] -5- ⁇ 7H-pyrrolo [2,3-d] pyrimidin-6-yl ⁇ -1H-pyrazole-3- Carboxamide Synthesis
  • Example Compound 26 was prepared by subjecting Intermediate 24 (115 mg, 0.324 mmol) to heating and stirring at 70 ° C. for 1 hour according to the same method as in Example Compound 22 to produce a crude brown solid. Obtained as Example Compound 26 (41 mg, 37% yield).
  • Example compound 27 1-methyl-N- [2- (morpholin-4-yl) ethyl] -5- [5- (trifluoromethyl) -1H-pyrrolo [3,2-b] pyridin-2-yl Synthesis of 1H-pyrazole-3-carboxamide
  • Example compound 28 1-methyl-5- ⁇ 5-methyl-1H-pyrrolo [2,3-b] pyridin-2-yl ⁇ -N- [2- (morpholin-4-yl) ethyl] -1H- Synthesis of pyrazole-3-carboxamide
  • Example compound 28 1-methyl-5- ⁇ 5-methyl-1H-pyrrolo [2,3-b] pyridin-2-yl ⁇ -N- [2- (morpholin-4-yl) ethyl] -1H- Pyrazole-3-carboxamide
  • Intermediate 26 460 mg, 1.25 mmol
  • tert-butoxypotassium 1200 mg, 10.7 mmol
  • This was purified by column chromatography using amine silica gel (dichloromethane / methanol 50/1 (v / v)), and further recrystallized from methanol and diisopropyl ether to give Example Compound 28 (229 mg, yield 50%).
  • Example compound 29 5- ⁇ 5-fluoro-1H-pyrrolo [2,3-b] pyridin-2-yl ⁇ -1-methyl-N- [2- (morpholin-4-yl) ethyl] -1H- Synthesis of pyrazole-3-carboxamide
  • Example compound 29 5- ⁇ 5-fluoro-1H-pyrrolo [2,3-b] pyridin-2-yl ⁇ -1-methyl-N- [2- (morpholin-4-yl) ethyl] -1H- Pyrazole-3-carboxamide
  • Example compound 30 5- ⁇ 5-cyano-1H-pyrrolo [3,2-b] pyridin-2-yl ⁇ -1-methyl-N- [2- (morpholin-4-yl) ethyl] -1H- Synthesis of pyrazole-3-carboxamide
  • Example compound 30 5- ⁇ 5-cyano-1H-pyrrolo [3,2-b] pyridin-2-yl ⁇ -1-methyl-N- [2- (morpholin-4-yl) ethyl] -1H- Pyrazole-3-carboxamide
  • Example compound 31 5- ⁇ 6-fluoro-1H-pyrrolo [3,2-b] pyridin-2-yl ⁇ -1-methyl-N- [2- (morpholin-4-yl) ethyl] -1H- Synthesis of pyrazole-3-carboxamide
  • Example compound 31 5- ⁇ 6-fluoro-1H-pyrrolo [3,2-b] pyridin-2-yl ⁇ -1-methyl-N- [2- (morpholin-4-yl) ethyl] -1H- Pyrazole-3-carboxamide
  • Intermediate 30 400 mg, 1.07 mmol
  • tert-butoxypotassium 603 mg, 5.37 mmol
  • This was purified by column chromatography using silica gel (dichloromethane / methanol 20/1 (v / v)), and recrystallization from methanol gave Example Compound 31 (71 mg, yield 18%) as white crystals. Obtained.
  • Example compound 32 1-methyl-N- [2- (morpholin-4-yl) ethyl] 5- ⁇ 5H-pyrrolo [2,3-b] pyrazin-6-yl ⁇ -1H-pyrazole-3-carboxamide Synthesis of
  • Example compound 32 1-methyl-N- [2- (morpholin-4-yl) ethyl] 5- ⁇ 5H-pyrrolo [2,3-b] pyrazin-6-yl ⁇ -1H-pyrazole-3-carboxamide
  • Intermediate 31 (267 mg, 0.75 mmol) and tert-butoxypotassium (420 mg, 3.76 mmol) in the same manner as in the synthesis process of Example Compound 22.
  • This was purified by column chromatography using silica gel (dichloromethane / methanol 20 / 1-15 / 1 (v / v)), and further recrystallized from methanol and diisopropyl ether to give Example Compound 32 (183 mg, yield).
  • Example compound 33 5- ⁇ 5-cyano-1H-pyrrolo [2,3-b] pyridin-2-yl ⁇ -1-methyl-N- [2- (morpholin-4-yl) ethyl] -1H- Synthesis of pyrazole-3-carboxamide
  • Example compound 33 5- ⁇ 5-cyano-1H-pyrrolo [2,3-b] pyridin-2-yl ⁇ -1-methyl-N- [2- (morpholin-4-yl) ethyl] -1H- Pyrazole-3-carboxamide
  • Phenyltrimethylammonium tribromide (148 mg, 0.40 mmol) was added to a THF solution (1 mL) of intermediate 33 (79 mg, 0.40 mmol), and the mixture was stirred at room temperature for 1.5 hours.
  • the obtained reaction liquid was poured into water (20 mL), and the aqueous layer was extracted with ether (20 mL ⁇ 2).
  • the obtained organic layer was dried over magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure.
  • Example Compound 34 Synthesis of 5- ⁇ imidazo [1,2-a] pyridin-2-yl ⁇ -1-methyl-N- [2- (morpholin-4-yl) ethyl] -1H-pyrazole-3-carboxamide To a solution of intermediate 36 (54 mg), 4- (2-aminoethyl) morpholine (32 mg, 0.24 mmol), and triethylamine (0.09 mL, 0.67 mmol) in acetonitrile (1 mL) was added hexafluorophosphate O-benzoate.
  • Example compound 35 5- (1,3-benzothiazol-2-yl) -1-methyl-N- [2- (morpholin-4-yl) ethyl] -1H-pyrazole-3-carboxamide intermediate 17 (100 mg, 0.275 mmol), benzothiazole (31 mg, 0.229 mmol), copper (I) iodide (44 mg, 0.229 mmol), triphenylphosphine (12 mg, 0.046 mmol) and tripotassium phosphate (97 mg) , 0.458 mmol) in DMSO (0.7 mL) was stirred at 160 ° C. for 1 hour under a nitrogen atmosphere.
  • Example compound 36 5- ⁇ 5-fluoro-1-methyl-1H-pyrrolo [2,3-b] pyridin-2-yl ⁇ -1-methyl-N- [2- (morpholin-4-yl) ethyl Synthesis of Example Compound 29 (30 mg, 0.08 mmol) and Cesium Carbonate (52 mg, 0.16 mmol) in Acetonitrile (5 mL) with methyl iodide (14.2 mg, 0.2 mg). 10 mmol) was added and the reaction solution was stirred at 60 ° C. for 3 hours. After cooling to room temperature, the reaction mixture was diluted with dichloromethane, washed with water and saturated brine, and dried over sodium sulfate.
  • Example compound 37 5- (5-fluoro-1H-indol-2-yl) -N- ⁇ 2-[(2R) -2- (hydroxymethyl) pyrrolidin-1-yl] ethyl ⁇ -1-methyl- 1H-pyrazole-3-carboxamide
  • reaction solution was stirred at room temperature for 16 hours.
  • Example compound 37 5- (5-fluoro-1H-indol-2-yl) -N- ⁇ 2-[(2R) -2- (hydroxymethyl) pyrrolidin-1-yl] ethyl ⁇ -1-methyl- 1H-pyrazole-3-carboxamide intermediate 38 (30 mg, 0.10 mmol), (R)-( ⁇ )-2-pyrrolidinemethanol (15 mg, 0.15 mmol), acetic acid (0.15 mL) in THF (4. 2 mL) was stirred at room temperature for 10 minutes. Thereafter, a solution of sodium triacetoxyborohydride (63 mg, 0.30 mmol) in THF (0.2 mL) was added and stirred overnight at room temperature.
  • sodium triacetoxyborohydride 63 mg, 0.30 mmol
  • Example compound 38 5- (5-fluoro-1H-indol-2-yl) -N- ⁇ 2-[(3R) -3- (hydroxypyrrolidin-1-yl] ethyl ⁇ -1-methyl-1H- Pyrazole-3-carboxamide
  • Example Compound 39 5- (5-Fluoro-1H-indol-2-yl) -N- ⁇ 2-[(3S) -3- (hydroxypiperidin-1-yl] ethyl ⁇ -1 -Methyl-1H-pyrazole-3-carboxamide
  • Example Compound 40 5- (5-Fluoro-1H-indol-2-yl) -1-methyl-N- ⁇ 2-[(1S, 4S) -2-oxa -5-Azabicyclo [2.2.1] heptan-5-yl] ethyl ⁇ -1H-pyrazole-3-carboxamide
  • Example Compound 41 N-
  • Example compound 17 As shown in the synthesis destination of 1-methyl-N- [2- (morpholin-4-yl) ethyl] -5- (quinolin-3-yl) -1H-pyrazole-3-carboxamide
  • intermediate 17 526 mg, 1.44 mmol
  • 3-quinolineboronic acid 250 mg, 1.44 mmol
  • potassium phosphate 458 mg, 2.16 mmol
  • Tris (dibenzylideneacetone) dipalladium (0) (66 mg, 0.0723 mmol) was added to a mixed solution of (40.4 mg, 0.14 mmol) of 1,4-dioxane (20 ml) and water (3 mL), and the reaction mixture was added.
  • Example Compound 17 (204 mg, 39% yield) as white crystals.
  • Example compound 48 1-methyl-N- [2- (morpholin-4-yl) ethyl] -5- (quinolin-6-yl) -1H-pyrazole-3-carboxamide
  • Example compound 49 1-methyl- N- [2- (morpholin-4-yl) ethyl] -5- (quinolin-7-yl) -1H-pyrazole-3-carboxamide
  • Example Compound 50 1-methyl-N- [2- (morpholine-4 -Yl) ethyl] -5- (naphthalen-2-yl) -1H-pyrazol-3-carboxamide
  • Example Compound 51 5- (6-methoxynaphthalen-2-yl) -1-methyl-N- [2- (Morpholin-4-yl) ethyl] -1H-pyrazol-3-carboxamide
  • Example Compound 52 5- (7-Methoxynaphthalen-2-yl) -1-methyl-N
  • Example compound 55 5- (1H-indol-3-yl) -1-methyl-N- [2- (morpholin-4-yl) ethyl] -1H-pyrazole-3-carboxamide synthesis intermediate 39 (271 mg) ) was dissolved in methanol (5 mL), 2M aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at 70 ° C. for 30 min. After cooling, water (10 mL) was added to the reaction solution, and extracted with dichloromethane (50 mL) three times. The combined organic layers were dried over magnesium sulfate, and then the desiccant was filtered and concentrated under reduced pressure.
  • Example Compound 56 1-methyl-5- (1-methyl-1H-indol-3-yl) -N- [2- (morpholin-4-yl) ethyl] -1H-pyrazole-3-carboxamide
  • Example compound 55 (50 mg) was dissolved in acetonitrile (1 mL), cesium carbonate (138 mg, 0.42 mmol) and methyl iodide (0.013 mL, 0.21 mmol) were added, and the mixture was heated to reflux for 1 hour. After cooling, insoluble matters were removed by filtration, and the filtrate was concentrated under reduced pressure.
  • Example compound 57 1-methyl-5- (3-methyl-1H-indol-5-yl) -N- [2- (morpholin-4-yl) ethyl] -1H-pyrazole-3-carboxamide
  • Example compound 58 1-Methyl-5- (2-methyl-1H-indol-5-yl) -N- [2- (morpholin-4-yl) ethyl] -1H-pyrazole-3-carboxamide
  • Example Compound 59 1 -Methyl-N- [2- (morpholin-4-yl) ethyl] -5- ⁇ 1H-pyrrolo [2,3-b] pyridin-3-yl ⁇ -1H-pyrazole-3-carboxamide
  • Example Compound 60 5- (5-Methoxy-1H-indol-3-yl) -1-methyl-N- [2- (morpholin-4-yl) ethyl] -1H-pyrazole-3-carboxamide
  • Example Compound 61 5- (
  • Example Compound 76 5- (4-Methanesulfonyl-1H-indol-2-yl) -1-methyl-N- [2- (morpholin-4-yl) ethyl] -1H-pyrazole-3-carboxamide intermediate Tetrabutylammonium fluoride monohydrate (140 mg, 0.53 mmol) was added to a solution of compound 52 (61 mg, 0.11 mmol) in THF (5 mL), and the mixture was stirred for 3 hours under heating to reflux. After cooling to room temperature, the residue obtained by concentration under reduced pressure was purified using SCX (strong cation exchange cartridge) in the same manner as Example Compound 1 to obtain a crude product 76 as a yellow solid. .
  • SCX strong cation exchange cartridge
  • Example Compound 76 (17 mg, yield 37%) as a yellow solid.
  • Example compound 78 5- (4-methanesulfonamido-1H-indol-2-yl) -1-methyl-N- [2- (morpholin-4-yl) ethyl] -1H-pyrazole-3-carboxamide Synthesis of
  • Example compounds are essentially the same as Step F-3 described above, and are performed under the conditions selected from Step F-3.
  • Example Compound 77 Synthesis of 5- (4-acetamido-1H-indol-2-yl) -1-methyl-N- [2- (morpholin-4-yl) ethyl] -1H-pyrazole-3-carboxamide
  • Example Compound 78 5- (4-Methanesulfonamido-1H-indol-2-yl) -1-methyl-N- [2- (morpholin-4-yl) ethyl] -1H-pyrazole-3-carboxamide intermediate
  • Example compound 77 and 78 shown in the following table were prepared using the presence of a base (triethylamine) in a 1,2-dichloroethane solution and a reagent (acetyl chloride or acetic anhydride, methanesulfonyl chloride), respectively. It was. For further purification, the preparative HPLC system (purification apparatus A) used in the purification of Example Compound 1 was used.
  • Example compound 80 5- (1-methanesulfonyl-3-methyl-1H-indol-5-yl) -1-methyl-N- [2- (morpholin-4-yl) ethyl] -1H-pyrazole-3 —Synthesis of carboxamide
  • Example compounds 79 and 80 shown in the following table were prepared using a base (sodium hydride) in the DMF solution and a reagent (methanesulfonyl chloride), respectively.
  • the preparative HPLC system purification apparatus A used in the purification of Example Compound 1 was used.
  • Example Compound 81 Synthesis of 1-methyl-5- (3-methyl-1H-indol-1-yl) -N- [2- (morpholin-4-yl) ethyl] -1H-pyrazole-3-carboxamide Form 17 (50 mg, 0.14 mmol) was dissolved in DMF (1 mL) and 3-methylindole (27 mg, 0.21 mmol), cesium carbonate (179 mg, 0.55 mmol) and copper (I) iodide (52 mg, 0 .28 mmol) was added, and the mixture was stirred at 110 ° C. for 20 hours. After cooling, insoluble matters were removed by filtration, and the filtrate was concentrated under reduced pressure.
  • Example compound 82 5- ⁇ 5-cyano-1H-pyrrolo [2,3-b] pyridin-2-yl ⁇ -N- [2- (3,3-difluoroazetidin-1-yl) ethyl]- Synthesis of 1-methyl-1H-pyrazol-3-carboxamide
  • Example compound 82 5- ⁇ 5-cyano-1H-pyrrolo [2,3-b] pyridin-2-yl ⁇ -N- [2- (3,3-difluoroazetidin-1-yl) ethyl]- Synthesis of 1-methyl-1H-pyrazol-3-carboxamide Following an analogous method to the synthesis process of Example Compound 22, Example Compound 82 (21 mg, 21 mg, Yield 72%).
  • Example compound 83 N- [2- (3,3-difluoroazetidin-1-yl) ethyl] -1-methyl-5- ⁇ 1H-pyrrolo [2,3-b] pyridin-2-yl ⁇ - Synthesis of 1H-pyrazol-3-carboxamide
  • Example compound 83 N- [2- (3,3-difluoroazetidin-1-yl) ethyl] -1-methyl-5- ⁇ 1H-pyrrolo [2,3-b] pyridin-2-yl ⁇ - Synthesis of 1H-pyrazol-3-carboxamide
  • Example compound 83 (37.9 mg, yield) as a pale yellow solid from intermediate 61 (50 mg, 0.075 mmol) according to the same method as the synthesis process of example compound 22 75%).
  • Example compound 84 5- ⁇ 6-fluoroimidazo [1,2-a] pyridin-2-yl ⁇ -1-methyl-N- [2- (morpholin-4-yl) ethyl] -1H-pyrazol -3-Synthesis of carboxamide
  • Example compound 84 5- ⁇ 6-fluoroimidazo [1,2-a] pyridin-2-yl ⁇ -1-methyl-N- [2- (morpholin-4-yl) ethyl] -1H-pyrazol Synthesis of -3-carboxamide According to the same method as the synthesis of Example Compound 1 shown above, intermediate 63 (67 mg, 0.257 mmol) and 4- (2-aminoethyl) morpholine (36.9 mg, 0.283 mmol) ) To give crude Example Compound 84 (52.3 mg, 54% yield) as white crystals. For further purification, the preparative HPLC system (purification apparatus A) used in the purification of Example Compound 1 was used. MS (ESI) m / z: [M + H] + 373.
  • Example compound 85 5- ⁇ 7-fluoroimidazo [1,2-a] pyridin-2-yl ⁇ -1-methyl-N- [2- (morpholin-4-yl) ethyl] -1H-pyrazol -3-Synthesis of carboxamide
  • Example compound 85 5- ⁇ 7-fluoroimidazo [1,2-a] pyridin-2-yl ⁇ -1-methyl-N- [2- (morpholin-4-yl) ethyl] -1H-pyrazol Synthesis of -3-carboxamide According to the same method as the synthesis of Example Compound 1 shown above, intermediate 65 (67 mg, 0.257 mmol) and 4- (2-aminoethyl) morpholine (36.9 mg, 0.283 mmol) ) Afforded crude example compound 85 (102 mg) as white crystals. For further purification, the preparative HPLC system (purification apparatus A) used in the purification of Example Compound 1 was used. MS (ESI) m / z: [M + H] + 373.
  • Example compound 86 5- ⁇ 6-cyanoimidazo [1,2-a] pyridin-2-yl ⁇ -1-methyl-N- [2- (morpholin-4-yl) ethyl] -1H-pyrazol -3-Synthesis of carboxamide
  • Example compound 86 5- ⁇ 6-cyanoimidazo [1,2-a] pyridin-2-yl ⁇ -1-methyl-N- [2- (morpholin-4-yl) ethyl] -1H-pyrazol -3-Carboxamide Synthesis Intermediate 68 (74.9 mg, 0.173 mmol), anhydrous zinc cyanide (12.5 mg, 0.107 mmol) and tetrakis (triphenylphosphine) palladium (20.0 mg, 0.017 mmol) The DMF mixed solution (4 mL) was stirred at 100 ° C. for 20 hours. After cooling to room temperature, the reaction mixture was added with water and extracted with a mixture of ethyl acetate / toluene (9/1).
  • Example Compound 87 N- [2- (3,3-difluoroazetidin-1-yl) ethyl] -1-methyl-5- (quinolin-3-yl) -1H-pyrazol-3-carboxamide
  • 1,4-dioxane of intermediate 57 224 mg, 0.605 mmol
  • 3-quinolineboronic acid 122 mg, 0.666 mmol
  • Example compound 81 (181 mg, 80% yield) was obtained as a brown solid. Furthermore, the Example compound (181 mg) was recrystallized from an ethyl acetate and hexane solution and purified to the Example compound 87 (121 mg).
  • Example compound 88 5- ⁇ 7-cyanoimidazo [1,2-a] pyridin-2-yl ⁇ -1-methyl-N- [2- (morpholin-4-yl) ethyl] -1H-pyrazol -3-Synthesis of carboxamide
  • Example compound 88 5- ⁇ 7-cyanoimidazo [1,2-a] pyridin-2-yl ⁇ -1-methyl-N- [2- (morpholin-4-yl) ethyl] -1H-pyrazol Synthesis of 3-carboxamide
  • Example 72 Reaction of intermediate 72 (174.1 mg, 0.455 mmol) with THF (5 mL) and 2M aqueous hydrochloric acid (2.5 mL) according to the same method as the synthesis of intermediate 57 of compound 82 The mixture was stirred at 50 degrees for 1 hour. After cooling to room temperature, the reaction mixture was adjusted to pH 10 or higher with 2M aqueous sodium hydroxide solution (2.5 mL), and extracted twice with ethyl acetate.
  • CHO-K1 cells introduced with human 5-HT 2B receptor were purchased from Euroscreen (catalog number; ES-314-F) and cultured. After culturing, the collected cells were suspended in 50 mM HEPES (pH 7.4) supplemented with a protease inhibitor cocktail (manufactured by SIGMA, 1: 100 at a ratio of 1: 100) and 1 mM EDTA. Using a Polytron crusher PT1200, homogenization was performed for 30 seconds at the maximum output.
  • the suspension was centrifuged (1,000 rpm, 4 ° C., 5 minutes), and the supernatant was frozen at ⁇ 80 ° C. for 10 minutes.
  • the frozen supernatant was resuspended in 50 mM HEPES (pH 7.4), homogenized, and subjected to the same centrifugation.
  • the obtained supernatant was further centrifuged (25,000 rpm, 4 ° C., 60 minutes), and the precipitate was resuspended in 50 mM HEPES (pH 7.4), homogenized, and then subdivided and used at ⁇ 80 ° C. until used. Saved with.
  • CHO-K1 cells introduced with human 5-HT 2B receptor were purchased from Euroscreen and cultured. Cells were UltraCHO supplemented with G418 (400 ⁇ g / mL), Zeocin (250 ⁇ g / mL), penicillin (100 U / mL), streptomycin (100 ⁇ g / mL), and dialyzed 1% (v / v) FBS (fetal bovine serum). The culture was performed at 37 ° C. and 5% CO 2 using a medium (Cambrex).
  • the cell culture solution was subjected to KRH buffer containing 5 ⁇ M Fura-2 AM (CaCl 2 : 1.8 mM, MgSO 4 : 1 mM, NaCl: 115 mM, KCl: 5.4 mM, D- glucose: 11 mM, NaH 2 PO 4 : 0.96 mM, HEPES: 25 mM, pH adjusted to pH 7.4 with NaOH).
  • the cells were incubated for 120 minutes at room temperature. After incubation, the cells were detached with 0.05% (w / w) Trypsin / 1 mM EDTA and washed with PBS.
  • the cells were suspended in KRH buffer so as to be 1.0 ⁇ 10 6 cells / mL.
  • the test compound of the present invention was dispensed into a 384 well plate at 50 ⁇ L per well.
  • 34 ⁇ L of cell suspension (3.4 ⁇ 10 4 cells) was then dispensed into a 384 well black assay plate (clear bottom) with a clear bottom.
  • the assay plate was fixed to FDSS6000 (manufactured by Hamamatsu Photonics) and signal measurement was started. After 30 seconds, 6 ⁇ L of the diluted test compound was automatically added to each well, and the measurement by FDSS6000 was further continued for 4 minutes and 30 seconds to determine the antagonistic activity of the test compound. The cells were then incubated in the dark for 10 minutes at room temperature.
  • the assay plate was again fixed to FDSS6000 and signal measurement was started. After 30 seconds, 20 ⁇ L of 9 nM 5-HT was automatically added to each well, and the IC 50 value of the test compound was determined by continuing the measurement with FDSS6000 for half an additional 4 minutes. For this experiment, see Br. J. et al. Pharmacol. , 1999 September; 128 (1): 13-20. Was referenced.
  • the antagonistic activity of the compound of the present invention on the 5-HT 2A receptor was determined by the following method. 3T3 cells introduced with human 5-HT 2A receptor were prepared and cultured. The cells were 37 ° C., 5% using DMEM medium (Invitrogen) supplemented with G418 (400 ⁇ g / mL), penicillin (100 U / mL), streptomycin (100 ⁇ g / mL), and 10% (v / v) FBS. Cultivation was performed under CO 2 conditions.
  • the cell culture solution was subjected to KRH buffer containing 5 ⁇ M Fura-2 AM (CaCl 2 : 1.8 mM, MgSO 4 : 1 mM, NaCl: 115 mM, KCl: 5.4 mM, D- glucose: 11 mM, NaH 2 PO 4 : 0.96 mM, HEPES: 25 mM, pH adjusted to pH 7.4 with NaOH).
  • the cells were incubated for 120 minutes at room temperature. After incubation, the cells were detached with 0.05% Trypsin / 1 mM EDTA and washed with PBS.
  • the cells were suspended in KRH buffer so as to be 0.3 ⁇ 10 6 cells / mL.
  • the test compound of the present invention was dispensed into a 384 well plate at 50 ⁇ L per well.
  • 34 ⁇ L of cell suspension (1.0 ⁇ 10 4 cells) was then dispensed into a 384 well black assay plate (clear bottom) with a clear bottom.
  • the assay plate was fixed to FDSS6000 (manufactured by Hamamatsu Photonics) and signal measurement was started. After 30 seconds, 6 ⁇ L of the diluted test compound was automatically added to each well, and the measurement by FDSS6000 was further continued for 4 minutes and 30 seconds to determine the antagonistic activity of the test compound. The cells were then incubated in the dark for 10 minutes at room temperature.
  • the assay plate was again fixed to FDSS6000 and signal measurement was started. After 30 seconds, 20 ⁇ L of 90 nM 5-HT was automatically added to each well, and the IC 50 value of the test compound was determined by continuing the measurement with FDSS6000 for half an additional 4 minutes. For this experiment, see Br. J. et al. Pharmacol. , 1999 September; 128 (1): 13-20. Was referenced.
  • the antagonistic activity of the compound of the present invention on the 5-HT 2c receptor was determined by the following method.
  • 3T3 cells introduced with human 5-HT 2c receptor were prepared and cultured.
  • the cells were prepared using DMEM medium (manufactured by Invitrogen) supplemented with G418 (20 ⁇ g / mL), penicillin (100 U / mL), streptomycin (100 ⁇ g / mL), and 10% (v / v) FBS (fetal bovine serum).
  • the cells were cultured under conditions of 37 ° C. and 5% CO 2 .
  • the cell culture solution was mixed with KRH buffer (CaCl 2 : 1.8 mM, MgSO 4 : 1 mM, NaCl: 115 mM, KCl: 5.4 mM, D-glucose containing 5 ⁇ M Fura-2AM. : 11 mM, NaH 2 PO 4 : 0.96 mM, HEPES: 25 mM, pH adjusted to pH 7.4 with NaOH).
  • KRH buffer CaCl 2 : 1.8 mM, MgSO 4 : 1 mM, NaCl: 115 mM, KCl: 5.4 mM, D-glucose containing 5 ⁇ M Fura-2AM. : 11 mM, NaH 2 PO 4 : 0.96 mM, HEPES: 25 mM, pH adjusted to pH 7.4 with NaOH.
  • the cells were incubated for 120 minutes at room temperature. After incubation, the cells were detached with 0.05% Trypsin / 1 m
  • the cells were suspended in KRH buffer so as to be 0.45 ⁇ 10 6 cells / mL.
  • the test compound of the present invention was dispensed into a 384 well plate at 50 ⁇ L per well.
  • 34 ⁇ L of cell suspension (1.5 ⁇ 10 4 cells) was then dispensed into a 384 well black assay plate (clear bottom) with a clear bottom.
  • the assay plate was fixed to FDSS6000 (manufactured by Hamamatsu Photonics) and signal measurement was started. After 30 seconds, 6 ⁇ L of the diluted test compound was automatically added to each well, and the measurement by FDSS6000 was further continued for 4 minutes and 30 seconds to determine the antagonistic activity of the test compound. The cells were then incubated in the dark for 10 minutes at room temperature.
  • the assay plate was again fixed to FDSS6000 and signal measurement was started. After 30 seconds, 20 ⁇ L of 3 nM 5-HT was automatically added to each well, and the IC 50 value of the test compound was determined by continuing the measurement with FDSS6000 for half an additional 4 minutes. For this experiment, see Br. J. et al. Pharmacol. , 1999 September; 128 (1): 13-20. Was referenced.
  • Example Compound 24 The animals after the operation were bred in a normal environment and used for drug evaluation after 7 days after the operation.
  • the test compound was evaluated using the colonic extension stimulation method (Dipharma L. et al., J Pharmacol Exp Ther. 302 (3): 1013-22 (2002)).
  • a 5 cm long balloon is inserted from the anus and placed so that the tip is located 10 cm from the anus.
  • the load was applied stepwise up to 70 mmHg by 5 mmHg.
  • Balloon pressure (mmHg) in which rats showed abdominal muscle contraction (Neurosi Lett. 24; 246 (2): 73-6, authored by Wesselmann U et al.) was evaluated as a pain threshold.
  • the results of Example Compound 24 are shown in FIG.
  • the number of animals in each group is 8.
  • the data in the graph shows the median value. Bars show 25% and 75% values.
  • Statistical analysis was performed by closed test using Mann-Whitney test.
  • the vertical axis represents pain threshold pressure. In this case, a significant improvement effect was shown by oral administration of 10 mg / kg against the decrease in pain threshold induced by TNBS. Therefore, it was shown that the novel pyrazole-3-carboxamide derivative having 5-HT 2B receptor antagonist activity of the present invention is also useful for the treatment of IBS.
  • the compound of the present invention is a compound useful as a selective antagonist of 5-HT 2B receptor, and is useful for prevention or treatment of various diseases in which this receptor is involved.
PCT/JP2009/069816 2008-11-21 2009-11-24 ５－ｈｔ２ｂ受容体拮抗活性を有する新規ピラゾール－３－カルボキサミド誘導体 WO2010058858A1 (ja)

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ES09827639.7T ES2549005T3 (es) 2008-11-21 2009-11-24 Nuevo derivado de pirazol-3-carboxamida que tiene actividad antagonista del receptor 5-HT2B
RU2011125314/04A RU2528406C2 (ru) 2008-11-21 2009-11-24 Новое производное пиразол-3-карбоксамида, обладающее антагонистической активностью в отношении рецептора 5-нт2в
CN200980146558.8A CN102224142B (zh) 2008-11-21 2009-11-24 具有5-ht2b受体拮抗活性的新型吡唑-3-羧酰胺衍生物
EP09827639.7A EP2386546B1 (en) 2008-11-21 2009-11-24 Novel pyrazole-3-carboxamide derivate having 5-ht2b receptor antagonist activity
US13/129,916 US8252790B2 (en) 2008-11-21 2009-11-24 Pyrazole-3-carboxamide derivative having 5-HT2B receptor antagonist activity
BRPI0921097A BRPI0921097B8 (pt) 2008-11-21 2009-11-24 composto ou seu sal farmaceuticamente aceitável, intermediário do composto, composição farmacêutica e uso do composto
CA2741511A CA2741511C (en) 2008-11-21 2009-11-24 Novel pyrazole-3-carboxamide derivative having 5-ht2b receptor antagonist activity
MX2011005221A MX2011005221A (es) 2008-11-21 2009-11-24 Nuevo derivado de la pirazol-3-carboxamida que tiene actividad de antagonista del receptor de 5-ht2b.
JP2010539267A JP5621148B2 (ja) 2008-11-21 2009-11-24 ５−ｈｔ２ｂ受容体拮抗活性を有する新規ピラゾール−３−カルボキサミド誘導体
HK12103083.8A HK1163063A1 (en) 2008-11-21 2012-03-28 Novel pyrazole-3-carboxamide derivate having 5-ht2b receptor antagonist activity 5-ht2b -3-

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EP3089972B1 (de) 2014-01-03 2018-05-16 Bayer Animal Health GmbH Neue pyrazolyl-heteroarylamide als schädlingsbekämpfungsmittel
WO2015116460A1 (en) * 2014-01-28 2015-08-06 Virginia Commonwealth University 2-substituted-5-hydroxy-4h-chromen-4-ones as novel ligands for the serotonin receptor 2b (5-ht2b)
WO2017070320A1 (en) 2015-10-21 2017-04-27 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Phenyl indole allosteric inhibitors of p97 atpase
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EP3753924A1 (en) 2019-06-18 2020-12-23 AnaMar AB New tricyclic 5-ht2 antagonists
KR20220097434A (ko) * 2019-11-01 2022-07-07 브리스톨-마이어스 스큅 컴퍼니 톨 수용체 억제제로서의 치환된 피라졸 화합물
KR20220014854A (ko) * 2020-07-29 2022-02-07 주식회사 비보존 mGluR5 및 5-HT2A 수용체의 이중 조절제 및 이의 용도
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US9394285B2 (en) 2013-03-15 2016-07-19 Pfizer Inc. Indole and indazole compounds that activate AMPK
EP4149459A1 (en) * 2020-05-12 2023-03-22 PMV Pharmaceuticals, Inc. Methods and compounds for restoring mutant p53 function

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