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WO2007052843A1 - Compose amide heterocyclique et son utilisation - Google Patents

Compose amide heterocyclique et son utilisation Download PDF

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Publication number
WO2007052843A1
WO2007052843A1 PCT/JP2006/322420 JP2006322420W WO2007052843A1 WO 2007052843 A1 WO2007052843 A1 WO 2007052843A1 JP 2006322420 W JP2006322420 W JP 2006322420W WO 2007052843 A1 WO2007052843 A1 WO 2007052843A1
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Japanese (ja)
Inventor
Shotaro Miura
Mitsuyuki Shimada
Shogo Marui
Norikazu Tamura
Yoshihisa Nakada
Ryuichi Tozawa
Junichi Sakamoto
Yasunori Funabashi
Hiroshi Hosono
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Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
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    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
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    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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Definitions

  • the present invention is composed of a compound having an inhibitory activity, or a salt thereof or a prodrug thereof, which has an inhibitory activity on a Farnesoid-one X receptor (hereinafter sometimes abbreviated as FXR).
  • FXR Farnesoid-one X receptor
  • the present invention relates to a preventive and Z or therapeutic agent for hyperlipidemia, low HDL cholesterol, oralemia, arteriosclerosis (eg, atherosclerosis, etc.), xanthoma and the like.
  • Background art-An abnormal increase in serum lipid concentration is called hyperlipidemia (hyperi idi em a, h i per i i em a).
  • Serum lipids include cholesterol nol (cholesterol ester, free cholesterol), phospholipids (lecithin, sulfinogen, etc.), triglycerides (neutral fats), free fatty acids, other sterols, etc.
  • the problem is the increase in cholesterol and tori thalelinide (COMMON DIS EAS ES ER IES No. 1 9 hyperlipidemia 'edited by Haruo Nakamura 1 99 1 year 1; issued on January 10, Minami-e-do).
  • hypercholesterolemia is an important risk factor for arteriosclerotic diseases such as myocardial infarction, angina pectoris and cerebral infarction, as well as hypertension and smoking.
  • arteriosclerotic diseases such as myocardial infarction, angina pectoris and cerebral infarction, as well as hypertension and smoking.
  • LDL low density lipoprotein
  • ischemic heart disease The treatment target value of LDL-cholesterol is considered to be less than 100 m, g / dL for patients who are at high risk of developing the disease, but the results of the latest large-scale outcome test etc. It has also been proposed that the treatment target value be less than 7 Omg / d L (Am. J. — C ardio ⁇ , 2005. 96 (45 A). 5 3 E— 59 E).
  • X-ray tumor (X anthoma tosis) is a pathological condition in which lipids are deposited in the skin or connective tissue, and the site is found in the eyelids and palms, the tendon, and the skin on the extension side of joints.
  • X anthoma tosis is a pathological condition in which lipids are deposited in the skin or connective tissue, and the site is found in the eyelids and palms, the tendon, and the skin on the extension side of joints.
  • the cell (foamed cell) which accumulated a large amount of lipid by taking in this is local It is known to accumulate in One of the factors promoting or exacerbating this process is hyperlipidemia, and the form of xanthoma formed is believed to depend on the type of hyperlipidemia.
  • Hypercholesterolemia particularly familial hypercholesterolemia, nodular xanthoma, tendon xanthoma, blepharomatous erythema, 5 hypertriglyceridemia, rash-type xanthoma, remnant lipoprotein increase
  • hyperlipidemia of the type nodular rash xanthomas, palmar xanthomas, palmar streak xanthomas are specifically observed.
  • eyelid xanthomas are always accompanied by hypercholesterolemia In some cases, it has been reported that there are cases where HDL-cholesterol is relatively lowered, in some cases (J. Am. Ac. Ad. Dermatl, 1 9 9 4, 30, 23 6 — 24 2).
  • Drugs that lower blood LDL-cholesterol levels include those that capture bile acids such as cholestyramine and colestipol and block their absorption, and block cholesterol transport systems in the small intestine cells such as ezetimibe so that cholesterol can be absorbed into the intestine.
  • Inhibitors of cholesterine, inhibitors of cholesterol biosynthesis such as atorvastatin, pravastatin, etc. which inhibit 3-hydro X y-. 3- methylglutary 1- coenz yme A (HMG-Co A) reductase are also clinically used.
  • HMG-C ⁇ reductase inhibitors are known to be the drugs that show the most potent action on LDL / cholesterol reduction, but in addition to biosynthesis of cholesterol nore, biological compounds such as ubiquinone, dolicol, heme ⁇ Since it also inhibits the biosynthesis of the components necessary for maintaining function, there are concerns about the side effects resulting therefrom.
  • nicotinic acid preparations that can be expected to have the most potent triglyceride lowering action and HD L-cholesterol raising action may limit their use due to frequent occurrence of flushing, rash, glucose intolerance etc. .
  • simultaneous administration of an HMG-CoA reductase inhibitor and a bile acid scavenger may result in inhibition of absorption of the HMG-COA reducing enzyme inhibitor by the bile acid scavenger.
  • the existing drugs are not sufficiently satisfactory in terms of side effects and efficacy, and have a novel mechanism of action that is more effective and can be used in combination with the above drugs LDL monocholesterol and triglyceride reducing agents And HD L-cholesterol enhancers are desired.
  • FXR is one of the nuclear receptor family that is highly expressed in the liver, small intestine, etc. and is composed of bile acids such as chenodeoxycholic acid.
  • FXR activation reduces the gene expression of CYP7A1, which is a rate-limiting enzyme of bile acid synthesis system, and apoprotein A-I, which is a major component protein of HDL particles, in the liver, and in the small intestine, bile acid is reactivated.
  • I-BABP ileal bile acid binding protein
  • FXR inhibitors are not only useful as novel LDL-cholesterol-lowering and HD L-cholesterol-increasing agents, but also useful as growth inhibitors, regression accelerators, and yellow-species improvers for atheroma-induced arterial disease Conceivable. , No '
  • Bile acids are produced in the liver, combined with glycine or taurine to form conjugated bile acids, and after being secreted from the biliary tract into the intestine, they are involved in the digestion and absorption of dietary lipids as' surfactants. Most of the bile acid in the intestine is reabsorbed from the end of the ileum and then recovered to the liver via the portal vein and reused.
  • physiological actions of bile acids in addition to surface-active actions derived from their physicochemical properties, pharmacological actions and metabolic regulatory actions of unknown mechanism via specific receptors such as the above-mentioned FXR are known. .
  • TGR 5 is one of the G-protein coupled receptors expressed in lung, spleen, digestive system tissue, muscle, adipose tissue, monocytes / macrophages, etc. Acids are used as ligands.
  • the activation of TGR 5 suppresses the production of inflammatory cytokines from lipopolysaccharide-stimulated monocyte cells (J. B io 1. C hem. 200 3, 278 (11), 94 3 5-40), bile acids may have anti-inflammatory effects in peripheral tissues.
  • activation of TGR5 in small intestinal cells has been reported to promote the production of glucagon-like peptide 1 (GLP-1) (Biochem. Biophys. Res.
  • GLP-1 is known to act as an endogenous insulin secretion promoting Z glucagon production inhibitory hormone, suggesting a diabetic ameliorating action by bile acid.
  • GLP-1 is known to act as an endogenous insulin secretion promoting Z glucagon production inhibitory hormone, suggesting a diabetic ameliorating action by bile acid.
  • TGR 5 since activation of TGR 5 in brown adipose tissue and skeletal muscle enhances local fatty acid oxidation ability (Nature 206, 439 (7075): 402-3), the anti-obesity effect of bile acids is Be expected.
  • the F XR inhibitor does not have TGR 5 antagonistic activity and raises bile acid concentration in the intestinal tract and plasma, it is possible to indirectly induce the above-mentioned T GR 5-dependent pharmacological activity.
  • the FXR inhibitor is considered to be useful as a novel drug which can be expected to have anti-inflammatory, anti-diabetic and anti-obesity effects
  • each represents an alkyl, phenyl, heteroaryl, etc. which may be substituted;
  • R 2 is a phenyl, a heteroaryl, etc. which may be substituted each;
  • R 3 and R 4 represent Independently, a hydrogen atom, an alkyl-substituted phenyl, a biphenyl which may be substituted, a biphenyl ether, etc., or R 3 and R 4 may be substituted together.
  • M may be 0, N or S, and X and Y may be independently hydrogen or methyl, or X and Y together to form a carbonyl. May)). Only The text does not specifically disclose the compound used as the FXR inhibitor of the present invention.
  • the plant component G uggulsterone disclosed on the page of Science, 2002, 296 (5 5 73) 1 703-6 was originally reported as an FXR inhibitor, but from the subsequent examination, it is known that FXR activation and other nuclear It has been revealed that the FXR modulator also has receptor activity (Mo 1. Pharmacol, 2005, 67 (3), pages 948-54). Also, no consistent results have been obtained for the plasma lipid-improving action in humans (J AMA. 200 3, 290 (6), 765-2).
  • WO 2004/043 5 51, WO 2005/03 7 1 9 9 and WO 20 03/03 7 32 disclose heterocyclic amide compounds, in which these compounds are compounds which are FXR inhibitors. It is not shown that it is.
  • WO 200 5/03 7 1 9 9, WO 200 3/0 3 72 74, WO 2 000 04 7 5 58, WO 9 9/24404, WO 9 9/0 5 1 04, US 6020 3 5, 7, WO 2000/069849 and WO 2004/08 76 54 also disclose heterocyclic amide compounds, but the document does not disclose that these compounds are FX R inhibitors. Also, it has not been disclosed that it is effective for the prevention and treatment of hyperlipidemia, low HDL cholesterol cholesterol, and atheroma arteriosclerosis.
  • heterocyclic amide compound is disclosed also in WO 2004 1 06 2 99, it is disclosed in the literature that this compound is an FXR inhibitor.
  • the compounds used as the FXR inhibitors of the present invention are not specifically disclosed. ..
  • the compound represented by (I ′) and the compound represented by the general formula (I) have excellent FXR inhibitory action (In the present invention, the FXR inhibitory action is the function of FXR
  • the present invention is as follows.
  • Ring A represents a 5- or 6-membered aromatic heterocycle
  • 1 ⁇ 1 group 1 2 is each independently a substituted or unsubstituted j 0 alkyl group, optionally substituted C ⁇ .
  • Alkylthio group may be substituted
  • R 3 has the formula: —CONH— (CR 6 R 7) n — Ar — (X) 1 — (Y) m — R (wherein, Ar represents an optionally substituted divalent ring ⁇ 3 ⁇ 4,
  • X may be substituted.
  • Y is — so 2 _, — SO —, —S—, —S—, —O—, —CO—, —CON (R 5) —, —N (R 5) CO— (wherein, R 5 is a hydrogen atom or Indicates an optionally substituted alkyl group, or one CH (OH) —
  • R is a hydrogen atom, an optionally substituted cyclic group, it may also be substituted I Amino groups, optionally substituted C 7 - 13 7 aralkyl group. Represents an alkoxy group, a hydroxy group, a haloalkyl group or a cyano group,
  • 'R 6 and R 7 each independently represent a hydrogen atom or a Ci-6 alkoxy group
  • R 3 is bonded to a carbon atom constituting ring A;
  • R 4 is a hydrogen atom, optionally substituted. Represents a ⁇ ⁇ / lycyl group, a cyano group or a halogen atom;
  • a compound indicated by 0 or a salt thereof (hereinafter, also referred to as compound ()) or a prodrug thereof.
  • Ring A represents a 5- or 6-membered aromatic heterocycle
  • R 1 and R 2 may together form a ring which may be substituted together with the constituent atoms of the 5- or 6-membered heteroaromatic ring to which they are bonded;
  • R 3 is the formula: 'one CONH-A r-(X) 1-(Y) m-R
  • Ar represents a divalent cyclic group which may be substituted
  • X may be substituted. Alkylene group or substituted
  • Y is — so 2 —, -so-, 1 s—, _o—, —CO—, -CON
  • R 5 mono-, mono-N (R 5) CO- (wherein R 5 represents a hydrogen atom or optionally substituted alkyl; it represents an alkyl group) or mono-CH (OH) 2-;
  • R is a hydrogen atom, an optionally substituted cyclic group, an optionally substituted amino group, an optionally substituted C 7 13 alkyl group, or the like.
  • Alkoxy, hydroxyl, halo. Represents an alkyl group or a cyano group, and
  • R 3 is bonded to a carbon atom constituting ring A;
  • R 4 is a hydrogen atom, which may be substituted .
  • ring A, R 1, R 2, R 3, R 4 and k are as defined above in [2].
  • ring A, R 1 is pyrazole, R 1 is bonded to 1-position of pyrazole, R 2 is bonded to 3-position of pyrazole, and R 1 may be substituted C 6
  • R 14 is a aryl group
  • R 2 is not an optionally substituted heterocyclic group
  • ring A is pyrazole, R 1 is at the 1-position of pyrazole, and R 2 is 5 of pyrazole.
  • position to bind to each other and R 1 and R 2 are each independently optionally substituted C 6 - when it is 14 Ariru group,
  • R 3 is the formula: -CONH-A r -Y-R
  • Y is _S 0 2 -or -CO-, and 'R is a cyclic group which may be substituted), a group represented by',
  • Ring A is pyrazole, R 1 is bonded to the 1-position of pyrazole, R 2 is bonded to the 5-position of pyrazole, and R 1 and R 2 may be each independently substituted.
  • c 6 _ 14 r when it is a reel group
  • R 3 is the formula: one CONH— ⁇ r— Y— R
  • Y is one so 2 _ or one CO—
  • R is a cyclic group which may be substituted
  • Ring A is not triazole
  • R 1 and R 2 may each independently be substituted .
  • Alkyl group which may be substituted.
  • Alkyl thio, optionally substituted C 3 - 10 cycloalkyl group, optionally substituted C 6 - is a 14 Ariru group or is an optionally substituted nitrogen-containing heterocyclic group, the above-mentioned [8] FX R inhibitor described in. '.
  • R 1 is optionally substituted C - alkyl group or a substituted also be a nitrogen-containing optionally heterocyclic group
  • R 2 is optionally substituted C 6 - 14 Ariru group The FXR inhibitor according to [8] above.
  • Ar is a C 6 _ 14 arylene group which may be substituted, a bivalent fused cyclic hydrocarbon group which may be substituted, or a bivalent heterocyclic group which may be substituted,
  • a 10 Aruke two alkylene groups, - 'X is substituted it may be also be ⁇ 10 alkylene group or substituted optionally ⁇ 2
  • Y is ⁇ so 2 —, —SO—, —S—, — 10 —, —CO —, —CON H—, —NHCO— or —CH 1 (OH) —
  • R is a hydrogen atom, a substituted optionally also be a nitrogen-containing and heterocyclic group, an optionally substituted C 6 _ 14 Ariru group may Cg substituted.
  • 1 and m are each independently a group represented by 0 or 1)
  • R 3 force Formula: 1 CONH-A r-Y-R (Wherein, Ar is a C 6 _ 14 arylene group which may be substituted or a divalent nitrogen-containing fused heterocyclic group which may be substituted,
  • Y is _S0 2 — or one CO —
  • R 3 is the formula: — CONH—A r— Y— R
  • ⁇ ⁇ ⁇ power may be substituted 6 — 14 arylene groups
  • the cocoon is one CO— and
  • ⁇ is a substituted or unsubstituted phenyl group
  • Ar is a divalent nitrogen-containing fused heterocyclic group which may be substituted
  • R is substituted optionally also be a nitrogen-containing and heterocyclic group, 25 had good substituted C 6 - 14 Ariru group or an optionally substituted C 7 - 13 Ru Ararukiru group Der)
  • Ar is an optionally substituted indolylene group, an optionally substituted indolylene group, an optionally substituted indazolylene group, or an optionally substituted pentaimidazole group, Or
  • R is a nitrogen-containing heterocyclic group which may be substituted, a C 4 aryl group which may be substituted, or a C 7 ⁇ 3 alkyl group which may be substituted X).
  • Ar is an optionally substituted indolylene group, an optionally substituted indolylene group, or an optionally substituted benzimidazolene group, and
  • R is an optionally substituted nitrogen-containing heterocyclic group, but it may also be optionally substituted C 6 - 14 7 Ru good C ⁇ 3 Ararukiru group Der be aryl group or substituted), '?. ,
  • R 1 may be substituted.
  • R 2 is a C! -Io alkyl group which may be substituted or a cyclic group which may be substituted;
  • Ar is a divalent cyclic group which may be substituted
  • X may be a substituted or unsubstituted alkylene group or may be substituted.
  • Y is one S0 2 — or one CO —
  • 1 and m are each independently 0 or 1)
  • R 1 may be substituted.
  • R 2 may be substituted.
  • Alkyl group optionally substituted C 3 ⁇ .
  • Ar is a C 6 _ 14 arylene group which may be substituted
  • X may be substituted.
  • Y is one S0 2 — or one CO —
  • the scale is a nitrogen-containing heterocyclic group which may be substituted
  • R 1 is located in an optionally substituted Ji 6 _ 14 Ariru group or an optionally substituted nitrogen-containing heterocyclic group -; '.
  • R 2 force optionally substituted C-alkyl group, optionally substituted C 3 _.
  • Ar is optionally substituted C 6 _ 14 7 Rylene group
  • X may be substituted .
  • Y is one CO—
  • '1 and m are each independently 0 or 1)
  • the FXR inhibitor according to [1] or [2] above which is an agent for preventing and / or treating hyperlipidemia, low HDL cholesterol Jfilosis, or atherosclerosis.
  • R 1 a may be substituted.
  • R 2 a represents a cyclic group which may be substituted, or
  • R 1 a may together form a ring which may be substituted together with the constituent atoms of the pyrazole ring to which they are attached;
  • R 3 is a compound represented by the formula: one CONH- (CR 6 R 7) n-A r'_ (X) 1- (Y) mR 5 (wherein A r is an optionally substituted divalent cyclic group Show,
  • X is optionally substituted Ci. Represents an alkylene group or an optionally substituted C 0 alkenylene group,
  • Y is _so 2 _, -so-, — s—, one o—, -co-, -CON
  • R 5 mono, -N (R 5) CO- (wherein R 5 represents a hydrogen atom or a substituted or unsubstituted Cio alkyl group) or-CH (OH)-
  • R is a hydrogen atom, an optionally substituted cyclic group, I substituted 'I Amino groups, optionally substituted C 7 - 13 Ararukiru group, Ji 10 alkoxy groups, human Dorokishi group, Haroji . Indicate an alkyl group or a chain,
  • R 6 and R 7 each independently represent a hydrogen atom or a C ⁇ 6 alkyl 15 nore group
  • '1, m and n each independently represent 0 or 1) and represent a group represented by';
  • R 4 represents a ⁇ atom, a C ⁇ ⁇ alkyl group which may be substituted, a cyano group or a halogen atom.
  • R 1 b Is an optionally substituted C! ⁇ O alkyl group, optionally substituted
  • R 2 b represents an optionally substituted phenyl group
  • R 3 b is the formula: — C ONH — A r b — (X) 1 -Y b -R
  • Ar b represents a bivalent cyclic group substituted with a ⁇ ⁇ alkyl group or a halogen atom
  • X is optionally substituted C ⁇ io alkylene group or an optionally substituted C 2 - shows a 10 Aruke two alkylene groups.
  • Y b is a single S0 2 -,-C 2 O-, a single C ON (R 5 b)-(wherein, R 5 b is a hydrogen atom or optionally substituted C ⁇ !.
  • An alkyl group is shown.
  • )-Also indicates one CH (OH) one
  • 'R is a hydrogen atom, an optionally substituted cyclic group, conversion is good I Amino group optionally, an optionally substituted C 7 _ 1 3 Ararukiru group, CO alkoxy
  • R 4 represents a permanent atom, a C ⁇ alkyl group which may be substituted, a cyano group or a halogen atom.
  • R l c is optionally substituted Ci-i. Represents an alkyl group or a cyclic group which may be substituted;
  • R 2 c represents a cyclic group which may be substituted
  • R 3 c is the formula: — CONH — A r — (X) 1 — Y c — R
  • ⁇ represents a divalent cyclic group which may be substituted
  • X may be substituted.
  • 'Y c is one S0 2- , one CO-or one CON (R 5 c)-(wherein
  • R 5 c may be a hydrogen atom or may be substituted. Indicating an alkyl group),
  • 'R is a hydrogen atom, a cyclic group which may be substituted, it may also be substituted I Amino groups, optionally substituted C 7 even if one 13 Ararukire group, flicking.
  • Alkoxy group, hydroxy group, halo group. Represents an alkyl group or a cyano group, and
  • R 1 d is optionally substituted C 1. Represents an alkyl group or an optionally substituted phenyl group;
  • R 2 d represents an optionally substituted phenyl group
  • R3 is a formula:-one CONH-Ar-(X) 1-(Y) m-R
  • Ar represents a divalent cyclic group which may be substituted
  • X may be substituted. There. By an alkylene group or an optionally substituted C 2 _. 10 7 Luque two alkylene groups not yet,
  • Y is one so 2- , one SO_, one S-, _0-, one CO-, one CON (R 5)-, -N (R 5) CO-(wherein, R 5 is a hydrogen atom or a substituent) May represent an alkyl group) or —CH 2 (OH) —,
  • R is a hydrogen atom, an optionally substituted cyclic group, it may also be substituted I Amino groups, optionally substituted C 7 - 13 Ararukiru group.
  • Alkoxy group, hydroxyl group, ⁇ . Represent an alkyl or cyano group, and
  • W represents C, CH or N
  • R4 represents a hydrogen atom, an optionally substituted C to 0 alkyl group, a cyano group or a halogen atom].
  • R 1 e may be substituted .
  • R 2 e represents a cyclic group which may be substituted;
  • R 3 is a formula: one CONH—Ar— (X) 1- (Y) m—R
  • Ar represents a divalent cyclic group which may be substituted
  • X is optionally substituted C i. Represents an alkylene group or an optionally substituted C 2 _ 10 alkenylene group;
  • Y is, _ S0 2 -, one S O_, one S-, one 0_, -CO-, -CON
  • R 5 is a hydrogen atom or optionally substituted C !, and represents an alkyl group) or one CH (OH)-
  • R is a hydrogen atom, an optionally substituted cyclic group, it may also be substituted I Amino groups, optionally substituted C 7 - 13 Ararukiru group.
  • Alkoxy group, hydroxy group, halo represents an alkyl group or a cyano group
  • V represents 0, S, N or NH
  • R 4 represents a hydrogen atom, an optionally substituted C 10 alkyl group, a cyano group or a halogen atom]
  • R 1 f may be substituted. Indicates an alkyl group or a cyclic group which may be substituted;
  • R 2 f represents an optionally substituted C 2 O alkyl group or an optionally substituted cyclic group
  • R 3 is the formula: —CONH— Ar— (X) 1 — (Y) m-R
  • Ar represents a divalent cyclic group which may be substituted, X may be substituted.
  • Y is one so 2- , one SO-, one S-, one O-, one CO-, -CON (R 5)-, -N (R 5) CO-(wherein R 5 is a 'hydrogen atom' Or an alkyl group which may be substituted) or one C, H (OH)
  • R is a hydrogen atom, an optionally substituted cyclic group, it may also be substituted I Amino groups, optionally substituted C '7 - 13 Ararukiru group, C -! Alkoxy group, arsenate Dorokishi group, halo Represents a C ⁇ alkyl group or a cyano group, and
  • R 3 is bonded to the carbon atom adjacent to the oxygen atom of oxazole ring
  • the alkyl group may be substituted.
  • R 3 g is the formula: — CONH— A r _ (X) 1 — Y g— R
  • Ar represents a divalent cyclic group which may be substituted
  • X may be substituted Ci-! .
  • Yg indicates one S ⁇ 2 — or one CO —
  • R is a hydrogen atom, an optionally substituted cyclic group, but it may also be substituted Amiso group, optionally substituted C 7 _ 1 3 even if Ararukiru group.
  • Alkoxy, hydroxy, halo. Represents an alkyl group or a cyano group, and
  • R 3 g is bonded to a carbon atom constituting the imidazoyl ring
  • R 4 g is a hydrogen atom, optionally C. Represents an alkyl group or a halogen atom,
  • 1-161-1 -Butyl- [4-chloro-3- ( ⁇ 4- [4-(2-hydroxy-2-methylpropyl) phe dinore] piperidine-yl ⁇ carbodi nore) One 5- (4-Fluorophoe-Nore) -1H-pyrazole-4-carboxamide, 4- ( ⁇ l- [5-( ⁇ [1-tert-butyl-5- (4-fluoro-phenyl-2-le]-1H-pyrazole- 4-inole] carbonyl ⁇ amino)-2-necked mouth Benzyl] piperidine- 4-yl ⁇ oxy) benzoic acid,.
  • the compound (I) exhibits FXR inhibitory action, so the compound is very useful as a preventive and / or therapeutic agent for hyperlipidemia, hypo HDL cholesterolemia, rollemia, or atelomerism. It is. .. Best mode for carrying out the invention
  • halogen atom means fluorine atom, chlorine atom, bromine atom and iodine atom, unless otherwise specified.
  • the "hydrocarbon group” in the present specification is C ⁇ i. Alkyl group, C 2 -J. An alkenyl group, 2-,. Alkynyl group, C 3 . Cycloalkyl group, C 3 . Cycloalkenyl group, I ⁇ cycloalkadienyl group, fused cyclic hydrocarbon group, C 6 14 aryl group, C 7 _ 13 aralkyl group, c 8 _ 13 aryl group. ⁇ Cycloalkyl-J ⁇ ⁇ alkyl group and the like. Unless otherwise specified, the term “alkyl group” in the present specification means methyl, alkyl group, and the like.
  • C 2 — ⁇ .Alkenyl block is, unless otherwise specified, tetininore,, 1-propenyl, 2-propeninore, 2-methinole 1 1 _propeninore, 1-1 Puteni Nore, 2-Buteno-Nore, 3-Buteno Nore, 3-Methinore _ 2 _ Buteno-Nore, 1-Pente 2 Nore, 2-Pente 2 Nore, 3-Pente 2 Nore, 4 _ Pente 2 Nore 4-methinole 1 3- penteninole, 1 _ hexeninole, 3-hexeninole, 5-hexeninole, 1-hepteni 'nole, 1-othatul and the like.
  • a C 2 _ 6 alkenyl group Preferably a C 2 _ 6 alkenyl group.
  • Alkynyl group ' is a fetuol, 1 propion, 2 propiel, 1-butul, 2 boutul, 3-peptii 15 nore, 1 _ pencenoure, unless otherwise specified.
  • C 2 - 6 ⁇ is Norekiniru. ',
  • Cycloalkyl group means cyclic 20-propyl, cyclobutynore, cyclopentinole, cyclohexanole, cycloheptynole, cyclooctyl and the like.
  • a C 3 _ 6 cycloalkyl group Preferably a C 3 _ 6 cycloalkyl group.
  • C 7 Also included are cycloalkyl groups.
  • C 3- .cycloalkenyl group is 2-cyclopentene 1 1 -inole, 3-cyclopentene 1-1 -inole, 2-cyclohe xene 1 1 r, 3 -cyclo Kisen 1 1 _ yl and so on.
  • it is a c 3 _ 6 cycloalkenyl group. -.
  • C 4 — i. Cycloalkadienyl group is, unless otherwise specified, 2, 4-cyclopentagen — 1 -inole, 2, 4-cyclohexadiene 1 — yl, 2,5-Cyclohexagen-means 1 ⁇ T, etc.
  • it is a C 4 — 6 cycloalkadienyl group.
  • Fused cyclic hydrocarbon group in the present specification, unless otherwise specified, C 3 _ 10 cyclo alkane, C 3 - 10 cycloalkyl alkene or c 4 _ 10 cycloalkadiene, respectively fused to a benzene ring refers to a group derived from a ring formed Te, the C 3- 10 cycloalkane, a C 3 _ 10 cycloalkenes and c 4 _ 10 cycloalkanols Jie Shi, the above Flip 3 _ 16 cycloalkyl group, Ji 3 _ 10 cycloalkenyl group Contact and C 4 _ i.
  • a ring corresponding to a cycloalkadienyl group can be mentioned.
  • Specific examples of the fused cyclic hydrocarbon group include indanyl, dihydronaphthyl, tetrahydronaphthyl, fluorenyl and the like.
  • Jc 6 — 14 aryl group in the graduate specification means, unless otherwise specified, phenyl, 'naphthyl', anthryl, phenanth 'yl, asenanaphthyrenyl, biphenylyl and the like. Preferably, it is a C 6 1 0 aryl group such as phenyl, 1-naphthyl and 2 -naphthyl.
  • C 7 - 13 Ararukiru group unless otherwise noted, benzyl, 2-Hue Nino les ethyl Honoré, 3-phenylene Norepuropinore, 4-phenylene Norev Chino les, 5-phenylene Norepenchinore, 6 ⁇ -fewino hexylone, 7--fewinole heptinole, ⁇ -acetylbenzyl, naphthylmethyl, biphenylylmethyl and the like.
  • Ji ⁇ 3 ⁇ reel alkenyl group in the present specification, unless otherwise specified, means a styryl like.
  • . ⁇ 3 _ 1 Shikuroarukiru - Ji 1 _ 6 Arukiru group means a cyclohexylmethyl like cyclohexane.
  • the alkoxy group is methoxy, ethoxy, propoxy, isopropoxy, butoxy ', isobutoxy, sec-butoxy, tert-butoxy, pentynoleoxy, hexinolyloxy, It means heptanolyoxy, oxykiroxy, nonyloxy, decyloxy etc.
  • Alkylthio group' in the present specification is methylthio, ketothio, propylthio, isopropylthio, pentylthio, isobutylthio, isobutylthio, sec- ptylthio, tert- petitenoretio, pentinoretio, hexoxy, unless otherwise specified. It means ruthio, heptylthio, octylthio, nonylthio, decylthio and the like. Preferably it is an alkylthio group.
  • dialkyl ⁇ . Alkylsulfonyl group in the present specification refers to methylo nosole nohononole, ecino nos nole phononore, propinores nore fonolet, isopropinores nore phononole, butino Les Nole Honinole, I Soobuchi Noles Nole Honinole, sec-Petite Noles Nole Seconds, tert-Buty Noles Nole Hononele, Pentinoles Nole Hononi Nole, Hexinores Nole Honi Nore, Heptinores No. Lehoninolee, Okucino Noles Noles Noleho-nore, Nonynoles Nolehokinole,.
  • it is _. 6 alkylsulfonyl group.
  • cyclic group is defined above, unless otherwise stated.
  • Cycloalkyl group C 3 _ 10 cycloalkenyl group, C i. Cycloalkanoyl diethyl group, fused cyclic hydrocarbon groups and ⁇ 6 _ 1 4 Ariru group, and means a heterocyclic group.
  • heterocyclic group means aromatic heterocyclic group and non-aromatic heterocyclic group.
  • aromatic heterocyclic group in the present specification contains 1-4 ring atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring constituting atom.
  • 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic It means a heterocyclic group and a fused aromatic heterocyclic group.
  • fused aromatic heterocyclic group examples include a ring corresponding to these 4 to 7-membered monocyclic aromatic heterocyclic group, and a 5- or 6-membered ring containing one or two nitrogen atoms, And 5-membered ring containing one sulfur atom, a group derived from a ring in which one or two benzene rings and the like are fused, and the like.
  • Preferred examples of the aromatic heterocyclic group are
  • Furinole eg, 2-furyl, 3-furyl
  • cenyl eg, 2-chenyl, 3-cenyl
  • 'pi. Lysyl eg, 2-pyri' yl, 3-pyridyl, 4-pyridyl
  • pyrimidinyl Eg, 2-pyrimidinyl, 4-pyrimidinyl, 5 _ pyrimidenyl
  • Pyridazinyl eg, 3-pyridazinyl, 4-pyridazinyl
  • pyrazinol eg, '2-pyradicinole
  • pyrrolinole eg, 1- Pyrrolinole, 2-pyrrolinole, 3-pyrrolyl
  • imidazolyl eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl
  • pyrazolyl eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl
  • Soryl eg, 3-isothiazolyl, 4-isothiazolyl, 5 _ Isothiazolyl
  • oxazolyl eg, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl
  • isoxazolyl eg, 3-isoxazolyl, 4-isooxazolyl, 5_'oxazolyl
  • oxazoyl eg, 1 , 2, 4-Oxadiazoyl, 5-lyl, 1, 3, 4-oxadiazole-l 2- ⁇ f
  • thiadiazolyl eg, 1, 3, 4-thiadiazolyl 2-yl
  • Riazorigure eg 1, 2, 4-Triazole 1-yl, 1, 2, 4 1 Triazo-Nore 1-3-Inole, 1, 2-3 Triazonole-1 1-Inole, 1, 2, 3 _ Triazonol 1-inole, 1, 2, 3-triazolone 1-4 nore
  • tetrazolyl eg
  • Quinolyl eg, 2 _ quinolyl, 3-quinolyl, 4-monoquinolyl, 6-quinolyl), isoquinolyl (eg, 3-isoquinolyl), quinazolyl (eg, 2-quinazolyl, 4-quinazolyl) quinoxalinole (eg, 2-quinoxalyl, 6-quinoxalinole), benzofuranine (eg, 2-benzofuran, 3-benzofuranyl), benzocheoneole (eg, 2-benzose dinore, (3) Benzo-se-ci-no-le) Benzoi-Squid Sazolyl (eg 2-Benzo-xazolisole) Benzo-iso-xazolyl (ex.
  • quinazolyl eg, 2-quinazolyl, 4-quinazolyl
  • quinoxalinole eg, 2-quinoxalyl, 6-quinoxalinole
  • benzofuranine eg,
  • non-aromatic heterocyclic group in the present specification is not limited to a carbon atom, and a nitrogen atom selected from an oxygen atom, a sulfur atom and a nitrogen atom is not particularly limited.
  • the 7-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclic group containing 4 and the fused non-aromatic heterocyclic group are meant.
  • fused non-aromatic heterocyclic group for example, a ring corresponding to these 47-membered monocyclic non-aromatic heterocyclic group, a 5- or 6-membered ring containing 1 to 2 nitrogen atoms, 1 Containing sulfur atoms Examples thereof include a group derived from a ring in which one or two 5-membered rings or a benzene ring and the like are fused. ⁇ '
  • nonaromatic heterocyclic group examples include:
  • Pyrrolidinyl eg, 1-pyrrolidinyl, 2_pylori 'dinyl
  • piperidinyl eg, piperidino, 2-piperidinyl, 3-piperidinyl, 3-piperidinyl, 4-piperidinyl
  • monoreholininore eg, morpholino
  • thiomonorehololi Nil eg, thiomorpholino
  • piperazinyl eg, 1-piperazinyl, 2-piperazinyl, 3-pipe, radizyl
  • hexamethylene iminyl eg, hexamethyleneimine 1 1 ⁇ f
  • Oxazolidinyl eg, oxazolidinediyl
  • thiazolidinyl eg, thiazolidinediyl
  • imidazolidine eg, imidazolidinediyl. -Yl, imidazolidine mono-yl
  • oxazolyl eg Eg oxazoline-l-yl
  • thiazolinyl eg thiazoline-l-yl
  • dioxolinole eg, 1, 3-dioxol _ 4 yl
  • dioxolanil eg, 1, 3-dioxolan _ 4 T
  • dihydro Oxadiazolinole eg, 4, 5-Dihydro-1, 2, 4 _ Oxadiazol- 1-yl
  • tetrahydrothiopyran 1 to 1 yl tetrahydriflinole
  • tetrahydrofuran 1 3-ylole tetrahydrofuran (2-yl
  • birazolizinyl eg, birazolizine-1-yl, pyrazolidine-1-3-yl
  • birazolinyl eg, pyrazoline-1-yl
  • tetrahydripyrimidone eg, tetrahydripyrimidinyl
  • dihydrotriazolinole e.g. 2, 3- dihydroi- nol 1.
  • H- 1, 2, 3-triazole-1-yl tetrahydrotriazolyl (e.g. 2, Tabled non-aromatic ring groups such as 3, 4, 5-tetrahydro- 1 H- 1, 2, 3-triazo-l-yl), dihydrooxazepiel, etc .; indolinyl, dihydroin.
  • 2,3-Dihydoro 1 1 H-Indol 1 1 ⁇ f le Dihydroisoindolyl (eg, 1, 3-Dihydro 1 2H-di soind ⁇ "le 1, 2 ⁇ f le ), Dihydro 'benzofuranyl (eg, 2, 3-Dihydro — 1-benzofuran 1 5-inole), Dihydorobenzodioxynoll (eg, 2, 3-Dihydro 1, 4 _ benzodioxy) Sur), dihi dorobenzo ⁇ okipieru (eg, 3; 4—dihidro 1 2H— 1, 5-benzo Dioxepyril), tetrahydrobenzofrael (eg, 4, 5, 6, 7-tetrahydro 1-benzofuran- 3-yl), chromel (eg, 4 H- chrome 1-f nore, 2H— Chromene (3-yl), dihydroquinolinyl (eg, 1, 2-d
  • the non-aromatic heterocyclic group also includes a cross-linked non-aromatic heterocyclic group such as 7-azabicyclo [2.2.
  • ring means a ring corresponding to the "cyclic group" defined above.
  • the "5- or 6-membered aromatic heterocyclic ring” in the present specification is a 5- or 6-membered ring corresponding to the "heterocyclic group” exemplified as the "cyclic group” defined above.
  • the "divalent cyclic group” in the present specification means a divalent group derived from a ring corresponding to the "cyclic group” defined above.
  • Alkylene group is _CH 2 —, one (CH 2 ) 2 —, — (CH 2 ) 3 _, — (CH 2 ) 4 —, — ( CH 2 ) 5 —, — (CH 2 ) 6 —, —CH (CH 3 ) —, — C (CH 3 ) 2 —, _CH (C 2 H 5 ) one, —CH (C 3 H 7 ) one, -CH (CH (CH 3 ) 2 )-,-(CH (CH 3)) 2- , 'CH 2 CH (CH 3 ) —,' one CH (CH 3 ) CH 2 —,-(CH 2 ) 2 C (CH 3 ) 2 —,-(, CH 2 ) 3 C (CH 3 ) 2 _, etc. are meant.
  • Preferred is a C 6 alkylene group.
  • it is a C 2 _ 6 alkenylene group.
  • halo page i. Alkyl group refers to P, fluoromethyl, chloro, methyl, bromo methinole, trifluro methinole, 1, 1, 1-, trifno reo oleno, 4-furonoleobuchi / le, 4, 4 _ 4-4-trifnoreobutynore, 5-fluoropentyl, 5, 5, 5-trifzoreo oral penpinole, 4, 4, 5, 5, 5-pentafnurooleo pentinole, 4, 5 5, 6, 6, 6-Penta-Funore means Hexinole, etc.
  • it is a halo Ci-6 alkyl group.
  • “. ⁇ 6 alkyl group” is, unless otherwise specified, methyl, hydroxyethyl, propionole, isopropiole, butynore, isobutynore, sec-butynore, tert-butynore, penty / le, isopenentinore, neopentinole, 1-Echinole Propinole, hexyl, isohexylone, 1, 1-dimethinolebutyl, 2, 2-dimethylbutyl, 3, 3-dimethylbutyl, 2-ethylpyl and the like.
  • the term "flexoxy group” means, unless otherwise stated, methoxy, ethoxy, propoxy, 'isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
  • C — 6 alkoxy-carbonyl group means methoxycarbonyl, tetrakisone: carbonyl, propoxycarbonyl, tert ′ monobutoxycarboyl and the like.
  • alkyl-carbonyl group means, unless otherwise specified, asecetyl, propanol, butanoyl, isobutanoyl, pentanoyl, isopentanoyl, hexanol and the like.
  • ... --_ 3 alkylenedioxy group in the present specification means methylenedioxy, ethylenedioxy and the like.
  • 13 ⁇ 4 1 ⁇ 13 ⁇ 4 2 independently represent optionally substituted ⁇ alkyl S, optionally substituted C! O alkylthio group, optionally substituted C i.
  • 1 ⁇ 1 13 13 ⁇ 4 2 may be each independently substituted
  • C ⁇ ! O alkyl group optionally substituted C i-.
  • An alkylthio group or a cyclic group which may be substituted is shown, or R 1 and R 2 are taken together and substituted together with the constituent atoms of the 5- or 6-membered aromatic heterocyclic ring to which they are bonded. And may form a ring.
  • a C 3 _ 10 cycloalkyl group which may be substituted by 3 substituents;
  • An aromatic heterocyclic group which may be substituted by 1 to 3 substituents selected from (4) It is substituted by 1 to 3 substituents selected from an alkyl group which may be substituted by 1 to 3 halogen atoms, a hydroxy group, a C ⁇ e alkoxy group, an alkoxy group and a halogen atom Also a non-aromatic heterocyclic group;
  • Aralkyl 1 carbonyl group eg, benzyl carbonyl, phyto nechinole kanore benore
  • Ci- 6 alkyl monofunctional rubamoyl group e.g. methylcarbamoyl, ethynol kanore bekiinole
  • C _ 6 alkyl sulfonyl group eg, methyl sulfonyl, hydroxyethyl sulfonyl, isopropyl sulfonyl
  • arylsulfonyl group eg, benzenesulfonyl, toluene snorrephoninole, 1 _ naphthalenes / lefoninole, 2 _ naphthalenes norolefonide
  • arylsulfonyl group eg, benzenesulfonyl, toluene snorrephoninole, 1 _ naphthalenes / lefoninole, 2 _ naphthalenes norolefonide
  • (xiii) an amino group which may be substituted by one or two substituents selected from C.sub.7 3- aranolylsulfodinore (eg, penzinores norefonyl);
  • amidino group (7) 1 to 3 halogen atoms optionally substituted-6 alkyl mono carbonyl groups;
  • aromatic heterocyclic ring may be mono- or di-substituted with a substituent selected from mono-alkyl groups (eg, furfuryl);
  • C] _ 6 alkoxy-power sulfonyl group C 3 _.
  • An alkoxy group which may be substituted by 1 to 3 substituents selected from a cycloalkyl group and a C 6 -i 4 aryl group;
  • (iii) may be substituted by 1 to 3 substituents selected from C- 6 alkoxy-monocarbonyl group, carboxyl group and hydroxyl group; C i- 6- anolequinole group,
  • One to three C 6 _ 14 may be substituted with a substituent Ariru Okishi group selected '' (e.g., phenoxy, Nafuchiruokishi);
  • C-6 alkyl-carboxy group eg, acetyloxy, ter t-butyl canole levoninoleoxy
  • alkyl thio group which may be substituted with 1 to 3 halogen atoms (eg, methylthio, acetylthio);
  • a heteroaromatic ring oxy group which may be substituted by 1 to 3 substituents selected from a carboxyl group and a C — 6 alkoxy monocarbonyl group (eg, pyridyloxy, chenyloxy, isoxazolyloxy );
  • one carbonyl group may be substituted ⁇ 6 - 14 Ariru - carbonyl group (eg, Benzoiru); ', and the like.
  • Ariru - carbonyl group eg, Benzoiru
  • ' e.g. Benzoiru
  • each substituent is identical or different! : 'You may.
  • cyclic group of the "optionally substituted cyclic group” represented by I or R 2 C 3 -i. Cycloalkyl group, C 6 - 14 Ariru group, a nitrogen-containing heterocyclic group and the like.
  • the “cyclic group” of the “optionally substituted cyclic group” represented by R 1 or R 2 may have 1 to 3 substituents at each substitutable position.
  • An alkyl group has: a group exemplified as a substituent which may be C;
  • (V) C- 6 alkyl-carbonyloxy group (e.g., acetyloxy, tert-putinolecanoleponinoreoxy),
  • Ci-e alkyl group optionally substituted by 1 to 3 substituents selected from
  • C 26 alkenyl group (eg, ethenyl, 1-propenyl);
  • C_ 6 alkyl group optionally substituted with 1 to 3 nitrogen atoms,, hydroxy group, Selected from alkoxy groups and halogen atoms 1 to
  • C 7 _ 13 aralkyl group which may be substituted by 3 substituents;-and the like. When two or more substituents are present, each substituent may be the same or different.
  • R.sup.1 and R.sup.2 together with the constituent atoms of the 5- or 6-membered aromatic heterocyclic ring to which they are attached
  • “optionally substituted ring” and “ring” include, for example, a heterocyclic ring Is preferred.
  • the "ring” of the “optionally substituted ring” may have 1 to 3 substituents at substitutable positions. Examples of such a substituent include those exemplified as the substituent which may be possessed by the “cyclic group” of the “optionally substituted cyclic group” represented by R 1 or R 2. When two or more substituents are present, each substituent may be the same or different.
  • R 1 and R 2 are each independently selected from
  • Halogen atom eg, fluorine atom
  • halogen atom eg, fluorine atom, chlorine atom, bromine atom
  • an alkyl group eg, methyl
  • 1 to 3 halogen atoms eg, fluorine atom
  • Heterocyclic groups eg, pyridyl, pyrimigel, phenyl!
  • R 1 and R 2 are each independently selected from
  • alkyl group which may be substituted with 1 to 3 substituents selected from, for example, (for example, methyl, acetyl, isopropyl, isopropyl, ter t-butyl, neopentyl),.
  • halogen atom eg, fluorine atom, chlorine atom, bromine atom
  • 1 to 3 halogen atoms eg, fluorine atom
  • which may be substituted-6 alkyl group eg, methyl
  • nitrogen-containing heterocyclic group eg, pyridyl, pyrimidinyl
  • R 1 and R 2 may be taken together to form a “optionally substituted ring” together with a constituent atom of a 5- or 6-membered aromatic ring to which they are attached: ⁇ heterocycle, And a ring which may be substituted by 1 to 3 substituents selected from Ci-6 alkyl group (eg, methyl), halogen atom (eg, fluorine source 'cow) and the like. Ring (eg, dihydrobenzoxazepine) 'and the like.
  • Ci-6 alkyl group eg, methyl
  • halogen atom eg, fluorine source 'cow
  • Ring eg, dihydrobenzoxazepine
  • ring A examples include pyrrole, pyrazole, imidazole, thiazole, oxazole, furan, thiophen, pyridine, pyrimidin and the like, with pyrazole being particularly preferable.
  • R 3 is
  • Ar represents a divalent cyclic group which may be substituted
  • X represents an optionally substituted alkylene group or an optionally substituted C 2 — 10 alkenylene group
  • Y is one so 2— , one so—, one s—, —o_, —CO—, —CON
  • R 5 mono, -N (R 5) CO-(wherein, R 5 represents a hydrogen atom or an optionally substituted di-alkyl group) or -C ⁇ I (OH)- ,
  • R is a hydrogen atom, an optionally substituted cyclic group, an optionally substituted amino group, an optionally substituted C 7 _ 13 alkyl group, a large number! .
  • Alkoxy group, hydroxy S, halo large. Represents an alkyl group or a cyano group,
  • R 6 and R 7 each independently represent a hydrogen atom or an alkyl group
  • R 3 is a compound of the formula: 1 CONH-A r- (X) 1- (Y) m-R wherein Ar is a divalent cyclic group which may be substituted,
  • X may be substituted .
  • Alkylene group or optionally substituted. Represents an alkenylene group, '
  • ⁇ is: ⁇ so 2 —, one so—, one s—, _o—, one CO_, —CON
  • R 5 is a hydrogen atom or may be substituted, and represents an alkyl group) or-CH (OH)
  • R represents a hydrogen atom, an optionally substituted cyclic group, an optionally substituted amino group, an optionally substituted C 7 13 aralkyl group, a 10 alkoxy group, a hydroxy group, a halo group .
  • R 3 is bonded to a carbon atom constituting Ring A.
  • a constituent atom of ring A to which R 2 is bonded be adjacent to a constituent atom of ring A to which R 3 is bonded.
  • the "divalent cyclic group J of" substituted 2 may be bivalent cyclic group "represented by A r, C 6 - 14 Ariren group, divalent condensed cyclic hydrocarbon group, a divalent heterocyclic Preferred examples of the divalent heterocyclic group are: indylene, indolinylene, benzimidazolylene, phenylene, indazolylene, isoindolylene, pyridinene, tetradroquinolylene, pyrrolylene, and the like.
  • divalent nitrogen-containing fused heterocyclic groups are preferred, and indolylene, indolinylene, benzimidazolene and indazolylene are more preferred, and indolylene, indolylene and benzimidazolylene are particularly preferred. .
  • the “divalent cyclic group” of the “optionally substituted divalent cyclic group” represented by A r may have 1 to 3 substituent groups at substitutable positions.
  • substituent groups for example, those exemplified as the substituent which the “cyclic group” of the “optionally substituted cyclic group” represented by R 1 or R 2 may have may be mentioned. .
  • each substituent may be one or different.
  • halogen atom eg, fluorine atom, chlorine atom
  • Ci- 6 alkyl group eg, methyl, acetyl, isopropyl
  • halogen atoms eg, fluorine atom
  • Alkoxy group eg, methoxy, ethoxy, isopropoxy
  • non-aromatic heterocyclic group eg, morpholinyl, pyrrolidinyl
  • C 6 _ 14 arylene group which may be substituted with 1 to 3 substituents selected from etc. (eg, phenylene),
  • Divalent fused cyclic hydrocarbon group which may be substituted with 1 to 3 alkoxy group etc. (eg, tetrahydnanaphthylene, fluoreni'len, indanylene), (3) (a) Ci-6 alkyl group (Eg methyl),.
  • halogen atom eg, fluorine atom, chlorine atom
  • a bivalent fused cyclic hydrocarbon group which may be substituted by 1 to 3 alkoxy group etc. (eg, tetrahydnanaphthylene, furoreorenylene),
  • Divalent heterocyclic group which may be substituted by 1 to 3 C ⁇ e alkyl groups (eg, methyl) etc. (eg, indylene, indolinylene, benzimidazolene, thiophenylene)
  • C ⁇ 10 alkylene group for example, — CH 2 —, one (CH 2 ) 2 —,-(CH 2 ) ′ 10 3 —,-(CH 2 ) 4 _,-(CH 2 ) 5 _, -(CH 2 ) 6 _, one (CH 2 ) 7 one),
  • the substituted or unsubstituted alkyl group” represented by R 5 may have 1 to 3 substituents at substitutable positions. .
  • a substituent for example, “'C ⁇ i.
  • Y preferably, one so 2- , one SO-, one s-, one o-, -co
  • R 5 is a hydrogen atom or Is a Ci-io alkyl group (e.g. methyl) or one CH (OH)-, more preferably one so 2 _, one SO-, one s-, one o_, one CO-, co
  • R 5 is a hydrogen atom or an alkyl group (eg, methyl)) or one CH (OH) one, particularly preferably one SO 2 _ or It is one CO-. ,.
  • the “cyclic group” of the “optionally substituted cyclic group” represented by R is a nitrogen-containing heterocyclic group, a C 6 — 14 7 reel group, .
  • Preferred is a cycloalkyl group or the like.
  • the “cyclic group” of the “optionally substituted cyclic group” represented by R may have 1 to 3 substituents at substitutable positions.
  • substituents for example, those exemplified as the substituent which the “cyclic group” of the “optionally substituted cyclic group” represented by R 1 or R 2 may have can be mentioned.
  • each substituent may be the same or different.
  • Examples of the “optionally substituted amino group” represented by R include, for example, each of which may be substituted.
  • Cycloalkenyl group a condensed cyclic hydrocarbon ⁇ , C '6 - 14 Ariru group, a heterocyclic, group; Ashiru 1 or 2 substituents which may ⁇ amino group optionally substituted by a group selected from such groups.
  • Examples of the “asyl group” exemplified as the “substituent” in the “optionally substituted amino group” represented by R and R include, for example, a group represented by the formula: one COR A , one CO—OR A , _ S 0 2 R A , SOR A , -CO-NR 3 'R B ,, -CS-NR A ' R B '
  • R A represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group.
  • R A ′ and R B ′ are the same or different and each represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, or R A ′ and R B ′ forms a nitrogen-containing heterocyclic ring which may be substituted together with the adjacent nitrogen atom] and the like.
  • hydrocarbon * group of the "optionally substituted hydrocarbon group” represented by R A , R A 'or R B ', 1 to 3 substituents can be substituted at substitutable positions You may have it.
  • a substituent for example, 'the said hydrocarbon group is . Alkyl group,. . An alkenyl group and .
  • the hydrocarbon group is a C 3 ⁇ 0 cycloalkyl group, a C 3 _ 10 cycloalkenyl group, or C 4 .
  • substituents which the "cyclic group" of the "optionally substituted cyclic group" represented by 2 may have are listed. When two or more substituents are present, each substituent may be the same or different.
  • heterocyclic group of the “optionally substituted heterocyclic group” represented by R a , R a ′ or R b ′ may have 1 to 3 substituents at substitutable positions. .
  • substituents those exemplified as the substituent which the “cyclic group” of the “optionally substituted cyclic group” represented by R 1 or R 2 may have may be mentioned.
  • each substituent may be the same or different.
  • the “nitrogen-containing heterocycle” in the “optionally substituted nitrogen-containing heterocycle” formed by R 3 ′ and R b ′ together with the adjacent nitrogen atom is, for example, at least one other than a carbon atom as a ring-constituting atom And a 5- to 7-membered nitrogen-containing heterocyclic ring which may contain one or two hetero atoms selected from oxygen atom, sulfur atom and nitrogen atom.
  • Preferred examples of the nitrogen-containing heterocycle include pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, oxopiperazine and the like.
  • the nitrogen heterocycle may have 1 to 3 (preferably 1 or 2) substituents at substitutable positions.
  • substituents those exemplified as the substituent which may be possessed by the “cyclic group” of the “optionally substituted cyclic group” represented by 1 or! 2 may be mentioned. If there are two or more substituents, each. Substituent may be the same or different.
  • halogen atom a cyano group, an optionally halogenated 6 alkyl group (that is, a 'C ⁇ 6 alkyl group optionally substituted with 1 to 3 halogen atoms), an alkoxy group, Carboxyl group, alkoxy monocal
  • C 6 _ 14 aryl 1 carbonyl group eg, benzoyl, 1-naphthoyl, 2-naphthoyl, which may be substituted by 1 to 3 substituents selected from the group consisting of bonyl group and sorbyl group; ;
  • C 6 _ 14 alyoxy 1-hydroxy mono-cane bonire group which may be substituted by 1 to 3 substituents selected from a carboxyl group, a C ⁇ 6 alkoxy-carbonyl group, and a force lvamoyl group-(eg, Fei noki Shikanole Boninole, Naftino Leoxy Canole Bonore);
  • C 6 alkylsulfiel group eg, methylsunolefinyl
  • C 7 _ 13 ⁇ aralkyl group of the "optionally substituted C 7 _ 13 Ararukiru group” represented by R may have 1 to 3 substituents at substitutable positions.
  • substituents for example, those exemplified as the substituent which the “cyclic group” of the “optionally substituted cyclic group” represented by R 1 or R 2 may have are exemplified. . When two or more substituents are present, each substituent may be the same or different. , ' ⁇
  • Non-aromatic heterocyclic group which may be substituted (eg, dihydrooxadiazolyl), (vii) halogen atom (eg, fluorine atom), (viii) C: — 6 alkenyloxy carbonyl Group (eg, aryl C ' 6 14 a ' reel group (', eg phenyl) optionally substituted with 1 to 3 substituents selected from
  • Non-aromatic heterocyclic group which may be substituted by 1 to 3 alkoxy group etc. (eg, Piveridinyl, pyrrolidine, dihydro'oxadiazolyl, morpholinyl, tetrahydro-n-midyl),
  • 'Basic ring group eg pyridyl, pyrimidinyl, thiazolyl
  • C 6 alkoxy monocarboyl group eg, methyl carbonyl, methoxy carbonyl, tert-butoxy rubonyl
  • halogen atom eg, fluorine atom
  • (k) Oxo group (1) (i) Carboxyl group, (ii) Ci-6 alkoxymonocarbonyl group (eg, .methoxycarbonyl, ethoxycarbonyl), and (iii) 1 to 3 Ci-6 alkoxy-carbonyl groups (eg, A C 6 _ 14 aryl group (eg phenyl), which may be substituted, eg, toxoxycarbonyl), iv) a hydroxy group, (V) 1 to 3 hydroxy groups, etc., and may be alkoxy An alkyl group optionally substituted by 1 to 3 substituents selected from groups (eg, ethoxy) and the like (eg, methyl, ethyl, propyl),
  • Ci-6 alkoxy monocarbonyl groups eg, methoxy carbonyl
  • aryl one carbonyl groups eg, benzoin
  • a nitrogen-containing heterocyclic group which may be substituted by 1 to 3 substituents selected from etc.
  • substituents selected from etc. eg pyrrolidinyl, isooxazolizinyl, piperidinyl, piperazyl, morpholinyl, thiomorpholinyl, dihydrosuphaazolyl Tetrazolinole, Thiazolyl, Imidazolyl, Pyridyl, Tetrahydroquinolyl, Indolyl,
  • halogen atom eg, fluorine atom, chlorine atom
  • Non-aromatic heterocyclic group which may be substituted by 1 to 3 alkoxy groups etc. (eg, morpholinyl) And C 6 _ 14 aryl group optionally substituted with 1 to 3 substituents selected from etc. (eg, phenyl, biphenyl);
  • Cs ⁇ optionally substituted by 1 to 3 substituents selected from S-ring alkyl group (eg, cyclohexyl, bicyclo [3. 1. 1] heptyl, etc. cyclo [2. 2. 1] heptinole) ⁇ ',
  • C 6 _ 14 T reel group eg, phenyl
  • C, 6 14 7 lyso ring group eg, phenyl
  • aromatic heterocyclic group e.g., pyridyl
  • 6 alkyl group optionally substituted by 1 to 3 substituents (e.g., methyl, acetyl, purine pinole, petitole),
  • Ci-6 alkyl groups eg, ', methyl
  • a cycloalkyl group eg, cyclopropyl, cyclohexyl, bicyclo [3. 1. 1] heptyl, bicyclo [2. 2. 1] heptyl
  • C 6 _ 14 aryl groups which may be substituted by 1 to 3 non-aromatic heterocyclic groups (eg, morpholinyl) etc. which may be substituted by 1 to 3 alkoxy groups etc. (eg , Fell-),
  • (Eg, main butoxycarbonyl) C may be Idei substituted with 1 to 3 substituents selected from such 6 - 14 Ariru group (e.g., phenyl)
  • C 7 _ 13 allayl thiazolyl group which may be substituted with 1 to 3 substituents selected from etc. (eg benzinole, 2-phenenoleethyl, 3-phenynolepinore, 4-pheninolebutynore, 5 _phene norepentinole 6 _ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ , 7 ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ —, a, alpha ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ), '
  • Halo C o alkyl group eg, trifluoromethyl, 4-fluorobutyl nore, 4, 4, 4, 1 trifno reo mouth ptyl, 5-fluoro 'mouth penty nole, 5, 5, 5-, trifnore' o lopentyl , 4,4,5,5,5-pentafluorochloropentyl, 5,5,6,6 6-pentafuranole hexyl
  • Ci-6 alkyl group which may be substituted by 1 to 3 substituents selected from hydroxy group, carboxyl group etc. (eg methyl, acetyl, isopropyl, isobutyl), (Ii) a carboxyl group, (iii) an alkoxy-carbonyl group (eg, methoxycarbonyl), (iv) a force rubamoyl group, (v) Siano group, (vi) Non-aromatic heterocyclic group optionally substituted by 1 to 3 oxo groups etc. (eg, dihydrooxadiazolyl), (vii) Halogen atom
  • non-aromatic heterocyclic groups which may be substituted, for example, with oxo, etc. (eg, piperidinyl, pyrrolidinyl, dihydrooxadiazolyl),
  • aromatic heterocyclic groups eg, pyridyl, pyrimidinyl
  • halogen atom eg, fluorine atom
  • nitrogen-containing heterocyclic group which may be substituted with 1 to 3 substituents selected from etc. (eg, pyrrolidinyl, isooxazolidinyl, piperizinyl, piperazinyl. Morpholininole, thiomophorinole, dihydroxioza) Zorinole, Tetrazolinole. Thiazolyl, imidazolinole, pyridyl, tetrahydroquinolyl, indolyl, 7-azabicyclo [2. 2. 1] heptyl),
  • Halogen atom eg, chlorine atom, fluorine atom
  • Cs ⁇ optionally substituted by 1 to 3 substituents selected from Thich-opening alkyl group (eg, cyclohexyl, bicyclo [3. 1. 1] heptyl, bicyclo [2. 2. 1] heptyl),
  • Thich-opening alkyl group eg, cyclohexyl, bicyclo [3. 1. 1] heptyl, bicyclo [2. 2. 1] heptyl
  • Ci-6 alkyl groups eg, methyl
  • C 6 _ 14 7 reel groups eg, fuynyl
  • Optionally substituted heterocyclic group eg, pyrrolidinyl, piveridinyl, piperajul, monolephoryl, nil, pyridyl
  • C 7 _ 13 3 ralalkyl group which may be substituted with 1 to 3 substituents selected from etc. (eg, 'benzenol ,, 2-phenylethyl, 3-phenylpropyl, 4-phenyl, pheninolebutinol, 5 —Hue Niole pentinole),
  • R 6 and R 7 are each independently
  • n is preferably 0.
  • R4 is a hydrogen atom, optionally substituted. It represents an alkyl group, a cyano group or a halogen atom. .
  • R 4 is a prime atom, optionally substituted. Indicates an alkyl group or a halogen atom. ,
  • the rc-o alkyl group of the "optionally substituted alkyl group” represented by R4 may have 1 to 3 substituents at substitutable positions.
  • substituents for example, the “optionally substituted alkyl group” of “optionally substituted C i. Alkyl group” represented by R 1 or R 2 may be exemplified as the substituent. The thing is mentioned. When two or more substituents are present, each substituent may be the same or different.
  • halogen atom eg chlorine atom
  • Alkyl group eg, methyl
  • Halogen atom eg, chlorine atom
  • R 4 may not exist (for example, in the cases of formulas (lb) and (Id) described later), and in this case, k is 0.
  • k is 0.
  • Ring A is pyrazole, R 1 is bonded to the 1-position of pyrazole, and R 2 is bonded to the 3-position of pyrazole, that is,
  • R 1 is substituted, have C 6 - when it is 14 Ariru group, R 2 is not an optionally substituted heterocyclic group, and
  • ring A is pyrazole
  • R 1 is bonded to the 1-position of pizole
  • R 2 is bonded to the 5-position of pyrazole, ie
  • R 1 and R 2 are each independently a C 6 _ 14 aryl group which may be substituted
  • R 3 is the formula: i CONH — Ar _ Y — R
  • Ar is a C 6 _ 14 7 Rylene group which may be substituted
  • Y is one S 2 2 -or one C ⁇ 1
  • R is a cyclic group which may be substituted) Is a group represented by
  • Ring A is pyrazole, R 1 is bonded to pyrazole O 1 position, R 2 is bonded to 3 position of pyrazo, that is,.
  • R 1 is an optionally substituted C 6 ⁇ 4 aryl group
  • R 2 is not an optionally substituted heterocyclic group
  • ring A is pyrazole, R 1 is bonded to the 1-position of pyrazole, and R 2 is bonded to the 5-position of pyrazole;
  • R 1 and R 2 are each independently a C n 4 aryl group which may be substituted
  • R 3 is the formula: —CONH—A r—Y— R
  • Ar is a C 6 _ 14 arylene group which may be substituted
  • Y is _S0 2 -or 1 CO-and
  • R is a cyclic group which may be substituted
  • Ring A is not triazole
  • the compound '(I') is preferably
  • Ring A is a 5- or 6-membered aromatic heterocyclic ring (eg, pyrrolyl, pyrazole, imidazol, thiazol, oxazole, furan, thiophen, pyridine, pyrimidin);
  • Ci- 6 alkyl-carbonyloxy group eg, acetyloxy
  • halogen atom eg, fluorine atom
  • Alkyl group eg, methyl, ethyl, isopropyl, isobutyl, tert-butyl, neopentyl
  • halogen atom eg, fluorine atom, chlorine atom, bromine atom
  • halogen atoms e.g., fluorine atom
  • C doctor 6 alkyl group or the like e.g., methyl
  • C 6 _ 14 aryl group eg, phenyl
  • C 6 _ 14 aryl group which may be substituted by 1 to 3 substituents selected from (6) Heterocyclic groups (eg, pyridyl, pyrimidinyl, furyl)
  • R 1 and R 2 taken together, together with the constituent atoms of the 5- or 6-membered heteroaromatic ring to which they are attached, a C_ 6 alkyl group (eg, methyl '), a halogen atom (eg, fluorine atom) And so on, which may be substituted with 1 to 3 substituted rings (eg, dihydrobenzoxazepine), and the like.
  • a C_ 6 alkyl group eg, methyl '
  • a halogen atom eg, fluorine atom
  • R 1 and R 2 taken together, together with the constituent atoms of the 5- or 6-membered heteroaromatic ring to which they are attached, a C_ 6 alkyl group (eg, methyl '), a halogen atom (eg, fluorine atom) And so on, which may be substituted with 1 to 3 substituted rings (eg, dihydrobenzoxazepine), and the like.
  • halogen atom eg, fluorine atom, chlorine atom
  • - 6 alkyl group e.g., methyl, Echiru, isopropyl
  • halogen atoms e.g., fluorine atom
  • 6 alkoxy group or the like e.g, main butoxy, Ethoxy, isopropyl
  • C 6 _ 14 arylene group eg, phenylene
  • arylene group which may be substituted by 1 to 3 substituents selected from non-aromatic heterocyclic groups (eg, morpholinyl, pyrrolidinyl) and the like
  • Divalent fused cyclic hydrocarbon group which may be substituted by 1 to 3 alkoxy group etc. (eg, tetrahydnanaphthylene, fluorenylene, indanylene), or
  • Etc Divalent heterocyclic group optionally substituted by 1 to 3 substituents selected (eg, indrylene, indolinylene, benzimidazolene, 'thiophenylene, indazolylene, isoindolilyene, phenylene, pyridylene, etc. Tetrahydroquinolirene, pyrrolylene)
  • substituents eg, indrylene, indolinylene, benzimidazolene, 'thiophenylene, indazolylene, isoindolilyene, phenylene, pyridylene, etc. Tetrahydroquinolirene, pyrrolylene
  • 'Y is one S0 2 _, _SO —, _S —, one O —, one CO —, one CON
  • R 5 (R 5)-(wherein R 5 is a hydrogen atom or an alkyl group (eg, methyl alcohol)) or one CH (OH) one;
  • HiKaoru aromatic in optionally substituted HiKaoru aromatic also be a Hajime Tamaki (e.g., dihydric mud O hexa di ⁇ benzisoxazolyl), (vii) a halogen atom (e.g., fluorine atom), (viii) C -!
  • Hajime Tamaki e.g., dihydric mud O hexa di ⁇ benzisoxazolyl
  • a halogen atom e.g., fluorine atom
  • Arukeniruokishi one carbo - Le group (eg, Ariru Okishikarubo - Le) one to three optionally substituted with a substituent C 6 one 14 Ariru group selected from such (eg, phenyl), (b) non-aromatic hetero ring which may be substituted by 1 to 3 alkoxy group etc., cyclic group (eg, piveridinyl, pyrrolidinyl, dihydrooxadiazolyl, morpholinyl, tetrahydro-pyrimidinyl),
  • (c) 1 to 3 carboxyl CI_ 6 alkyl group (e.g., methyl) 5 teeth 3 1 may be substituted with such groups an aromatic substituted with such multi heterocyclic group (e.g. Pyridyl, pyrimidiyl, thiazolyl), '
  • 4- arylsnolefonino group eg, benzenesulfoel
  • a 6- membered alkoxycarbonyl group eg, tert-butoxycarbonyl
  • An amino group which may be
  • halogen atom eg, fluorine atom
  • an aromatic heterocyclic oxy group which may be substituted by 1 to 3 substituents selected from (e.g. methoxycarbonyl) etc. (e.g. pyridyloxy, chenyloxy,, isoxazolyloxy),
  • a nitrogen-containing heterocyclic group which may be substituted by 1 to 3 substituents selected from etc.
  • substituents selected from etc. eg pyrrolidinyl, isooxazolizinyl, piperidiyl, piperazier, morpholinyl, thiomorpholinyl, dihydrooxadiazolyl Tetrazolyl, thiazolyl, imidazolyl, pyridyl, tetrahydroquinolyl, indolyl, 7-pazabicyclo [2.2. 1] heptyl
  • Non-aromatic heterocyclic group which may be substituted by 1 to 3 alkoxy groups etc. (eg, morpholinyl)
  • C 6 _ 14 aryl group which may be substituted with 1 to 3 substituents selected from etc. (eg, phenyl, biphenyl),
  • Ci—6 alkyl group eg, methyl
  • 3 to 10 cycloalkyl group optionally substituted by 1 to 3 substituents selected from etc. (eg, siglohexyl, bicyclo [3. 1. 1] heptyl, bicyclo [2. 2. 1] Heptyl),
  • C 6 _ 14 Ariru group eg, Fueeru
  • C 6 one 14 Ariruokishi group eg, Fueno alkoxy
  • an aromatic Hajime Tamaki e.g. , Pyridyl
  • 1 to 3 substituents selected from 1 to 3 substituents (eg, methyl, acetyl, p-quinole, pentyl)
  • '(B) 1 to 3 C 6 alkyl group e.g., methylene
  • C 3 - 10 cycloalkyl group e.g., cyclopropyl, cyclohexyl, bicyclo [3.1.1 ] Heptyl, bicyclo [2. 2. 1] heptyl
  • reel groups eg, phenyl and the like, which may be substituted by 1 to 3 6 6 alkyl groups (eg, methyl) and the like;
  • Heterocyclic groups eg, pyrrolidinyl, piveridinyl, piperazinyl, morpholinyl, pyridyl
  • Ci-6 alkoxy-carbonyl group e.g., methoxy carbonyl, hydroxyl group levoninole
  • (b) cane levoxyl group, (.
  • (c) (i) carboxyl group, (ii) C Medicine 6 alkoxy one carbonyl group C may be substituted 1 to 3 substituents selected from such 6 - 14 Aryl group (eg, phenyl)
  • C 7 ⁇ ⁇ 13 7 L alkyl group optionally substituted with 1 to 3 substituents selected from etc. (eg, benzynole, 2—phenylethinole, 3—phenynoleno pinole, 4-phenynobutyl, 5— --Norepentyl ', 6- ⁇ - ⁇ - ⁇ xinole, 7- ⁇ - ⁇ - ⁇ - ⁇ - ⁇ - ⁇ - ⁇ -, le, ⁇ , ⁇ - jetino, levendil),
  • substituents selected from etc.
  • alkoxy group eg, methyl, methoxy, tert-butoxy
  • C-io alkyl group eg, tribromomethyl, 4-fluorobutyl ester, 4,4,4-trifluorobutyl, 5-phenolo pentyl, 5,5,5-triflophene
  • I3 ⁇ 4 6 and R 7 are each independently hydrogen atom or - be 6 alkyl Le group (eg, Echinore); and
  • Alkyl group eg, methyl
  • halogen atom eg chlorine atom
  • the compound (I) is preferably
  • Ring A is a 5'- or 6-membered aromatic heterocyclic ring (eg, pyrrole, pyrazole, imidazo,-, thiazol, oxa, / yl, furan, thiophen, pyridine, pyrimidin);
  • aromatic heterocyclic ring eg, pyrrole, pyrazole, imidazo,-, thiazol, oxa, / yl, furan, thiophen, pyridine, pyrimidin
  • R 1 and R 2 forces, each independently,
  • halogen atom eg, fluorine atom
  • substituents selected from ⁇ ⁇ alkyl group (eg, methinole, ethinole, isopropynore, isobutynore, ter t -butynore, neopentyl),
  • ⁇ ⁇ alkyl group eg, methinole, ethinole, isopropynore, isobutynore, ter t -butynore, neopentyl
  • halogen atom eg, fluorine atom, chlorine atom, bromine atom
  • C ⁇ 6 alkyl group eg, methyl
  • halogen atoms eg, fluorine atom
  • a C 6 ⁇ 4 aryl group (eg, phenyl) which may be substituted by 1 to 3 substituents selected from
  • Heterocyclic groups eg, pyridyl, pyrimidinyl, furyl
  • R 1 and R 2 together, together with the constituent atoms of the 5- or 6-membered heteroaromatic ring to which they are attached, a C ⁇ 6 alkyl group (eg methyl), a halogen atom (eg fluorine atom), etc.
  • a complex ring optionally substituted by 1 to 3 substituents selected from (for example, dihydroben benzoxazepine); R 3 is
  • halogen atoms eg, fluorine atom, chlorine atom
  • identical alkyl groups eg, methyl, ethyl, isopropyl
  • Ci 6 alkoxy group optionally substituted by 1 to 3 halogen atoms (eg, fluorine atom) and the like (eg, methoxy, ethoxy, isoproboxy),
  • halogen atoms eg, fluorine atom
  • the like eg, methoxy, ethoxy, isoproboxy
  • Divalent fused cyclic carbon which may be substituted with 1 to 3 alkoxy groups, etc., hydrogen group ('example, tetrahydrohydranylene, fluorenylene, indanylene), or'
  • a divalent heterocyclic group which may be substituted by 1 to 3 substituents selected from etc. (eg, indylene, indolinylene, benzimidazolene, thiophenidene, indazolylene, isoindolinylene, pyridinene, tetraphenyl) Drokinoliren, pyrrolylene)
  • Ci— 10 alkylene group eg, one CH 2 —,-(CH 2 ) 2 —, one (CH 2 ) 3 -,-(CH 2 ) 4 —,-(CH 2 ) 5 —, — ( CH 2 ) 6 _, one (CH 2 ) 7 —) or — '
  • Y is one so 2 _, one SO ⁇ , one S ⁇ , one o _, -CO-, -CON (R 5)-, wherein R 5 is a hydrogen atom or an alkyl group (eg, Methyl) is) or one CH (OH) is one;
  • Non-aromatic rod heterocyclic group which may be substituted (eg, dihydrooxadiazolyl),, (vii) halogen atom (eg, fluorine source ⁇ ), (v iii) C — 6 alkenyloxy carbonyl group (e.g., Ariru O alkoxycarbonyl) 1 selected from such to three substituents in the optionally substituted C 6 - 14 Ariru group (e.g., phenyl),
  • Non-aromatic heterocyclic group which may be substituted by 1 to 3 alkoxy group etc. (eg, Piveridinyl, pyrrolidinyl, dihydrooxadiazolyl, morpholinyl, tetrahydronylimidinyl)
  • an aromatic complex ring group which may be substituted by 1 to 3 carboxyl groups etc. 1 or 3 C ⁇ e alkyl groups (eg methyl) etc. (example , Pyridyl, pyrimidinyl, thiazolyl), (d) (i) C 3 - 10 cycloalkyl group (e.g., cyclopropyl), (ii) C 6 _ 14 ⁇ reel sulfonyl group (e.g., benzenesulfonyl), (iii) ⁇ - 6 ⁇ alkoxy one carbonyl An amino group which may be substituted by one or two substituents selected from groups (eg, tert-butoxycarbonyl) and the like;
  • alkoxy-carbonyl group eg, methoxycarbonyl, hydroxyl group, hydroxyl group, hydroxyl group),. '.
  • Ci-6 alkyl group eg, methyl, isopropyl which may be substituted by 1 or 3 substituents (eg, methyl, isopropyl), (iv) halogen atom (eg, fluorine atom), (V) cyano group , (vi) an aromatic Hajime Tamaki (e.g., tetrazolyl) 1 to 3 substituents substituted by C 6 _ 14 optionally Ariruokishi group selected from such (eg, phenoxy),
  • C 6 _ 14 a reelyl monocarbonyl group (eg, benzoin) which may be substituted by 1 to 3 C i-6 alkoxy monocarbonyl groups (eg, methoxy carbonyl) and the like
  • a nitrogen-containing heterocyclic group which may be substituted by 1 to 3 substituents selected from etc.
  • substituents selected from etc.
  • halogen atom eg, fluorine atom, chlorine atom
  • non-aromatic heterocyclic groups optionally substituted by 1 to 3 alkoxy group etc. (eg, morpholinyl),.
  • Good C 6 _ 14 aryl group eg phenyl, biphenyl
  • One to three optionally substituted with a substituent C 3 selected from such - 10 consequent opening alkyl group e.g., cyclohexyl, bicyclo [3.1.1] heptyl, bicyclo [2.2.1 ] Heptyl
  • a substituent C 3 selected from such - 10 consequent opening alkyl group e.g., cyclohexyl, bicyclo [3.1.1] heptyl, bicyclo [2.2.1 ] Heptyl
  • Ci-e alkoxy monocarbonyl group e.g., met) Alkoxycarbonyl
  • carboxyl group c 6 - 14 Ariruokishi group (eg, Fueno carboxymethyl) one to three optionally substituted with a substituent C 6 _ 14 Ariru group selected from such (eg, phenyl), ( iii) C 6 one 14 Ariruokishi S (eg, Fueno alkoxy), (iv) an aromatic Hajime Tamaki (e.g., - pyridyl) to 1, etc.
  • Ci- 6 alkyl Go e.g., methyl, Echiru, flop port Pinore, Buchinore
  • '(b) 1 to 3 CI- 6 alkyl group e.g., methyl
  • C 3 - 10 cycloalkyl Groups eg, cyclopropynore, cyclohexyl bicyclo [3. 1. 1] heptyl, bicyclo [2. 2. 1] heptyl
  • (d) 1 to 3 to 1 may be substituted with Okiso group 3 nonaromatic Hajime Tamaki (e.g., Moruhorieru) C may be substituted with such 6 - 14 Ariru group (e.g. , Phenyl),.
  • Okiso group 3 nonaromatic Hajime Tamaki e.g., Moruhorieru
  • Ariru group e.g. , Phenyl
  • Ariru group (eg, full - Le) 3 alkyl group (e.g., methyl) to 1 may be substituted with the like may also be substituted by an Heterocyclic groups (eg, pyrrolidinyl, piperizinyl, piperazinyl, monoreholinyl, pi, lysyl)
  • C 7 _ 13 halal quinole group which may be substituted with 1 to 3 substituents selected from etc. (eg, benzinole, 2-phenenoleethinole, 3-fue dinore pizole, 4-f Henino rebuchi nore, 5- ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ , 6 _ ⁇ ⁇ ⁇ ⁇ , 7 ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ , ⁇ _ '' ⁇ ⁇ ⁇ benzilnore),
  • Nono B C -. 10 alkyl group e.g., Torifuruorome chill, 4 Furuoropuchi Honoré, 4, 4, 4 Ichito Li Funoreorobuchiru, 5- Funoreo port Penchinore, 5, 5, 5, Torifunoreo port Penchinore, 4 , 4, 5, 5, 5 _ Pentaphoro lopenotinole, 5, 5, 6, 6, 6 6-Pentafunole mouth hexyl
  • 1 and m are each independently a group represented by 0 or 1), and R 3 is bonded to a carbon atom constituting ring A;
  • k force is 0 or 1
  • Ring A is a 5- or 6-membered aromatic heterocyclic ring (eg, pyrrole, pyrazole, imidazole, thiazole, oxazole, furan, thiophen, pyridine, pyrimidin); R 1 and R 2 are each independently
  • Ci 1 to Ci one 6 alkoxy group (e.g., main butoxy) of 3fe which may be substituted by an C 6 - 14 Ariru group (e.g., Hue ') yl,
  • Ci-6 alkoxylcarbonyl group e.g., methoxy carbonyl, hydroxyl force / reposinol
  • Ci-6 alkyl-carbonyloxy group eg, acetyloxy
  • halogen uraiko eg, fluorine atom
  • C 1 optionally substituted with 1 to 3 substituents selected from Alkyl groups (eg, methyl, ethyl, isopropyl, isobutyl, ter t-butyl, neopentyl),,
  • Alkyl groups eg, methyl, ethyl, isopropyl, isobutyl, ter t-butyl, neopentyl
  • halogen atom eg, fluorine atom, chlorine atom, bromine atom
  • Ci-6 alkyl group eg, methyl
  • halogen atoms eg, fluorine atom
  • Nitrogen-containing heterocyclic groups eg, pyridyl, pyrimidinyl
  • R 3 is an 'one: CONH-A r-(X) 1-(Y) m-R
  • halogen atom eg, fluorine atom, chlorine atom
  • Ci- 6 alkyl group eg, methyl, isopropyl
  • Divalent fused cyclic hydrocarbon group which may be substituted by 1 to 3 alkoxy group etc. (eg, tetrahydnanaphthylene, furoreorenylene), or
  • Divalent heterocyclic group which may be substituted by 1 to 3 Ci-6 alkyl groups (eg, methyl) etc. (eg, indylene, indolinylene, benzimidazolene, thiophenylene) And;
  • alkylene group eg, —CH 2 —, — (CH 2 ) 2 —, one (CH 2 ) 3 —, — (CH 2 ) 4 —, one (CH 2 ) 5 —
  • Y is, - so 2 -, -so-; - S-, one O-, -CO-, -CON, (R 5) mono-, (wherein, R 5 forces a hydrogen atom or a C10 alkyl group (e.g., methylcarbamoyl Nore)) or one CH (OH)-and-R is
  • (V) 'Siano group (vi) non-aromatic heterocyclic group optionally substituted by 1 to 3 alkoxy group etc.,' (eg dihydrooxadiazolyl), (vii ) halogen atom, (e.g., full 'Tsu atom) C may be substituted 1 to 3 substituents selected from such 6 - 14 Ariru group (e.g., phenyl),
  • Non-aromatic heterocyclic group which may be substituted by 1 to 3 alkoxy group etc. (eg, piveridinyl, pyrrolidinyl, dihydrooxadiazolyl),
  • aromatic heterocyclic groups eg, pyridyl, pyrimidinyl
  • a nitrogen-containing heterocyclic group which may be substituted by 1 to 3 substituents selected from etc. (eg, pyrrolidine-, isooxazolidiyl, piperizinyl, piperazinyl, morpholinyl, thiomorpholinyl, dihydroxazolia Zoryl, tetrazolyl.
  • C 6 _ 14 7 aryl group optionally substituted by 1 to 3 substituents selected from, for example, phenyl (eg, phenyl),
  • a substituent C 3 selected from such - 10 consequent opening alkyl group e.g., cyclohexyl, bicyclo [3.1.1] heptyl, bicyclo [2.2.1 [Hepti Nore)]
  • a substituent C 3 selected from such - 10 consequent opening alkyl group e.g., cyclohexyl, bicyclo [3.1.1] heptyl, bicyclo [2.2.1 [Hepti Nore)]
  • (a) '( i) 1 to 3 of C ⁇ 6 alkyl group (e.g., methyl) C may be substituted with such 3 - 10 cycloalkyl group (e.g., cyclopropyl, bicyclo
  • alkyl groups eg, methyl
  • reel groups eg, phenyl
  • Ring groups eg, pyrrolidinyl, piperizinyl, piperazur, morpholinyl, pi, lysyl
  • C 7 _ 13 Alkyl which may be substituted by 1 to 3 substituent (s) selected from etc. (eg, benzyl, 2 _ phenylethyl, 3-phenylpropyl, 4-phenylenolebutinole, 5-phenylenole pentylenole ),
  • An alkoxy group (eg, methoxy, ethoxy, ter t-butoxy),
  • R 1 and m are each independently a group represented by 0 or 1), and R 3 is bonded to a carbon atom constituting ring A; R 4 is
  • k force is 0 or 1
  • the compound (I) is preferred.
  • the compound (I ′) and the compound (I) are preferably represented by the formula (la) to the formula (I i): ',-
  • a compound represented by the following formula (hereinafter abbreviated as a compound (la) to a compound (Ii), respectively). Particularly preferred is a compound in which the constituent atom of the ring to which R 2 is bonded is adjacent to the constituent atom of the ring to which R 3 is bonded. Preferred compounds are listed below for each of the compounds U a) to compounds (I i).
  • the compound (I a) is preferably of the formula (I aa):
  • R 2 is bonded to the 3-position of pyrazole and R 1 is a C 6 _ 14 aryl group which may be substituted, R 2 is not a heterocyclic group which may be substituted. ,.
  • R 2 is attached to the 5-position of pyrazole and R 1 and R 2 each independently represent an optionally substituted C 6 _ 14 aryl group
  • R3 is the formula: — CONH— A r — Y— R
  • Ar is a 6 to 14 arylene group which may be substituted
  • 'Y is one S0 2 _ or one CO—
  • R is a cyclic group which may be substituted), and is a group represented by '. ,.
  • R 1 is optionally substituted C — i. Alkyl, optionally substituted-! .
  • R 2 is preferably an optionally substituted alkylthio group or an optionally substituted cyclic group.
  • R 1 is a C 6 _ 14 aryl group which may be substituted
  • R 2 is not a heterocyclic group which may be substituted.
  • R 2 is attached to the 5-position of pyrazole and R 1 and R 2 each independently is a C 6 -14 7 reel group which may be substituted,
  • R 3 is the formula: —CONH— Ar— Y— R
  • Ar is a C 6- . 14 -arene group which may be substituted
  • Y is one S ⁇ 2 -or one CO-
  • R is a cyclic group which may be substituted).
  • R 3 is the formula: one CONH—A r—S 0 2 —R, or
  • N [3 — (4-morpholinylsulfoninole) ferrite] 1, 3-Diphenone 1; LH-pyrazole 4-force zolevaxamide, '-3-(4-black mouth dye 2)
  • 13 ⁇ 4112 is preferably each independently a C — io alkyl group which may be substituted, and g which may be substituted.
  • Alkylthio group optionally substituted C! .
  • R 1 and R 2 together form a heterocyclic ring which may be substituted together with the constituent atoms of the pyrazole ring to which they are attached

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Abstract

L’invention concerne un inhibiteur des récepteurs FXR comprenant un composé répondant à la formule (I') ou l’un de ses sels, ou un promédicament dudit composé ou sel. Dans la formule (I'), tous les symboles sont tels que définis dans la description. Ledit inhibiteur possède un excellent effet d’inhibition des récepteurs FXR. Il peut diminuer de manière significative le taux de cholestérol LDL sanguin ou le taux de cholestérol non-HDL sanguin ; il possède également un effet de diminution du taux de triglycérides, un effet d’augmentation du taux de cholestérol HDL et il favorise l'excrétion d’acide biliaire dans les selles.
PCT/JP2006/322420 2005-11-04 2006-11-02 Compose amide heterocyclique et son utilisation Ceased WO2007052843A1 (fr)

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JP2006-251883 2006-09-15

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US12440481B2 (en) 2019-01-10 2025-10-14 Vertex Pharmaceuticals Incorporated Esters and carbamates as modulators of sodium channels
WO2020262603A1 (fr) 2019-06-28 2020-12-30 小野薬品工業株式会社 Antagoniste d'ep2
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CN111269224A (zh) * 2020-02-25 2020-06-12 华东理工大学 含悉尼酮或悉尼酮亚胺的二酰胺类化合物及其制备和用途
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