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WO2008056687A1 - Nouveau dérivé de spiropipéridine - Google Patents

Nouveau dérivé de spiropipéridine Download PDF

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Publication number
WO2008056687A1
WO2008056687A1 PCT/JP2007/071605 JP2007071605W WO2008056687A1 WO 2008056687 A1 WO2008056687 A1 WO 2008056687A1 JP 2007071605 W JP2007071605 W JP 2007071605W WO 2008056687 A1 WO2008056687 A1 WO 2008056687A1
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Prior art keywords
group
pyridazine
compound
formula
chromene
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PCT/JP2007/071605
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English (en)
Japanese (ja)
Inventor
Yoshikazu Uto
Yohei Kiyotsuka
Original Assignee
Daiichi Sankyo Company, Limited
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Publication of WO2008056687A1 publication Critical patent/WO2008056687A1/fr

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P19/00—Drugs for skeletal disorders
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    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems

Definitions

  • the present invention suppresses the action of stearoyl CoA desaturase, thereby preventing various human diseases associated with stearonole CoA desaturase such as diabetes, arteriosclerosis, obesity, non-alcoholic steatohepatitis, hyperlipidemia, and hypertension.
  • the present invention relates to a compound having a specific chemical structure which is effective for treatment 'prevention or a pharmacologically acceptable salt thereof.
  • the acyl-CoA desaturase enzyme catalyzes the formation of double bonds in fatty acids that are taken up by cells or produced by intracellular synthesis. In animals, there are four types of acyl-CoA desaturase enzymes that introduce double bonds at the delta-9, delta-6, delta-5, and delta-4 positions of the fatty chain, respectively.
  • Stearoyl CoA desaturase (hereinafter also referred to as SCD! /, U) is an enzyme that introduces a double bond at the delta-9 position of saturated fatty acids, and mainly produces palmitoyl CoA and stear mouth CoA in vivo. These products are converted into palmitole oil CoA and oleoyl CoA, respectively, and these products are used as the main components of phospholipids, triglycerides and cholesterol esters.
  • the ratio of stearic acid to oleic acid affects the fluidity of cell membranes and has been implicated in diabetes, obesity, arteriosclerosis, hypertension, neurological disease, heart disease, cancer, and aging (Non-patent Document 1) .
  • Mouse liver SCD was highly expressed in leptin-deficient ob / ob mice, an appetite-suppressing hormone, and its expression was suppressed to normal levels by leptin administration.
  • SCD-deficient mice have lower liver triglycerides, lower liver cholesterol esters, and lower adipose tissue weight compared to normal mice. Under high fat diet, body weight gain is suppressed and glucose tolerance and insulin sensitivity are increased compared to normal animals. did. Crossing with ob / ob mice resulted in weight loss, increased metabolism, and normalization of fatty liver (Non-patent Documents 2 and 3).
  • SCD inhibitors contributed to the improvement of insulin resistance, hyperglycemia, anti-obesity, liver function, and arteriosclerosis due to their wide-ranging effects on the lipid metabolism system. Presumed to be a target.
  • Patent Document 1 describes compounds in which a carbonyl group or an amino group or the like is bonded to the 4-position of piperidine and their use as an SCD inhibitor. .
  • Patent Document 2 describes an example of a compound in which a carbonyl group or a cyclic group is bonded to the 4-position of piperidine.
  • there is no example of a compound having a spiro structure at the 4-position of piperidine but it is described as an angiogenesis inhibitor, but it is used as an SCD inhibitor. Is not listed at all!
  • Patent Document 1 International Publication No. 2006/034338 Pamphlet
  • Patent Document 2 International Publication No. 97/26258 Pamphlet
  • Patent Document 3 International Publication No. 2005/011653 Pamphlet
  • Patent Document 4 International Publication No. 2005/5011654 Pamphlet
  • Patent Document 5 US 2005/0119251
  • Patent Document 6 International Publication No. 2006/086447 Pamphlet
  • Non-Patent Document 1 Prog Lipid Res. 1995; 34 (2): 139-150.
  • Non-Patent Document 2 Science. 2002; 297 (5579): 240_3
  • Non-Patent Document 3 Proc Natl Acad Sci U S A. 2002; 99 (17): 11482-6.
  • Non-Patent Document 4 J Clin Invest. 2005; 115 (4): 1030-8
  • the inventors have conducted extensive research on compounds having an SCD inhibitory action, and as a result, It has been found that a compound having a certain chemical structure has an excellent SCD inhibitory action.
  • this compound is obesity, obesity, hyperlipidemia, hypertriglyceridemia, fat metabolism disorder, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetes Peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes mellitus, polycystic ovary syndrome, arteriosclerosis (arteries resulting from the diseases described above and below) Sclerosis), atherosclerosis, diabetic arteriosclerosis, fatty liver, and non-alcoholic steatohepatitis as an active ingredient in medicine for the prevention and / or treatment of selected diseases Or the following diseases caused by obesity: hyperlipidemia, hypertriglyceridemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (d
  • the present invention relates to (1) general formula (I)
  • A represents a group represented by the formula CONHR 1 or a group represented by the formula ER 2 ;
  • R 1 may be independently substituted with 1 to 5 groups independently selected from substituent group a ⁇ C alkyl group or 1 to 3 groups independently substituted with group selected from substituent group a
  • E represents a 1,3,4-oxadiazole group, a 1,2,4 oxadiazole group or an imidazole group (however, the nitrogen atom of the imidazole group is bonded to pyridazine or pyridine, and the carbon atom is bonded to R 2 ).
  • R 2 is a hydrogen atom or a group selected from the substituent group a and may be independently substituted with 1 to 5 CC anoleno quinole group, phenyloxy group, phenyl alumino group or pyridylamino group
  • R 3 represents a hydrogen atom, a halogen atom or a CC alkyl group
  • R 4 represents a hydrogen atom, a halogen atom or a CC alkyl group
  • R 5 is a hydrogen atom, a halogen atom, a C 2 -C anorequinole group, a C—C halogenated alkyl
  • R 6 is a hydrogen atom, a halogen atom, a C 1 -C anolenoquinole group, a C—C halogenated alkyl
  • R 7 is a hydrogen atom, a halogen atom, a C 2 -C anorequinole group, a C—C halogenated alkyl
  • R 8 is a hydrogen atom, a halogen atom, a C 2 -C anoleno quinole group, a C—C halogenated alkyl
  • 1 6 c 1 -c represents a halogenated alkoxy group
  • U represents a single bond, a methylene group, a group represented by the formula CH (OH), a carbonyl group, an oxygen atom, a sulfur atom, a sulfiel group, or a sulfonyl group;
  • V represents a single bond, a methylene group or a group represented by the formula —CH 2 (OH) —,
  • a group (Q 2 represents a CC alkyl group) or an oxygen atom
  • W and V are groups represented by the formula 1 N (Q 3 ) —CH—CH— as W—V (Q 3 is C
  • 2 2 1 C represents an alkyl group. A nitrogen atom is attached to the phenyl ring.
  • n 0 or 1
  • n 0 or 1, excluding
  • Substituent group a is a halogen atom, C C cycloalkyl group, hydroxy group, C C alkyl
  • Substituent group b is a halogen atom, a C C alkyl group, a C C halogenated alkyl group,
  • a group consisting of a strong rubermoyl group, a nitro group and an amino group is shown. Or a pharmacologically acceptable salt thereof.
  • R 1 is independently 1 in a group selected from (hydroxy group, 1 to 3 independently substituted with a group selected from substituent group b, V, may! /, Phenyl and pyridinole groups) To 3 substituted CC alkyl groups or (independently a hydroxy group or a group selected from substituent group b)
  • R 1 is 2- (3 pyridyl) ethyl group, 2 hydroxy-2 phenylethyl group, 2 hydroxy-2- (3 pyridyl) ethyl group, 2 hydroxy-2- (4 pyridyl) ethyl group, (3 pyridyl) methyl group or A compound which is trans-2- (3 pyridyl) -cyclopropyl group or a pharmacologically acceptable salt thereof.
  • R 1 is a 2- (3 pyridyl) ethyl group, 2 hydroxy-2- (3 pyridyl) ethyl group or trans 2- (3 pyridyl) -cyclopropyl group.
  • a compound which is a group represented by the formula ER 2 or a pharmacologically acceptable salt thereof is a group represented by the formula ER 2 or a pharmacologically acceptable salt thereof.
  • R 2 is a hydrogen atom (from a hydroxy group, a CC alkoxycarbonyl group, a substituent group
  • a compound which is a xyl group or a phenylamino group or a pharmacologically acceptable salt thereof is a compound which is a xyl group or a phenylamino group or a pharmacologically acceptable salt thereof.
  • Basic force S represented by the formula ER 2 , 5-ethoxycarbonylmethyl-1,3,4-oxadiazo mononor 2 ynole, 5 benzyl mono 1,3,4 oxadiazo leu ro 2 yl, 5-(2 — Pyridyl) methyl-1,3,4 oxadiazole-2-yl group, 5-(3 pyridyl) methylol 1,3,4 oxazodiazole 2-yl group, 5- (4 pyridyl) methyl-1,3,4 Xadiazol-2-yl group, 5-- (a-hydroxybenzyl) 1,3,4 oxadiazo mononole 2-inole group, 5 phenyl 1,3,4 oxadiazolo luoyl group, 5 phenylamino-1,3,4 oxadiazo mono
  • ER 2 5-ethoxycarbonylmethyl-1,3,4-oxadiazo mononor 2 ynole, 5 benzy
  • R 3 and R 4 force S, a compound which is a hydrogen atom, or a pharmacologically acceptable salt thereof.
  • R 8 is a hydrogen atom, a halogen atom, a CC alkyl group or a CC halogenated alkyl.
  • R 8 is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group or a trifluoromethyl group.
  • U force A compound having a single bond, methylene group, carbonyl group, oxygen atom or sulfur atom, or a pharmacologically acceptable salt thereof.
  • V force A compound or a pharmacologically acceptable salt thereof which is a methylene group or a group represented by the formula —CH 2 (OH) —.
  • -CH (OH) is a group represented by one
  • U is an oxygen atom
  • - ⁇ — ⁇ — is a formula ⁇ 1 (0 ⁇ 1) —when a group represented by one CH
  • U is a sulfur atom
  • W—V is a group represented by the formula CH 2 —CH 1
  • W—V— is a group represented by the formula CH 2 —CH
  • U is a carbonyl group
  • W—V is a group represented by the formula N (iPr) —CH 2 —CH 1
  • U is an oxygen atom
  • A represents a group represented by the formula CONHR 1 or a group represented by the formula ER 2
  • R 1 is a CC alkyl group which may be independently substituted with 1 to 5 groups independently selected from the substituent group a.
  • 1 to 3 substituents independently selected from a group selected from the substituent group a
  • E represents a 1,3,4-oxadiazole group, a 1,2,4 oxadiazole group or an imidazole group (however, the nitrogen atom of the imidazole group is bonded to pyridazine or pyridine, and the carbon atom is bonded to R 2 ).
  • R 2 is a hydrogen atom or a group selected from the substituent group a and may be independently substituted with 1 to 5 CC anoleno quinole group, phenyloxy group, phenyl alumino group or pyridylamino group
  • R 3 represents a hydrogen atom, a halogen atom or a CC alkyl group
  • R 4 represents a hydrogen atom, a halogen atom or a CC alkyl group
  • R 5 is a hydrogen atom, a halogen atom, a C 2 -C anorequinole group, a C—C halogenated alkyl
  • R 6 is a hydrogen atom, a halogen atom, a C 1 -C anolenoquinole group, a C—C halogenated alkyl A group, c -c alkoxy group or c -c halogenated alkoxy group,
  • R 7 is a hydrogen atom, a halogen atom, a C 2 -C anorequinole group, a C—C halogenated alkyl
  • R 8 is a hydrogen atom, a halogen atom, a C 2 -C anoleno quinole group, a C—C halogenated alkyl
  • U represents a single bond, a methylene group, a group represented by the formula CH (OH), a carbonyl group, an oxygen atom, a sulfur atom, a sulfiel group, or a sulfonyl group;
  • V represents a single bond, a methylene group or a group represented by the formula —CH (OH) —,
  • W represents a methylene group, a group represented by the formula CH (OH) —, a group represented by the formula CH OQ 1 ) —
  • a group (Q 2 represents a CC alkyl group) or an oxygen atom
  • n 0 or 1
  • n 0 or 1, excluding
  • Substituent group a is a halogen atom, C C cycloalkyl group, hydroxy group, C C alkyl
  • a C C aryl group that may be independently substituted with 1 to 5 groups selected from
  • Substituent group b is a halogen atom, a C C alkyl group, a C C halogenated alkyl group,
  • A is a group represented by the formula CONHR 1 , and R 1 is independently substituted with 1 to 3 groups selected from a hydroxy group and a group selected from the substituent group b! /, May! /, A phenyl group and CC alkyl group or (hydroxy group) that is independently substituted with 1 to 3 groups independently of the selected group.
  • R 4 , R 6 and R 7 are hydrogen atoms
  • R 8 is a hydrogen atom, a halogen atom, a C —C alkyl group or a c —c halogenated alkyl group
  • Z and Y are nitrogen atoms.
  • W—V— is a group represented by the formula CH 2 —CH
  • U is an oxygen atom
  • U is a methylene group
  • W—V— is represented by the formula CH ( ⁇ nBu) —CH—.
  • a compound or a pharmacologically acceptable salt thereof which is an elementary atom and m and n are 1.
  • A is a group represented by the formula —CONHR 1 and R 1 is 2— (3 pyridyl) ethyl group, 2 hydroxy-2-phenylethyl group, 2 hydroxy-2 -— (3 pyridyl) ethyl group, 2 hydroxy 2— (4 Pyridyl) ethyl group, (3 pyridyl) methyl group or trans 2- (3-pyridyl) -cyclopropyl group, R 4 , R 5 , R 6 and R 7 are hydrogen atoms, R 8 is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group or a trifluoromethyl group, Z and Z are nitrogen atoms, When W—V— is a group represented by the formula CH 2 —CH, U is an acid
  • W—V is a group represented by the formula CH (OH) —CH—, U is an oxygen atom,
  • W—V is a group represented by the formula CH —CH ( ⁇ H) —, U is an oxygen atom, W—V
  • W— V is a group represented by the formula CH 2 —CH 1
  • A is a group represented by the formula —CONHR 1 ;
  • R 1 is a 2- (3 pyridyl) ethyl group, a 2-hydroxy-2- (3 pyridyl) ethyl group or a trans 2- (3 pyridyl) -cyclopropyl group;
  • R 3 , R 4 , R 5 , R 6 and R 7 are hydrogen atoms,
  • R 8 is a hydrogen atom, fluorine atom, chlorine atom, methyl group or trifluoromethyl group, and Z and Y are nitrogen atoms.
  • V is a group represented by the formula N (iPr) —CH 2 —CH 1
  • U is an oxygen atom
  • m is an oxygen atom
  • a compound wherein n is 1 or a pharmacologically acceptable salt thereof.
  • A is a group represented by the formula ER 2 , E is a 1,3,4-oxadiazole group, 1,2,4 oxadiazole group or imidazole group, R 2 is a hydrogen atom, (hydroxy group, CC
  • Alkoxycarbonyl group 1 to 3 groups independently substituted with a group selected from Substituent Group b, may be! /, Phenyl and pyridyl groups) 1 to 3 independently with selected groups A C 1 -C alkyl group, a phenyloxy group or a phenylamino group which is substituted, R 3 , R 4 ,
  • R 5 , R 6 and R 7 are hydrogen atoms
  • R 8 is hydrogen atom, halogen atom, CC alkyl group Or a CC halogenated alkyl group
  • Z and Y are nitrogen atoms
  • W—V is
  • U is an oxygen atom
  • ⁇ — ⁇ — is represented by the formula ⁇ 1 (0 ⁇ 1) —
  • U is a sulfur atom
  • W—V is a group represented by the formula CH ( ⁇ nBu) —CH—, U is an oxygen atom,
  • A is a group represented by the formula ER 2 and the group represented by the formula ER 2 is a 5-ethoxycarbonylmethyl 1,3,4-oxadiazol-2-yl group, a 5-benzyl-1,3,4-oxazazole-2-yl group , 5— (2 Pyridyl) methyl-1,3,4 oxaziazol 2-yl group, 5 -— (3 Pyridyl) methyl- 1,3,4 oxaziazol 2-yl group, 5 -— (4 Pyridyl) methyl-1, 3,4 oxadiazoluyl 2-yl group, 5--hydroxybenzyl) 1,3,4 oxadiazoluyl 2-yl group, 5 phenyl1,3,4- oxadiazoluyl 2-yl group, 5 phenylamino-1, 3,4 oxazodiol 2-yl group, 3- (3-pyridyl) methyl 1,2,4-oxazodiazole-5 yl group or 1-imidazo
  • U is an oxygen atom
  • W—V is a group represented by the formula CH 2 —CH 1
  • U is a methylene group
  • - ⁇ — ⁇ — is a group represented by the formula ⁇ 1 (01: 611) —
  • W—V— is a group represented by the formula CH 2 —CH
  • U is carbonyl
  • W—V is a group represented by the formula —N (iPr) —CH 2 —CH 1
  • U is an oxygen atom
  • M and n are 1, or a pharmacologically acceptable salt thereof.
  • A is a group represented by the formula ER 2
  • a group represented by the formula ER 2 is a 5- (2 pyridyl) methyl-1,3,4 oxadiazo 2-yl group, 5- (3 pyridyl) methyl-1,3 , 4 oxaziazol 2-yl group, 5- (4 pyridyl) methyl- 1,3,4 oxazizo mononole 2-inole group, 5-( ⁇ -hydroxybenzinole) 1,3,4 oxadiazonore 2 —Yl group or 1-imidazolyl group, R 3 , R 4 , R 5 , R 6 and R 7 are hydrogen atoms, is a hydrogen atom, fluorine atom, chlorine atom, methyl group or trifluoromethyl group Z and Y are nitrogen atoms, and W—V— is a group represented by the formula CH 2 —CH 1, U is oxygen
  • W—V is a group represented by the formula CH (OH) —CH—, U is an oxygen atom,
  • ⁇ ⁇ is the formula. !! In the group represented by CH ( ⁇ H) — U is an oxygen atom, W—V—
  • U is a methylene group,- ⁇ -is a formula-(11 ( ⁇ 1 811)-(
  • U is an oxygen atom
  • W—V is a group represented by the formula CH 2 —CH 1
  • a stearoyl CoA desaturase inhibitor comprising the compound according to any one of (1) to (32) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a pharmaceutical composition comprising the compound according to any one of (1) to (32) or a pharmacologically acceptable salt thereof as an active ingredient.
  • the pharmaceutical composition is obesity, obesity, hyperlipidemia, hypertriglyceridemia, dyslipidemia disease, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral nerve) Disorders, including diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes mellitus, polycystic ovary syndrome, arteriosclerosis (arteriosclerosis caused by the diseases mentioned above and below)
  • arteriosclerosis arteriosclerosis caused by the diseases mentioned above and below
  • the use according to (43) which is a composition for treating and / or preventing atherosclerosis, diabetic arteriosclerosis, fatty liver or nonalcoholic steatohepatitis.
  • the pharmaceutical composition is a composition for the treatment and / or prevention of obesity, obesity or hyperlipidemia resulting from obesity, hypertriglyceridemia, diabetes, hypertension or arteriosclerosis Use as described in (43).
  • composition for the treatment and / or prevention of fatty liver or nonalcoholic steatohepatitis.
  • the disease is obesity, obesity, hyperlipidemia, hypertriglyceridemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy , Including diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataracts, gestational urineuria, polycystic ovary syndrome, arteriosclerosis (Including pulse sclerosis), atherosclerosis, diabetic arteriosclerosis, fatty liver or nonalcoholic steatohepatitis (53).
  • the following diseases are caused by obesity: hyperlipidemia, hypertriglyceridemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic) Peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes mellitus, polycystic ovary syndrome, arteriosclerosis (arteriosclerosis caused by the diseases shown above and below) (Including), atherosclerosis, diabetic arteriosclerosis, hypertension, cerebrovascular disorder, coronary artery disease, fatty liver, respiratory abnormalities, low back pain, knee osteoarthritis, gout or cholelithiasis (53) The method described.
  • the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Preferred are a fluorine atom, a chlorine atom or a bromine atom, and more preferred is a fluorine atom or a chlorine atom.
  • C C alkyl group is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms.
  • alkyl group For example, methyl, ethyl, propyl, isopropyl, butyl, isobutinol, s butinole, t-butinole, pentinole, isopentinole, 2-methinolevinore, neopentinole, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl , 2-methylpentyl, 1-methylpentyl, 3,3 dimethylbutyl, 2,2 dimethylbutyl, 1,1-dimethylbutyl, 1,2 dimethylbutyl, 1,3 dimethylbutynole, 2,3 dimethylbutyl, 1 ethylbutyl or 2 ethylbutyl Yes, suitable Is a linear or branched alkyl group having 1 to 4 carbon atoms (CC alkyl group),
  • Q 1 is more preferably a butyl group
  • Q 3 is still more preferably an isopropyl group.
  • C C halogenoalkyl group is the same or different 1 to 5
  • halogen atom is bonded to the “c-c alkyl group”.
  • the "C-C alkoxy group” means that the "C-C alkyl group” is an oxygen atom.
  • It is a group bonded to a child and is a linear or branched alkoxy group having 1 to 6 carbon atoms.
  • C alkoxy group more preferably methoxy group, ethoxy group, propoxy group or iso
  • a propoxy group (C C alkoxy group), and even more preferably a methoxy group or an ethoxy group.
  • a group bonded to a “C 1 -C alkoxy group” C 1 -C halogen
  • the "pyridinoreamino group” is preferably a 3-pyridinoreamino group or a 4-pyridinoreamino group.
  • C C cycloalkyl group means a cyclopropyl group, cyclobutyl
  • a cyclopentyl group or a cyclohexyl group is a cyclopropyl group
  • C 1 -C alkoxycarbonyl group means one of the above-mentioned "C 1 -C alkyl groups”.
  • "2 7 1 6 Coxy group” is a group bonded to a carbonyl group.
  • C alkoxycarbonyl group more preferably methoxycarbonyl or ethoxycarbonyl.
  • a sulfonyl group (c-c alkoxycarbonyl group), and even more preferably an ethoxycarbonyl.
  • the “C C aryl group” is an aromatic hydrocarbon having 6 to 10 carbon atoms.
  • it is a phenyl, indul or naphthyl group, preferably a phenylol or naphthyl group, and more preferably a phenyl group.
  • the “pyridyl group” is preferably a 3 pyridyl group or a 4 pyridyl group.
  • the “chenyl group” is preferably a 2-chenyl group.
  • the “thiazolyl group” is preferably a 2 thiazolyl group.
  • C C alkylcarbonyloxy group means one of the above “C C C
  • a carbonyl group to which a “2 7 1 6 alkyl group” is bonded is bonded to an oxygen atom.
  • Toxyl, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, bivalyloxy, valeryloxy or isovaleryloxy group and preferably a carbonyl group to which one of the above-mentioned ⁇ CC alkyl groups '' is bonded to an oxygen atom. Bonded group (
  • Nyloxy group (C C alkylcarbonyloxy group), and even more preferably,
  • C 1 -C alkoxycarbonyloxy group means one of the above “C 1 -C 4 C
  • a carbonyl group to which "2 7 1 alkoxy group" is bonded to an oxygen atom For example,
  • the “CC alkyl group which may be independently substituted with 1 to 5 groups independently selected from the substituent group a” is independently 1 to 1 groups independently selected from the substituent group a. 5 pieces
  • a C C alkyl group independently substituted with 1 to 3 groups independently selected from a phenyl group and a pyridinole group optionally substituted with 1 to 3 groups independently selected from b;
  • an ethoxycarbonylmethyl group More preferably, an ethoxycarbonylmethyl group, a benzyl group, a (2-pyridyl) methyl group, ( (3-pyridyl) methyl group, (4-pyridyl) methyl group or hydroxybenzyl) group, and more preferably (2 pyridyl) methyl group, (3 pyridyl) methyl group, (4 pyridyl) methyl or ( ⁇ -hydroxybenzyl) group.
  • CC cycloalkyl group which may be independently substituted with 1 to 3 groups selected from substituent group a is independently 1 with a group selected from substituent group a.
  • c-c cycloalkyl group may be optionally substituted.
  • a CC aryl group which may be independently substituted with 1 to 5 groups selected from substituent group b is independently 1 to 1 groups selected from substituent group b. 5 pieces
  • c-c aryl group may be substituted. Preferably, it is selected from substituent group b.
  • a phenyl group which may be independently substituted by 1 to 5 groups, more preferably a 2 fluorophenyl group, a 3 fluorophenyl group, a 4 fluorophenyl group or a phenyl group, and even more.
  • Preferable is a phenyl group.
  • the “group represented by the formula —CONHR 1 ” is a group in which one amino group to which R 1 is bonded is bonded to a carbonyl group. Preferably, it is independently substituted with a group selected from (hydroxy group, 1 to 3 independently substituted with a group selected from substituent group b! /, May! /, Phenyl group and pyridinole group). 1 to 3 substituted CC alkyl groups or (hydroxy
  • Group independently selected from 1 to 3 groups selected from a group selected from the group of substituents b and 1 to 3 independently substituted with a group selected from a phenyl group and a pyridyl group which may be substituted independently.
  • 3-6 is a group in which an amino group to which an alkyl group is bonded is bonded to a carbonyl group, more preferably a 2- (3 pyridyl) ethylaminocarbonyl group, 2 hydroxy-2 phenylamino minocanorepinole group, 2 hydroxy group 2- (3 Pyridyl) ethylaminocarbonyl group, 2-Hydroxy-2- (4 Pyridyl) ethylaminocarbonyl group, (3 Pyridyl) methylaminocarbonyl group or Trans 2- (3 Pyridyl) -cyclopropylaminocarbonyl group And even more preferably, 2- (3 pyridyl) ethylaminocarbonyl group, 2 hydroxy C2- (3 Pyridyl) ethylaminocarbonyl group or trans 2- (3 Pyridyl) cyclopropylaminocarbonyl group.
  • the "group represented by the formula-ER 2 " is a group in which 1 or independently 3 R 2 are bonded to E.
  • a phenyl group and a pyridinole group which may be independently substituted with 1 to 3 groups selected from b) a C 1 -C alkyl group which is independently substituted with 1 to 3 groups;
  • the oxy group or phenylamino group is a 1,3,4-oxadiazol 2-yl group or a group bonded to a 1,2,4 oxadiazo 5-yl group or a 1 imidazolyl group.
  • the “group represented by the formula CH 2 OQ 1 ) — is a group in which one group represented by the formula OQ 1 is bonded to a methylene group.
  • it is a methoxymethylene group, an ethoxymethylene group or a butoxymethylene group, and is preferably a butoxymethylene group.
  • the “group represented by the formula N (Q 3 ) —CH 2 —CH 1” is, for example, the formula N A group represented by (Me) -CH 2 CH—, a group represented by the formula N (Et) —CH—CH—
  • N (iPr) —CH 2 —CH is a group represented by the formula N (iPr) —CH 2 —CH, preferably the formula N (iPr) —CH
  • suitable R 1 is independently a group selected from a hydroxy group and a substituent group b.
  • a CC cycloalkyl group which is independently substituted with 1 to 3 groups independently selected with 1 to 3 substituents independently selected from a group selected from phenyl group and pyridinole group) Yes
  • R 1 is 2- (3 pyridyl) ethyl group, 2 hydroxy-2 phenylethyl group, 2-hydroxy-2- (3 pyridyl) ethyl group, 2 hydroxy-2- (4 pyridyl) ethyl group, (3 pyridyl) R 1 is a methyl group or trans-2- (3-pyridyl) -cyclopropyl group, and more preferably R 1 is a 2- (3 pyridyl) ethyl group, 2 hydroxy-2- (3 pyridyl) ethyl group or trans 2- (3 pyridyl) ) -Cyclopropyl group.
  • preferred E is a 1,3,4-oxadiazole group or imidazole group, and more preferred E is a 1,3,4-oxadiazole group.
  • preferred R 2 is a hydrogen atom, (hydroxy group, CC alkoxycarbo
  • R 16 is an alkyl group, a phenyloxy group, or a phenylamino group, and more preferably R 2 is a group selected from a hydroxy group, a CC alkoxycarbonyl group, and a substituent group b.
  • Phenyl and pyridinole groups are also independently selected groups of 1 to 3 C-C alkyl groups, phenyloxy groups or phenylamino groups
  • a preferable group represented by the formula ER 2 is 5 ethoxycarbonylmethyl.
  • preferred R 3 is a hydrogen atom or a methyl group, and more preferred R 3 is a hydrogen atom.
  • R 4 is preferably a hydrogen atom.
  • preferred R 5 is a hydrogen atom or a fluorine atom, a more preferred R 5 is water atom.
  • R 6 is preferably a hydrogen atom.
  • R 7 is preferably a hydrogen atom.
  • R 8 is preferably a hydrogen atom, a halogen atom, a CC alkyl group, or C
  • C is a halogenated alkyl group
  • R 8 is more preferably a hydrogen atom, a fluorine atom, or a chlorine atom.
  • a preferable soot is a nitrogen atom.
  • a preferable cage is a nitrogen atom.
  • preferable U is a single bond, a methylene group, a carbonyl group, an oxygen atom or a sulfur atom, and more preferable U is an oxygen atom.
  • preferred V is a methylene group or a group represented by the formula CH (OH).
  • preferred W is a methylene group, a group represented by the formula CH (OH), a formula C
  • W and V are represented by the formula N (iPr) —CH—CH as W—V—.
  • W, V, and U are represented by the formula ⁇ 1 -CH.
  • W—V— is a group represented by the formula —CH—CH (OH) —
  • U is an oxygen atom
  • U is a carbonyl group
  • U is an oxygen atom.
  • m is preferably 1.
  • n is preferably 1.
  • Q 1 is preferably a butyl group.
  • Q 2 is preferably a methyl group.
  • Q 3 is preferably an isobutyl group.
  • the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has all isomers (ketoeenol isomer, diastereoisomer, optical isomer, rotational isomer, etc.).
  • the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has various isomers since an asymmetric carbon atom is present in the molecule.
  • these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Accordingly, the present invention includes all of these isomers and mixtures of these isomers in any proportion.
  • stereoisomers as described above stereospecific raw material compounds are used, or asymmetric synthesis is performed.
  • asymmetric induction method by synthesizing the compound according to the present invention using an asymmetric induction method, or by isolating the synthesized compound according to the present invention using a conventional optical resolution method or separation method, if desired.
  • the "pharmacologically acceptable salt thereof” means that the compound having the general formula (I) of the present invention has a basic group such as an amino group, and is reacted with an acid. If it has an acidic group such as a carboxyl group, it can be converted into a salt by reacting with a base, so that salt is shown.
  • Examples of the salt based on a basic group include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide, nitrates, perchlorates, Inorganic acid salts such as sulfates and phosphates; C-C alkyl sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfate
  • Organic acid salts such as arylate sulfonates such as phosphate, acetate, malate, fumarate, succinate, succinate, ascorbate, tartrate, succinate, maleate; and And amino acid salts such as glycine salt, lysine salt, arginine salt, ornitine salt, glutamate salt, and aspartate salt.
  • arylate sulfonates such as phosphate, acetate, malate, fumarate, succinate, succinate, ascorbate, tartrate, succinate, maleate
  • amino acid salts such as glycine salt, lysine salt, arginine salt, ornitine salt, glutamate salt, and aspartate salt.
  • examples of the salt based on an acidic group include alkali metal salts such as sodium salt, potassium salt and lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt and iron salt.
  • Metal salts such as ammonium salt, toctylamine salt, dibenzylamine salt, morpholine salt, darcosamine salt, phenyldaricin alkyl ester salt, ethylenediamine salt, N-methyldarcamamine salt, guanidine salt, jetylamine salt, Triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, black pro-in salt, pro-in salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetra Of methylammonium salt, tris (hydroxymethyl) aminomethane salt Amine salts such as Una organic salt; and, glycine salts, lysine salts,
  • the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof absorbs moisture by adsorbing water by being left in the air or by recrystallization. Or hydrate Such hydrates are also encompassed by the salts of the present invention.
  • the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may absorb a certain other solvent and become a solvate, and such a solvate may also be absorbed. It is included in the salt of the present invention.
  • Me represents a methyl group
  • Et represents an ethyl group
  • iPr represents i propyl group
  • nBu n butyl group
  • Ph represents a phenylol group
  • CONHCH CH (3-Py) represents a 2- (3-pyridyl) ethylaminocarbonyl group
  • CONHCH CH (OH) (3— Py) is 2— (3 pyridyl) 2 hydroxyethylamino
  • CONHCyc (A) represents a trans-2- (3 pyridyl) -cyclopropylaminocarbonyl group
  • Het (A) — represents a 1,3,4 oxaziazol 2yl group having a substituent at the 5-position.
  • Het (A) —Me represents a 5-methyl-1,3,4-oxadiazol-2-yl group
  • Het (A) -CH (3-Py) represents 5- (3-pyridyl) methyl-1,3,4— Oxaziazole
  • Het (A) —CH (OH) Ph represents a 5- ( ⁇ -hydroxybenzenole) 1,3,4-oxaziazo one-ru 2-yl group
  • Het (B)-CH (2— Py) is 3- (2 pyridyl) methyl-1,2,4 oxadiazonole

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Abstract

L'objet de l'invention est un composé présentant une excellente activité inhibitrice de la stéaroyl-CoA-désaturase ou l'un de ses sels pharmacologiquement acceptables. L'invention propose un composé ayant la formule générale (I) ou l'un de ses sels pharmacologiquement acceptables. (I) dans laquelle A représente un groupe représenté par la formule : -CONHR1 ou -ER2 (où R1 représente un groupe alkyle en C1 à C6 qui peut être substitué par 1 à 5 groupes choisis indépendamment parmi les membres d'un groupe de substituants « a », ou analogues ; E représente un groupe 1,3,4-oxadiazole, un groupe 1,2,4-oxadiazole ou un groupe imidazole ; et R2 représente un groupe alkyle en C1 à C6 substitué par 1 à 5 groupes choisis indépendamment parmi les membres d'un groupe de substituants « a », ou analogues) ; R3 représente un atome d'hydrogène ou analogues ; R4 représente un atome d'hydrogène ou analogues ; R5 représente un atome d'hydrogène ou analogues ; R6 représente un atome d'hydrogène ou analogues ; R7 représente un atome d'hydrogène ou analogues ; R8 représente un atome d'hydrogène, un atome d'halogène ou analogues ; Z représente un atome d'azote ou analogues ; Y représente un atome d'azote ou analogues ; U représente une liaison simple, un groupe méthylène ou analogues ; V représente une liaison simple, un groupe méthylène ou analogues ; W représente un groupe méthylène, un groupe représenté par la formule : -CH(OH)-, ou analogues ; m représente un nombre de 0 ou 1 ; n représente un nombre de 0 ou 1 ; le groupe de substituants « a » comprend un atome d'halogène, un groupe hydroxy et un groupe aryle en C6 à C10 qui peut être substitué par 1 à 5 groupes choisis indépendamment parmi les membres d'un groupe de substituants « b » ; et le groupe de substituants « b » comprend un atome d'halogène, un groupe alkyle en C1 à C6, un groupe alkyle en C1 à C6 halogéné, un groupe hydroxyle et analogues.
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WO2010094120A1 (fr) * 2009-02-17 2010-08-26 Merck Frosst Canada Ltd. Nouveaux composés spiro utiles comme inhibiteurs de la stéaroyl-coenzyme a delta-9 désaturase
WO2011011506A1 (fr) * 2009-07-23 2011-01-27 Schering Corporation Composés oxazépine spirocyclique en tant qu'inhibiteurs de la stéaroyl-coenzyme a delta-9 désaturase
WO2011011508A1 (fr) * 2009-07-23 2011-01-27 Schering Corporation Composés d’oxazépine benzofusionnés en tant qu’inhibiteurs de la coenzyme-stéaroyle a delta-9 désaturase
WO2011047481A1 (fr) * 2009-10-23 2011-04-28 Merck Frosst Canada Ltd. Nouveaux composés spiro utiles en tant qu'inhibiteurs de stéaroyl-coenzyme a delta-9 désaturase
US8383643B2 (en) 2009-07-28 2013-02-26 Merck Canada Inc. Spiro compounds useful as inhibitors of stearoyl-coenzyme A delta-9 desaturase
WO2013056148A2 (fr) 2011-10-15 2013-04-18 Genentech, Inc. Procédés d'utilisation d'antagonistes de scd1
WO2013175474A2 (fr) 2012-05-22 2013-11-28 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Inhibiteurs sélectifs de cellules indifférenciées
US8710043B2 (en) 2011-06-24 2014-04-29 Amgen Inc. TRPM8 antagonists and their use in treatments
US8778941B2 (en) 2011-06-24 2014-07-15 Amgen Inc. TRPM8 antagonists and their use in treatments
US8952009B2 (en) 2012-08-06 2015-02-10 Amgen Inc. Chroman derivatives as TRPM8 inhibitors
WO2018129403A1 (fr) 2017-01-06 2018-07-12 Yumanity Therapeutics Méthodes de traitement de troubles neurologiques
US11873298B2 (en) 2017-10-24 2024-01-16 Janssen Pharmaceutica Nv Compounds and uses thereof
US11970486B2 (en) 2016-10-24 2024-04-30 Janssen Pharmaceutica Nv Compounds and uses thereof
US12098146B2 (en) 2019-01-24 2024-09-24 Janssen Pharmaceutica Nv Compounds and uses thereof
US12180221B2 (en) 2018-03-23 2024-12-31 Janssen Pharmaceutica Nv Compounds and uses thereof
US12268687B2 (en) 2019-11-13 2025-04-08 Janssen Pharmaceutica Nv Compounds and uses thereof

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WO2009037542A3 (fr) * 2007-09-20 2009-05-22 Glenmark Pharmaceuticals Sa Composés spirocycliques en tant qu'inhibiteurs de stéaroyle coa désaturase
WO2010094120A1 (fr) * 2009-02-17 2010-08-26 Merck Frosst Canada Ltd. Nouveaux composés spiro utiles comme inhibiteurs de la stéaroyl-coenzyme a delta-9 désaturase
JP2012517960A (ja) * 2009-02-17 2012-08-09 メルク カナダ インコーポレイテッド ステアロイル−補酵素ａデルタ−９デサチュラーゼの阻害剤として有用な新規スピロ化合物
US9168248B2 (en) 2009-02-17 2015-10-27 Merck Canada Inc. Spiro compounds useful as inhibitors of stearoyl-coenzyme A delta-9 desaturase
WO2011011506A1 (fr) * 2009-07-23 2011-01-27 Schering Corporation Composés oxazépine spirocyclique en tant qu'inhibiteurs de la stéaroyl-coenzyme a delta-9 désaturase
WO2011011508A1 (fr) * 2009-07-23 2011-01-27 Schering Corporation Composés d’oxazépine benzofusionnés en tant qu’inhibiteurs de la coenzyme-stéaroyle a delta-9 désaturase
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WO2011047481A1 (fr) * 2009-10-23 2011-04-28 Merck Frosst Canada Ltd. Nouveaux composés spiro utiles en tant qu'inhibiteurs de stéaroyl-coenzyme a delta-9 désaturase
US9096527B2 (en) 2011-06-24 2015-08-04 Amgen Inc. TRPM8 antagonists and their use in treatments
US8778941B2 (en) 2011-06-24 2014-07-15 Amgen Inc. TRPM8 antagonists and their use in treatments
US8710043B2 (en) 2011-06-24 2014-04-29 Amgen Inc. TRPM8 antagonists and their use in treatments
WO2013056148A2 (fr) 2011-10-15 2013-04-18 Genentech, Inc. Procédés d'utilisation d'antagonistes de scd1
US9358250B2 (en) 2011-10-15 2016-06-07 Genentech, Inc. Methods of using SCD1 antagonists
US9456998B2 (en) 2012-05-22 2016-10-04 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Selective inhibitors of undifferentiated cells
WO2013175474A2 (fr) 2012-05-22 2013-11-28 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Inhibiteurs sélectifs de cellules indifférenciées
US8952009B2 (en) 2012-08-06 2015-02-10 Amgen Inc. Chroman derivatives as TRPM8 inhibitors
US11970486B2 (en) 2016-10-24 2024-04-30 Janssen Pharmaceutica Nv Compounds and uses thereof
WO2018129403A1 (fr) 2017-01-06 2018-07-12 Yumanity Therapeutics Méthodes de traitement de troubles neurologiques
US10973810B2 (en) 2017-01-06 2021-04-13 Yumanity Therapeutics, Inc. Methods for the treatment of neurological disorders
US11873298B2 (en) 2017-10-24 2024-01-16 Janssen Pharmaceutica Nv Compounds and uses thereof
US12275723B2 (en) 2017-10-24 2025-04-15 Janssen Pharmaceutica Nv Compounds and uses thereof
US12180221B2 (en) 2018-03-23 2024-12-31 Janssen Pharmaceutica Nv Compounds and uses thereof
US12098146B2 (en) 2019-01-24 2024-09-24 Janssen Pharmaceutica Nv Compounds and uses thereof
US12268687B2 (en) 2019-11-13 2025-04-08 Janssen Pharmaceutica Nv Compounds and uses thereof

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