WO2013056679A1 - Nouveaux dérivés amino-hétéroaryle - Google Patents

Nouveaux dérivés amino-hétéroaryle Download PDF

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WO2013056679A1
WO2013056679A1 PCT/CN2012/083248 CN2012083248W WO2013056679A1 WO 2013056679 A1 WO2013056679 A1 WO 2013056679A1 CN 2012083248 W CN2012083248 W CN 2012083248W WO 2013056679 A1 WO2013056679 A1 WO 2013056679A1
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esi
compound
synthesized
pyrimidin
methyl
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PCT/CN2012/083248
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English (en)
Inventor
Bo Zhang
Jun Yang
Jinming Liu
Hai Huang
Yong Wu
Ran TAO
Jiangcheng XU
Ning SHEN
Sunghwan Moon
Maengsup KIM
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Beijing Hanmi Pharmaceutical Co., Ltd
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Publication of WO2013056679A1 publication Critical patent/WO2013056679A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to Novel Heteroaryl-amino Derivatives having activities as diacylglycerol acyltransferase 1 (DGAT-1) inhibitors and the pharmaceutical compositions and use thereof.
  • DGAT-1 diacylglycerol acyltransferase 1
  • Triglycerides are the main form for storing energy in eukaryotes. In mammals, these compounds are synthesized mainly in three tissues: small intestine, liver and fat cells. Triglycerides have three main functions: absorbing fats in the diet, packaging newly synthesized fatty acids, and storing them in fat tissues (Subauste A, Burant CR, Curr Drug Targets Immune Endocr Metabol Disord., 4(3), 263-270, 2003).
  • Diacylglycerol acyltransferase is an enzyme catalyzing the formation of triglycerides in the last step of the biosynthesis of triglyceride, and mainly found in the endoplasmic reticulum of cells.
  • DGAT is found in the microsomes of cells sap, and catalyzes the last step of the synthesis of triglycerides in the triglyceride phosphate route.
  • DGAT is considered to be an important factor in the synthesis of triglyceride in cells, and may promote the linkage between diglyceride and fatty acid acyl co-enzyme A which finally leads to the synthesis of triglycerides.
  • DGAT-1 DGAT-1 gene is identified and determined by searching the sequence database (Sylvaine Cases, et al, Proceedings of the National Academy of Sciences, 95(22), 13018-13023, 1998).
  • DGAT-1 activity has been found in many mammal tissues (including fat cells, e.g. rat fat cells, differentiated 3T3-L1 fat cells, intestinal cells of small intestine and mammal glands).
  • fat cells e.g. rat fat cells, differentiated 3T3-L1 fat cells, intestinal cells of small intestine and mammal glands.
  • triglyceride is used for oxidation metabolism as a fat reserve in skeletal muscle and myocardium which also exhibit DGAT activities.
  • DGAT-1 is significantly up-regulated during the differentiation of fat cells.
  • DGAT-l-knocked-out mouse (Dgatl-/-) can survive and can synthesize triglyceride. Comparing with wild mouse, Dgatl-/- mouse exhibits lesser baseline fat tissue, and can resist obesity induced by diet. Under both normal diet and high- fat diet conditions, the metabolic rates in Dgatl-/- mouse are about 20% higher than those of wild mouse (Steven J. Smith, et al, Nature Genetics, 25(1), 87-90, 2000). The increase in the energy output in Dgatl-/- mouse is due to the increase in its physical activity. Dgatl-/- mouse also exhibits increased insulin sensitivity and glucose metabolic rate. The amount of fat in Dgatl-/- mouse decreases by about 50%; in line with this, the leptin level in Dgatl-/- mouse also decreases by 50%>.
  • DGAT-1 needs to be involved in the production of infective hepatitis C virus particles and catalyzes the synthesis of lipid droplets used for assembly instead of utilizing the lipid droplets randomly occurred around the virus; furthermore, DGAT- 1 binds to core protein of virus and concentrates the lipid droplets synthesized under the catalysis of DGAT-1 around the core protein of the virus, thereby transferring the RNA replication complex of the virus to an appropriate cite for virus assembly to conduct the assembly of the virus particles (Eva Herker, Nature Medicine, 16(11), 1295- 1298, 2010; Patrice Andre, Future Virology, 6(2), 179-182, 2011).
  • new drugs developed using DGAT-1 as a target and aiming at its signal transduction route may effectively inhibit the synthesis of triglycerides, and may be used in treating diseases such as obesity, hyperlipidemia, atherosclerosis, type-II diabetes, hepatitis C, and the like.
  • International application WO 2004/047755 relates to fused bicyclic nitrogen-containing heterocyclic compounds having DGAT inhibiting activities.
  • International application WO 2006/004200 relates to urea and amino derivatives having DGAT-1 inhibiting activities.
  • International application WO 2007/138304 discloses a group of 1 ,3,4-oxadiazole derivatives having DGAT- 1 inhibiting activities.
  • Novartis AG WO 2010/007046
  • An objective of the present invention is to provide a compound as a DGAT-1 inhibitor, thereby clinically providing a new drug for treating DGAT-1 related diseases.
  • A independently represents C3-C 10 heteroaryl, wherein the heteroaryl is selected from:
  • B each independently represents phenyl or C5-C 6 heteroaryl
  • Qi and Q 2 each independently represent -CH- or N;
  • Q 3 each independently represents NR 3 , O or S;
  • Ri and R 2 each independently represent hydrogen, halogen, cyano (-CN), optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted mono- or di-cyclic aryl or heteroaryl, wherein the substituent is selected from one or more of halogen, hydroxy and amino, and the numbers of Ri and R 2 are independently one or two;
  • R 3 each independently represents hydrogen or C 1 -C 4 alkyl
  • R m and R n each independently represent hydrogen, halogen or Ci-C 6 alkyl; and the numbers of R m and R n are one or two;
  • R x independently represents hydrogen or C 1 -C 4 alkyl
  • R 4 and R 5 each independently represent hydrogen or Ci-C 6 alkyl; or, R 4 and R 5 together form C3-C 6 eye lo alkyl,
  • ring B in the above formula I independently represents phenyl or pyridinyl.
  • a in the above formula I independently represents one of the following structures:
  • a in the above formula I represents one of the following structures:
  • Ri and R 2 each independently represent hydrogen, fluoro, chloro, methyl, cyano, methoxy, trifluoromethyl, trifluoromethoxy, phenyl;
  • R 3 independently represents hydrogen, methyl, ethyl;
  • R m and R n each independently represent hydrogen, fluoro, chloro, methyl;
  • R x independently represents hydrogen, methyl, ethyl;
  • L is selected from one of the following structures,
  • R 4 and R 5 each independently represent methyl or ethyl; or R 4 and R 5 together form C 3 -C 6 cycloalkyl.
  • L is selected from one of the following structures:
  • the methylene in any of the above structures 1-6 for L is attached to O in the formula I.
  • the compound is selected from:
  • the pharmaceutically acceptable salt of the compound of the present invention is selected from base addition salt and acid addition salt.
  • the base addition salt is selected from any of the group consisting of sodium, potassium, calcium, lithium, magnesium, zinc, ammonium, tetramethyl ammonium, tetraethyl ammonium, dimethyl ammonium, triethyl ammonium, trimethyl ammonium, ethyl ammonium and diethanol ammonium salts, arginine and lysine salts; and the acid addition salt is selected from any of the group consisting of hydrochloride, hydrobromide, phosphate, sulfate, mesylate and p-toluene sulfonate. More preferably, the pharmaceutically acceptable salt is selected from sodium, potassium and calcium salts.
  • a pharmaceutical composition which comprises the compound of the present invention, or a pharmaceutically acceptable salt, a solvate or a prodrug thereof, and a pharmaceutically acceptable excipient.
  • a drug combination which comprises the compound of the present invention, or a pharmaceutically acceptable salt, a solvate or a prodrug thereof, in combination with another drug
  • said another drug is selected from at least one of the following: anti-obesity drug, hypoglycemic drug, hypolipidemic drug, antihypertensive drug, coagulation regulating drug, non-steroidal anti-inflammatory drug, steroidal anti-inflammatory drug and anti hepatitis C virus drug.
  • the compound of the present invention or a pharmaceutically acceptable salt, a solvate or a prodrug thereof, and said another drug may be formulated to a single pharmaceutical composition (a single dosage form), or may be formulated to separate pharmaceutical compositions (multiple separate dosage forms).
  • the anti-obesity drug includes, but is not limited to, gastrointestinal pancreatic lipase inhibitors (orlistat), central nerve inhibitors affecting the intake of food (sibutramine), and other drugs affecting nutrition absorption or energy consumption.
  • the hypoglycemic drug includes, but is not limited to, sulfonylureas promoting insulin secretion, postprandial glucose regulators, DPP-IV (dipeptidyl peptidase-4) inhibitors, GLP-1 (glucagon- like peptide-1) agonists, insulin sensitizers including PPAR-Y (peroxisome proliferator activated receptor- Y) agonists, PPAR-a (peroxisome proliferator activated receptor-a) and PPAR-Y (peroxisome proliferator activated receptor- Y) combined agonists, biguanides deferring the uptake of glucose through the gastrointestinal tract and increasing the utilization of peripheral glucose by promoting insulin sensitivity, fructose 1 ,
  • the hypolipidemic drug includes, but is not limited to, HMG-CoA (P-hydroxy-P-methylglutaryl coenzyme A) reductase inhibitor (statins), PPAR-a (peroxisome proliferator activated receptor-a) agonists (fibrates), fish oils, nicotinic acid and analogues thereof, cholic acid absorption inhibitors, cholic acid multi-valent chelators, cholesterol absorption inhibitors (plant stanols or synthesized inhibitors), and the like.
  • HMG-CoA P-hydroxy-P-methylglutaryl coenzyme A reductase inhibitor
  • PPAR-a peroxisome proliferator activated receptor-a
  • cholic acid absorption inhibitors cholic acid multi-valent chelators
  • cholesterol absorption inhibitors plant stanols or synthesized inhibitors
  • the antihypertensive drug includes, but is not limited to, ⁇ receptor blockers, ACE (angiotensin I converting enzyme) inhibitors, calcium-channel blockers, angiotensin II receptor antagonists, urinary system drugs, and the like.
  • the coagulation regulating drug includes, but is not limited to, plasminogen activators, thrombin receptor antagonists, blood coagulation factor Xa inhibitors, blood coagulation factor Vila inhibitors, platelet aggregation inhibitors, anticoagulant drugs, and the like.
  • said another drug is selected from hypolipidemic drugs, such as statins, fibrates, nicotinic acids, and fish oils.
  • the present invention relates to use of the compound of the present invention, or a pharmaceutically acceptable salt, a solvate or a prodrug thereof in preparing a medicament for inhibiting DGAT-1 activities.
  • the medicament is for treating and/or preventing a disease, disorder or condition selected from the group consisting of obesity, coronary disease, hypertension, hyperlipidemia, arteriosclerosis, type II diabetes, stroke and hepatitis C.
  • the present invention relates to use of the compound of the present invention, or a pharmaceutically acceptable salt, a solvate or a prodrug thereof in preparing a medicament for treating and/or preventing DGAT-1 related diseases.
  • the DGAT-1 related diseases include, but not limited to obesity, coronary disease, hypertension, hyperlipidemia, arteriosclerosis, type II diabetes, stroke and hepatitis C.
  • the present invention relates to a method for inhibiting DGAT-1 activities, the method comprising a step of contacting the compound of the present invention, or a pharmaceutically acceptable salt, a solvate or a prodrug thereof, with the DGAT-1.
  • the method may be used in vivo, and also can be used in vitro.
  • Another aspect of the present invention relates to a method for inhibiting DGAT-1 activities in a mammal, especially in human, the method comprising administering a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt, a solvate or a prodrug thereof, or the pharmaceutical composition or the drug combination of the present invention, to the mammal in need thereof, especially human.
  • Another aspect of the present invention relates to a method for treating and/or preventing DGAT-1 related diseases in a mammal, especially human, the method comprising administering a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt, a solvate or a prodrug thereof, or the pharmaceutical composition or the drug combination of the present invention, to the mammal in need thereof, especially human.
  • the DGAT-1 related diseases are selected from obesity, coronary disease, hypertension, hyperlipidemia, arteriosclerosis, type II diabetes, stroke and hepatitis C.
  • Ci-C 6 alkyl describes an alkyl group, as defined below, having a total of 1 to 6 carbon atoms
  • C3-C10 heteroaryl describes a heteroaryl group, as defined below, having a total of 3 to 10 carbon atoms.
  • the total number of carbons in the shorthand notation does not include carbons that may exist in substituents of the group described.
  • alkyl refers to a straight or branched radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and which is attached to the rest of the molecule by a single bond.
  • An alkyl may have for example from 1 to 12 (preferably from 1 to 8, more preferably from 1 to 6, further preferably from 1 to 4) carbon atoms.
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl, hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, decyl, and the like.
  • alkoxy refers to the group "-OR a ", wherein R a is alkyl as defined above.
  • alkoxy include, but are not limited to, methoxy, ethoxy, iso-propoxy, and the like.
  • cycloalkyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, for example, having from 3 to 15 carbon atoms (preferably from 3 to 10, from 3 to 8, more preferably from 3 to 6), and which is saturated or unsaturated and attached to the rest of the molecule by a single bond through any appropriate carbon atom.
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, lH-indenyl, 2,3-dihydroindenyl, 1 ,2,3,4-tetrahydro-naphthyl, 5.6.7.8- tetrahydro-naphthyl, 8,9-dihydro-7H- benzocyclohepten-6-yl,
  • aryl refers to a ring system radical comprising from 6 to 18 (preferably from 6 to 10) carbon atoms and at least one aromatic ring.
  • aryl radical may be a monocyclic, bicyc lie, tricyclic or tetracyclic ring system etc., which may include fused or bridged ring systems.
  • the aryl radical is attached to the rest of the molecule by a single bond through an aromatic ring atom.
  • aryl examples include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, fluorenyl, 2-benzoxazolinone, 2H-1 ,4- Benzoxazin-3(4H)-on-7-yl, and the like.
  • heteroaryl refers to a 5- to 16-membered ring radical which includes from 1 to 15 (preferably from 1 to 10, or from 3 to 10) carbon atoms and from 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; on condition that the attachment point is an aromatic ring atom.
  • the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; and the nitrogen atom may be optionally quaternized.
  • the heteroaryl is preferably a stable 4- to 11-membered (or 4- to 10-membered, or 4- to 9-membered) aromatic mono- or bi-cyclic radical containing from 3 to 8 carbon atoms and from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, or a stable 4- to 8-membered aromatic monocyclic radical containing from 3 to 6 carbon atoms and from 1 to 2 heteroatoms selected from nitrogen, oxygen and sulfur.
  • heteroaryl examples include, but are not limited to, thiophenyl, furanyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, benzopyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, triazinyl, pyrimidinyl, pyridazinyl, indolizinyl, indolyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolinyl, isoquinolinyl, phenodiazinyl, naphthyridinyl, quinazolinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, thiazolyl, isothiazolyl, benzothiazolyl, be
  • halogen refers to bromo, chloro, fluoro or iodo.
  • alkyl optionally substituted by one or more halogens means that the alkyl is not substituted or is substituted by one or more halogens, and that the description includes substituted alkyl and unsubstituted alkyl.
  • pharmaceutically acceptable salt includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness of the free bases, without any additional biologically undesirable effects, which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, formic acid, acetic acid, trifluoro acetic acid, propionic acid, octanoic acid, caproic acid, capric acid, undecylenic acid, glycolic acid, gluconic acid, lactic acid, oxalic acid, sebacic acid, adipic acid, glutaric acid, malonic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, stearic acid, oleic acid, cinnamic acid, lauric acid, malic acid, glutamic acid, pyroglutamic acid, aspartic
  • “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness of the free acids, without any additional biologically undesirable effects. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine,
  • the compound of the present invention may comprise multiple cations and anions.
  • solvate refers to an aggregate that comprises one or more molecules of a compound of the invention with one or more molecules of solvent. It either reacts in a solvent or precipitates or crystallizes from the solvent.
  • the solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent.
  • the solvate of the compound of the present invention is also within the scope of the invention.
  • prodrug is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound of the invention.
  • prodrug refers to a metabolic precursor of a compound of the invention that is pharmaceutically acceptable.
  • a prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the invention.
  • Prodrugs are typically rapidly transformed in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood, prodrug
  • the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism.
  • an ester of a compound which contains carboxyl group e.g. a compound of the present invention
  • a pharmaceutically acceptable ester may be used as a prodrug of the compound of the present invention, and it may be decomposed to the parent acid in human or animal body.
  • the pharmaceutically acceptable ester may include, but not limited to, Ci_ 6 alkyl esters such as methyl ester, ethyl ester, propyl ester, or the like; Ci _ 6 alkoxymethyl esters such as methoxymethyl ester; Ci _ 6 acyloxymethyl esters such as acetyloxymethyl ester; alkyl substituted formamido alkyl esters such as ⁇ , ⁇ -dimethylformamidomethyl ester and N,N-diethylformamidomethyl ester, etc (see, for example, patent document US5073641).
  • pharmaceutical composition refers to a formulation of a compound of the present invention and a vehicle generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans.
  • a vehicle includes a pharmaceutically acceptable excipient.
  • pharmaceutically acceptable excipient includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by a relevant government administration as being acceptable for use in humans or domestic animals.
  • therapeutically effective amount refers to that amount of a compound of the invention which, when administered to a mammal, preferably a human, is sufficient to effect treatment of a disease, disorder or condition in the mammal, preferably a human.
  • the amount of a compound of the invention which constitutes a “therapeutically effective amount” will vary depending on the compound, the specific disease to be treated, cause of the disease, target of the drug, severity of the disease, the manner of administration, and the age, weight and body condition of the mammal to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
  • drug combination may refer to that all the active ingredients constituting the drug combination together with a excipient form a pharmaceutical composition (i.e. a single dosage form), and may also refer to that all the active ingredients constituting the drug combination form individual pharmaceutical compositions with a excipient, respectively, in which case the drug combination comprises multiple individual dosage forms.
  • DGAT-1 related diseases, disorders or conditions related to abnormal lipid metabolism include but not limited to hyperlipidemia, hyperglycemia, hypertension, obesity, fatty liver, coronary disease, stroke, atherosclerosis, hepatitis C, and the like.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, a solvate or a prodrug thereof:
  • the compounds of the invention may contain one or more chiral carbon atoms, and each asymmetric carbon atom may be R or S configuration, both configurations being within the scope of the present invention.
  • the compound may be present as enantiomer, diastereomer or mixtures thereof.
  • the above compounds may be prepared by choosing racemates, diastereomers or enantiomers as raw materials or intermediates.
  • Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization.
  • compositions which comprises a compound of the present invention and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition of the present invention may be formulated into preparations in solid, semi- so lid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols.
  • compositions of the invention may be prepared by methodologies well known in the pharmaceutical art.
  • a pharmaceutical composition intended to be administered by injection can be prepared by combining a compound of the invention with sterile, distilled water so as to form a solution.
  • a surfactant may be added to facilitate the formation of a homogeneous solution or suspension.
  • Actual methods of preparing a pharmaceutical composition are known in the art. See, for example, The Science and Practice of Pharmacy, 20 th Edition (Philadelphia College of Pharmacy and Science, 2000).
  • the routes of administering the pharmaceutical composition include, without limitation, oral, topical, transdermal, intramuscular, intravenous inhalation, parenteral, sublingual, rectal, vaginal, and intranasal.
  • dosage forms suitable for oral administration include capsule, tablet, granule, syrup, and the like.
  • the compound of the present invention contained in these dosage forms may be in a form of solid powders or granules; solution or suspension in an aqueous or non-aqueous liquid; water-in-oil or oil-in-water emulsion; etc.
  • the above dosage forms may be prepared by common pharmaceutical methodologies from active compounds and one or more carriers or excipients.
  • the above carriers shall be compatible with the active compound or other excipients.
  • non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, and the like.
  • Carriers used for liquid dosage forms include, but are not limited to, water, physiological saline, glucose aqueous solution, ethylene glycol, polyethylene glycol, and the like.
  • the active compound may form a solution or a suspension with the above carriers.
  • the specific administration route and dosage form may depend on the physical and chemical properties of the compound and the severity of the disease to be treated. A person skilled in the art can determine the specific administration route depending on the above factors in combination with his own knowledge.
  • Another aspect of the present invention relates to use of the compound of the present invention or a pharmaceutical composition of the present invention in preparing a medicament for inhibiting DGAT-1 activities and treating and/or preventing DGAT-1 related diseases.
  • the DGAT-1 related diseases are selected from obesity, coronary disease, hypertension, hyperlipidemia, arteriosclerosis, type II diabetes, stroke and hepatitis C.
  • Another aspect of the present invention relates to a method for inhibiting DGAT-1 activities in a mammal, especially human, the method comprising administering a therapeutically effective amount of the compound of the present invention or the pharmaceutical composition or the drug combination of the present invention to the mammal in need thereof, especially human.
  • Another aspect of the present invention relates to a method for inhibiting DGAT-1 activities and treating and/or preventing DGAT- 1 related diseases in a mammal, especially human, the method comprising administering a therapeutically effective amount of the compound of the present invention or the pharmaceutical composition or the drug combination of the present invention to the mammal in need thereof, especially human.
  • the DGAT-1 related diseases are selected from obesity, coronary disease, hypertension, hyperlipidemia, arteriosclerosis, type II diabetes, stroke and hepatitis C.
  • the compound or the composition of the present invention is suitable for warm-blooded animals; in another aspect, the compound or the composition of the present invention is suitable for mammals, such as human.
  • composition of the present invention is formulated, quantified and administered in a way which meets the regulations of medicinal practice.
  • the "therapeutically effective amount" of the compound of the present invention mainly depends on the factors such as the specific disease to be treated, the subject to be treated, the cause of the disease, the target of the drug, and the manner of administration.
  • the pharmaceutical composition is in a form suitable for administration including but not limited to oral administration, parenteral administration, topical administration and rectal administration.
  • the pharmaceutical composition is in the form of a tablet, capsule, pill, powder, sustained release formulation, solution and suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
  • the pharmaceutical composition is in unit dosage forms suitable for single administration of precise dosages.
  • the amount of compound of formula I is in the range of about 0.001 to about 1000 mg/kg body weight/day.
  • the amount of compound of formula I is in the range of about 0.5 to about 50 mg/kg body weight/day. In further or additional embodiments the amount of compound of formula I is about 0.001 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.002 to about 6 g/day. In further or additional embodiments the amount of compound of formula I is about 0.005 to about 5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.01 to about 5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.02 to about 5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.05 to about 2.5 g/day.
  • the amount of compound of formula I is about 0.1 to about 1 g/day. In further or additional embodiments, dosage levels below the lower limit of the aforesaid range may be more than adequate. In further or additional embodiments, dosage levels above the upper limit of the aforesaid range may be required. In further or additional embodiments the compound of formula I is administered in a single dose, once daily. In further or additional embodiments the compound of formula I is administered in multiple doses, more than once per day. In further or additional embodiments the compound of formula I is administered twice daily. In further or additional embodiments the compound of formula I is administered three times per day. In further or additional embodiments the compound of formula I is administered four times per day.
  • the compound of formula I is administered more than four times per day.
  • the pharmaceutical composition is for administration to a mammal.
  • the mammal is human.
  • the pharmaceutical composition further comprises a pharmaceutical carrier, excipient and/or adjuvant.
  • the pharmaceutical composition further comprises at least one therapeutic agent.
  • the composition comprising a compound of formula I is administered orally, intraduodenally, parenterally (including intravenous, subcutaneous, intramuscular, intravascular or by infusion), topically or rectally.
  • the pharmaceutical composition is in a form suitable for oral administration.
  • the pharmaceutical composition is in the form of a tablet, capsule, pill, powder, sustained release formulations, solution and suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
  • the pharmaceutical composition is in unit dosage forms suitable for single administration of precise dosages.
  • the individual is a mammal.
  • the individual is a human.
  • the composition comprising a compound of formula I may be used in combination with an additional therapy.
  • the ranges of effective doses provided herein are not intended to be limiting and represent some preferred dose ranges. However, the most preferred dosage will be tailored to the individual subject, as is understood and determinable by one skilled in the relevant arts (see, e.g., Berkowet al, eds., The Merck Manual, 16 th edition, Merck and Co., Rahway, N.J., 1992).
  • the compounds of the invention or the pharmaceutically acceptable salts, sovaltes or prodrugs thereof may be usefully combined with one or more other compounds of the invention or one or more other therapeutic agents or as any combinations thereof.
  • the said other therapeutic agents include, but not limited to:
  • anti-obesity drugs decreasing body weight by affecting the food intake, nutrient absorption, or energy consumption, such as orlistat and analogues;
  • anti-diabetic drugs such as sulfonylurea drugs promoting the excretion of insulin (libenclamide, glipzide), post-prandial glucose regulators (repaglinide, nateglinide), drugs promoting the functions of incretin (DPP-IV inhibitors, GLP-1 agonist), insulin sensitizers (PPAR- ⁇ agonists, PPAR-a and PPAR- ⁇ dual agonists), drugs regulating liver glucose balance (metformin, fructose 1 ,6-diphosphatase inhibitors, glycogen phosphorylase kinase inhibitors, glycogen synthetase inhibitors, glucorinase activators), drugs decreasing glucose absorption in small intestine (acarbose), drugs blocking glucose re-absorption route in kidney (SGLT inhibitors) and drugs for treating chronic hyperglycemia complications (aldose reductase inhibitors);hypolipidemia drugs, such as HMG-CoA (P
  • antihypertensive drugs such as ⁇ receptor blockers (atenolol, proparnolol), ACE (angiotensin I converting enzyme) inhibitors (lisinopril), calcium-channel blockers (amlodipine), angiotensin II receptor antagonists (telmisartan), urinary system drugs (furosemide, benzthiazide);
  • Anti-virus drugs such as anti hepatitis C virus drugs (pegasys).
  • Suitable protecting groups include hydroxy, amino, mercapto and carboxylic acid.
  • Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like.
  • Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like.
  • Suitable protecting groups for mercapto include -C(0)-R" (where R" is alkyl, aryl or arylalkyl), p-methoxybenzyl, trityl and the like.
  • Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters.
  • Protecting groups may be added or removed in accordance with standard techniques, which are known to one skilled in the art and as described herein.
  • protecting groups are described in detail in Greene, T.W. and R G. M. Wuts, Greene 's Protective Groups in Organic Synthesis (2006), 4th Ed., Wiley.
  • the protecting group may also be a polymer resin.
  • the reaction scheme I includes the following steps:
  • Step 1 a compound of formula 1 is subjected to a substitution reaction with bis(pinacolato)diboron to prepare a borate compound of formula 2.
  • a palladium catalyst is used, which may be selected from bis(triphenylphosphine) palladium(II) dichloride (Pd(PPh 3 ) 2 Cl 2 ), tetrakis(triphenylphosphine) palladium(O) (Pd(PPh 3 ) 4 ), palladium acetate (Pd(OAc) 2 ), [l , l'-bis(diphenylphosphino)ferrocene] palladium(II) dichloride (Pd(dppf)Cl 2 ) and palladium(II) dichloride (PdCl 2 ).
  • the reaction temperature may be 80°C to 160°C.
  • the solvent which can be used in this reaction may be selected from 1 ,4-dioxane, tetrahydrofuran, toluene, and the like.
  • the reaction is preferably conducted in the presence of a base, which may be selected from potassium acetate, sodium carbonate, potassium carbonate, and the like.
  • Step 2 the borate compound of formula 2 is subjected to a Suzuki coupling reaction with a compound of formula 3 to prepare a compound of formula 4.
  • a palladium catalyst which may be selected from bis(triphenylphosphine) palladium(II) dichloride (Pd(PPh 3 ) 2 Cl 2 ), tetrakis(triphenylphosphine) palladium(O) (Pd(PPh 3 ) 4 ), palladium acetate (Pd(OAc) 2 ), [l , l'-bis(diphenylphosphino)ferrocene] palladium(II) dichloride (Pd(dppf)Cl 2 ), Pd/C and palladium(II) dichloride (PdCl 2 ).
  • the reaction temperature may be 80 °C to 160 °C.
  • the solvent which can be used in this reaction may be selected from 1 ,4-dioxane, toluene, ethanol and water.
  • the reaction is preferably conducted in the presence of a base, which is preferably an inorganic base, such as sodium carbonate, potassium carbonate, and the like.
  • Step 3 the compound of formula 4 is hydro lyzed under a basic condition to give a corresponding compound of formula I(P).
  • the base which can be used may be selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like.
  • the solvent which can be used in this reaction may be selected from methanol, ethanol, THF, water, and the like.
  • Step 4 a compound of formula 3 is subjected to a substitution reaction with bis(pinacolato)diboron to prepare a borate compound of formula 7.
  • a palladium catalyst is used, which may be selected from bis(triphenylphosphine) palladium(II) dichloride (Pd(PPh 3 ) 2 Cl 2 ), tetrakis(triphenylphosphine) palladium(O) (Pd(PPh 3 ) 4 ), palladium acetate (Pd(OAc) 2 ), [l , l'-bis(diphenylphosphino)ferrocene] palladium(II) dichloride (Pd(dppf)Cl 2 ) and palladium(II) dichloride (PdCl 2 ).
  • the reaction temperature may be 80 °C to 160 °C.
  • the solvent which can be used in this reaction may be selected from 1 ,4-dioxane, tetrahydrofuran, toluene, and the like.
  • the reaction is preferably conducted in the presence of a base, which may be selected from potassium acetate, sodium carbonate, potassium carbonate, and the like.
  • Step 5 the borate compound of formula 7 is subjected to a Suzuki coupling reaction with a compound of formula 1 to prepare a compound of formula 4.
  • a palladium catalyst which may be selected from bis(triphenylphosphine) palladium(II) dichloride (Pd(PPh 3 ) 2 Cl 2 ), tetrakis(triphenylphosphine) palladium(O) (Pd(PPh 3 ) 4 ), palladium acetate (Pd(OAc) 2 ), [l , l'-bis(diphenylphosphino)ferrocene] palladium(II) dichloride (Pd(dppf)Cl 2 ), Pd/C and palladium(II) dichloride (PdCl 2 ).
  • the reaction temperature may be 80 °C to 160 °C.
  • the solvent which can be used in this reaction may be selected from 1 ,4-dioxane, toluene, ethanol and water.
  • the reaction is preferably conducted in the presence of a base, which is preferably an inorganic base, such as sodium carbonate, potassium carbonate, and the like.
  • Step 3 the compound of formula 4 is hydro lyzed under a basic condition to give a corresponding compound of formula I(P).
  • the base which can be used may be selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like.
  • the solvent which can be used in this reaction may be selected from methanol, ethanol, THF, water, and the like.
  • reaction scheme III includes the following steps:
  • Step 6 the borate compound of formula 8 is subjected to a Suzuki coupling reaction with a compound of formula 3 to prepare a compound of formula 9.
  • a palladium catalyst which may be selected from bis(triphenylphosphine) palladium(II) dichloride (Pd(PPh 3 ) 2 Cl 2 ), tetrakis(triphenylphosphine) palladium(O) (Pd(PPh 3 ) 4 ), palladium acetate (Pd(OAc) 2 ), [l , l'-bis(diphenylphosphino)ferrocene] palladium(II) dichloride (Pd(dppf)Cl 2 ), Pd/C and palladium(II) dichloride (PdCl 2 ).
  • the reaction temperature may be 80°C to 160°C.
  • the solvent which can be used in this reaction may be selected from 1 ,4-dioxane, toluene, ethanol and water.
  • the reaction is preferably conducted in the presence of a base, which is preferably an inorganic base, such as sodium carbonate, potassium carbonate, and the like.
  • Step 7 the compound of formula 10 to is subjected to a substitution reaction with a compound of formula 9 to prepare a compound of formula 4.
  • X is mainly selected from CI, Br, I and the reaction is generally catalyzed by base such as Na 2 C0 3 , K 2 C0 3 , Cs 2 C0 3 , NaOH, NaH, KOH or may not need any catalyst.
  • the temperature of this reaction may be room temperature to 160 °C generally.
  • the solvent which can be used in this reaction may be selected from DMF, 1 ,4-dioxane, i-propanol, ethanol, butanol, i-butanol, ⁇ , ⁇ -Dimethylacetamide, N-Methyl pyrrolidone, ethylene glycol dimethyl ether, etc.
  • Step 3 the compound of formula 4 is hydro lyzed under a basic condition to give a corresponding compound of formula I(P).
  • the base which can be used may be selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like.
  • the solvent which can be used in this reaction may be selected from methanol, ethanol, THF, water, and the like.
  • the unit of the temperature is degree Celsius (°C); and the room temperature is defined as 18-25°C;
  • the organic solvents were dried over anhydrous magnesium sulfate or anhydrous sodium sulfate; and were evaporated with rotary evaporator under reduced pressure and elevated temperature (e.g. 15 mmHg, 30 °C);
  • N-(4-Bromophenyl)-4-fluorobenzothiazol-2-ylamine 3A (100 mg, 0.31 mmol), 2,2-dimethyl-3-((5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl) pyrimidin-2-yl)oxy) propionic acid methyl ester 2D (156 mg, 0.465 mmol), ⁇ , ⁇ - bis(diphenylphosphino)ferrocene] palladium(II) dichloride (25 mg, 0.031 mmol) and sodium carbonate (66 mg, 0.62 mmol) were placed into a microwave tube, to which were added 5 mL of 1,4-dioxane and 1 mL of water.
  • N-(4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-phenyl)-benzothiazol-2-ylamine IB (100 mg, 0.28 mmol), l-(((5-bromopyrimidin-2-yl)oxy)methyl) cyclopentanecarboxylic acid methyl ester 6C (74 mg, 0.24 mmol), palladium acetate (5 mg, 0.024 mmol), tricyclohexylphosphine (13 mg, 0.048 mmol) and potassium acetate (47 mg, 0.48 mmol) were placed in a flask, to which were added 5 mL of 1,4-dioxane and 1 mL of water.
  • Example 1 The intermediate 7C was synthesized from intermediate 7B
  • the intermediate 9A was synthesized from 5-fluoro-2-iodoaniline and
  • the intermediate 10B was synthesized from intermediate 1 OA (ethyl l-(((5-bromopyrimidin-2-yl)oxy)methyl) cyclohexanecarboxylate) and IB following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS data for 10B (ESI, m/z): [M+H] + : 489.2)
  • the intermediate 1 OA was synthesized from 5-bromopyrimidin-2-ol and ethyl
  • the intermediate 12A was synthesized from 2-chloroquinazoline and 4-bro mo aniline similar to that described for intermediate 1 A in Example 1.
  • Example 1 The MS data for 14C (ESI, m z): [M+H] + : 385.1).
  • the intermediate 14B was synthesized from 14A (N-(4-bromophenyl)thiazol-2-amine) using a similar procedure described for intermediate IB in Example 1 (The MS data for 14B (ESI, m/z): [M+H] + : 303.2).
  • the intermediate 14A was synthesized from 2-chlorothiazole and 4-bromoaniline using a similar synthetic procedure that was described for intermediate 1 A in Example 1 (The MS data for 14A (ESI, m/z): [M+H] + : 257.0).
  • the intermediate 15A was synthesized from 2,4-difluoro-6-iodoaniline and
  • the intermediate 18C was synthesized from intermediate 18B (2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)amino)benzo[d]thiazole-6-carbonitr ile) and intermediate 10A following a Suzuki coupling procedure similar to that described for intermediate ID in Example l(The MS data forl8C: MS (ESI, m/z): [M+H] + : 514.3).
  • the intermediate 18B was synthesized from 18 A
  • intermediate 26A N-(4-bromophenyl)-4-phenylthiazol-2-amine
  • intermediate 2D Following a Suzuki coupling procedure similar to that described for intermediate 3B in Example 3 (The MS data for 26B MS (ESI, m/z): [M+H] + : 461.2).
  • the intermediate 26A was synthesized from 2-chloro-4-phenylthiazole and 4-bromoaniline using a similar synthetic procedure that was described for intermediate 4B in Example 4 (The MS data for 26A MS (ESI, m/z): [M+H] + : 332.9).
  • the intermediate 28A was synthesized from 6-bromopyridin-3 -amine and 2-chlorobenzo[d]thiazole using a similar synthetic procedure that was described for intermediate 1 A in Example 1 (The MS data for 28A (ESI, m/z): [M+H] + : 306.1).
  • the intermediate 30B was synthesized from 30A
  • the intermediate 30A was synthesized from 2, 4-dichloro-6-iodoaniline and
  • the intermediate 36A was synthesized from 2-chloropyrimidine and 4-bromoaniline similar to that described for intermediate 1 A in Example 1.
  • the intermediate 40A was synthesized from ethyl 1 -(hydro xymethyl)cyclobutanecarboxylate and 5-bromopyrimidin-2-ol using a similar synthetic procedure that was described for intermediate 5B in Example 5 (The MS and 1H-NMR data for 40A (ESI, m/z): [M+H] + : 315.1; 1H-NMR (300 MHz, CDC1 3 ) ⁇ : 8.52 (s,2H), 4.61 (s,2H), 4.20 (m, 2H), 2.47-2.57 (m, 2H), 1.97-2.19 (m, 4H), 1.26 (m,3H).).
  • the intermediate 46B was synthesized from intermediate 46A (N-(4-bromo-2-fluorophenyl)benzo[d]oxazol-2-amine) and intermediate 2D following a Suzuki coupling procedure similar to that described for intermediate 3B in Example 3 (The MS data for 46B (ESI, m/z): [M+H] + : 437.1).
  • the intermediate 46A was synthesized from 4-bromo-2-fluoroaniline and 2-chlorobenzo[d]oxazole using a similar synthetic procedure that was described for intermediate 1 A in Example 1 (The
  • the intermediate 50B was synthesized from intermediate 50A (N-(4-bromo-2-fluorophenyl)-6-fluorobenzo [d]thiazol-2-amine) and intermediate 2D following a Suzuki coupling procedure similar to that described for intermediate 3B in Example 3 (The MS data for 50B (ESI, m/z): [M+H] + : 471.1).
  • the intermediate 50A was synthesized from 4-bromo-2-fluoroaniline and
  • the intermediate 52A was synthesized from diethyl 2,2-diethylmalonate and 5-bromopyrimidin -2-ol similar to that described for intermediate 5B in Example 5 (The MS data for 52A: MS (ESI, m/z): [M+H] + :331.0). The MS and 1H-NMR data for Example 52:
  • the intermediate 54A was synthesized from 4-bromo-3-fluoroaniline and 2-chlorobenzo[d]oxazole using a similar synthetic procedure that was described for intermediate 1 A in Example 1 (The MS data for 54A (ESI, m/z): [M-H] ⁇ : 305.3).
  • the intermediate 66A was synthesized from 4-bromo-3-chloroaniline and 2-chlorobenzo[d]thiazole using a similar synthetic procedure that was described for intermediate 1 A in Example 1 (The MS data for 66A (ESI, m/z): [M+H] + : 337.0 ).
  • the intermediate 70A was synthesized from 4-bromo-2-chloroaniline and 2-chlorobenzo[d]thiazole using a similar synthetic procedure that was described for
  • the intermediate 72A was synthesized from 2-iodo-4,6-dimethylaniline and l-bromo-4-isothiocyanatobenzene using a similar synthetic procedure that was described for intermediate 3 A in Example 3 (The MS and 1H-NMR data for 72A (ESI, m z): [M+H] + : 334.9; 1H-NMR (300 MHz, CDC1 3 ) ⁇ : 7.43-7.50 (m, 4H), 7.29 (s, 1H), 7.01 (s, 1H), 2.59 (s, 3H), 2.39 (s, 3H). ).
  • intermediate 73 C was synthesized from intermediate 73B
  • Example 75 The title compound was synthesized from intermediate 75 A (ethyl)
  • the intermediate 78A was synthesized from 4-bromoaniline and 2-chloroquinoxaline using a similar synthetic procedure that was described for intermediate lA in Example l(The MS data for 78A (ESI, m/z): [M+H] + : 301.9).

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Abstract

La présente invention concerne un composé de formule (I), dans laquelle R1, R2, L, Rm et Rn sont tels que définis dans la description. Le composé de formule (I) peut être utilisé pour prévenir et / ou traiter des maladies associées à l'acyl CoA-diacylglycérol acyltransférase 1(DGAT-1), telles que l'obésité, les maladies coronariennes, l'hypertension, l'hyperlipidémie, l'artériosclérose, le diabète de type II, une attaque, l'hépatite C et les maladies associées.
PCT/CN2012/083248 2011-10-21 2012-10-19 Nouveaux dérivés amino-hétéroaryle WO2013056679A1 (fr)

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JP2016523902A (ja) * 2013-06-27 2016-08-12 エルジー・ライフ・サイエンシーズ・リミテッドＬＧ Ｌｉｆｅ Ｓｃｉｅｎｃｅｓ Ｌｔｄ． Ｇｐｒ１２０アゴニストとしてのビアリール誘導体
JP2018501269A (ja) * 2014-12-24 2018-01-18 エルジー・ケム・リミテッド Ｇｐｒ１２０アゴニストとしてのビアリール誘導体
JP2018508513A (ja) * 2015-02-27 2018-03-29 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア 軟骨若返りを可能とする小分子
WO2021081207A1 (fr) * 2019-10-25 2021-04-29 Gilead Sciences, Inc. Composés modulateurs de glp-1r
WO2022090481A1 (fr) 2020-11-02 2022-05-05 Boehringer Ingelheim International Gmbh 1h-pyrazolo[4,3-c]pyridines substituées et leurs dérivés utilisés comme inhibiteurs d'egfr
RU2808433C1 (ru) * 2020-09-04 2023-11-28 ЭлДжи КЕМ, ЛТД. Новое биарильное производное, применяемое в качестве ингибитора диацилглицерол-ацилтрансферазы 2, и его применение
US11851419B2 (en) 2020-11-20 2023-12-26 Gilead Sciences, Inc. GLP-1R modulating compounds
US11858918B2 (en) 2021-04-21 2024-01-02 Gilead Sciences, Inc. GLP-1R modulating compounds
US12091404B2 (en) 2021-03-11 2024-09-17 Gilead Sciences, Inc. GLP-1R modulating compounds
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WO2022090481A1 (fr) 2020-11-02 2022-05-05 Boehringer Ingelheim International Gmbh 1h-pyrazolo[4,3-c]pyridines substituées et leurs dérivés utilisés comme inhibiteurs d'egfr
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US12091404B2 (en) 2021-03-11 2024-09-17 Gilead Sciences, Inc. GLP-1R modulating compounds
US11858918B2 (en) 2021-04-21 2024-01-02 Gilead Sciences, Inc. GLP-1R modulating compounds

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