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  • C07C59/40—Unsaturated compounds
  • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
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  • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
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Definitions

• the present invention relates to novel tricyclic compound wool and its use, and more particularly, to tricyclic compound wool having the formula I and its prevention or treatment for various diseases including diabetes mellitus.
• Type 2 diabetes is characterized by increased insulin resistance associated with inappropriate insulin secretion after compensatory hyperinsulinemia.
• Free fatty acids FLAs
• GSIS glucose-stimulated insulin secretion
• GPR Coupled receptors
• GPR40 also known as fatty acid receptor l (FFARl)
• FFARl fatty acid receptor l
• GPR40 wool-regulating compounds are known to exert an incretin effect to promote GSIS as well as to be used to treat diabetes and the like in combination with a wide range of antidiabetic drugs.
• the compounds that modulate GPR40 include, in addition to diabetes, impaired glucose tolerance, keronosis, acidosis, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, macular edema, hyperlipidemia, genital disorders, skin disease, arthrosis, osteopenia, arteriosclerosis , Thrombotic disease, indigestion, memory and learning difficulties, depression, mood swings, schizophrenia, attention deficit hyperactivity disorder, visual disorders, appetite disorders (eg, anorexia), obesity, hypoglycemia, high blood pressure, swelling, Insulin resistance, Unstable diabetes, Fat atrophy, Insulin allergy, Insulinoma, Lipid toxicity, Intestinal fatigue, Hyperinsulinemia, Cancer (eg breast cancer), Metabolic syndrome, Immune disorders (eg Immunodeficiency syndrome) And inflammatory diseases (eg, enteritis, arthritis, allergies), multiple sclerosis, acute renal failure, and the like.
• diabetes impaired glucose tolerance, keronosis, acidosis, diabetic neuro
• a number of harmonized wools have been reported that have GPR40 receptor modulating action and are useful as a prophylaxis or treatment for diabetes.
• WO 2004/106276 and WO 2005/051890 disclose compounds having a GPR40 receptor modulating action.
• WO 2008/001931, WO 2008/130514 and WO 2012/010413 disclose compounds which have a GPR40 receptor modulating action and which are useful as prevention or treatment of diabetes.
• Another object of the present invention is to provide a pharmaceutical use of the tricyclic compound.
• the present invention provides a compound selected from the group consisting of tricyclic compounds of the formula I, pharmaceutically acceptable salts, isomers, solvates and prodrugs thereof:
• V, W, X, Y, Z, Ar, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , n and o are as defined in the specification.
• the present invention provides a compound selected from the group consisting of the tricyclic compound of Formula I, a pharmaceutically acceptable salt thereof, isomer I, solvation and prodrugs,
• diabetes impaired glucose tolerance, ketosis, acidosis, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, macular edema, hyperlipidemia, genital disorders, skin diseases, arthrosis, osteopenia, sinus sclerosis, thrombotic disease, indigestion, Memory and learning disorders, depression, mood swings, schizophrenia, attention deficit hyperactivity disorder, visual disorders, appetite disorders, obesity, hypoglycemia, hypertension, edema, insulin resistance, unstable diabetes, fat atrophy, insulin allergy, phosphorus Good in the group consisting of suulinoma, lipid toxicity, bowel fatigue, hyperinsulinemia, cancer, metabolic syndrome, autoimmune diseases, inflammatory diseases, multiple sclerosis and acute renal failure
• the disease is to provide a use of the manufacture of a medicament for the
• the present invention is a compound selected from the group consisting of the tricyclic compound of Formula (I), a pharmaceutically acceptable salt thereof, this agent, solvate and prodrug, and pharmaceutically acceptable It provides a pharmaceutical composition for the prophylaxis or treatment of various diseases related to the GRP40 including possible dilution.
• the present invention comprises administering to the mammal a compound selected from the group consisting of the tricyclic compound of Formula I, a pharmaceutically acceptable salt thereof, this agent, a solvate and a prodrug, said GRP40 in mammals It provides a method for preventing or treating various diseases related to the disease.
• halogen as used herein includes fluoro, chloro, bromo and iodo
• alkyl or alkyllian refers to a branched chain having a specified number of carbon atoms or Straight swaeeu and I contains a saturated aliphatic hydrocarbon, for example, "_ 6 alkyl,”"represents the to know having 1 to 6 carbon atoms.
• alkyl groups examples include meryl (Me), aryl (Et), propyl (eg, ⁇ -propyl and isopropyl), buryl (eg, n-butyl, isoburyl, t-buryl) and phenyl (Eg, n-phenyl, isopentyl, L1
• alkoxy refers to a ⁇ 0-alkyl group.
• C 1 6 alkoxy includes alkoxy groups of C 1 ( C 2 , C 3 , C 4 , C 5 and Q. Examples of specific alkoxy groups include mesooxy, ethoxy, propoxy (eg n -Propoxy and isopropoxy) and t-butoxy
• alkylthio refers to a specified number of carbon atoms which are trivalent via sulfur crosslinking. Alkyl groups having, for example, -S-meryl group and -S-eryl group.
• amino refers to a mono- or di- 6 alkyl-amino group (eg, merylamino, ethylamino, propylamino, dimerylamino, dietylamino), mono- or di-C 6 - 14 aryl-amino group (e.g., phenylamino, diphenylamino, 1-or ruffle amino, 2-naphthylamino), a mono- or di -C 7 - 16 ahreu to know eu amino group (e.g., benzyl Amino, phenarylamino), Nd.6 alkyl-NC 6 .
• aryl-amino group e.g., phenylamino, diphenylamino, 1-or ruffle amino, 2-naphthylamino
• a mono- or di -C 7 - 16 ahreu to know eu amino group e.g., benz
• Aral-amino group eg, N-methyl- N ⁇ phenylamino, N-ethyl-N-phenylamino
• Nd. 6 alkyl-NC 7-16 aralkyl-amino groups (eg, N-meryl-N-benzylamino, N-eryl-N-benzylamino).
• acyl as used in the present invention is a formyl group, a carboxyl group, a carbamoyl group, de-alkyl-carbonyl, -6 alkoxy-carbonyl group, C 3 - 8 cycloalkyl-carbonyl, C 6 _ 14 ahreol-carbonitrile Nil group, C 16 aralkyl-carbo Group, Q i 14 aryloxy-carbonyl group, C 7 - 16 aralkyloxy eu carbonyl group, mono- or di- ⁇ _ 6 alkyl carbamoyl group, a mono- or di -C 6-14 ahkwil-carbamoyl, C 3 - 8 cycloalkyl-carbamoyl, ⁇ : 7-16 ahreu al keel-carbamoyl group, a nitrogen-containing heterocyclyl eu by interrogating a carbonyl group, thio carbamo
• substituted or unsubstituted is used to refer to a compound which is unsubstituted or unsubstituted by one to three alicyclic groups selected from the examples below.
• carbocyclic refers to any stable 3-, 4-, 5 ′, 6-, 7- or 8-membered monocyclic or bicyclic, or 7-, 8-, 9- Or a radical group of a 10-membered bicyclic ring, which may be pohochemistry, partially unsubhomochemistry, unsaturated or aromatic.
• carbocyclics examples include cyclopropyl, cycloburyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclonuclear, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, Cyclooctenyl, cyclooctadiene, fluorenyl, phenyl, naphthyl, indanyl and adamantyl.
• preferred carbocyclics are cyclopropyl, cycloburyl, cyclopentyl, cyclonucleus, phenyl or naphthyl.
• “carbocyclic” When “carbocyclic” is used, it includes “aryl". "Aral” groups are for example monocyclic or bicyclic aromatic carbonoxy hydrogen groups, including phenyl and napryl. "Bicyclic carbocycles” contain two fused rings and consist of carbon atoms. A stable 9- or 10-membered carbocyclic group, of which two rings are benzo rings fused to a second ring; the second ring is a 5-fold, partially unsaturated or unsaturated. Or a 6-membered carbon ring A bicyclic carbocyclyl group can be attached to its pendant group at any carbon atom that produces a stable structure.
• aromatic heterocyclyl examples include thienyl, fural, pyrimill , Thiazolyl, oxazolyl, pyrazinyl, pyrimidinyl, pirral, imidazolyl, pyrazolal, triazolyl, tetrazoleal, pyridazinyl, isothiazolyl, isoxazolyl, indole, 2 -Benzothiazolyl, 2-benzoxazolyl, benzimidazolyl, benzo [b] thienyl, benzo [b] furanyl, quinolal and isoquinolyl, but are not limited to these.
• tetracyclyl examples include pyridinyl, oxazolidinyl, imidazolinyl, piperidinyl, pipera Carbonyl, morpholinyl carbonyl replicon, thiomorpholinyl, 1,1-oxido Tet La dihydro -2H- thio pyranyl and include, tetrahydropyranyl, neunda not are not limited to.
• phrases "pharmaceutically acceptable” as used herein is intended for use in contact with human and wool tissues without undue toxicity, irritation, allergic reactions, and / or other problems or complications within the scope of fair medical judgment. Appropriate, rational benefit / risk violates balance, blends, compositions and / or dosage forms.
• the present invention provides compounds selected from the group consisting of the following tricyclic compounds of Formula I, their pharmaceutically acceptable salts, isomers, solvates and prodrugs:
• Y is alkylene
• Ar is any one of the following substituent structural formulas (a) to (c),
• B is alkyllian
• R 1 is hydrogen, halogen, hydroxy, amino, nitro, cyano, C 1-6 alkyl, Q ⁇ 10 alkoxy, C 1-6 alkyl thio, acyl, _ 6 alkylsulfonyloctane
• R 6 and R 7 are each hydrogen dock tipjeok, halogen, amino, cyano, alkyl, Q-6 alkoxy, Q-6 alkylthio, acyl, [3 - 12 carbocycle-held, Or S-14 membered heterocyclic;
• R 9 and R 10 are each independently hydrogen, halogen, hydroxyl, C 1-6 alkyl, or C 1-6 alkoxy;
• RU is hydroxy, amino, or C 1-6 alkoxy
• R 12 is hydrogen, C 1-6 allyl, C 2 . 6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxyne, C 1-6 alkoxy 6 alkyl, C 3 .
• X2 carbo cyclic quill, or 5-14 membered heterocyclyl
• 1 3 is hydrogen or C 1-6 alkyl
• R 14 is hydrogen, halogen, amino, -CF 3 , nitro, cyano, C 1-6 alkyl, alkoxyne, C 1-6 alkyl E
• R 15 is hydrogen or alkyl
• n, 0 and p are each independently 0, 1, 2 or 3;
• Alkyl, alkyl, alkenyl, alkynyl, alkoxy, allyl thio, amino, acyl, alkylsulfonyloxy, carbocyclyl, carbocyclyloxy, carbocyclylsulfonyloxy, heterocyclyl, hu Klyryloxy and heterocyclylsulfonyloxy are each independently selected from 4 ⁇ 7 membered heterocyclyl (with 1 to 3 alicyclic groups selected from hydroxy, halogenated C 1-6 alkyl and d- 6 alkoxyin-carbonyl).
• C 3-8 cycloalkyl hydroxy, [ 1-6 alkoxy, halokenated alkoxy, agu I-no, mono- or di- [ 1-6 allyl-amino, N ⁇ Q_ 6 allyl -NQ- 6 alkyl-carbonyl-ami No, -16 aralkyloxy, c 1-6 alkylthio, c 1-6 alglysulfinyl, c 6 alkylsulfonyl, and mono- or di
• -d-6 alkyl-phosphono may be substituted with one or more substituents selected from the group consisting of;
• the compound of formula I is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
• X is -CH 2- , ⁇ 0-, -0-CH2-0-, -S-, or -NR 15- ;
• Y is C 1-3 alkylene
• Z is a -0-, -S-, or -NR 15 eu, wherein Z is an alicyclic carbon to two times or three times Cha of Ar;
• Ar is any one of the alicyclic group structural formulas (a) to (c);
• A is -CH 2- , -CF 2- , -0- or -NR 1S- ;
• B is C 1-2 alkyllian
• R 1 is hydrogen, halogen, hydroxy, amino, nitro, cyano, C 1-6 alkyl, Q- 10 alkoxy
• R 2 is hydrogen, halogen, amino, cyano, C 1-6 allyl, d- 6 alkoxy, C 1-6 alkyl thio, C 3 — 12 carbocyclyl, or 5-14 membered heterocyclic;
• R 3 , R 4 , R S and R 6 are each independently hydrogen, halogen, amino, — 6 alkyl, or C 1-6 alkoxy;
• R 7 is hydrogen, halogen, amino, cyano, C 1-6 alkyl, Q_ 6 alkoxy, [ 1-6 alkylthio, C 3-12 carbocyclyl, or 5-14 membered heterocyclyl;
• R 8 is hydrogen, halogan, amino, d- 6 alkyl, or C 1-6 alkoxy;
• R 9 and R 10 are each independently hydrogen, halogen, hydroxy, C 1-6 alkyl, or Q- 6 alkoxy;
• R 11 is hydroxy or C 1-6 alkoxy
• R 12 is hydrogen, C 1-6 alkyl, C 2 . 6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxyne, d_ 6 alkoxy C 1-6 alkyl, C 3 -i2 Carbocyclic, or 5-14 membered heterocyclyl;
• R is hydrogen or d_ 6 alkyl
• R is hydrogen, halogen, amino, -CF 3, Q_ 6 alkyl, Q- 6 alkoxy, acyl, [3-12 carbocyclyl, or 5-14 won by interrogating cycle and barrels;
• R 1S is hydrogen or C 1-6 alkyl
• N, o and p are each poisonally 0, 1 or 2;
• alkyllian, alkyl, alkynyl, alkoxyl I, alkylthio, amino, acyl, alkylsulfonyloxy, carbocyclyl, carbocyclicoxy, carbocyclylsulfonyloxy, heterocyclic and heterocyclic oxy are each independently 4-7 won by interrogating heterocyclyl (hydroxy, halogenated C 1-6 alkyl and C 1-6 alkoxyl ⁇
• - carbonyl not one to three substituents selected from the group consisting of alicyclic or aliphatic), C 3 - 8 Cycloalkyl, hydroxy, alkoxy, halogenated C 1-6 alkoxy, amino, mono- or di-C 1-6 alkyl-amino, N-Cw alkyl-N-Cw allyl-carbonyl-amino, C 7-16 are One or more alicyclics selected from the group consisting of alkyloxane I, C 1-6 allyl thio, d
• the compound of Formula I is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
• X is -CH 2 - ( -O-CH2-O-, -0-, -S-, or -NR 15- ;
• Y is C «alkyllian
• Z is -0-, -S-, or -NR 15- , and Z is aliphatic to carbon number 2 or 3 of Ar; Ar is any of the substituents (a) to (c);
• A is -CH 2- , -CF 2- , -0- or -NR 15- ;
• B is C 1-2 alkyllian
• R 1 is hydrogen, halogen, hydroxy, amino, C 1-6 alkyl, 10 alkoxy, acyl, _ 6 alkylsulfonyl oxy-carbonyl, C 3 - 12 carbocycle rilok ⁇
• R 2 , R 3 , 4 , 5 , R 6 , R 7 and R 8 are each independently hydrogen, halogen, amino, C 6 alkyl, or _ 6 alkoxy; R 9 and R 10 are each independently hydrogen or halogen;
• R ′′ is hydroxy or C 1-6 alkoxy
• R is hydrogen, d_ 6 alkyl, C 2 _ 6 alkenyl carbonyl, C 2 - 6 alkynyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, carbocycle -12 barrels, or 5 14 membered heterocyclic;
• R 13 is hydrogen
• R 14 is hydrogen, halogen, amino, alkyl, C 1-6 alkoxy, or acyl
• R 1S is hydrogen, meryl, aryl or isopropyl
• N, o and p are each independently 0, 1 or 2;
• alkyllian, alkyl, alkynyl, alkoxy, amino, acyl, alkylsulfonyloxy, carbocyclyloxy, heterocyclyl and heterocyclyloxy are each independently a 4-7 membered heterocyclic (hydroxy) , halogen call to know and a C 1-6 ( ⁇ 6 alkoxy-carbonyl with 1 to 3 aliphatic shed some light ventilated selected from carbonyl or not aliphatic), C 3 - 8 cycloalkyl, hydroxyl ⁇
• the compound of Formula I is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
• X is -CH 2- , -0-, -0-CH 2 -or -N (CH 2 CH 3 )-;
• Y is methylphene
• Z is -0- or -NH-, wherein Z is substituted with carbon site 2 or 3 of Ar;
• Ar is any one of the alicyclic group structural formulas (a) to (c);
• A is -0- and B is ethylene
• R 1 is merylsulfonylpropoxy, etylsulfonylpropoxy, ethoxyethoxy, morpholino, mor
• R 2 is hydrogen or methyl
• R 3 , R 4 , R s and R 6 are each independently hydrogen or methyl
• R 7 and R 8 are each independently hydrogen or fluoro
• R 9 and R 10 are hydrogen
• R 11 is hydroxy
• R 13 is Hydrogen;
• N and o are each independently 0, 1 or 2;
• P may be 0 or 1
• the present invention includes pharmaceutically acceptable salts, isomers, solvates and prodrugs of the compound of formula (I) above.
• “Pharmaceutically acceptable salts” as used herein refer to derivatives in which the parent compound is prepared by modifying its parent compound with an acid or a base thereof.
• Examples of pharmaceutically acceptable salts include, but are not limited to, basic groups I inorganic. Or organic acid salts such as amines; acidic groups I alkalis or organic salts such as carboxylic acids, etc.
• Pharmaceutically acceptable salts are conventional examples of the parent compound, for example formed from non-toxic inorganic or organic acids.
• Phosphorus non-toxic salts or quaternary ammonium salts for example, such conventional non-toxic spirits include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid; and organic acids.
• salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, these salts are in the form of free acids or bases in wool or organic solvents, or in mixtures thereof (generally non-aqueous media such as ether, aryl acetate, ethanol, isopropanol or acetonitrile). Compound wool can be prepared by reacting with a stoichiometric amount of the appropriate base or acid.
• the compound of formula (I) may have a form in which a hydrogen atom in the carboxyl group (-COOH) contained therein is substituted and an alkali-based metal (Li, Na, K, etc.) is ion-bonded, and such an ionic salt compound is Pharmaceutically acceptable salt forms of the compounds of I may be included within the scope of the present invention.
• the compound of formula (I) may comprise one or more non-clearly alicyclic carbon atoms and may be separated in optically active or racemic form.
• optically active or racemic form may comprise one or more non-clearly alicyclic carbon atoms and may be separated in optically active or racemic form.
• optically active forms are well known in the art.
• a mixture of granular isomers can be prepared by standard techniques including separation of racemic ⁇ ⁇ , normal phase, reverse phase and chiral chromatography, salt formation first, recrystallization, or the like. From I, or by chiral synthesis by synthesis of target chiral centers.
• the compound wool of formula (I) may have a solvent hose form.
• Solvate refers to the physical association of a compound of the invention with one or more solvent molecules (whether organic or inorganic). The physical association includes a hydrogen bond. In certain cases, solvates will be isolateable, for example when one or more solvent molecules are introduced into the crystal lattice of the crystalline solid. The solvent molecules in the solvate may be present in a canonical and / or non-regular arrangement. Solvation wool may comprise stoichiometric or non stoichiometric amounts of solvent molecules. “Solvent wool” 'includes both solution-phase and isolable solvates. Exemplary solvates include, but are not limited to, hydride wool, ethanolate, methanolate and isopropanolate. Is generally known in the art.
• the chemical formulas I can have proforma forms. Any compound that will be converted in the biologic to provide a bioactive agent (ie, a compound of formula I) is a prodrug within the scope and spirit of the present invention.
• a prodrug within the scope and spirit of the present invention.
• Various forms of prodrugs and methods for their preparation are well known in the art.
• Compounds containing a carboxyl group can form physiologically hydrolysable esters that function as prodrugs to produce compounds of formula (I) by hydrolysis in a formulation.
• prodrugs are administered orally because in many cases hydrolysis occurs primarily under the influence of digestive enzymes. Parenteral administration can be used when the ester itself is active or when hydrolysis occurs in the blood.
• the compounds of the present invention can be prepared using the following methods, methods described in the following examples, known methods or methods known to those skilled in the art, or modified methods thereof. If not explained, they are as defined above.
• L is a leaving group or a hydroxy group
• the cationic compound la can be synthesized by the combined reaction of the intermediate agent ⁇ and Ilia in the presence of a suitable base (e.g., sodium hydrogen hydride, calcium carbonate, cesium carbonate, etc.) when L is a leaving group. If L is a hydroxy group, it can be synthesized by the ⁇ I phenobu reaction (Mitsunobu reaction).
• a suitable reducing agent e.g., sodium borohydride, sodium triacetoxyhydroxide, sodium borohydride, etc.
• the imine agent which is an intermediate agent
• it may be synthesized through a separate reduction reaction after obtaining the imine agent. Said call a hapul la, lb, or if it is not R "is hydroxy in Ic, compound la, lb or when hydrolyzed under been acid or base existential the Ic synthesized compound la ', lb', or Ic 'having a carboxyl group can do.
• Intermediates ⁇ and ⁇ of Scheme 1 may be prepared by the following Scheme 3 or a similar method. In some cases, it can be produced by applying a variety of known synthetic methods using features based on the type of the basic skeleton or alicyclic group.
• a suitable protecting group at the stage of the raw material or intermediate agent, that is, a group which can be easily converted into the functional group.
• the protecting group can then be removed as needed to obtain the desired catalyst compound.
• Intermediate ⁇ of Scheme 1 can be prepared by intramolecular high-hormone reaction in the presence of a suitable base as in step 3, and in some cases by Suzuki reaction as in step 3 '. It can also be prepared.
• the intermediate ⁇ ' is a suitable oxidizing agent (eg manganese oxide, Dess Martin)
• suitable oxidizing agent eg manganese oxide, Dess Martin
• intermediates V and V 'of Scheme 3 can be prepared by binding reaction in the presence of a suitable base such as in reaction formula 5 below.
• the compounds of the present invention prepared as described above are isolated and purified as their salts in a free state or by performing a salt-treating treatment by a conventional method. Isolation and purification are carried out by applying common chemical operations such as extraction, concentration, distillation, crystallization, high resolution, recrystallization, and various chromatography.
• Various isomers can be isolated by conventional methods using the difference in physicochemical properties between the isomers.
• the racemic mixture is separated into optically pure isomers by general racemic fractionation or various chromatography methods, such as those derived by optically partitioning the diastereomeric salts with general optically active acids such as tartaric acid. can do.
• the diastereomer mixture can be separated by, for example, fractional crystallization or various chromatography.
• an optically active phosphorus compound can also be manufactured by using a suitable optically active raw material.
• the compound of the formula (I) comprises granular isomers, both isomers alone and mixtures of each isomer are included within the scope of the invention.
• the compounds of formula (I) may be hydrates or non-hydrates.
• Compounds of formula (I) may be labeled with isotopes (eg, 3H, 14C, 35S, etc.) and the like.
• the tricyclic compound of Formula I according to the present invention a compound selected from pharmaceutically acceptable salts, isomers, solvates and prodrugs thereof, has a GPR40 receptor function modulating action (GPR40 receptor agonist activity and GPR40 receptor antagonist activity, in particular GPR40 receptor agonist activity, exhibits low toxicity and fewer side effects (eg, acute toxicity, chronic toxicity, genotoxicity, developmental toxicity, cardiac toxicity, drug interactions and carcinogenesis) Sex). Therefore, the compounds of the present invention are useful as safe GPR40 receptor function modulators, preferably GPR40 agonists.
• GPR40 receptor function modulating functions in mammals (eg, mice, rats, hangsters, rabbits, cats, dogs, cattle, sheep, monkeys, humans, etc.). It is useful as a regulator of physiological function in which the GPR40 receptor is involved, or as a prophylactic or treatment agent for a disease involving the GPR40 receptor.
• the compounds of the present invention are useful as insulin secretion regulators (preferably insulin secretagogues), hypoglycemic drugs and pancreatic ⁇ cell protective agents.
• insulin secretion regulators preferably insulin secretagogues
• hypoglycemic drugs preferably pancreatic ⁇ cell protective agents.
• pancreatic ⁇ cell protective agents preferably insulin secretagogues
• the compound of the present invention or a pharmaceutical composition comprising the same, diabetes mellitus, impaired glucose tolerance, hypogonia, acidosis, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, macular edema, hyperlipidemia, Genital disorders, skin disorders, arthrosis, osteopenia, bronchosclerosis, thrombotic disorders, indigestion, memory and learning disorders, depression, mood swings, schizophrenia, attention deficit hyperactivity disorder, visual disorders, appetite control disorders (e.g., appetite Hyperactivity), obesity, hypoglycemia, high «pressure, swelling, insulin resistance, atypical diabetes, fat atrophy, insulin allergy, insulinoma, lipid toxicity, intestinal fatigue, hyperinsulinemia, cancer (e.g.
• Diseases such as metabolic syndrome, immune diseases (eg immunodeficiency), inflammatory diseases (eg enteritis, arthritis, allergies), multiple sclerosis, acute renal failure, and the like;
• immune diseases eg immunodeficiency
• inflammatory diseases eg enteritis, arthritis, allergies
• multiple sclerosis acute renal failure, and the like
• diabetes mellitus impaired glucose tolerance, ketosis, acidosis, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, macular edema, hyperlipidemia, genital disorders, skin disease, arthrosis, osteopenia, arteriosclerosis, thrombosis, indigestion
• It is useful as a preventive or curative agent for diseases such as memory and learning disabilities.
• diabetes can include type 1 diabetes, type 2 diabetes and gestational diabetes.
• Hyperlipidemia also includes hypertriglyceridemia, hypercholesterolemia, hyper HDL-emia, postprandial hyperlipidemia and the like.
• the compounds of the present invention, or pharmaceutical compositions comprising them can be used for the prevention or treatment of type 2 diabetes.
• the compounds of the present invention can be used in combination with other drugs in addition to the compounds of the present invention.
• drugs that can be used in combination with the compounds of the present invention include diabetic medications, diabetic complications, hyperlipidemia agents, antihypertensive agents, anti-obesity agents, diuretics, chemotherapy agents, immunotherapy agents, anti-inflammatory drugs, antithrombotic agents , Osteoporosis medications, vitamins, anti-retardants, urinary incontinence or urinary medications, urination disorders medications, and the like, but are not limited thereto.
• compositions comprising the compounds of the present invention can be prepared according to conventional manufacturing methods using pharmaceutically acceptable diluents, excipients, and the like, commonly used in the art.
• compositions according to the invention can be prepared and administered in various forms of dosage forms-the route of administration of the formulations is oral administration by tablets, pills, capsules, granules, powders, solutions and the like, or intraarticular, intravenous, Parenteral administration by intramuscular injections, suppositories, eye drops, ophthalmic ointments, transdermal solutions, ointments, transdermal adhesives, transmucosal solutions, transmucosal adhesives, inhalants and the like.
• solid dosage forms for oral administration include tablets, pills, powders, granules, and the like.
• These formulations contain one or two or more active ingredients containing one or more pharmacologically inert excipients such as lactose, mannitol, glucose, hydroxypropylcellose, microcrystalline cellulose, starch, polybees. It is prepared by mixing with nilpyrlidone and / or magnesium metasilicate aluminate.
• the formulations may contain pharmacologically inert additives such as disintegrants, stabilizers, dissolution aids such as lubricants such as magnesium stearate or carboxymethyl staple sodium. Tablets or pills may also be coated with a film of sugar or gastric or enteric material as needed.
• liquid formulations for oral administration include, for example, emulsions, solutions, suspensions, syrups or elixirs, which are commonly used pharmacologically inert diluents, for example purified water. Or ethanol.
• the liquid formulation may further contain solubilizers, wetting agents, auxiliaries such as suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.
• Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions.
• aqueous solvent include distilled water for injection or physiological saline solution.
• water-insoluble I solvent for example, vegetable oils such as propyllyglycol, polyethyllylene glycol or olive oil, alcohols such as ethanol, or polysorbate 80 and the like.
• Such compositions may further comprise isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers or dissolution aids. These are sterilized, for example, by means of a filter with a bacterial retention filter, by the combination or irradiation of the fungicides. In addition, these may be used by preparing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.
• Example 1 2-((3S) -6-((ll-meryl-9- (3- (merylsulfonyl) propoxy) -6,7-dihydro-SH-dibenzo [a, c] [ Preparation of Gianylene 4-yl) methoxy) -2,3-dihydrobenzofuran-3-yl) acetic acid
• Trifenylphosphine in a solution of meryl 3-bromo-2- (bromomeryl) benzoate (prepared according to the method described in US 6518257 B1; 4.2 g, 13.64 mmol) in toluene (100 mL) ( 3.58 g, 13.64 mm) was added and stirred at 95 0 C for 15 hours. The resulting compound was cooled down to room temperature, diluted with nucleic acid (100 mL) and stirred at room temperature for at least 10 minutes. The mixture was filtered and washed with hexane, and the resulting solid was dried in vacuo to yield the title compound (white solid, 7.0 g, 12.27 mmol, 90% aqueous).
• Chloroform (10 mL) was substituted with argon (CuOTf) 2 -toluene (39.8 mg, 0.077 mmol) and (2R) -4-tert-butyl-2- ⁇ l-[(4R) -4-tert-buryl- 4,5-dihydro-1,3-oxazol-2-yl] -1-methyl aryl ⁇ -4,5-dihydro-1,3-oxazole (453 mg, 0.154 mmol) was added and Stirred for 1 hour 10 minutes.
• Acetic acid 4-vinyl-phenyl ester (2.5 g, 15.4 mmol) was dissolved in chloroform (10 mL), aliborated with argon, and then the solution prepared above was added thereto.
• Diazo-acetic acid ethyl ester (2.1 mL, 17.0 mmol) was dissolved in chloroform (30 mL), substituted with argon, and added slowly to the mixture over 3 hours.
• the reaction mixture was filtered through silica gel, washed with EtOAc / dichloromethane (1/9), concentrated under reduced pressure and purified by silica gel chromatography to give the title compound (colorless oil, 3.6 g, 94% sool). .
• the title compound (diluted solid, 74.5 mg, 79% mercury) was obtained from the compound obtained in ⁇ 2-16>.
• the compound wool (90 mg, 0.26 mm) obtained in ⁇ 3-1> was dissolved in THF (5 mL), to which LiAIH 4 (0.53 mL, 0.53 mmol) was slowly added at 0 ° C., Stir at room temperature for 1 hour.
• the reaction mixture was cooled to 0 ° C. and diluted with saturated aqueous sodium sulfate solution.
• the layers were separated, the organic layer was dried over sodium sulfate and concentrated under reduced pressure, and then purified by silica gel chromatography to give the title compound (colorless oil, 80 mg, 97% aq.).
• the title compound wool (white solid, 424 mg, 98% mercury) was obtained from the compound obtained in ⁇ 5-7>.
• the title compound wool (white solid, 338 mg, 87% mercury) was obtained from the compound wool obtained in ⁇ 5-8>.
• the title compound (white foaming agent, 103 mg, 84% yield) was obtained from the compound obtained in ⁇ 5-9>.
• the title compound (white foaming agent, 81 mg, 83% yield) was obtained from the compound obtained in ⁇ 5 ⁇ 10>.
• the title compound (white foaming agent, 115 mg, 97% number) was obtained from the compound wool obtained in ⁇ 6-1>.
• Example 7 2-((3S) -6-((ll-meryl-9- (3- (merylsulfonyl) propoxy) -6,7-dihydro-5H-dibenzo [a, c] [ 7] Preparation of anylene-2-yl) methoxy) -2,3-dihydrobenzofuran-3-yl) acetic acid
• the title compound (E / Z mixture, colorless oil, 3.04 g, 94%) was obtained from the compound obtained in ⁇ 5-1> and the compound obtained in ⁇ 1-1>. Number).
• the title compound (colorless oil, 2.68 g, 88% mercury) was obtained from the compound obtained in ⁇ 7-1>.
• the title compound (white foaming agent, 345 mg, 97% mercury) was obtained from the compound obtained in ⁇ 7-5>.
• the title compound (white foaming agent, 285 mg, 93% mercury) was obtained from the compound obtained in ⁇ 7-6>.
• the title compound (white foaming agent, 59 mg, 36.3% mercury) was obtained from the compound obtained in ⁇ 7-8>.
• the title compound (white foam, 27 mg, 47% mercury) was obtained from the compound obtained in ⁇ 7-9>.
• the compound (840 mg, 2.15 mmol) obtained in ⁇ 8-4> was suspended in THF (25 mL), and LiAlH 4 (lM THF solution, 3.23 mL, 3.23 mmol) was added at 0 ° C., and the temperature was increased to room temperature. After stirring for 2 hours. Saturated aqueous sodium sulfate solution was added to the reaction mixture at 0 ° C., followed by addition of water, followed by extraction with dichloromethane. The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (white foam, 652 mg, 84% yield).
• the title compound (white foaming agent, 90.2 mg, 91% sool) was obtained from the compound obtained in ⁇ 8-5>.
• the title compound (reddish brown foam, 57.5 mg, 48% mercury) was obtained from the compound obtained in ⁇ 8-7> according to the procedure described in ⁇ 3-5>.
• the title compound wool (white solid, 95.2 mg, 96%) was obtained from the compound obtained in ⁇ 9-6>.
• ⁇ 10-5> Preparation of methyl gmethoxin 1-5-metal-9,10-dihydrophenanthrene-carboxylate Compound (2.87 g, 7.90 mmol) obtained in ⁇ 10-4> was dissolved in ⁇ , ⁇ -dimerylacetamide (26 mL), and tricyclonucleosilphosphine tetrafluoroborate (407 mg, 1.10 mm) and K 2 CO 3 (2.18 g, 15.80 mmol) were added and aliphatic with nitrogen. Palladium (1) acetate (124 mg, 0.55 mmol) was then added and stirred at 135 ° C. for 15 hours.
• the title compound (colorless oil, 1.86 g, 85% mercury) was obtained from the compound obtained in ⁇ 11-2>.
• the title compound (colorless oil, 1.23 g, 86% mercury) was obtained from the compound obtained in ⁇ 11-3>.
• the title compound (colorless oil, 115 mg, 80% mercury) was obtained from the compound obtained in ⁇ 11-7>.
• the title compound (white solid, 101 mg, 92% mercury) was obtained from the compound obtained in ⁇ 11-8>.
• the title compound (yellow oil, 410 mg, -100% mercury) was obtained from the compound obtained in ⁇ 11-5>.
• the title compound (white solid, 332 mg, 95% mercury) was obtained from the compound wool obtained in ⁇ 12-1>.
• the title compound (colorless oil, 135 mg, 84% mercury) was obtained from the compound obtained in ⁇ 12-2>.
• the title compound (white foaming agent, 93 mg, 77% yield) was obtained from the compound wool obtained in ⁇ 12-3>.
• Example 13 2-((3S) -6-((ll-meryl-9- (3- (merylsulfonyl) propoxy) -6,7-dihydrodibenzo [b, d] oxefen-4 Preparation of -yl) methoxy) -2,3-dihydrobenzofuran-3-yl) acetic acid
• the title compound (colorless oil, 7 mg, 75% mercury) was obtained from the compound obtained in ⁇ 13-6>.
• the title compound (white foaming agent, 7 mg, 72% yield) was obtained from the compound wool obtained in ⁇ 13-8>.
• Example 14 2-((3S) -6-((ll-meryl-9- (3- (merylsulfonyl) propoxy) -6,7-dihydrodibenzo [b, d] oxepene-2 Preparation of -yl) methoxy) -2,3-dihydrobenzofuran-3-yl) acetic acid
• the title compound (white foaming agent, 266 mg, 85% mercury) was obtained from the compound obtained in ⁇ 14-6>.
• the title compound (white foaming agent, 138 mg, 96% mercury) was obtained from the compound wool obtained in ⁇ 15-1>.
• the title compound (light yellow oil, 207 mg, 99% mercury) was obtained from the compound obtained in ⁇ 16-2>.
• the title compound wool (light yellow oil, 137 mg, 99% mercury) was obtained from the compound obtained in ⁇ 16-3>.
• Example 18 (1S, 2S) -2- (4-(((9- (3- (merylsulfonyl) propoxy) -5,7-dihydrodibenzo [c, rioxfun-2-yl) (Meryl) amino) phenyl) cyclopropanecarboxylic acid
• the title compound wool (colorless oil, 63 mg, 32% mercury) was obtained from the compound wool obtained in ⁇ 19-5>.
• the title compound (white solid, 40 mg, 85% mercury) was obtained from the compound obtained in ⁇ 19-9>.
• the title compound (off-white foaming agent, 130.1 mg, 87% mercury) was obtained from the compound obtained in ⁇ 18-8>.
• the title compound (white solid, 26 mg, 59% mercury) was obtained from the compound wool obtained in ⁇ 21-8>.
• the title compound (light yellow oil, 26 mg, 99% sool) was obtained from the compound obtained in ⁇ 21-9>.
• the title compound (light yellow oil, 19 mg, 73% mercury) was obtained from the compound obtained in ⁇ 21-10>.
• the title compound (light yellow oil, 15 mg, 51% mercury) was obtained from the compound obtained in ⁇ 21-11>.
• the title compound (white solid, 12 mg, 85% mercury) was obtained from the compound obtained in ⁇ 21-12>.
• the title compound (white solid, 99 mg, 100% mercury) was obtained from the compound obtained in ⁇ 23-1>.
• the title compound wool (white foaming agent, 104 mg, 78% yield) was obtained from the compound wool obtained in ⁇ 24-1>.
• the title compound was obtained (light yellow oil, 111 mg, 87% yield) from the compound wool obtained in ⁇ 5-9>.
• the title compound wool (white foaming agent, 88.3 mg, 86% yield) was obtained from the compound obtained in ⁇ 25-1>.
• the title compound (colorless foaming agent, 43 mg, 50% mercury) was obtained from the compound obtained in ⁇ 26-1>.
• the title compound (white solid, 102 mg, 71% Soul) was obtained from the compound wool obtained in ⁇ 27-2>.
• the title compound wool (white foaming agent, 116 mg, 79% sool) was obtained from the compound obtained in ⁇ 29-1>.
• the title compound wool (white foaming agent, 132 mg, 87% yield) was obtained from the compound obtained in ⁇ 9-6>.
• the title compound (white solid, 73 mg, 85% mercury) was obtained from the compound obtained in ⁇ 31-1>.
• Example 32 (S) -2- (6-((9- (3- (merylsulfonyl) propoxy) -6,7-dihydrodibenzo [b, d] oxefen-2-yl) meth Preparation of Toxyl) -2,3-dihydrobenzofuran-3-yl) acetic acid ⁇ 32-l> (S) -meryl 2- (6-((9- (3- (merylsulfonyl) propoxy) -6,7-dihydrodibenzo [b, d] oxepin-2-yl Preparation of) methoxy) -2,3-dihydrobenzofuran-3-yl) acetate
• the title compound (white foaming agent, 90 mg, 84% mercury) was obtained from the compound obtained in ⁇ 32-1>.
• Example 33 2-((3S) -6-((ll-meryl-9- (3- (merylsulfonyl) propoxy) -5,7-dihydrodibenzo [c, e] oxepin-2 Preparation of -yl) methoxy) -2,3-dihydrobenzofuran-3-yl) acetic acid Preparation of ⁇ 33-l> meryl 4- (bromoethyl) -3- (4,4,5,5-tetrameryl-1,3,2-dioxaborolan-2-yl) benzoate
• methyl 4- (bromomethyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxa borane-2-yl) benzo Obtained the title compound (white solid, 3.0 g, 92% yield) from Eight (prepared according to the method of Chemical Communications (Cambridge, United Kingdom), 2012, vol. 48, # 34, p. 4115-4117). It was.
• the title compound (white solid, 11 mg, 46% mercury) was obtained from the compound obtained in ⁇ 33-7>.

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