Patent Application
20160355483
The present invention relates to a compound binding to PPARG but not acting as a promoter and a pharmaceutical composition for treating PPARG-related diseases comprising the compound as an active ingredient.
According to CDC (Centers for Disease Control and Prevention, USA) data, 24 million people, which are 8% of the total US population, are diabetic patients in US. Over the past decades, the number of diabetic patients has been growing and so has the diabetic drug market. The dominant diabetic-treating drug has been insulin so far, but treatment using insulin injection has a problem of the inconvenience of using a syringe.
Further, it can only supplement the shortage of insulin but cannot be a fundamental solution for diabetes. Therefore, a variety of alternative drugs have been developed and are currently on the market, including sulfonylurea, which increases insulin secretion; metformin, which slowly isolates glucose deposited in the liver; acarbose, which suppresses glycolysis to inhibit sugar adsorption; and rosiglitazone, which increases the sensitivity of insulin receptors. In spite of these drugs, treating diabetes is unsatisfactory and cannot meet the needs of diabetic patients. Recently, understanding of the cause and the mechanism of diabetes has been enhanced, and thereby, the diabetic drug market has become a new land of opportunity.
Thiazolidinedione (TZD) drugs, such as rosiglitazone and pioglitazone, activate the transcription of PPARG (peroxisome proliferator activated receptor-gamma), the nuclear receptor, and thereby increase insulin sensitivity to generate an anti-diabetic effect. It is well-known that this type of drug is effective in regulating PPARG, but recently, it was also confirmed that this type of drug affects another biochemical pathway. The involvement of this drug in the obesity-like insulin resistance mechanism is an example. The known cause of the insulin resistance observed in diabetic patients is phosphorylation of the 273rd amino acid of PPARG, serine, by CDK5 (cyclin-dependent kinase 5), which can be induced by mutation. It has been additionally confirmed that blocking CDK5 from interacting with PPARG is an important approach for developing an efficient anti-diabetic agent.
A patent document (US2012-0309757 A1) introduces compounds that bind to PPARG with high affinity but do not induce transcription of PPARG by acting as an agonist and thereby suppress insulin resistance by blocking CDK5, such that they display anti-diabetic effects (e.g., SR1664 and SR1824). Those compounds were also confirmed in a comparative experiment to have a significantly lower chance of producing side effects, such as weight gain and fluid retention, which frequently accompany conventional drugs, such as rosiglitazone. From a cell culture test, it was confirmed that SR1664 does not induce problems such as fat generation in bone cells, which is a side effect of rosiglitazone. The above results confirm that SR1664 can specifically block CDK5-mediated PPARG phosphorylation.
Even though the said SR1664 has many advantages, there is a problem with developing it as a drug due to poor pharmaco-kinetic (PK) pharmacophysical properties, which render in vivo absorption difficult.
It is an object of the present invention to provide a compound that binds PPARG but does not act as a promoter, an optical isomer thereof, or a pharmaceutically acceptable salt of the same.
It is another object of the present invention to provide a method for preparing the compound above.
It is also an object of the present invention to provide a pharmaceutical composition for treating PPARG-related disease which comprises the compound above, the optical isomer thereof, or the pharmaceutically acceptable salt of the same as an active ingredient.
To achieve the above objectives, the present invention provides a compound represented by formula 1 below, an optical isomer thereof, or a pharmaceutically acceptable salt of the same.
In formula 1,
R1 is H, unsubstituted or substituted C1-10 straight or branched alkyl wherein one or more halogens are substituted, or unsubstituted or substituted C1-10 straight or branched alkoxy wherein one or more halogens are substituted;
R2 is unsubstituted or substituted C6-10 aryl, unsubstituted or substituted C6-10 aryl C1-10 straight or branched alkyl, or unsubstituted or substituted 5-10 membered heteroaryl containing one or more hetero atoms selected from the group consisting of N, O, and S.
In the said substituted C6-10 aryl, the substituted C6-10 aryl C1-10 straight or branched alkyl, and the substituted 5-10 membered heteroaryl, one or more substituents selected from the group consisting of C1-10 straight or branched alkyl unsubstituted or substituted with one or more halogens, C1-10 straight or branched alkoxy unsubstituted or substituted with one or more halogens, C1-10 straight or branched alkylsulfonyl unsubstituted or substituted with one or more halogens, C1-10 straight or branched alkoxycarbonyl, halogen, nitrile, and nitro can be substituted.
In the said unsubstituted or substituted C6-10 aryl, phenyl or 5-8 membered heterocycloalkyl containing one or more hetero atoms selected from the group consisting of N, O, and S can be fused.
R1 and R2 can form C5-10 cycloalkyl, 5-10 membered heterocycloalkyl containing one or more hetero atoms selected from the group consisting of N, O, and S, or 5-10 membered heteroaryl containing one or more hetero atoms selected from the group consisting of N, O, and S along with the carbon atoms which are conjugated to the same.
In the said C5-10 cycloalkyl, the 5-10 membered heterocycloalkyl, or the 5-10 membered heteroaryl, phenyl can be fused.
R3, R4, R5, and R6 are independently H, halogen, unsubstituted or substituted C1-10 straight or branched alkyl wherein one or more halogens are substituted, unsubstituted or substituted C1-10 straight or branched alkoxy wherein one or more halogens are substituted, or unsubstituted or substituted C6-10 aryl.
In the said substituted C6-10 aryl, one or more substituents selected from the group consisting of halogen, unsubstituted or substituted C1-10 straight or branched alkyl wherein one or more halogens are substituted, hydroxycarbonyl, aminocarbonyl, and sodiumoxycarbonyl can be substituted.
A is —CH2— or —O—.
The present invention also provides a method for preparing the compound represented by formula 1 comprising the following steps, as shown in reaction formula 1 below:
substituting t-butoxy group of the compound represented by formula 7 prepared in step 3 with —OH group (step 4).
(In the reaction formula 1, R1-R6 and A are as defined in formula 1, and RA, RB, and RC are independently as defined in R3-R6).
The present invention also provides a method for preparing the compound represented by formula 1 comprising the following steps, as shown in reaction formula 2 below:
preparing the compound represented by formula 9 by reacting the compound represented by formula 8 with the compound represented by formula 6 (step 1);
preparing the compound represented by formula 7 by reacting the compound represented by formula 9 prepared in step 1 with the compound represented by formula 3 (step 2); and
substituting t-butoxy group of the compound represented by formula 7 prepared in step 2 with —OH group (step 3).
(In the reaction formula 2, R1-R6 and A are as defined in formula 1, and RA, RB, and RC are independently as defined in R3-R6).
The present invention further provides a method for preparing the compound represented by formula 1, as shown in reaction formula 3 below, comprising the step of substituting carboxyl group of the compound represented by formula 1A with sodiumoxycarbonyl group or amide group (step 1).
(In the reaction formula 3, R1-R6 and A are as defined in formula 1, and RA, RB, and RC are independently as defined in R3-R6).
In addition, the present invention provides a pharmaceutical composition for treating PPARG-related diseases comprising the compound represented by formula 1, the optical isomer thereof, or the pharmaceutically acceptable salt of the same as an active ingredient.
The compound represented by formula 1 or the optical isomer thereof of the present invention binds to PPARG with a high affinity but does not act as an agonist and thereby does not induce gene transcription of the same and blocks CDK5, which is a cause of PPARG phosphorylation. Therefore, the compound or the optical isomer thereof of the invention does not cause the side effects of the conventional anti-diabetic agents but is easily formulated as a drug with improved pharmacophysical properties and is excellent in treating PPARG-related diseases, indicating that the compound or the optical isomer thereof of the invention can be effectively used as a pharmaceutical composition for PPARG-related diseases.
Thus, the present inventors tried to develop a compound that can be formulated as a drug with improved pharmaco-kinetic pharmacophysical properties. In the course of the study, the present inventors confirmed that a compound with a specific structure that binds to PPARG with high affinity but does not induce transcriptional activity, suggesting that the compound does not act as an agonist but can block CDK5 activity so as to improve insulin resistance, and thereby confirmed that the compound is more excellent in lowering blood sugar and weight than SR1664 and SR1824 and does not significantly inhibit CYP enzyme activity, the drug-drug interaction index. As a result, the inventors confirmed that the compound above can be effectively used for treating PPARG related diseases, leading to the completion of the present invention.
Hereinafter, the present invention is described in detail.
The present invention provides a compound represented by formula 1 below, an optical isomer thereof, or a pharmaceutically acceptable salt of the same.
In the formula 1,
R1 is H, unsubstituted or substituted C1-10 straight or branched alkyl wherein one or more halogens are substituted, or unsubstituted or substituted C1-10 straight or branched alkoxy wherein one or more halogens are substituted.
R2 is unsubstituted or substituted C6-10 aryl, unsubstituted or substituted C6-10 aryl C1-10 straight or branched alkyl, or unsubstituted or substituted 5-10 membered heteroaryl containing one or more hetero atoms selected from the group consisting of N, O, and S.
In the said substituted C6-10 aryl, the substituted C6-10 aryl C1-10 straight or branched alkyl, and the substituted 5-10 membered heteroaryl, one or more substituents selected from the group consisting of C1-10 straight or branched alkyl unsubstituted or substituted with one or more halogens, C1-10 straight or branched alkoxy unsubstituted or substituted with one or more halogens, C1-10 straight or branched alkylsulfonyl unsubstituted or substituted with one or more halogens, C1-10 straight or branched alkoxycarbonyl, halogen, nitrile, and nitro can be substituted.
In the said unsubstituted or substituted C6-10 aryl, phenyl or 5-8 membered heterocycloalkyl containing one or more hetero atoms selected from the group consisting of N, O, and S can be fused.
R1 and R2 can form C5-10 cycloalkyl, 5-10 membered heterocycloalkyl containing one or more hetero atoms selected from the group consisting of N, O, and S, or 5-10 membered heteroaryl containing one or more hetero atoms selected from the group consisting of N, O, and S along with the carbon atoms which are conjugated to the same.
In the said C5-10 cycloalkyl, the 5-10 membered heterocycloalkyl, or the 5-10 membered heteroaryl, phenyl can be fused.
R3, R4, R5, and R6 are independently H, halogen, unsubstituted or substituted C1-10 straight or branched alkyl wherein one or more halogens are substituted, unsubstituted or substituted C1-10 straight or branched alkoxy wherein one or more halogens are substituted, or unsubstituted or substituted C6-10 aryl.
In the said substituted C6-10 aryl, one or more substituents selected from the group consisting of halogen, unsubstituted or substituted C1-10 straight or branched alkyl wherein one or more halogens are substituted, hydroxycarbonyl, aminocarbonyl, and sodiumoxycarbonyl can be substituted.
A is —CH2— or —O—.
Preferably, R1 is H, unsubstituted or substituted C1-5 straight or branched alkyl wherein one or more halogens are substituted, or unsubstituted or substituted C1-5 straight or branched alkoxy wherein one or more halogens are substituted.
R2 is unsubstituted or substituted C6-8 aryl, unsubstituted or substituted C6-8 aryl C1-5 straight or branched alkyl, or unsubstituted or substituted 5-8 membered heteroaryl containing one or more hetero atoms selected from the group consisting of N, O, and S.
In the said substituted C6-8 aryl, the substituted C6-8 aryl C1-5 straight or branched alkyl, and the substituted 5-8 membered heteroaryl, one or more substituents selected from the group consisting of C1-5 straight or branched alkyl unsubstituted or substituted with one or more halogens, C1-5 straight or branched alkoxy unsubstituted or substituted with one or more halogens, C1-5 straight or branched alkylsulfonyl unsubstituted or substituted with one or more halogens, C1-5 straight or branched alkoxycarbonyl, halogen, nitrile, and nitro can be substituted.
In the said unsubstituted or substituted C6-8 aryl, phenyl or 5-8 membered heterocycloalkyl containing one or more hetero atoms selected from the group consisting of N, O, and S can be fused.
R1 and R2 can form C5-8 cycloalkyl, 5-8 membered heterocycloalkyl containing one or more hetero atoms selected from the group consisting of N, O, and S, or 5-8 membered heteroaryl containing one or more hetero atoms selected from the group consisting of N, O, and S along with the carbon atoms which are conjugated to the same.
In the said C5-8 cycloalkyl, the 5-8 membered heterocycloalkyl, or the 5-8 membered heteroaryl, phenyl can be fused.
R3, R4, R5, and R6 are independently H, halogen, unsubstituted or substituted C1-5 straight or branched alkyl wherein one or more halogens are substituted, unsubstituted or substituted C1-5 straight or branched alkoxy wherein one or more halogens are substituted, or unsubstituted or substituted C6-8 aryl.
In the said substituted C6-8 aryl, one or more substituents selected from the group consisting of halogen, unsubstituted or substituted C1-5 straight or branched alkyl wherein one or more halogens are substituted, hydroxycarbonyl, aminocarbonyl, and sodiumoxycarbonyl can be substituted.
A is —CH2— or —O—.
More preferably, R1 is H, methyl, or ethyl.
R2 is unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, or unsubstituted or substituted 5-6 membered heteroaryl containing one or more hetero atoms selected from the group consisting of N and O.
In the said substituted phenyl, the substituted benzyl, and the substituted 5-6 membered heteroaryl, one or more substituents selected from the group consisting of C1-5 straight or branched alkyl unsubstituted or substituted with one or more halogens, C1-5 straight or branched alkoxy unsubstituted or substituted with one or more halogens, C1-5 straight or branched alkylsulfonyl unsubstituted or substituted with one or more halogens, C1-5 straight or branched alkoxycarbonyl, halogen, nitrile, and nitro can be substituted.
In the said unsubstituted or substituted phenyl, phenyl or 6 membered heterocycloalkyl containing one or more hetero atoms selected from the group consisting of N and O can be fused.
R1 and R2 can form C5-8 cycloalkyl, 5-8 membered heterocycloalkyl containing one or more hetero atoms selected from the group consisting of N, O, and S, or 5-8 membered heteroaryl containing one or more hetero atoms selected from the group consisting of N, O, and S along with the carbon atoms which are conjugated to the same.
In the said C5-8 cycloalkyl, the 5-8 membered heterocycloalkyl, or the 5-8 membered heteroaryl, phenyl can be fused.
R3, R4, R5, and R6 are independently H, fluoro, or unsubstituted or substituted phenyl.
In the said substituted phenyl, one or more substituents selected from the group consisting of hydroxycarbonyl, aminocarbonyl, and sodiumoxycarbonyl can be substituted.
A is —CH2— or —O—.
More preferably, R1 is H, methyl, or ethyl;
R3 is H, F,
R4 is H, F,
R5 is H,
R6 is H,
A is —CH2— or —O—.
The compound represented by formula 1 or the optical isomer thereof of the present invention can be exemplified by the following compounds:
The compound represented by formula 1 of the present invention can be used as a form of a pharmaceutically acceptable salt, in which the salt is preferably an acid addition salt formed by pharmaceutically acceptable free acids. The acid addition salt herein can be obtained from inorganic acids, such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, and phosphorous acid; non-toxic organic acids, such as aliphatic mono/dicarboxylate, phenyl-substituted alkanoate, hydroxy alkanoate, alkandioate, aromatic acids, and aliphatic/aromatic sulfonic acids; or organic acids, such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, and fumaric acid. The pharmaceutically non-toxic salts are exemplified by sulfate, pyrosulfate, bisulfate, sulphite, bisulphite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutylate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, cabacate, fumarate, maliate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutylate, citrate, lactate, hydroxybutylate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate.
The acid addition salt in this invention can be prepared by conventional methods known to those in the art. For example, the compound represented by formula 1 is dissolved in an organic solvent, such as methanol, ethanol, acetone, methylenechloride, or acetonitrile, to which an organic acid or an inorganic acid is added to induce precipitation. Next, the precipitate is filtered and dried to give the salt. Alternatively, the solvent and the excessive acid are distillated under reduced pressure and dried to give the salt. As an additional alternative, the precipitate is crystallized in an organic solvent to give the same.
The present invention includes not only the compound represented by formula 1 but also a pharmaceutically acceptable salt thereof and a solvate, a hydrate, or an isomer possibly produced from the same.
The present invention also provides a method for preparing the compound represented by formula 1 comprising the following steps, as shown in reaction formula 1 below:
preparing the compound represented by formula 4 by reacting the compound represented by formula 2 with the compound represented by formula 3 (step 1);
preparing the compound represented by formula 5 by substituting methoxycarbonyl group of the compound represented by formula 4 prepared in step 1 with carboxy group (step 2);
preparing the compound represented by formula 7 by reacting the compound represented by formula 5 prepared in step 2 with the compound represented by formula 6 (step 3); and
substituting t-butoxy group of the compound represented by formula 7 prepared in step 3 with —OH group (step 4).
(In the reaction formula 1, R1-R6 and A are as defined in formula 1, and RA, RB, and RC are independently as defined in R3-R6).
The method for preparing the compound of the invention is described below in more detail step-by-step.
In the preparation method of the invention, step 1 is to prepare the compound represented by formula 4 by reacting the compound represented by formula 2 with the compound represented by formula 3.
Particularly, the compound represented by formula 2 was reacted with the compound represented by formula 3 via alkylation in an organic solvent in the presence of a base, and as a result, the compound represented by formula 4 was obtained. At this time, the reaction time was 1-30 hours, and the reaction temperature was −20-100° C.
The organic solvent used herein was selected from the group consisting of tetrahydrofuran; dioxan; ether solvents including ethyl ether and 1,2-dimethoxyethane, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane (DCM), dichloroethane, acetonitrile, toluene, chlorobenzene, and acetone.
The base used herein was selected from the group consisting of organic bases, such as pyridine, triethylamine, N,N-diisopropylethylamine (DIPEA), and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), and inorganic bases, such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydride, which can be used by equivalent or excessive amounts.
Upon completion of the reaction above, extraction was performed using an organic solvent, followed by drying, filtering, and distillation under reduced pressure. Column chromatography was additionally performed to give the compound represented by formula 4.
In the preparation method of the invention, step 2 is to substitute methoxycarbonyl group of the compound represented by formula 4 with carboxyl group.
Particularly, the compound represented by formula 4 was stirred in an organic solvent in the presence of a base. Upon completion of the reaction, the compound was acidified to give the compound represented by formula 5. At this time, the reaction time was 1-30 hours and the reaction temperature was −20-100° C.
The organic solvent used herein was selected from the group consisting of lower alcohols including ethanol, propanol, and butanol; tetrahydrofuran, and water.
The base used herein was selected from the group consisting of inorganic bases, such as sodium hydroxide and lithium hydroxide, which can be used by equivalent or excessive amounts.
Further, the acid used herein was HCl.
Upon completion of the reaction above, extraction was performed using an organic solvent, followed by drying, filtering, and distillation under reduced pressure. Column chromatography was additionally performed to give the compound represented by formula 5.
In the preparation method of the invention, step 3 is to prepare the compound represented by formula 7 by reacting the compound represented by formula 5 with the compound represented by formula 6.
Particularly, the compound represented by formula 5 was reacted with the compound represented by formula 6 via dehydrating condensation in an organic solvent to form a peptide bond, leading to the preparation of the compound represented by formula 7. At this time, the reaction time was 1-30 hours and the reaction temperature was −20-100° C.
The organic solvent used herein was selected from the group consisting of dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane (DCM), and dichloroethane.
The base used herein was selected from the group consisting of organic bases, such as DIPEA (N,N′-Diisopropylethylamine), pyridine, and triethylamine, which can be used by equivalent or excessive amounts.
The catalyst used herein was HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate).
Upon completion of the reaction above, extraction was performed using an organic solvent, followed by drying, filtering, and distillation under reduced pressure. Column chromatography was additionally performed to give the compound represented by formula 7.
In the preparation method of the invention, step 4 is to substitute t-butoxy group of the compound represented by formula 7 prepared in step 3 with —OH group.
Particularly, the compound represented by formula 7 was reacted in an organic solvent in the presence of an acid to prepare the compound represented by formula 1. At this time, the reaction time was 1-30 hours and the reaction temperature was −20-100° C.
The organic solvent used herein was selected from the group consisting of dichloromethane (DCM) and dichloroethane.
The acid used herein was selected from the group consisting of TFA (trifluoroacetic acid), HCl, and H2SO4.
Upon completion of the reaction above, extraction was performed using an organic solvent, followed by drying, filtering, and distillation under reduced pressure. Column chromatography was additionally performed to give the compound represented by formula 1.
The present invention also provides a method for preparing the compound represented by formula 1 comprising the following steps, as shown in reaction formula 2 below:
preparing the compound represented by formula 9 by reacting the compound represented by formula 8 with the compound represented by formula 6 (step 1);
preparing the compound represented by formula 7 by reacting the compound represented by formula 9 prepared in step 1 with the compound represented by formula 3 (step 2); and
substituting t-butoxy group of the compound represented by formula 7 prepared in step 2 with —OH group (step 3).
(In the reaction formula 2, R1-R6 and A are as defined in formula 1, and RA, RB, and RC are independently as defined in R3-R6).
The method for preparing the compound of the invention is described below in more detail step-by-step.
In the preparation method of the invention, step 1 is to prepare the compound represented by formula 9 by reacting the compound represented by formula 8 with the compound represented by formula 6.
Particularly, the compound represented by formula 8 was reacted with the compound represented by formula 6 via dehydrating condensation in an organic solvent to form a peptide bond, leading to the preparation of the compound represented by formula 9. At this time, the reaction time was 1-30 hours, and the reaction temperature was −20-100° C.
The organic solvent used herein was selected from the group consisting of dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane (DCM), and dichloroethane.
The base used herein was selected from the group consisting of organic bases, such as DIPEA (N,N′-Diisopropylethylamine), pyridine, and triethylamine, which can be used by equivalent or excessive amounts.
The catalyst used herein was HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate).
Upon completion of the reaction above, extraction was performed using an organic solvent, followed by drying, filtering, and distillation under reduced pressure. Column chromatography was additionally performed to give the compound represented by formula 9.
In the preparation method of the invention, step 2 is to prepare the compound represented by formula 7 by reacting the compound represented by formula 9 with the compound represented by formula 3.
Particularly, the compound represented by formula 9 was reacted with the compound represented by formula 3 via alkylation in an organic solvent in the presence of a base, and as a result, the compound represented by formula 7 was obtained. At this time, the reaction time was 1-30 hours and the reaction temperature was −20-100° C.
The organic solvent used herein was selected from the group consisting of tetrahydrofuran; dioxan; ether solvents including ethyl ether and 1,2-dimethoxyethane, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane (DCM), dichloroethane, acetonitrile, toluene, chlorobenzene, and acetone.
The base used herein was selected from the group consisting of organic bases such as pyridine, triethylamine, N,N-diisopropylethylamine (DIPEA), and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU); and inorganic bases, such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydride, which can be used by equivalent or excessive amounts.
Upon completion of the reaction above, extraction was performed using an organic solvent, followed by drying, filtering, and distillation under reduced pressure. Column chromatography was additionally performed to give the compound represented by formula 7.
In the preparation method of the invention, step 3 is to substitute t-butoxy group of the compound represented by formula 7 prepared in step 2 with —OH group.
Particularly, the compound represented by formula 7 was reacted in an organic solvent in the presence of an acid to prepare the compound represented by formula 1. At this time, the reaction time was 1-30 hours, and the reaction temperature was −20-100° C.
The organic solvent used herein was selected from the group consisting of dichloromethane (DCM) and dichloroethane.
The acid used herein was selected from the group consisting of TFA (trifluoroacetic acid), HCl, and H2SO4.
Upon completion of the reaction above, extraction was performed using an organic solvent, followed by drying, filtering, and distillation under reduced pressure. Column chromatography was additionally performed to give the compound represented by formula 1.
The present invention further provides a method for preparing the compound represented by formula 1, as shown in reaction formula 3A below, comprising the step of substituting carboxyl group of the compound represented by formula 1A with sodiumoxycarbonyl group (step 1).
(In the reaction formula 3A, R1-R6 and A are as defined in formula 1, and RA, RB, and RC are independently as defined in R3-R6).
Particularly, the compound represented by formula 1A was stirred in an organic solvent in the presence of a base to give the compound represented by formula 1. At this time, the reaction time was 1-30 hours, and the reaction temperature was −20-100° C.
The organic solvent used herein was selected from the group consisting of lower alcohols including methanol, ethanol, propanol, and butanol; dichloromethane (DCM), dichloroethane, and ethylether.
The base used herein was sodium hydroxide, which can be used by equivalent or excessive amounts.
Upon completion of the reaction above, extraction was performed using an organic solvent, followed by drying, filtering, and distillation under reduced pressure. Column chromatography was additionally performed to give the compound represented by formula 1.
The present invention further provides a method for preparing the compound represented by formula 1, as shown in reaction formula 3B below, comprising the step of substituting carboxyl group of the compound represented by formula 1A with amide group (step 1).
(In the reaction formula 3B, R1-R6 and A are as defined in formula 1, and RA, RB, and RC are independently as defined in R3-R6).
Particularly, the compound represented by formula 1A was stirred in an organic solvent in the presence of a catalyst and a base to give the compound represented by formula 1. At this time, the reaction time was 1-30 hours, and the reaction temperature was −20-100° C.
The organic solvent used herein was selected from the group consisting of ammonium hydroxide, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane (DCM), dichloroethane, and water.
The catalyst used herein was selected from the group consisting of EDCI (1-Ethyl-3-(3-dimethylaminopropyl)carbodi-imide), DMAP (4-Dimethylamino pyridine), and HOBt (Hydroxybenzotriazole).
Upon completion of the reaction above, extraction was performed using an organic solvent, followed by drying, filtering, and distillation under reduced pressure. Column chromatography was additionally performed to give the compound represented by formula 1.
The present invention also provides a pharmaceutical composition for treating PPARG-related disease which comprises the compound represented by formula 1, the optical isomer thereof, or the pharmaceutically acceptable salt of the same as an active ingredient. Particularly, the PPARG-related disease herein includes diabetes, insulin resistance, impaired glucose tolerance, pre-diabetes, hyperglycemia, hyperinsulinemia, obesity, and inflammation, but not always limited thereto.
The compound represented by formula 1 or the optical isomer thereof binds to PPARG with a high affinity but does not act as an agonist and thereby does not induce gene transcription thereof, so that it can block CDK5, which is a cause of PPARG phosphorylation, to suppress the side effects of the conventional anti-diabetic agents. Particularly, the said side effects are exemplified by weight gain, edema, impairment of bone growth or formation, and cardiac hypertrophy, but not always limited thereto.
The cause of the said side effects is phosphorylation of the 273rd amino acid serine of PPARG of CDK5 kinase induced by various gene mutations. Therefore, it will be an important step for the development of an anti-diabetic agents to suppress PPARG gene transcription or to block CDK5 mediated phosphorylation. In particular, when CDK5 binds to S273 among the sites that are available for the conjugation specifically with PPARG structure (helix, H11, H12, and S273), it induces phosphorylation there, which causes side effects.
The present inventors performed an experiment to investigate whether or not the compounds prepared in the example of the invention could inhibit the phosphorylation of serine, the 273rd amino acid of PPARG. As a result, it was confirmed that the compounds of the examples of the invention bound to PPARG (peroxisome proliferator activated receptor-gamma) but did not act as a CDK5 (cyclin-dependant kinase 5) promoter and thereby exhibited excellent inhibitory effects on the phosphorylation of serine, the 273rd amino acid of PPARG (see Experimental Example 1).
The present inventors also investigated the PPARG (peroxisome proliferator activated receptor-gamma) transcriptional activity of the compounds prepared in the example of the invention. As a result, it was confirmed that the compounds prepared in the example of the invention had excellent activity of binding to PPARG (peroxisome proliferator activated receptor-gamma) but did not induce the transcription or activation of PPARG (peroxisome proliferator activated receptor-gamma) (see Experimental Example 2).
The present inventors also investigated the inhibitory effect of the compounds prepared in the examples of the invention on CYP (cytochrome P450) activity. As a result, it was confirmed that the compounds of examples 14, 36, 44, 56, 57, 58, 60, 74, 96, 110, 113, 115, 118, 123, 131, and 139 inhibited CYP isozymes 1A2, 2C9, 2C19, and 2D6 activity less strongly than the compounds of the Comparative Examples (SR1664 and SR1824).
Particularly, SR1664 inhibited the activity of CYP isozyme 2C9 so that 96% of the substance was not decomposed and instead remained, suggesting that, when SR1664 is administered as a drug, the amount of the drug that reaches a target is much greater than a proper dose, which might induce toxicity.
However, the compounds of the present invention inhibited CYP activity properly, better than SR1664, so the drug was decomposed at least 10 times more than SR1664, suggesting that only the proper amount of the drug reaches the target (see Experimental Example 3).
Further, the present inventors performed another experiment to evaluate the cardiotoxicity of the compounds prepared in the examples of the invention.
As a result, the compounds of the invention displayed a significantly low IC50 (2.7 μM), which was significantly lower than the IC50 that induces cardiotoxicity (less than 10 μM) of the compound of the Comparative Example (SR-1664). The above result indicates that the compound of the Comparative Example has a high chance of causing cardiotoxicity as a drug.
However, the compounds prepared in the examples of the invention displayed very high IC50, which was much higher than IC50 that could cause cardiotoxicity (less than 10 μM), indicating that the compounds had a significantly low chance of causing cardiotoxicity (see Experimental Example 4).
The present inventors also investigated the blood sugar-lowering effect and the weight-reducing effect of the compounds prepared in the examples of the invention. As a result, the compounds of examples 56, 155, 156, and 157 (10 mpk, each) reduced body weight at least 5% even at a comparatively low dose, while the compound of the Comparative Example (SR-1664, 20 mpk) reduced body weight by 1.6%.
The compounds of the examples 56, 156, and 157 (10 mpk respectively) reduced blood sugar at least 24% even at a comparatively low dose, while the compound of the Comparative Example (SR-1664, 20 mpk) reduced blood sugar by 14% (see Experimental Example 5).
The compound represented by formula 1, the optical isomer thereof, or the pharmaceutically acceptable salt thereof of the present invention can be prepared for oral or parenteral administration.
The formulations for oral administration are exemplified by tablets, pills, hard/soft capsules, solutions, suspensions, emulsions, syrups, granules, elixirs, and troches. These formulations can include diluents (for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and/or glycine) and lubricants (for example, silica, talc, stearate and its magnesium or calcium salt, and/or polyethylene glycol) in addition to the active ingredient. Tablets can include binding agents, such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrolidone, and if necessary disintegrating agents, such as starch, agarose, alginic acid or its sodium salt or azeotropic mixtures and/or absorbents; coloring agents, flavours, and sweeteners can be additionally included.
The pharmaceutical composition comprising the compound represented by formula 1 as an active ingredient can be administered by parenterally, and the parenteral administration includes subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.
To prepare the composition as a formulation for parenteral administration, the compound represented by formula 1, the optical isomer thereof, or the pharmaceutically acceptable salt thereof is mixed with a stabilizer or a buffering agent in water to produce a solution or suspension, which is then formulated as ampoules or vials. The composition herein can be sterilized and additionally contains preservatives, stabilizers, wettable powders or emulsifiers, salts and/or buffers for the regulation of osmotic pressure, and other therapeutically useful materials, and the composition can be formulated by the conventional mixing, granulating or coating method.
The effective dosage of the pharmaceutical composition comprising the compound represented by formula 1 as an active ingredient of the present invention can be determined according to age, weight, gender, administration method, health condition, and severity of disease. The dosage is preferably 0.01-1000 mg/kg/day, which can be administered several times a day or preferably 1-3 times a day.
The preparation method of the compound represented by formula 1 of the present invention is described in more detail in preparative examples or examples. The following preparative examples or examples are only examples to describe the method for preparing the compound represented by formula 1 and the present invention is not limited thereto. The preparation methods described in the following preparative examples or examples are performed under the conditions with proper reagents well-known in the field of organic synthesis.
1,2,3,4-tetrahydroquinoline-6-carboxylic acid (50 g, 282 mmol) was dissolved in MeOH (500 mL) in a 2 L flask, to which AcCl (100 mL) was added at 0° C., followed by stirring at room temperature for 12 hours. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to give methyl 1,2,3,4-tetrahydroquinoline-6-carboxylate (45 g).
Methyl 1,2,3,4-tetrahydroquinoline-6-carboxylate (2 g, 10.46 mmol) was dissolved in DMF (20 ml) in a 1 L flask, to which NaH (628 mg, 15.69 mmol) and tert-butyl 4′-(bromomethyl)-[1,1′-biphenyl]-2-carboxylate (4.36 g, 12.55 mmol) were added, followed by stirring at room temperature for 12 hours. The organic layer was separated by using ethyl acetate and brine. The organic layer was dried over MgSO4 and filtered. The solvent was eliminated from the mixture via vacuum distillation, followed by column chromatography to give methyl 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (4 g, 8.55 mmol, 85%).
Methyl 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (4 g, 8.55 mmol) was mixed with NaOH (1.48 g, 37 mmol) dissolved in EtOH (50 mL)/H2O (50 mL) in a 250 mL flask, followed by stirring at room temperature for 12 hours. Upon completion of the reaction, the solvent was concentrated, and the pH was adjusted to 5 with 2N HCl. Extraction was performed with EA, and the organic layer was dried over MgSO4 and filtered. As a result, 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid was obtained (3.55 g, 8.0 mmol, 90%).
4-amino-3-hydroxybenzoic acid (50 g, 326 mmol) was dissolved in MeOH (500 mL) in a 2 L flask, to which AcCL (100 mL) was added at 0° C., followed by stirring at room temperature for 12 hours. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to give 4-amino-3-hydroxybenzoate (50 g).
Methyl 4-amino-3-hydroxybenzoate (55 g, 329 mmol) prepared in step 1 and 1,2-dibromoethane (185 g, 986 mmol) were dissolved in DMF (1 L) in a 2 L flask, to which K2CO3 (227 g, 1645 mmol) was added, followed by stirring at room temperature for 36 hours. The organic layer was separated by using ethyl acetate and brine. The separated organic layer was dried over MgSO4 and filtered. The solvent was eliminated from the mixture via vacuum distillation, followed by column chromatography to give methyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (41.3 g, 213 mmol, 65%).
Methyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (8.08 g, 41.8 mmol) obtained in step 2 was dissolved in DMF (50 ml) in a 500 mL flask, to which NaH (2 g, 50.2 mmol) and tert-butyl 4′-(bromomethyl)-[1,1′-biphenyl]-2-carboxylate (17.4 g, 50.2 mmol) were added, followed by stirring at room temperature for 12 hours. The organic layer was separated by using ethyl acetate and brine. The separated organic layer was dried over MgSO4 and filtered. The solvent was eliminated from the mixture via vacuum distillation, followed by column chromatography to give methyl 4-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (28.4 g, 68.03 mmol, 68%).
Methyl 4-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (11.8 g, 28.43 mmol) obtained in step 3 was mixed with NaOH (5.68 g, 142 mmol) dissolved in EtOH (50 ml) and H2O (50 ml) in a 250 mL flask, followed by stirring at room temperature for 12 hours. Upon completion of the reaction, the solvent was concentrated. PH of the reaction mixture was adjusted to 5 by using 2N-HCl.
The mixture was extracted with EA. The organic layer was dried over MgSO4 and filtered. As a result, 4-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid was obtained (10.3 g, 25.53 mmol, 90%).
2-bromobenzoic acid (25 g, 124 mmol), DMAP (1.52 g, 12.4 mmol), and t-butanol (9.2 g, 124 mmol) were dissolved in dichloromethane (500 ml) in a 1 L flask, to which DCC (25.7 g, 124 mmol) was added, followed by stirring at room temperature for 12 hours. The organic layer was separated by using ethyl acetate and brine. The separated organic layer was dried over MgSO4 and filtered. The solvent was eliminated from the mixture via vacuum distillation, followed by column chromatography to give tert-butyl 2-bromobenzoate (30 g).
Tert-butyl 2-bromobenzoate (10 g, 64.8 mmol), (3-fluoro-4-methylphenyl)boronic acid (14 g, 54 mmol), Pd(PPh3)4(624 mg, 0.54 mmol), and Na2CO3 (11.4 g, 108 mmol) were dissolved in IPA (60 ml) and H2O (60 ml) in a 1 L flask, followed by reflux-stirring for 12 hours. The reaction mixture was concentrated under reduced pressure. The organic layer was separated by using ethyl acetate and brine. The separated organic layer was dried over MgSO4 and filtered. The mixture was separated by column chromatography to give tert-butyl 3′-fluoro-4′-methyl-[1,1′-biphenyl]-2-carboxylate (14 g).
Tert-butyl 3′-fluoro-4′-methyl-[1,1′-biphenyl]-2-carboxylate (14 g, 48.9 mmol), NBS (9.57 g, 53.79 mmol), and AIBN (2.4 g, 14.67 mmol) were dissolved in CCl4(50 ml) in a 1 L flask, followed by reflux-stirring for 12 hours. The reaction mixture was concentrated under reduced pressure. The organic layer was separated by using dichloromethane and brine. The separated organic layer was dried over MgSO4 and filtered. The mixture was separated by column chromatography to give tert-butyl 4′-(bromomethyl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylate (7.4 g).
Methyl 1,2,3,4-tetrahydroquinoline-6-carboxylate (3 g, 15.69 mmol) was dissolved in DMF (20 ml) in a 250 mL flask, to which NaH (753 mg, 18.83 mmol) and tert-butyl 4′-(bromomethyl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylate (5.7 g, 15.69 mmol) were added, followed by stirring at room temperature for 12 hours. The organic layer was separated by using ethyl acetate and brine. The separated organic layer was dried over MgSO4 and filtered. The solvent was eliminated from the mixture via vacuum distillation, followed by column chromatography to give methyl 1-((2′-(tert-butoxycarbonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)methyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (4 g).
Methyl 1-((2′-(tert-butoxycarbonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)methyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (4 g, 8.4 mmol) was mixed with NaOH (1.48 g, 37 mmol) dissolved in EtOH (50 ml) and H2O (50 ml) in a 250 mL flask, followed by stirring at room temperature for 12 hours. Upon completion of the reaction, the solvent was concentrated. PH of the reaction mixture was adjusted to 5 by using 2N-HCl. The mixture was extracted with EA. The organic layer was dried over MgSO4 and filtered. As a result, 1-((2′-(tert-butoxycarbonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)methyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid was obtained (3 g).
2-bromobenzoic acid (25 g, 124 mmol), DMAP (1.52 g, 12.4 mmol), and t-butanol (9.2 g, 124 mmol) were dissolved in dichloromethane (500 ml) in a 1 L flask, to which DCC (25.7 g, 124 mmol) was added, followed by stirring at room temperature for 12 hours. The organic layer was separated by using ethyl acetate and brine. The separated organic layer was dried over MgSO4 and filtered. The solvent was eliminated from the mixture via vacuum distillation, followed by column chromatography to give tert-butyl 2-bromobenzoate (30 g).
Tert-butyl 2-bromobenzoate (22.7 g, 88.26 mmol), meta-toluoylboronic acid (8 g, 58.84 mmol), Pd(PPh3)4 (680 mg, 0.58 mmol), and Na2CO3 (12.47 g, 117 mmol) were dissolved in IPA (50 ml) and H2O (50 ml) in a 1 L flask, followed by reflux-stirring for 12 hours. The reaction mixture was concentrated under reduced pressure. The organic layer was separated by using ethyl acetate and brine. The separated organic layer was dried over MgSO4 and filtered. The mixture was separated by column chromatography to give tert-butyl 3′-methyl-[1,1′-biphenyl]-2-carboxylate (7.2 g).
Tert-butyl 3′-methyl-[1,1′-biphenyl]-2-carboxylate (7.2 g, 26.83 mmol), NBS (5.73 g, 32.2 mmol), and AIBN (1.32 g, 8.05 mmol) were dissolved in CCl4 (100 ml) in a 500 mL flask, followed by reflux-stirring for 12 hours. The reaction mixture was concentrated under reduced pressure. The organic layer was separated by using dichloromethane and brine. The separated organic layer was dried over MgSO4 and filtered. The mixture was separated by column chromatography to give tert-butyl 3′-(bromomethyl)-[1,1′-biphenyl]-2-carboxylate (5.2 g).
Methyl 1,2,3,4-tetrahydroquinoline-6-carboxylate (3 g, 15.69 mmol) was dissolved in DMF (20 ml) in a 100 mL flask, to which NaH (753 mg, 18.83 mmol) and tert-butyl 3′-(bromomethyl)-[1,1′-biphenyl]-2-carboxylate (5.45 g, 15.69 mmol) were added, followed by stirring at room temperature for 12 hours. The organic layer was separated by using ethyl acetate and brine. The separated organic layer was dried over MgSO4 and filtered. The solvent was eliminated from the mixture via vacuum distillation, followed by column chromatography to give methyl 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-3-yl)methyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (4.76 g).
Methyl 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-3-yl)methyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (4.76 g, 10.4 mmol) was mixed with NaOH (2.08 g, 52 mmol) dissolved in EtOH (50 ml) and H2O (50 ml) in a 250 mL flask, followed by stirring at room temperature for 12 hours. Upon completion of the reaction, the solvent was concentrated. The pH of the reaction mixture was adjusted to 5 by using 2N HCl. The mixture was extracted with EA. The organic layer was dried over MgSO4 and filtered. As a result, 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-3-yl)methyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid was obtained (2.7 g).
2-bromobenzoic acid (25 g, 124 mmol), DMAP (1.52 g, 12.4 mmol), and t-butanol (9.2 g, 124 mmol) were dissolved in dichloromethane (500 ml) in a 1 L flask, to which DCC (25.7 g, 124 mmol) was added, followed by stirring at room temperature for 12 hours. The organic layer was separated by using ethyl acetate and brine. The separated organic layer was dried over MgSO4 and filtered. The solvent was eliminated from the mixture via vacuum distillation, followed by column chromatography to give tert-butyl 2-bromobenzoate (30 g).
Tert-butyl 2-bromobenzoate (33.38 g, 129.8 mmol), (2-fluoro-3-methylphenyl)boronic acid (10 g, 64.9 mmol), Pd(PPh3)4(749 mg, 0.65 mmol), and Na2CO3 (13.75 g, 129.8 mmol) were dissolved in IPA (60 ml) and H2O (60 ml) in a 1 L flask, followed by reflux-stirring for 12 hours. The reaction mixture was concentrated under reduced pressure. The organic layer was separated by using ethyl acetate and brine. The separated organic layer was dried over MgSO4 and filtered. The mixture was separated by column chromatography to give tert-butyl 2′-fluoro-3′-methyl-[1,1′-biphenyl]-2-carboxylate (15 g).
Tert-butyl 2′-fluoro-3′-methyl-[1,1′-biphenyl]-2-carboxylate (18.58 g, 64.89 mmol), NBS (17.3 g, 97.33 mmol), and AIBN (3.2 g, 19.46 mmol) were dissolved in CCl4 (100 ml) in a 500 mL flask, followed by reflux-stirring for 12 hours. The reaction mixture was concentrated under reduced pressure. The organic layer was separated by using dichloromethane and brine. The separated organic layer was dried over MgSO4 and filtered. The mixture was separated by column chromatography to give tert-butyl 3′-(bromomethyl)-2′-fluoro-[1,1′-biphenyl]-2-carboxylate (12.5 g).
Methyl 1,2,3,4-tetrahydroquinoline-6-carboxylate (4 g, 20.9 mmol) was dissolved in DMF (20 ml) in a 250 mL flask, to which NaH (1 g, 25.08 mmol) and tert-butyl 3′-(bromomethyl)-2′-fluoro-[1,1′-biphenyl]-2-carboxylate (12.5 g, 34.22 mmol) were added, followed by stirring at room temperature for 12 hours. The organic layer was separated by using ethyl acetate and brine. The separated organic layer was dried over MgSO4 and filtered. The solvent was eliminated from the mixture via vacuum distillation, followed by column chromatography to give methyl 1-((2′-(tert-butoxycarbonyl)-2-fluoro-[1,1′-biphenyl]-3-yl)methyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (6.2 g).
Methyl 1-((2′-(tert-butoxycarbonyl)-2-fluoro-[1,1′-biphenyl]-3-yl)methyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (6.2 g, 13.04 mmol) was mixed with NaOH (2.6 g, 65.2 mmol) dissolved in EtOH (50 ml) and H2O (50 ml) in a 250 mL flask, followed by stirring at room temperature for 12 hours. Upon completion of the reaction, the solvent was concentrated. The pH of the reaction mixture was adjusted to 5 by using 2N HCl. The mixture was extracted with EA. The organic layer was dried over MgSO4 and filtered. As a result, 1-((2′-(tert-butoxycarbonyl)-2-fluoro-[1,1′-biphenyl]-3-yl)methyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid was obtained (4 g).
2-bromobenzoic acid (25 g, 124 mmol), DMAP (1.52 g, 12.4 mmol), and t-butanol (9.2 g, 124 mmol) were dissolved in dichloromethane (500 ml) in a 1 L flask, to which DCC (25.7 g, 124 mmol) was added, followed by stirring at room temperature for 12 hours. The organic layer was separated by using ethyl acetate and brine. The separated organic layer was dried over MgSO4 and filtered. The solvent was eliminated from the mixture via vacuum distillation, followed by column chromatography to give tert-butyl 2-bromobenzoate (30 g).
Tert-butyl 2-bromobenzoate (33.38 g, 129.8 mmol), (4-fluoro-3-methylphenyl)boronic acid (10 g, 64.9 mmol), Pd(PPh3)4(749 mg, 0.64 mmol), and Na2CO3 (13.7 g, 129.8 mmol) were dissolved in IPA (50 ml) and H2O (50 ml) in a 1 L flask, followed by reflux-stirring for 12 hours. The reaction mixture was concentrated under reduced pressure. The organic layer was separated by using ethyl acetate and brine. The separated organic layer was dried over MgSO4 and filtered. The mixture was separated by column chromatography to give tert-butyl 4′-fluoro-3′-methyl-[1,1′-biphenyl]-2-carboxylate (13 g).
Tert-butyl 4′-fluoro-3′-methyl-[1,1′-biphenyl]-2-carboxylate (13 g, 45.4 mmol), NBS (12.12 g, 68.1 mmol), and AIBN (2.24 g, 13.62 mmol) were dissolved in CCl4 (100 ml) in a 500 mL flask, followed by reflux-stirring for 12 hours. The reaction mixture was concentrated under reduced pressure. The organic layer was separated by using ethyl acetate and brine. The separated organic layer was dried over MgSO4 and filtered. The mixture was separated by column chromatography to give tert-butyl 3′-(bromomethyl)-4′-fluoro-[1,1′-biphenyl]-2-carboxylate (11.25 g).
Methyl 1,2,3,4-tetrahydroquinoline-6-carboxylate (4 g, 20.9 mmol) was dissolved in DMF (20 ml) in a 250 mL flask, to which NaH (1 g, 25.08 mmol) and tert-butyl 3′-(bromomethyl)-4′-fluoro-[1,1′-biphenyl]-2-carboxylate (11.25 g, 30.8 mmol) were added, followed by stirring at room temperature for 12 hours. The organic layer was separated by using ethyl acetate and brine. The separated organic layer was dried over MgSO4 and filtered. The solvent was eliminated from the mixture via vacuum distillation, followed by column chromatography to give methyl 1-((2′-(tert-butoxycarbonyl)-4-fluoro-[1,1′-biphenyl]-3-yl)methyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (6.45 g).
Methyl 1-((2′-(tert-butoxycarbonyl)-4-fluoro-[1,1′-biphenyl]-3-yl)methyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (6.45 g, 13.56 mmol) was mixed with NaOH (2.71 g, 67.8 mmol) dissolved in EtOH (50 ml) and H2O (50 ml) in a 250 mL flask, followed by stirring at room temperature for 12 hours. Upon completion of the reaction, the solvent was concentrated. The pH of the reaction mixture was adjusted to 5 by using 2N HCl. The mixture was extracted with EA. The organic layer was dried over MgSO4 and filtered. As a result, 1-((2′-(tert-butoxycarbonyl)-4-fluoro-[1,1′-biphenyl]-3-yl)methyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid was obtained (5.2 g).
Methyl 4-iodobenzoate (5 g, 19 mmol), ortho-toluylboronic acid (3.1 g, 22.9 mmol), Pd(PPh3)4 (1.1 g, 0.95 mmol), and Na2CO3 (8.5 g, 38 mmol) were dissolved in IPA (50 ml) and H2O (50 ml) in a 100 mL flask, followed by reflux-stirring for 12 hours. The reaction mixture was concentrated under reduced pressure. The organic layer was separated by using ethyl acetate and brine. The separated organic layer was dried over MgSO4 and filtered. The mixture was separated by column chromatography to give methyl 2′-methyl-[1,1′-biphenyl]-4-carboxylate (4.3 g).
Methyl 2′-methyl-[1,1′-biphenyl]-4-carboxylate (1.1 g, 4.86 mmol), NBS (951 mg, 5.34 mmol), and AIBN (239 mg, 1.45 mmol) were dissolved in CCl4 (10 ml) in a 50 mL flask, followed by reflux-stirring for 12 hours. The reaction mixture was concentrated under reduced pressure. The organic layer was separated by using dichloromethane and brine. The separated organic layer was dried over MgSO4 and filtered. The mixture was separated by column chromatography to give methyl 2′-(bromomethyl)-[1,1′-biphenyl]-4-carboxylate (1 g).
Methyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (1 g, 5.2 mmol) was dissolved in MeOH (5 ml) and THF (10 ml) in a 25 mL flask, to which LiOH (2 g) dissolved in H2O (5 ml) was added, followed by stirring at room temperature for 12 hours. Upon completion of the reaction, the solvent was concentrated. The pH of the reaction mixture was adjusted to 5 by using 2N HCl. The mixture was extracted with EA. The organic layer was dried over MgSO4 and filtered. As a result, 3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid was obtained (1.2 g).
Methyl 4-iodobenzoate (5 g, 19 mmol), ortho-toluylboronic acid (3.1 g, 22.9 mmol), Pd(PPh3)4 (1.1 g, 0.95 mmol), and Na2CO3 (8.5 g, 38 mmol) were dissolved in IPA (50 ml) and H2O (50 ml) in a 100 mL flask, followed by reflux-stirring for 12 hours. The reaction mixture was concentrated under reduced pressure. The organic layer was separated by using ethyl acetate and brine. The separated organic layer was dried over MgSO4 and filtered. The mixture was separated by column chromatography to give methyl 2′-methyl-[1,1′-biphenyl]-4-carboxylate (4.3 g).
Methyl 2′-methyl-[1,1′-biphenyl]-4-carboxylate (1.1 g, 4.86 mmol), NBS (951 mg, 5.34 mmol), and AIBN (239 mg, 1.45 mmol) were dissolved in CCl4 (10 ml) in a 50 mL flask, followed by reflux-stirring for 12 hours. The reaction mixture was concentrated under reduced pressure. The organic layer was separated by using dichloromethane and brine. The separated organic layer was dried over MgSO4 and filtered. The mixture was separated by column chromatography to give methyl 2′-(bromomethyl)-[1,1′-biphenyl]-4-carboxylate (1 g).
2-bromobenzoic acid (25 g, 124 mmol), DMAP (1.52 g, 12.4 mmol), and t-butanol (9.2 g, 124 mmol) were dissolved in dichloromethane (500 ml) in a 1 L flask, to which DCC (25.7 g, 124 mmol) was added, followed by stirring at room temperature for 12 hours. The organic layer was separated by using ethyl acetate and brine. The separated organic layer was dried over MgSO4 and filtered. The solvent was eliminated from the mixture via vacuum distillation, followed by column chromatography to give tert-butyl 2-bromobenzoate (30 g).
Tert-butyl 2-bromobenzoate (7 g, 27 mmol), (2-fluoro-4-methylphenyl)boronic acid (5 g, 32.5 mmol), Pd(PPh3)4(312 mg, 0.27 mmol), and Na2CO3 (5.7 g, 54 mmol) were dissolved in IPA (30 ml) and H2O (30 ml) in a 1 L flask, followed by reflux-stirring for 12 hours. The reaction mixture was concentrated under reduced pressure. The organic layer was separated by using ethyl acetate and brine. The separated organic layer was dried over MgSO4 and filtered. The mixture was separated by column chromatography to give tert-butyl 2′-fluoro-4′-methyl-[1,1′-biphenyl]-2-carboxylate (5.2 g).
Tert-butyl 2′-fluoro-4′-methyl-[1,1′-biphenyl]-2-carboxylate (3 g, 10.5 mmol), NBS (1.9 g, 10.5 mmol), and AIBN (43 mg, 0.025 mmol) were dissolved in CCl4 (10 ml) in a 1 L flask, followed by reflux-stirring for 12 hours. The reaction mixture was concentrated under reduced pressure. The organic layer was separated by using ethyl acetate and brine. The separated organic layer was dried over MgSO4 and filtered. The mixture was separated by column chromatography to give tert-butyl 4′-(bromomethyl)-2′-fluoro-[1,1′-biphenyl]-2-carboxylate (2.75 g).
Methyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (10 g, 51.7 mmol) was dissolved in DMF (50 ml) in a 250 mL flask, to which NaH (6.2 g, 155.3 mmol) and tert-butyl 4′-(bromomethyl)-2′-fluoro-[1,1′-biphenyl]-2-carboxylate (2.5 g, 67.3 mmol) were added, followed by stirring at room temperature for 12 hours. The organic layer was separated by using ethyl acetate and brine. The separated organic layer was dried over MgSO4 and filtered. The solvent was eliminated from the mixture via vacuum distillation, followed by column chromatography to give methyl 4-((2′-(tert-butoxycarbonyl)-2-fluoro-[1,1′-biphenyl]-4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (15.4 g).
Methyl 4-((2′-(tert-butoxycarbonyl)-2-fluoro-[1,1′-biphenyl]-4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (15 g) was mixed with NaOH (1.48 g, 37 mmol) dissolved in EtOH (50 ml) and H2O (50 ml) in a 250 mL flask, followed by stirring at room temperature for 12 hours. Upon completion of the reaction, the solvent was concentrated. The pH of the reaction mixture was adjusted to 5 by using 2N-HCl. The mixture was extracted with EA. The organic layer was dried over MgSO4 and filtered. As a result, 4-((2′-(tert-butoxycarbonyl)-2-fluoro-[1,1′-biphenyl]-4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid was obtained (13 g).
1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (300 mg, 0.67 mmol) obtained in Preparative Example 1 was dissolved in CH2Cl2 (10 ml) in a 100 mL flask, to which HATU (280 mg, 0.74 mmol) and DIPEA (350 ul, 2.01 mmol) were added, followed by stirring at room temperature for 12 hours. Upon completion of the reaction, the organic layer was separated by using CH2Cl2 and H2O. The separated organic layer was dried over MgSO4 and filtered. The mixture was separated by column chromatography (EA/n-Hex=1:1) to give (S)-tert-butyl 4′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylate (311 mg, 0.56 mmol, 85%).
1H NMR (400 MHz, CDCl3) δ 7.79 (dd, J=1.2, 8.0 Hz, 1H), 7.52-7.23 (m, 14H), 6.51 (d, J=8.8 Hz, 1H), 6.14 (d, J=8.0 Hz, 1H), 5.34 (m, 1H), 4.60 (s, 2H), 3.48 (t, J=5.6 Hz, 2H), 2.86 (t, J=6.0 Hz, 2H), 2.05 (m, 2H), 1.59 (d, J=6.8 Hz, 3H), 1.26 (s, 9H).
(S)-tert-butyl 4′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylate (311 mg, 0.57 mmol) obtained in step 1 was dissolved in CH2Cl2 (20 ml) in a 50 mL flask, to which 30% TFA (9 ml) was added, followed by stirring at room temperature for 5 hours. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure. The mixture was separated by column chromatography (EA) to give (S)-4′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid (176 mg, 0.53 mmol, 63%).
1H NMR (400 MHz, DMSO-d6) δ 12.73 (br, OH, 1H), 8.32 (d, J=8.0 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.60-7.48 (m, 3H), 7.43 (t, J=7.6 Hz, 1H), 7.40-7.25 (m, 9H), 7.19 (t, J=7.2 Hz, 1H), 6.52 (d, J=8.4 Hz, 1H), 5.12 (m, 1H), 4.69 (s, 2H), 3.49 (t, J=4.0 Hz, 2H), 2.81 (t, J=4.0 Hz, 2H), 1.95 (m, 2H), 1.42 (d, J=7.2 Hz, 3H).
(S)-4′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid (50 mg, 0.1 mmol) obtained in Example 1 was dissolved in CH2Cl2 (2 ml) in a 25 mL flask, to which EDCI (38 mg, 0.2 mmol) and HOBt (38 mg, 0.3 mmol) were added, followed by stirring. Ammonium hydroxide solution (2 ml) was added thereto, followed by stirring at room temperature for 5 hours. Upon completion of the reaction, the organic layer was separated by using CH2Cl2 and H2O. The separated organic layer was dried over MgSO4 and filtered. The mixture was separated by column chromatography (MeOH/n-Hex/CH2Cl2=0.5:0.5:9) to give (S)-1-((2′-carbamoyl-[1,1′-biphenyl]-4-yl)methyl)-N-(1-phenylethyl)-1,2,3,4-tetrahydroquinoline-6-carboxamide (21 mg, 0.04 mmol, 43%).
1H NMR (400 MHz, DMSO-d6) δ 8.31-8.29 (m, 1H), 7.66 (m, 1H), 7.52-7.18 (m, 16H), 6.53-6.50 (m, 1H), 5.14-5.10 (m, 1H), 4.61 (s, 2H), 3.48-3.45 (m, 2H), 2.81-2.78 (m, 2H), 1.99-1.95 (m, 2H), 1.44-1.42 (m, 3H).
The target compound was obtained by the same manner as described in Example 1 except that (S)-1-(4-nitrophenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.76 (br, OH, 1H), 8.49 (d, J=7.6 Hz, 1H), 8.19 (d, J=8.8 Hz, 2H), 7.71 (m, 1H), 7.62 (d, J=8.8 Hz, 2H), 7.57-7.25 (m, 9H), 6.52 (d, J=8.0 Hz, 1H), 5.19 (m, 1H), 4.64 (s, 2H), 3.49 (t, J=4.0 Hz, 2H), 2.71 (t, J=4.0 Hz, 2H), 1.95 (m, 2H), 1.47 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 1 except that (S)-1-(4-fluoro-2-methylphenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.73 (br, OH, 1H), 8.22 (d, J=8.0 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.60-7.25 (m, 12H), 6.52 (d, J=8.4 Hz, 1H), 5.12 (m, 1H), 4.69 (s, 2H), 3.49 (t, J=4.0 Hz, 2H), 2.81 (t, J=4.0 Hz, 2H), 2.28 (s, 3H), 1.95 (m, 2H), 1.42 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 1 except that (S)-1-(3-fluoro-4-methylphenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.63 (br, OH, 1H), 8.29 (d, J=8.0 Hz, 1H), 7.70 (dd, J=1.2, 7.6 Hz, 1H), 7.57-7.48 (m, 3H), 7.43 (td, J=1.2, 7.6 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.30 (m, 3H), 7.19 (t, J=7.2 Hz, 1H), 7.11-7.05 (m, 2H), 6.53 (d, J=8.4 Hz, 1H), 5.09 (m, 1H), 4.62 (s, 2H), 3.47 (t, J=5.2 Hz, 2H), 2.80 (t, J=6.0 Hz, 2H), 2.18 (s, 3H), 1.95 (m, 2H), 1.41 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 1 except that (S)-1-(4-fluorophenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.63 (br, OH, 1H), 8.34 (d, J=8.0 Hz, 1H), 7.71 (dd, J=1.2, 7.6 Hz, 1H), 7.57-7.35 (m, 7H), 7.30 (m, 4H), 7.13 (m, 2H), 6.52 (d, J=8.8 Hz, 1H), 5.12 (m, 1H), 4.62 (s, 2H), 3.47 (t, J=5.2 Hz, 2H), 2.80 (t, J=6.0 Hz, 2H), 1.95 (m, 2H), 1.41 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 1 except that (S)-1-(4-bromophenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.71 (br, OH, 1H), 8.34 (d, J=8.0 Hz, 1H), 7.71 (m, 1H), 7.57-7.35 (m, 7H), 7.30 (m, 6H), 6.52 (d, J=8.8 Hz, 1H), 5.12 (m, 1H), 4.62 (s, 2H), 3.47 (t, J=5.2 Hz, 2H), 2.80 (t, J=6.0 Hz, 2H), 1.95 (m, 2H), 1.41 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 1 except that (4-nitrophenyl)methaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.63 (br, OH, 1H), 8.75 (t, J=6.0 Hz, 1H), 8.19 (d, J=7.6 Hz, 2H), 7.70 (dd, J=1.2, 8.0 Hz, 1H), 7.57-7.50 (m, 5H), 7.44 (td, J=1.2, 7.6 Hz, 1H), 7.37 (d, J=7.6 Hz, 1H), 7.30 (m, 4H), 6.54 (d, J=7.2 Hz, 1H), 4.63 (s, 2H), 4.54 (d, J=6.0 Hz, 2H), 3.48 (t, J=5.6 Hz, 2H), 2.80 (t, J=6.0 Hz, 2H), 1.98 (m, 2H).
The target compound was obtained by the same manner as described in Example 1 except that (S)-1-(3-chlorophenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.73 (br, OH, 1H), 8.36 (d, J=7.6 Hz, 1H), 7.70 (d, J=6.8 Hz, 1H), 7.60-7.22 (m, 13H), 6.53 (d, J=7.2 Hz, 1H), 5.11 (m, 1H), 4.62 (s, 2H), 3.47 (t, J=5.2 Hz, 2H), 2.80 (t, J=5.6 Hz, 2H), 1.95 (m, 2H), 1.43 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 1 except that (S)-1-(naphthalene-1-yl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.73 (br, OH, 1H), 8.46 (d, J=7.6 Hz, 1H), 8.19 (d, J=7.6 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.70 (d, J=6.8 Hz, 1H), 7.60-7.35 (m, 10H), 7.28 (m, 4H), 6.52 (d, J=8.8 Hz, 1H), 5.93 (m, 1H), 4.61 (s, 2H), 3.46 (t, J=5.2 Hz, 2H), 2.78 (t, J=5.6 Hz, 2H), 1.95 (m, 2H), 1.57 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 1 except that (S)-1-(4-(trifluoromethoxy)phenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.73 (br, OH, 1H), 8.37 (d, J=7.6 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.60-7.40 (m, 7H), 7.40-7.25 (m, 6H), 6.52 (d, J=8.8 Hz, 1H), 5.14 (m, 1H), 4.62 (s, 2H), 3.58 (t, J=5.2 Hz, 2H), 2.79 (t, J=6.0 Hz, 2H), 1.95 (m, 2H), 1.44 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 1 except that (S)-1-(4-(trifluoromethyl)phenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.66 (br, OH, 1H), 8.43 (d, J=8.0 Hz, 1H), 7.75-7.65 (m, 3H), 7.60-7.50 (m, 5H), 7.44 (t, J=7.6 Hz, 1H), 7.37 (d, J=7.2 Hz, 1H), 7.30-7.20 (m, 4H), 6.53 (d, J=8.8 Hz, 1H), 5.16 (m, 1H), 4.62 (s, 2H), 3.47 (t, J=5.2 Hz, 2H), 2.81 (t, J=6.0 Hz, 2H), 1.95 (m, 2H), 1.46 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 1 except that (S)-1-(4-((trifluoromethyl)thio)phenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.83 (br, OH, 1H), 8.41 (d, J=7.6 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.70-7.40 (m, 11H), 7.40-7.25 (m, 6H), 6.53 (d, J=8.4 Hz, 1H), 5.14 (m, 1H), 4.62 (s, 2H), 3.47 (t, J=5.6 Hz, 2H), 2.80 (t, J=5.6 Hz, 2H), 1.95 (m, 2H), 1.45 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 1 except that (S)-1-(4-cyanophenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.66 (br, OH, 1H), 8.42 (d, J=7.6 Hz, 1H), 7.87 (d, J=7.0 Hz, 2H), 7.69 (d, J=7.6 Hz, 1H), 7.58-7.49 (m, 5H), 7.43 (t, J=7.6 Hz, 1H), 7.38 (d, J=7.2 Hz, 1H), 7.32-7.25 (m, 4H), 6.53 (d, J=8.4 Hz, 1H), 5.15 (m, 1H), 4.62 (s, 2H), 3.47 (t, J=5.2 Hz, 2H), 2.80 (t, J=6.0 Hz, 2H), 1.96 (m, 2H), 1.44 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 1 except that cromene-3-amine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.62 (br, OH, 1H), 7.97 (m, 1H), 7.71 (m, 1H), 7.60-7.40 (m, 4H), 7.40-7.33 (m, 1H), 7.26 (m, 4H), 7.09 (m, 2H), 6.84 (t, J=8.0 Hz, 1H), 6.79 (d, J=8.0 Hz, 1H), 6.54 (d, J=8.4 Hz, 1H), 4.62 (s, 2H), 4.30 (m, 1H), 4.18 (m, 1H), 3.82 (m, 1H), 3.47 (t, J=5.6 Hz, 2H), 3.05-2.89 (m, 2H), 2.80 (t, J=5.6 Hz, 2H), 1.97 (m, 2H).
The target compound was obtained by the same manner as described in Example 1 except that (S)-1-(2,6-difluorophenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.73 (br, OH, 1H), 8.26 (d, J=6.8 Hz, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.58-7.40 (m, 4H), 7.36 (d, J=7.6 Hz, 1H), 7.31-7.23 (m, 5H), 7.00 (t, J=8.0 Hz, 1H), 6.51 (d, J=8.8 Hz, 1H), 5.35 (m, 1H), 4.61 (s, 2H), 3.47 (t, J=5.2 Hz, 2H), 2.78 (t, J=5.6 Hz, 2H), 1.97 (m, 2H), 1.53 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 1 except that (S)-1-(3-fluorophenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.81 (br, OH, 1H), 8.32 (d, J=7.6 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.58-7.50 (m, 3H), 7.44 (t, J=7.2 Hz, 1H), 7.38-7.25 (m, 6H), 7.18 (m, 1H), 7.02 (m, 1H), 6.54 (d, J=8.8 Hz, 1H), 5.13 (m, 1H), 4.62 (s, 2H), 3.45 (t, J=5.2 Hz, 2H), 2.80 (t, J=5.6 Hz, 2H), 1.97 (m, 2H), 1.44 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 1 except that (S)-1-(3-(trifluoromethoxy)phenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.73 (br, OH, 1H), 8.37 (d, J=8.0 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.58-7.46 (m, 3H), 7.44 (t, J=7.2 Hz, 2H), 7.38 (t, J=7.6 Hz, 2H), 7.35-7.25 (m, 5H), 7.19 (d, J=7.6 Hz, 1H), 6.54 (d, J=8.4 Hz, 1H), 5.15 (m, 1H), 4.62 (s, 2H), 3.47 (t, J=5.2 Hz, 2H), 2.80 (t, J=5.6 Hz, 2H), 1.97 (m, 2H), 1.44 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 1 except that S)-1-(3-(trifluoromethyl)phenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.81 (br, OH, 1H), 8.42 (d, J=8.0 Hz, 1H), 7.73-7.65 (m, 3H), 7.59-7.50 (m, 5H), 7.4 (td, J=1.2, 7.6 Hz, 1H), 7.39 (d, J=7.2 Hz, 1H), 7.31-7.25 (m, 4H), 6.54 (d, J=7.6 Hz, 1H), 5.19 (m, 1H), 4.62 (s, 2H), 3.47 (t, J=5.2 Hz, 2H), 2.80 (t, J=6.0 Hz, 2H), 1.97 (m, 2H), 1.47 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 1 except that (S)-1-(naphthalene-2-yl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.73 (br, OH, 1H), 8.41 (d, J=8.0 Hz, 1H), 7.89-7.81 (m, 4H), 7.70 (d, J=7.6 Hz, 1H), 7.60-7.42 (m, 7H), 7.37 (d, J=7.6 Hz, 1H), 7.31-7.25 (m, 4H), 6.54 (d, J=8.8 Hz, 1H), 5.28 (m, 1H), 4.62 (s, 2H), 3.47 (t, J=5.2 Hz, 2H), 2.80 (t, J=5.6 Hz, 2H), 1.97 (m, 2H), 1.54 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 1 except that (S)-1-(3,4-difluorophenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.73 (br, OH, 1H), 8.33 (d, J=8.0 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.60-7.15 (m, 12H), 6.53 (d, J=8.4 Hz, 1H), 5.10 (m, 1H), 4.62 (s, 2H), 3.47 (t, J=5.2 Hz, 2H), 2.80 (t, J=5.6 Hz, 2H), 1.97 (m, 2H), 1.54 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 1 except that (S)-1-(3-methoxyphenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.73 (br, OH, 1H), 8.28 (d, J=8.4 Hz, 1H), 7.70 (dd, J=1.2, 7.6 Hz, 1H), 7.60-7.46 (m, 3H), 7.45 (m, 1H), 7.38 (m, 1H), 7.34-7.19 (m, 5H), 6.95 (m, 2H), 6.78 (m, 1H), 6.52 (d, J=8.4 Hz, 1H), 5.10 (m, 1H), 4.62 (s, 2H), 3.74 (s, 3H), 3.47 (t, J=5.2 Hz, 2H), 2.80 (t, J=5.6 Hz, 2H), 1.97 (m, 2H), 1.42 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 1 except that (S)-1-(2-methoxyphenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.73 (br, OH, 1H), 8.23 (d, J=8.0 Hz, 1H), 7.70 (dd, J=1.2, 7.6 Hz, 1H), 7.60-7.15 (m, 11H), 7.0-6.86 (m, 2H), 6.52 (d, J=8.4 Hz, 1H), 5.39 (m, 1H), 4.62 (s, 2H), 3.82 (s, 3H), 3.47 (t, J=5.2 Hz, 2H), 2.80 (t, J=5.6 Hz, 2H), 1.97 (m, 2H), 1.34 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 1 except that (S)-1-(2-fluorophenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.73 (br, OH, 1H), 8.31 (d, J=8.0 Hz, 1H), 7.70 (d, J=7.2 Hz, 1H), 7.60-7.10 (m, 13H), 6.53 (d, J=8.8 Hz, 1H), 5.35 (m, 1H), 4.62 (s, 2H), 3.47 (t, J=5.2 Hz, 2H), 2.80 (t, J=5.6 Hz, 2H), 1.97 (m, 2H), 1.42 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 1 except that (S)-1-(2-(trifluoromethyl)phenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.81 (br, OH, 1H), 8.48 (d, J=7.2 Hz, 1H), 7.92 (d, J=7.6 Hz, 1H), 7.71-7.60 (m, 3H), 7.59-7.35 (m, 6H), 7.32-7.20 (m, 4H), 6.52 (d, J=8.4 Hz, 1H), 5.41 (m, 1H), 4.62 (s, 2H), 3.46 (t, J=5.2 Hz, 2H), 2.80 (t, J=5.6 Hz, 2H), 1.97 (m, 2H), 1.42 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 1 except that pyridine-2-ylmethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.75 (br, OH, 1H), 8.68-8.67 (m, 1H), 8.52-8.51 (m, 1H), 7.81-7.77 (m, 1H), 7.70-7.69 (m, 1H), 7.57-7.54 (m, 3H), 7.46-7.42 (m, 1H), 7.38-7.36 (m, 1H), 7.31-7.26 (m, 6H), 4.63 (s, 2H), 4.53-4.52 (m, 2H), 3.34 (m, 2H), 2.80 (m, 2H), 1.97 (m, 2H).
The target compound was obtained by the same manner as described in Example 1 except that pyridine-4-ylmethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.75 (br, OH, 1H), 8.74-8.72 (m, 1H), 8.58-8.56 (m, 2H), 7.71-7.69 (m, 1H), 7.57-7.51 (m, 3H), 7.46-7.42 (m, 3H), 7.38-7.36 (m, 1H), 7.31-7.26 (m, 4H), 6.56-6.53 (m, 1H), 4.63 (s, 2H), 4.50-4.48 (m, 2H), 3.49-3.46 (m, 2H), 2.81-2.79 (m, 2H), 1.98-1.95 (m, 2H).
The target compound was obtained by the same manner as described in Example 1 except that phenylmethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.75 (br, OH, 1H), 7.71-7.68 (m, 1H), 7.57-7.49 (m, 3H), 7.46-7.42 (m, 1H), 7.38-7.36 (m, 1H), 7.32-7.25 (m, 8H), 7.23-7.19 (m, 1H), 6.53-6.51 (m, 1H), 4.62 (s, 2H), 4.43-4.41 (m, 2H), 3.48-3.45 (m, 2H), 2.81-2.78 (m, 2H), 1.99-1.91 (m, 2H).
The target compound was obtained by the same manner as described in Example 1 except that (2-bromophenyl)methaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 8.63-8.60 (m, 1H), 7.65-7.59 (m, 2H), 7.56-7.53 (m, 2H), 7.50-7.47 (m, 1H), 7.41-7.32 (m, 5H), 7.26-7.24 (m, 3H), 7.21-7.18 (m, 1H), 6.56-6.53 (m, 1H), 4.62 (s, 2H), 4.44-4.42 (m, 2H), 3.49-3.47 (m, 2H), 2.82-2.79 (m, 2H), 1.97 (m, 2H).
The target compound was obtained by the same manner as described in Example 1 except that (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.75 (br, OH, 1H), 8.50-8.47 (m, 1H), 7.56-7.41 (m, 4H), 7.38-7.36 (m, 1H), 7.31-7.25 (m, 4H), 6.83-6.71 (m, 3H), 6.53-6.51 (m, 1H), 4.61 (s, 2H), 4.29-4.28 (m, 2H), 4.19 (s, 4H), 3.47-3.45 (m, 2H), 2.80-2.77 (m, 2H), 1.97-1.94 (m, 2H).
The target compound was obtained by the same manner as described in Example 1 except that (4-bromophenyl)methaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, CDCl3) δ 7.94 (d, J=7.2 Hz, 1H), 7.95-7.20 (m, 13H), 6.49 (d, J=8.8 Hz, 1H), 6.25 (s, 1H), 4.59-4.55 (m, 4H), 3.50 (t, J=5.6 Hz, 2H), 2.86 (t, J=6.0 Hz, 2H), 2.07-1.98 (m, 2H).
The target compound was obtained by the same manner as described in Example 1 except that (3-(trifluoromethoxy)phenyl)methaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.60-7.02 (m, 13H), 6.47 (d, J=8.4 Hz, 1H), 6.37 (s, 1H), 4.60-4.55 (m, 4H), 3.51-3.45 (m, 2H), 2.84 (m, 2H), 1.94-1.90 (m, 2H).
The target compound was obtained by the same manner as described in Example 2 except that (S)-4′-((6-((1-(4-(trifluoromethyl)phenyl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 12 was used instead of (S)-4′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J=7.6 Hz, 1H), 7.68-7.73 (m, 3H), 7.60-7.35 (m, 10H), 7.28-2.22 (m, 3H), 6.53 (d, J=8.8 Hz, 1H), 5.16 (m, 1H), 4.61 (s, 2H), 3.47 (t, J=5.2 Hz, 2H), 2.80 (t, J=5.6 Hz, 2H), 1.97 (m, 2H), 1.46 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 2 except that (S)-4′-((6-((1-(4-(trifluoromethoxy)phenyl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 11 was used instead of (S)-4′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J=8.0 Hz, 1H), 7.65 (s, 1H), 7.58-7.23 (m, 15H), 6.52 (d, J=8.4 Hz, 1H), 5.14 (m, 1H), 4.61 (s, 2H), 3.47 (t, J=5.2 Hz, 2H), 2.80 (t, J=5.6 Hz, 2H), 1.97 (m, 2H), 1.44 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 2 except that (S)-4′-((6-((1-(3-chlorophenyl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 9 was used instead of (S)-4′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J=7.6 Hz, 1H), 7.63 (m, 1H), 7.55-7.25 (m, 15H), 6.54 (d, J=8.4 Hz, 1H), 5.10 (m, 1H), 4.61 (s, 2H), 3.47 (t, J=5.2 Hz, 2H), 2.80 (t, J=5.6 Hz, 2H), 1.97 (m, 2H), 1.43 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 2 except that (S)-4′-((6-((1-(4-fluorophenyl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 6 was used instead of (S)-4′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J=7.6 Hz, 1H), 7.64 (m, 1H), 7.56-7.35 (m, 10H), 7.28-2.22 (m, 3H), 7.15-1.08 (m, 2H), 6.52 (d, J=8.8 Hz, 1H), 5.12 (m, 1H), 4.60 (s, 2H), 3.47 (t, J=5.2 Hz, 2H), 2.79 (t, J=5.6 Hz, 2H), 1.97 (m, 2H), 1.44 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 2 except that (S)-4′-((6-((1-(4-bromophenyl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 7 was used instead of (S)-4′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J=8.0 Hz, 1H), 7.63 (m, 1H), 7.55-7.20 (m, 15H), 6.52 (d, J=8.4 Hz, 1H), 5.08 (m, 1H), 4.61 (s, 2H), 3.47 (t, J=5.2 Hz, 2H), 2.79 (t, J=6.0 Hz, 2H), 1.97 (m, 2H), 1.42 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 2 except that (S)-4′-((6-((1-(naphthalene-1-yl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 10 was used instead of (S)-4′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J=8.0 Hz, 1H), 8.19 (d, J=8.0 Hz, 1H), 7.93 (m, 1H), 7.68-7.32 (m, 12H), 7.28-7.22 (m, 3H), 6.53 (d, J=8.8 Hz, 1H), 5.92 (m, 1H), 4.60 (s, 2H), 3.46 (t, J=5.2 Hz, 2H), 2.79 (t, J=5.6 Hz, 2H), 1.95 (m, 2H), 1.59 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 2 except that (S)-4′-((6-((1-(3,4-fluorophenyl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 21 was used instead of (S)-4′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J=8.0 Hz, 1H), 7.66 (m, 1H), 7.55-7.15 (m, 13H), 6.52 (d, J=8.8 Hz, 1H), 5.08 (m, 1H), 4.61 (s, 2H), 3.47 (t, J=5.2 Hz, 2H), 2.80 (t, J=6.0 Hz, 2H), 1.97 (m, 2H), 1.42 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 2 except that (S)-4′-((6-((1-(3-methoxyphenyl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 22 was used instead of (S)-4′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J=7.6 Hz, 1H), 7.65 (m, 1H), 7.55-7.20 (m, 12H), 6.93 (m, 1H), 6.77 (d, J=6.8 Hz, 1H), 6.52 (d, J=8.4 Hz, 1H), 5.09 (m, 1H), 4.61 (s, 2H), 3.73 (s, 3H), 3.47 (t, J=5.2 Hz, 2H), 2.80 (t, J=6.0 Hz, 2H), 1.97 (m, 2H), 1.42 (d, J=6.0 Hz, 3H).
The target compound was obtained by the same manner as described in Example 2 except that (S)-4′-((6-((1-(2-methoxyphenyl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 23 was used instead of (S)-4′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J=8.0 Hz, 1H), 7.60 (m, 1H), 7.55-7.25 (m, 13H), 6.95 (d, J=7.6 Hz, 1H), 6.88 (t, J=7.6 Hz, 1H), 6.52 (d, J=8.4 Hz, 1H), 5.39 (m, 1H), 4.61 (s, 2H), 3.82 (s, 3H), 3.47 (t, J=5.2 Hz, 2H), 2.80 (t, J=6.0 Hz, 2H), 1.97 (m, 2H), 1.34 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 2 except that (S)-4′-((6-((1-(2-fluorophenyl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 24 was used instead of (S)-4′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J=8.0 Hz, 1H), 7.63 (s, 1H), 7.55-7.10 (m, 15H), 6.52 (d, J=8.8 Hz, 1H), 5.35 (m, 1H), 4.61 (s, 2H), 3.47 (t, J=5.2 Hz, 2H), 2.79 (t, J=6.0 Hz, 2H), 1.97 (m, 2H), 1.42 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 2 except that (S)-4′-((6-((1-(2-(trifluoromethyl)phenyl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 25 was used instead of (S)-4′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J=7.2 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.68-7.60 (m, 3H), 7.55-7.35 (m, 9H), 7.30-7.20 (m, 3H), 6.52 (d, J=8.4 Hz, 1H), 5.41 (m, 1H), 4.61 (s, 2H), 3.47 (t, J=5.2 Hz, 2H), 2.80 (t, J=6.4 Hz, 2H), 1.97 (m, 2H), 1.42 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 2 except that (S)-4′-((6-((1-(naphthalene-2-yl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 20 was used instead of (S)-4′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, CDCl3) δ 7.84-7.82 (m, 4H), 7.78-7.76 (m, 1H), 7.53-7.40 (m, 9H), 7.37-7.35 (m, 1H), 7.30-7.28 (m, 3H), 6.50-6.48 (m, 1H), 6.22-6.20 (m, NH, 1H), 5.53-5.48 (m, 1H), 5.44 (br, NH, 1H), 5.30 (br, NH, 1H), 4.59 (s, 2H), 3.51-3.47 (m, 2H), 2.89-2.86 (m, 2H), 2.09-2.04 (m, 2H), 1.74-1.68 (m, 3H).
The target compound was obtained by the same manner as described in Example 2 except that (S)-4′-((6-((1-(3-fluorophenyl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 17 was used instead of (S)-4′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, DMSO-d6) δ 8.34-8.32 (m, 1H), 7.66 (m, 1H), 7.52-7.31 (m, 9H), 7.27-7.24 (m, 3H), 7.19-7.15 (m, 2H), 7.05-7.00 (m, 1H), 6.54-6.51 (m, 1H), 5.14-5.11 (m, 1H), 4.61 (s, 2H), 3.47-3.43 (m, 2H), 2.80-2.79 (m, 2H), 1.99-1.96 (m, 2H), 1.44-1.42 (m, 3H).
The target compound was obtained by the same manner as described in Example 2 except that (S)-4′-((6-((1-(3-(trifluoromethoxy)phenyl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 18 was used instead of (S)-4′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J=8.0 Hz, 1H), 7.67 (s, 1H), 7.55-7.19 (m, 15H), 6.53 (d, J=8.4 Hz, 1H), 5.15 (m, 1H), 4.61 (s, 2H), 3.47 (t, J=5.2 Hz, 2H), 2.80 (t, J=5.6 Hz, 2H), 1.96 (m, 2H), 1.46 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 2 except that (S)-4′-((6-((1-(3-(trifluoromethyl)phenyl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 19 was used instead of (S)-4′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J=8.0 Hz, 1H), 7.75-7.24 (m, 16H), 6.53 (d, J=8.8 Hz, 1H), 5.18 (m, 1H), 4.61 (s, 2H), 3.47 (t, J=5.2 Hz, 2H), 2.79 (t, J=5.6 Hz, 2H), 1.95 (m, 2H), 1.46 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 2 except that 4′-((6-((pyridine-4-ylmethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 27 was used instead of (S)-4′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, DMSO-d6) δ 8.67-8.64 (m, 1H), 8.48-8.47 (m, 2H), 7.65 (m, 1H), 7.53-7.35 (m, 8H), 7.27-7.25 (m, 5H), 6.55-6.53 (m, 1H), 4.62 (s, 2H), 4.44-4.42 (m, 2H), 3.49-3.46 (m, 2H), 2.82-2.79 (m, 2H), 1.98-1.97 (m, 2H).
The target compound was obtained by the same manner as described in Example 2 except that (S)-4′-((6-((1-(3-fluoro-4-methyl)phenyl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 5 was used instead of (S)-4′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, CDCl3) δ 7.74 (d, J=8.0 Hz, 1H), 7.59-7.25 (m, 9H), 7.13 (d, J=8.0 Hz, 1H), 7.03 (t, J=8.0 Hz, 1H), 6.46 (d, J=7.6 Hz, 1H), 6.19 (d, J=7.6 Hz, 1H), 5.66 (s, 1H), 5.39 (s, 1H), 5.26 (m, 1H), 4.58 (s, 2H), 3.49 (t, J=5.2 Hz, 2H), 2.86 (t, J=6.0 Hz, 2H), 2.24 (s, 3H), 2.05 (m, 2H), 1.54 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 2 except that 4′-((6-(benzylcarbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 28 was used instead of (S)-4′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, CDCl3) δ 7.53-7.49 (m, 2H), 7.45-7.41 (m, 4H), 7.37-7.35 (m, 5H), 7.33-7.28 (m, 3H), 6.49-6.47 (m, 1H), 6.23-6.21 (m, NH, 1H), 5.49 (br, NH, 1H), 5.32 (br, NH, 1H), 4.64-4.63 (m, 2H), 4.59 (s, 2H), 3.59-3.47 (m, 2H), 2.89-2.85 (m, 2H), 2.09-2.03 (m, 2H).
The target compound was obtained by the same manner as described in Example 2 except that 4′-((7-((2-bromobenzyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 29 was used instead of (S)-4′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, CDCl3) δ 7.78-7.76 (m, 1H), 7.57-7.55 (m, 1H), 7.54-7.35 (m, 8H), 7.31-7.29 (m, 3H), 7.17-7.13 (m, 1H), 6.49-6.47 (m, 1H), 6.47-6.46 (m, NH, 1H), 5.50 (br, NH, 1H), 5.32 (br, NH, 1H), 4.70-4.69 (m, 2H), 4.60 (s, 2H), 3.50-3.48 (m, 2H), 2.89-2.86 (m, 2H), 2.09-2.03 (m, 2H).
The target compound was obtained by the same manner as described in Example 2 except that 4′-((6-(((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 30 was used instead of (S)-4′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, CDCl3) δ 7.78-7.76 (m, 1H), 7.53-7.48 (m, 2H), 7.46-7.41 (m, 4H), 7.37-7.35 (m, 1H), 7.30-7.28 (m, 2H), 6.86 (m, 1H), 6.83 (m, 2H), 6.14-6.12 (m, NH, 1H), 5.46 (br, NH, 1H), 5.31 (br, NH, 1H), 4.59 (s, 2H), 4.52-4.51 (m, 2H), 4.26 (s, 4H), 3.50-3.47 (m, 2H), 2.88-2.85 (m, 2H), 2.09-2.03 (m, 2H).
The target compound was obtained by the same manner as described in Example 2 except that 4′-((6-((4-bromobenzyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 31 was used instead of (S)-4′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, CDCl3) δ 7.78-7.76 (m, 1H), 7.54-7.36 (m, 10H), 7.30-7.22 (m, 3H), 6.49 (d, J=8.8 Hz, 1H), 6.23 (t, J=5.6 Hz, 1H), 5.44 (s, 1H), 5.32 (s, 1H), 4.60-4.58 (m, 4H) 4.50 (t, J=5.6 Hz, 2H), 2.88 (t, J=6.0 Hz, 2H), 2.10-2.04 (m, 2H).
The target compound was obtained by the same manner as described in Example 2 except that 4′-((6-((3-(trifluoromethoxy)benzyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 32 was used instead of (S)-4′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, CDCl3) δ 7.78-7.76 (m, 1H), 7.54-7.30 (m, 11H), 7.20 (s, 1H), 7.15-7.13 (m, 1H), 6.50 (d, J=8.4 Hz, 1H), 6.28 (t, J=5.6 Hz, 1H), 5.42 (s, 1H), 5.31 (s, 1H), 4.66 (d, J=5.6 Hz, 1H), 4.61 (s, 2H), 3.50 (t, J=5.6 Hz, 2H), 2.89 (t, J=6.0 Hz, 2H), 2.11-2.06 (m, 2H).
(S)-4′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid (300 mg, 0.61 mmol) obtained in Example 2 was dissolved in MeOH (10 ml) in a 25 mL flask, to which NaOH (24.4 mg, 0.61 mmol) was added, followed by stirring at room temperature for 5 hours. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure. As a result, sodium (S)-4′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylate was obtained (300 mg).
1H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J=8.0 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.60-7.46 (m, 3H), 7.43 (m, 1H), 7.42-7.25 (m, 9H), 7.19 (m, 1H), 6.52 (m, 1H), 5.12 (m, 1H), 4.69 (s, 2H), 3.49 (t, J=4.0 Hz, 2H), 2.81 (t, J=4.0 Hz, 2H), 1.95 (m, 2H), 1.42 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 55 except that (S)-4′-((6-((1-(3-fluoro-4-methylphenyl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 5 was used instead of (S)-4′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J=8.0 Hz, 1H), 7.50-7.42 (m, 4H), 7.30 (m, 1H) 7.35-7.05 (m, 8H), 6.53 (d, J=8.8 Hz, 1H), 5.08 (m, 1H), 4.57 (s, 2H), 3.46 (t, J=5.2 Hz, 2H), 2.79 (t, J=6.0 Hz, 2H), 2.18 (s, 3H), 1.95 (m, 2H), 1.40 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 55 except that (S)-4′-((6-((1-(4-cyanophenyl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 14 was used instead of (S)-4′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J=6.8 Hz, 1H), 7.77 (d, J=8.0 Hz, 2H), 7.60-7.42 (m, 6H), 7.30-7.13 (m, 6H), 6.53 (d, J=9.2 Hz, 1H), 5.14 (m, 1H), 4.58 (s, 2H), 3.47 (t, J=5.2 Hz, 2H), 2.79 (t, J=5.6 Hz, 2H), 1.95 (m, 2H), 1.43 (d, J=6.8 Hz, 3H).
4-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid (300 mg, 0.67 mmol) obtained in Preparative Example 2 was dissolved in CH2Cl2 (10 ml) in a 100 mL flask, to which HATU (280 mg, 0.74 mmol) and DIPEA (350 ul, 2.01 mmol) were added, followed by stirring. (S)-1-phenylethylamine (90 mg, 0.74 mmol) was added thereto, followed by stirring at room temperature for 12 hours. Upon completion of the reaction, the organic layer was separated by using CH2Cl2 and H2O. The separated organic layer was dried over MgSO4 and filtered. The mixture was separated by column chromatography (EA/n-Hex=1:1) to give(S)-tert-butyl 4′-((7-((1-phenylethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylate (341 mg, 0.62 mmol, 93%).
1H NMR (400 MHz, CDCl3) δ 7.80 (d, J=8.0 Hz, 1H), 7.61-7.23 (m, 15H), 6.68 (d, J=8.4 Hz, 1H), 6.14 (d, J=7.6 Hz, 1H), 5.34 (m, 1H), 4.59 (s, 2H), 4.30 (t, J=4.4 Hz, 2H), 3.52 (t, J=4.4 Hz, 2H), 1.54 (d, J=7.2 Hz, 3H).
(S)-tert-butyl 4′-((7-((1-phenylethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylate (341 mg, 0.62 mmol) obtained in step 1 was dissolved in CH2Cl2 (20 ml) in a 50 mL flask, to which 30% TFA (9 ml) was added, followed by stirring at room temperature for 5 hours. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure. The mixture was separated by column chromatography (EA) to give (S)-4′-((7-((1-phenylethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid (156 mg, 0.31 mmol, 51%).
1H NMR (400 MHz, DMSO-d6) δ 12.66 (br, OH, 1H), 8.39 (d, J=8.0 Hz, 1H), 7.70 (d, J=7.2 Hz, 1H), 7.61-7.18 (m, 14H), 6.73 (d, J=8.4 Hz, 1H), 5.11 (m, 1H), 4.63 (s, 2H), 4.25 (t, J=4.0 Hz, 2H), 3.51 (t, J=4.0 Hz, 2H), 1.43 (d, J=7.2 Hz, 3H).
1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (300 mg, 0.67 mmol) obtained in Example 57 was dissolved in CH2Cl2 (2 ml) in a 25 mL flask, to which EDCI (38 mg, 0.2 mmol) and HOBt (38 mg, 0.3 mmol) were added, followed by stirring. Ammonium hydroxide solution (2 ml) was added thereto, followed by stirring at room temperature for 5 hours. Upon completion of the reaction, the organic layer was separated by using CH2Cl2 and H2O. The separated organic layer was dried over MgSO4 and filtered. The mixture was separated by column chromatography (MeOH/n-Hex/CH2Cl2=0.5:0.5:9) to give (S)-4-((2′-carbamoyl-[1,1′-biphenyl]-4-yl)methyl)-N-(1-phenylethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (23 mg, 0.04 mmol, 44%).
1H NMR (400 MHz, CDCl3) δ 7.74 (d, J=7.6 Hz, 1H), 7.51 (td, J=1.2, 7.6 Hz, 1H), 7.47-7.24 (m, 13H), 6.63 (d, J=9.2 Hz, 1H), 6.20 (d, J=8.0 Hz, 1H), 5.61 (s, 1H), 5.39 (s, 1H), 5.32 (m, 1H), 4.57 (s, 2H), 4.30 (t, J=4.4 Hz, 2H), 3.50 (t, J=4.4 Hz, 2H), 1.48 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 58 except that (S)-1-(4-nitrophenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.76 (br, OH, 1H), 8.57 (d, J=7.6 Hz, 1H), 8.16 (d, J=8.8 Hz, 2H), 7.70 (m, 1H), 7.69-7.52 (m, 3H), 7.47-7.28 (m, 8H), 6.74 (d, J=8.0 Hz, 1H), 5.19 (m, 1H), 4.64 (s, 2H), 4.26 (t, J=4.0 Hz, 2H), 3.52 (t, J=4.0 Hz, 2H), 1.47 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 58 except that (S)-1-(4-bromophenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.76 (br, OH, 1H), 8.43 (d, J=7.6 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.58-7.41 (m, 4H), 7.39-7.28 (m, 9H), 6.73 (d, J=8.4 Hz, 1H), 5.08 (m, 1H), 4.63 (s, 2H), 4.25 (t, J=4.0 Hz, 2H), 3.52 (t, J=4.0 Hz, 2H), 1.42 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 58 except that (S)-1-phenylpropane-1-amine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.76 (br, OH, 1H), 8.34 (d, J=8.4 Hz, 1H), 7.70 (dd, J=1.2, 8.0 Hz, 1H), 7.54 (m, 1H), 7.47-7.19 (m, 12H), 6.53 (d, J=8.4 Hz, 1H), 4.85 (q, J=8.4 Hz, 1H), 4.63 (s, 2H), 4.25 (t, J=4.0 Hz, 2H), 3.53 (t, J=4.0 Hz, 2H), 1.78 (m, 2H), 0.87 (t, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 58 except that (S)-1-(4-fluorophenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.86 (br, OH, 1H), 8.42 (d, J=8.0 Hz, 1H), 7.72 (dd, J=1.2, 8.0 Hz, 1H), 7.65-7.28 (m, 13H), 6.74 (d, J=8.4 Hz, 1H), 5.13 (m, 1H), 4.63 (s, 2H), 4.28 (t, J=4.0 Hz, 2H), 3.58 (t, J=4.0 Hz, 2H), 1.42 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 58 except that (S)-1-(4-chlorophenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.76 (br, OH, 1H), 8.46 (d, J=7.6 Hz, 1H), 7.72 (m, 1H), 7.55 (m, 1H), 7.47-7.28 (m, 12H), 6.74 (d, J=8.0 Hz, 1H), 5.09 (m, 1H), 4.63 (s, 2H), 4.26 (t, J=4.0 Hz, 2H), 3.52 (t, J=4.0 Hz, 2H), 1.42 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 58 except that (S)-1-(3-chlorophenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.86 (br, OH, 1H), 8.45 (d, J=8.0 Hz, 1H), 7.72 (m, 1H), 7.56 (m, 1H), 7.47-7.28 (m, 12H), 6.74 (d, J=8.0 Hz, 1H), 5.09 (m, 1H), 4.63 (s, 2H), 4.26 (t, J=4.0 Hz, 2H), 3.52 (t, J=4.0 Hz, 2H), 1.42 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 58 except that (4-nitrophenyl)methaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.83 (br, OH, 1H), 8.75 (m, 1H), 8.19 (dd, J=1.2, 8.8 Hz, 1H), 7.71-7.19 (m, 12H), 6.73 (d, J=8.4 Hz, 1H), 4.63 (s, 2H), 4.52 (d, J=6.0 Hz, 1H), 4.25 (t, J=4.0 Hz, 2H), 3.53 (t, J=4.0 Hz, 2H).
The target compound was obtained by the same manner as described in Example 58 except that phenylmethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.63 (br, OH, 1H), 8.75 (t, J=6.0 Hz, 1H), 7.71 (dd, J=1.2, 8.8 Hz, 1H), 7.58-7.19 (m, 14H), 6.76 (d, J=8.8 Hz, 1H), 4.67 (s, 2H), 4.42 (d, J=6.0 Hz, 1H), 4.25 (t, J=4.0 Hz, 2H), 3.53 (t, J=4.0 Hz, 2H).
The target compound was obtained by the same manner as described in Example 58 except that 2-phenylethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.63 (br, OH, 1H), 8.17 (t, J=5.6 Hz, 1H), 7.71 (dd, J=1.2, 8.8 Hz, 1H), 7.58-7.19 (m, 14H), 6.72 (d, J=8.4 Hz, 1H), 4.62 (s, 2H), 4.25 (t, J=4.0 Hz, 1H), 4.52 (t, J=4.0 Hz, 2H), 3.40 (m, 2H), 2.74 (t, J=7.6 Hz, 2H).
The target compound was obtained by the same manner as described in Example 58 except that furan-2-ylmethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.88 (br, OH, 1H), 8.56 (t, J=5.6 Hz, 1H), 7.73 (dd, J=1.2, 8.8 Hz, 1H), 7.58-7.19 (m, 10H), 6.72 (d, J=8.8 Hz, 1H), 6.37 (m, 1H), 6.21 (m, 1H), 4.62 (s, 2H), 4.41 (d, J=6.0 Hz, 1H), 4.25 (t, J=4.0 Hz, 2H), 3.51 (t, J=4.0 Hz, 2H).
The target compound was obtained by the same manner as described in Example 58 except that (S)-1-(naphthalene-1-yl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.76 (br, OH, 1H), 8.57 (d, J=8.4 Hz, 1H), 8.18 (d, J=8.4 Hz, 1H), 7.93 (m, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.70 (dd, J=1.2, 7.6 Hz, 1H), 7.62-7.25 (m, 13H), 6.70 (d, J=8.8 Hz, 1H), 5.91 (m, 1H), 4.62 (s, 2H), 4.25 (t, J=4.0 Hz, 2H), 3.51 (t, J=4.0 Hz, 2H), 1.57 (d, J=6.8 Hz, 1H).
The target compound was obtained by the same manner as described in Example 58 except that methyl 4-(aminomethyl)benzoate was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.86 (br, OH, 1H), 8.75 (t, J=6.0 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.91 (m, 3H), 7.70 (d, J=7.6 Hz, 1H), 7.56 (t, J=7.6 Hz, 1H), 7.47-7.19 (m, 11H), 6.74 (d, J=8.8 Hz, 1H), 4.63 (s, 2H), 4.49 (d, J=5.2 Hz, 1H), 4.25 (t, J=4.0 Hz, 2H), 3.83 (s, 3H), 3.51 (t, J=4.0 Hz, 2H).
The target compound was obtained by the same manner as described in Example 58 except that (3-methoxyphenyl)methaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.76 (br, OH, 1H), 7.70 (dd, J=1.2, 8.0 Hz, 1H), 7.56 (m, 1H), 7.46 (m, 1H), 7.40-7.19 (m, 8H), 6.85-6.82 (m, 2H), 6.79-6.74 (m, 1H), 6.73 (d, J=8.8 Hz, 1H), 4.63 (s, 2H), 4.39 (d, J=6.0 Hz, 1H), 4.25 (t, J=4.0 Hz, 2H), 3.72 (s, 3H), 3.51 (t, J=4.0 Hz, 2H).
The target compound was obtained by the same manner as described in Example 58 except that (4-bromophenyl)methaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.76 (br, OH, 1H), 8.69 (t, J=6.0 Hz, 1H), 7.70 (dd, J=1.2, 8.4 Hz, 1H), 7.62-7.20 (m, 13H), 6.73 (d, J=8.4 Hz, 1H), 4.63 (s, 2H), 4.42 (d, J=8.0 Hz, 1H), 4.25 (t, J=4.0 Hz, 2H), 3.51 (t, J=4.0 Hz, 2H).
The target compound was obtained by the same manner as described in Example 58 except that (S)-1-(4-cyanophenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.74 (br, OH, 1H), 8.51 (d, J=7.6 Hz, 1H), 7.80 (m, 2H), 7.61-7.18 (m, 10H), 6.74 (d, J=8.0 Hz, 1H), 5.12 (m, 1H), 4.63 (s, 2H), 4.25 (t, J=4.0 Hz, 2H), 3.51 (t, J=4.0 Hz, 2H), 1.44 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 58 except that (S)-1-(4-(trifluoromethoxy)phenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.90 (br, OH, 1H), 8.44 (d, J=8.0 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.71-7.18 (m, 13H), 6.74 (d, J=8.4 Hz, 1H), 5.13 (m, 1H), 4.63 (s, 2H), 4.25 (t, J=4.0 Hz, 2H), 3.51 (t, J=4.0 Hz, 2H), 1.44 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 58 except that (S)-1-(4-(trifluoromethyl)phenyl)ethaneamine used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.73 (br, OH, 1H), 8.50 (d, J=8.0 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.75-7.43 (m, 6H), 7.48-7.40 (m, 1H), 7.38-7.25 (m, 6H), 6.74 (d, J=8.4 Hz, 1H), 5.16 (m, 1H), 4.63 (s, 2H), 4.25 (t, J=4.0 Hz, 2H), 3.52 (t, J=4.0 Hz, 2H), 1.46 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 58 except that (S)-1-(4-((trifluoromethyl)thio)phenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.63 (br, OH, 1H), 8.49 (d, J=8.0 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.65 (m, 2H), 7.60-7.50 (m, 3H), 7.45 (m, 1H), 7.40-7.15 (m, 5H), 6.74 (d, J=8.4 Hz, 1H), 5.15 (m, 1H), 4.63 (s, 2H), 4.25 (t, J=4.0 Hz, 2H), 3.52 (t, J=4.0 Hz, 2H), 1.44 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 58 except that (S)-1-(4-(tert-butyl)phenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.63 (br, OH, 1H), 8.35 (d, J=8.0 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.65-7.15 (m, 13H), 6.73 (d, J=8.4 Hz, 1H), 5.10 (m, 1H), 4.63 (s, 2H), 4.25 (t, J=4.0 Hz, 2H), 3.51 (t, J=4.0 Hz, 2H), 1.42 (d, J=7.2 Hz, 3H), 1.25 (s, 9H).
The target compound was obtained by the same manner as described in Example 58 except that (S)-1-(4-fluoro-2-methylphenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.63 (br, OH, 1H), 8.41 (d, J=8.0 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.60-7.52 (m, 1H), 7.47-7.10 (m, 6H), 6.98 (m, 2H), 6.72 (d, J=8.0 Hz, 1H), 5.23 (m, 1H), 4.62 (s, 2H), 4.25 (t, J=4.0 Hz, 2H), 3.52 (t, J=4.0 Hz, 2H), 2.36 (s, 3H), 1.38 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 58 except that (S)-1-(3-fluoro-4-methylphenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.71 (br, OH, 1H), 8.39 (d, J=8.0 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.60-7.00 (m, 12H), 6.74 (d, J=8.4 Hz, 1H), 5.08 (m, 1H), 4.63 (s, 2H), 4.25 (t, J=4.0 Hz, 2H), 3.52 (t, J=4.0 Hz, 2H), 2.18 (s, 3H), 1.41 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 58 except that (R)-1-(4-cyanophenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 2H), 7.66 (s, 1H), 7.54 (d, J=8.0 Hz, 2H), 7.50-7.20 (m, 11H), 6.74 (d, J=8.4 Hz, 1H), 5.14 (m, 1H), 4.62 (s, 2H), 4.26 (t, J=4.0 Hz, 2H), 3.52 (t, J=4.0 Hz, 2H), 1.42 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 58 except that cromene-3-amine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.74 (br, OH, 1H), 8.08 (m, 1H), 7.95 (m, 1H), 7.72 (m, 1H), 7.45 (m, 1H), 7.40-7.28 (m, 6H), 7.13-7.05 (m, 2H), 6.88 (m, 1H), 6.80-6.71 (m, 2H), 4.63 (s, 2H), 4.31-4.13 (m, 4H), 3.83 (m, 1H), 3.51 (t, J=4.0 Hz, 2H), 3.03-2.86 (m, 2H).
The target compound was obtained by the same manner as described in Example 58 except that (S)-1-(2,6-difluorophenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.78 (br, OH, 1H), 8.40 (d, J=6.8 Hz, 1H), 7.70 (dd, J=0.8, 7.6 Hz, 1H), 7.56 (td, J=1.2, 7.2 Hz, 1H), 7.44 (td, J=0.8, 7.2 Hz, 1H), 7.38-7.25 (m, 8H), 7.01 (t, J=8.0 Hz, 1H), 6.72 (d, J=8.8 Hz, 1H), 5.34 (m, 1H), 4.62 (s, 2H), 4.24 (t, J=4.0 Hz, 2H), 3.51 (t, J=4.0 Hz, 2H), 1.53 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 58 except that (S)-1-(3-fluorophenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.68 (br, OH, 1H), 8.42 (d, J=8.0 Hz, 1H), 7.71 (d, J=6.8 Hz, 1H), 7.56 (td, J=1.2, 7.6 Hz, 1H), 7.45 (m, 1H), 7.40-7.28 (m, 8H), 7.23-7.15 (m, 2H), 7.02 (td, J=2.0, 8.4 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 5.12 (m, 1H), 4.63 (s, 2H), 4.25 (t, J=4.0 Hz, 2H), 3.51 (t, J=4.0 Hz, 2H), 1.44 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 58 except that (S)-1-(3-(trifluoromethoxy)phenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.72 (br, OH, 1H), 8.47 (d, J=8.0 Hz, 1H), 7.71 (dd, J=0.8, 7.6 Hz, 1H), 7.55 (td, J=1.2, 7.6 Hz, 1H), 7.49-7.28 (m, 11H), 7.20 (m, 1H), 6.75 (d, J=7.6 Hz, 1H), 5.15 (m, 1H), 4.63 (s, 2H), 4.26 (t, J=4.0 Hz, 2H), 3.52 (t, J=4.0 Hz, 2H), 1.46 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 58 except that (S)-1-(3-(trifluoromethyl)phenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.74 (br, OH, 1H), 8.51 (d, J=7.6 Hz, 1H), 7.80-7.20 (m, 14H), 6.75 (d, J=8.4 Hz, 1H), 5.19 (m, 1H), 4.63 (s, 2H), 4.25 (t, J=4.0 Hz, 2H), 3.51 (t, J=4.0 Hz, 2H), 1.46 (d, J 10=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 58 except that (S)-1-(naphthalene-2-yl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.72 (br, OH, 1H), 8.50 (d, J=8.0 Hz, 1H), 7.90-7.80 (m, 4H), 7.71 (d, J=7.6 Hz, 1H), 7.58-7.28 (m, 12H), 6.74 (d, J=8.4 Hz, 1H), 5.29 (m, 1H), 4.63 (s, 2H), 4.25 (t, J=4.0 Hz, 2H), 3.51 (t, J=4.0 Hz, 2H), 1.54 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 58 except that pyridine-2-ylmethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.75 (br, OH, 1H), 8.76-8.73 (m, 1H), 8.53-8.52 (m, 1H), 7.83-7.80 (m, 1H), 7.71-7.69 (m, 1H), 7.57-7.54 (m, 1H), 7.46-7.42 (m, 1H), 7.38-7.30 (m, 9H), 6.76-6.74 (m, 1H), 4.64 (s, 2H), 4.54-4.52 (m, 2H), 4.26-4.25 (m, 2H), 3.52-3.38 (m, 2H).
The target compound was obtained by the same manner as described in Example 58 except that pyridine-3-ylmethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.75 (br, OH, 1H), 8.82-8.76 (m, 1H), 8.60 (m, 1H), 8.54-8.53 (m, 1H), 7.89-7.87 (m, 1H), 7.71-7.69 (m, 1H), 7.57-7.50 (m, 2H), 7.46-7.42 (m, 1H), 7.38-7.32 (m. 7H), 6.75-6.73 (m, 1H), 4.64 (s, 2H), 4.48-4.46 (m, 2H), 4.25-4.24 (m, 2H), 3.52 (m, 2H).
The target compound was obtained by the same manner as described in Example 58 except that pyridine-4-ylmethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.75 (br, OH, 1H), 8.84-8.81 (m, 1H), 8.60 (m, 2H), 7.71-7.69 (m, 1H), 7.58-7.54 (m, 1H), 7.49-7.42 (m, 3H), 7.38-7.35 (m, 2H), 7.33-7.31 (m, 5H), 6.77-6.75 (m, 1H), 4.65 (s, 2H), 4.52-4.50 (m, 2H), 4.26-4.25 (m, 2H), 3.54-3.53 (m, 2H).
The target compound was obtained by the same manner as described in Example 58 except that phenylmethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.75 (br, OH, 1H), 8.69-8.66 (m, 1H), 7.71-7.69 (m, 1H), 7.58-7.54 (m, 1H), 7.46-7.42 (m, 1H), 7.38-7.26 (m, 1H), 7.23-7.20 (m, 1H), 6.75-6.72 (m, 1H), 4.63 (s, 2H), 4.43-4.41 (m, 2H), 4.26-4.24 (m, 2H), 3.52-3.50 (m, 2H).
The target compound was obtained by the same manner as described in Example 58 except that (2-bromophenyl)methaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.75 (br, OH, 1H), 8.71-8.64 (m, 1H), 7.71-7.69 (m, 1H), 7.62-7.59 (m, 1H), 7.58-7.54 (m, 1H), 7.46-7.42 (m, 1H), 7.39-7.33 (m, 8H), 7.28-7.24 (m, 1H), 7.22-7.18 (m, 1H), 6.77-6.75 (m, 1H), 4.65 (s, 2H), 4.44-4.43 (m, 2H), 4.28-4.25 (m, 2H), 3.54-3.52 (m, 2H).
The target compound was obtained by the same manner as described in Example 58 except that (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methylamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 8.62-8.59 (m, 1H), 7.56-7.54 (m, 1H), 7.41-7.39 (m, 2H), 7.35-7.30 (m, 4H), 7.25-7.23 (m, 3H), 6.78-6.71 (m, 4H), 4.60 (s, 2H), 4.29-4.27 (m, 2H), 4.26-4.25 (m, 2H), 4.19 (s, 4H), 3.51 (m, 2H).
The target compound was obtained by the same manner as described in Example 59 except that (R)-4′-((7-((1-(4-cyanophenyl)ethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 81 was used instead of (S)-4′-((7-((1-phenylethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid (50 mg, 0.1 mmol).
1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 2H), 7.66 (s, 1H), 7.54 (d, J=8.0 Hz, 2H), 7.50-7.20 (m, 11H), 6.74 (d, J=8.4 Hz, 1H), 5.14 (m, 1H), 4.62 (s, 2H), 4.26 (t, J=4.0 Hz, 2H), 3.52 (t, J=4.0 Hz, 2H), 1.42 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 59 except that (S)-4′-((7-((1-(3-fluorophenyl)ethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 84 was used instead of (S)-4′-((7-((1-phenylethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid (50 mg, 0.1 mmol).
1H NMR (400 MHz, CDCl3) δ 7.77-7.75 (m, 1H), 7.54-7.50 (m, 1H), 7.46-7.43 (m, 3H), 7.38-7.28 (m, 6H), 7.17-7.15 (m, 1H), 7.09-7.06 (m, 1H), 6.98-6.94 (m, 1H), 6.67-6.65 (m, 1H), 6.15-6.13 (m, NH, 1H), 5.46 (br, NH, 1H), 5.34-5.27 (m, 2H), 4.59 (s, 2H), 4.33-4.31 (m, 2H), 3.54-3.47 (m, 2H), 1.58-1.56 (m, 3H).
The target compound was obtained by the same manner as described in Example 59 except that (S)-4′-((7-((1-(naphthalene-2-yl)ethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 87 was used instead of (S)-4′-((7-((1-phenylethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid (50 mg, 0.1 mmol).
1H NMR (400 MHz, CDCl3) δ 7.85-7.82 (m, 4H), 7.77-7.74 (m, 1H), 7.53-7.42 (m, 8H), 7.37-7.35 (m, 1H), 7.33-7.29 (m, 3H), 6.66-6.64 (m, 1H), 6.25-6.23 (m, NH, 1H), 5.51-5.46 (m, 1H), 5.46 (br, NH, 1H), 5.32 (br, NH, 1H), 4.58 (s, 2H), 4.32-4.30 (m, 2H), 3.53-3.49 (m, 2H), 1.67-1.67 (m, 3H).
The target compound was obtained by the same manner as described in Example 59 except that 4′-((7-((pyridine-3-ylmethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 89 was used instead of (S)-4′-((7-((1-phenylethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid (50 mg, 0.1 mmol).
1H NMR (400 MHz, DMSO-d6) δ 8.72-8.70 (m, 1H), 8.51 (m, H), 8.44-8.43 (m, 1H), 7.68-7.64 (m, 2H), 7.48-7.26 (m, 12H), 6.75-6.72 (m, 1H), 4.62 (s, 2H), 4.44-4.42 (m, 2H), 4.26-4.24 (m, 2H), 3.53-3.50 (m, 2H).
The target compound was obtained by the same manner as described in Example 59 except that 4′-((7-((pyridine-4-ylmethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 90 was used instead of (S)-4′-((7-((1-phenylethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid (50 mg, 0.1 mmol).
1H NMR (400 MHz, DMSO-d6) δ 8.76-8.73 (m, 1H), 8.49-8.47 (m, 2H), 7.65 (m, 1H), 7.49-7.43 (m, 1H), 7.41-7.35 (m, 6H), 7.32-7.25 (m, 6H), 6.76-6.74 (m, 1H), 4.63 (s, 2H), 4.44-4.42 (m, 2H), 4.27-4.25 (m, 2H), 3.54-3.52 (m, 2H).
The target compound was obtained by the same manner as described in Example 59 except that (S)-4′-((7-((1-(4-((trifluoromethyl)thio)phenyl)ethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 77 was used instead of (S)-4′-((7-((1-phenylethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid (50 mg, 0.1 mmol).
1H NMR (400 MHz, DMSO-d6) δ 8.50-8.48 (m, 1H), 7.67-7.65 (m, 3H), 7.51-7.27 (m, 13H), 6.74-6.72 (m, 1H), 5.16-5.13 (m, 1H), 4.62 (s, 2H), 4.26-4.25 (m, 2H), 3.52-3.51 (m, 2H), 1.46-4.11 (m, 3H).
The target compound was obtained by the same manner as described in Example 59 except that 4′-((7-(benzylcarbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 91 was used instead of (S)-4′-((7-((1-phenylethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid (50 mg, 0.1 mmol).
1H NMR (400 MHz, CDCl3) δ 7.77-7.74 (m, 1H), 7.54-7.50 (m, 1H), 7.49-7.42 (m, 3H), 7.38-7.28 (m, 10H), 6.66-6.64 (m, 1H), 6.24-6.21 (m, NH, 1H), 5.59 (br, NH, 1H), 5.34 (br, NH, 1H), 4.64-4.63 (m, 2H), 4.59 (s, 2H), 4.32-4.30 (m, 2H), 3.53-3.51 (m, 2H).
The target compound was obtained by the same manner as described in Example 59 except that 4′-((7-((2-bromobenzyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 92 was used instead of (S)-4′-((7-((1-phenylethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid (50 mg, 0.1 mmol).
1H NMR (400 MHz, CDCl3) δ 7.70-7.75 (m, 1H), 7.58-7.56 (m, 1H), 7.54-7.48 (m, 2H), 7.46-7.42 (m, 4H), 7.38-7.36 (m, 1H), 7.33-7.28 (m, 4H), 7.18-7.14 (m, 1H), 6.66-6.64 (m, 1H), 6.49-6.46 (m, NH, 1H), 5.48 (br, NH, 1H), 5.32 (br, NH, 1H), 4.70-4.69 (m, 2H), 4.59 (s, 2H), 4.33-4.30 (m, 2H), 3.54-3.51 (m, 2H).
The target compound was obtained by the same manner as described in Example 59 except that 4′-((7-(((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 93 was used instead of (S)-4′-((7-((1-phenylethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid (50 mg, 0.1 mmol).
1H NMR (400 MHz, CDCl3) δ 7.77-7.75 (m, 1H), 7.53-7.50 (m, 1H), 7.48-7.42 (m, 3H), 7.38-7.36 (m, 1H), 7.33-7.31 (m, 2H), 7.28-7.27 (m, 2H), 6.86-6.81 (m, 3H), 6.65-6.63 (m, 1H), 6.16-6.14 (m, NH, 1H), 5.50 (br, NH, 1H), 5.34 (br, NH, 1H), 4.58 (s, 2H), 4.51-4.50 (m, 2H), 4.32-4.30 (m, 2H), 4.26 (s, 4H), 3.53-3.51 (m, 2H).
(S)-4′-((7-((1-phenylethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid (300 mg, 0.61 mmol) obtained in Example 58 was dissolved in MeOH (10 ml) in a 25 mL flask, to which NaOH (24.4 mg, 0.61 mmol) was added, followed by stirring at room temperature for 5 hours.
Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure. As a result, sodium (S)-4′-((7-((1-phenylethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylate was obtained (300 mg).
1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J=8.0 Hz, 1H), 7.48 (m, 2H), 7.39-7.25 (m, 7H), 7.23-7.15 (m, 6H), 6.74 (d, J=8.4 Hz, 1H), 5.12 (m, 1H), 4.58 (s, 2H), 4.24 (t, J=4.0 Hz, 2H), 3.51 (t, J=4.0 Hz, 2H), 1.44 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 103 except that (S)-4′-((7-((1-(4-cyanophenyl)ethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 74 was used instead of (S)-4′-((7-((1-phenylethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J=7.6 Hz, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.54, (d, J=8.4 Hz, 2H), 7.49-7.42 (m, 3H), 7.39-7.30 (m, 2H), 7.28-7.15 (m, 5H), 6.73 (d, J=8.4 Hz, 1H), 5.14 (m, 1H), 4.56 (s, 2H), 4.22 (t, J=4.0 Hz, 2H), 3.48 (t, J=4.0 Hz, 2H), 1.44 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 103 except that (S)-4′-((7-((1-(4-nitrophenyl)ethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 60 was used instead of (S)-4′-((7-((1-phenylethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J=7.6 Hz, 1H), 8.16 (d, J=8.4 Hz, 2H), 7.61 (d, J=8.8 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 7.37-7.16 (m, 8H), 6.75 (d, J=8.8 Hz, 1H), 5.18 (m, 1H), 4.59 (s, 2H), 4.25 (t, J=4.0 Hz, 2H), 3.52 (t, J=4.0 Hz, 2H), 1.46 (d, J=7.2 Hz, 3H).
1-((2′-(tert-butoxycarbonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)methyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (300 mg, 0.67 mmol) obtained in Preparative Example 3 was dissolved in CH2Cl2 (10 ml) in a 100 mL flask, to which HATU (386 mg, 1.01 mmol) and DIPEA (353 ul, 2.02 mmol) were added, followed by stirring at room temperature for 12 hours. Upon completion of the reaction, the organic layer was separated by using CH2Cl2 and H2O. The separated organic layer was dried over MgSO4 and filtered. The mixture was separated by column chromatography (EA/n-Hex=1:1) to give (S)-tert-butyl 3′-fluoro-4′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylate (169 mg, 0.295 mmol, 44%).
(S)-tert-butyl 3′-fluoro-4′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylate (168 mg, 0.3 mmol) obtained in step 1 was dissolved in CH2Cl2 (10 ml) in a 50 mL flask, to which 30% TFA (3 ml) was added, followed by stirring at room temperature for 5 hours. Upon completion of the reaction the reaction mixture was concentrated under reduced pressure. The mixture was separated by column chromatography (EA) to give (S)-1-((2′-carbamoyl-3-fluoro-[1,1′-biphenyl]-4-yl)methyl)-N-(1-phenylethyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (83 mg, 0.16 mmol, 54%).
1H NMR (400 MHz, CDCl3) δ 7.93 (d, J=7.2 Hz, 1H), 7.56-7.25 (m, 10H), 7.10-7.07 (m, 2H), 7.02-7.00 (m, 1H), 6.45 (d, J=7.6 Hz, 1H), 6.16 (d, J=7.6 Hz, 1H), 5.38-5.32 (m, 1H), 4.60 (s, 2H), 3.47 (t, J=4.0 Hz, 2H), 2.85 (t, J=4.0 Hz, 2H), 2.03 (t, J=4.0 Hz, 2H), 1.57 (d, J=6.8 Hz, 3H).
(S)-1-((2′-carbamoyl-3-fluoro-[1,1′-biphenyl]-4-yl)methyl)-N-(1-phenylethyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (78 mg, 0.15 mmol) obtained in Example 106 was dissolved in CH2Cl2 (2 ml) in a 25 mL flask, to which EDCI (45 mg, 0.23 mmol) and HOBt (24 mg, 0.18 mmol) were added, followed by stirring. Ammonium hydroxide solution (3 ml) was added thereto, followed by stirring at room temperature for 5 hours. Upon completion of the reaction, the organic layer was separated by using CH2Cl2 and H2O. The separated organic layer was dried over MgSO4 and filtered. The mixture was separated by column chromatography (MeOH/n-Hex/CH2Cl2=0.5:0.5:9) to give (S)-1-((2′-carbamoyl-3-fluoro-[1,1′-biphenyl]-4-yl)methyl)-N-(1-phenylethyl)-1,2,3,4-tetrahydroquinoline-6-carboxamide (76 mg, 0.14 mmol, 97.6%).
1H NMR (400 MHz, CDCl3) δ 7.73-7.71 (m, 1H), 7.54-7.25 (m, 10H), 7.23-7.14 (m, 3H), 6.46 (d, J=8.8 Hz, 1H), 6.14 (d, J=8.0 Hz, 1H), 5.51 (s, 1H), 5.40 (s, 1H), 5.38-5.31 (m, 1H), 4.62 (s, 2H), 3.49 (t, J=5.6 Hz, 2H), 2.87 (t, J=6.4 Hz, 2H), 2.10-2.04 (m, 2H), 1.59 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 106 except that (S)-1-(naphthalene-2-yl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.82-7.80 (m, 4H), 7.54-7.36 (m, 8H), 7.32-7.30 (m, 1H), 7.09-7.07 (m, 2H), 7.02-6.98 (m, 1H), 6.43 (d, J=8.4 Hz, 1H), 6.26 (d, J=7.6 Hz, 1H), 5.51-5.47 (m, 1H), 4.58 (s, 2H), 3.44 (t, J=4.0 Hz, 2H), 2.83 (t, J=4.0 Hz, 2H), 2.01 (t, J=4.0 Hz, 2H), 1.65 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 106 except that (S)-1-(4-nitrophenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, CDCl3) δ 8.17 (d, J=8.8 Hz, 2H), 7.97 (d, J=7.6 Hz, 1H), 7.61-7.57 (m, 1H), 7.53-7.42 (m, 5H), 7.35 (d, J=7.6 Hz, 1H), 7.16-7.09 (m, 2H), 7.03 (d, J=8.0 Hz, 1H), 6.48 (d, J=8.4 Hz, 1H), 6.27 (d, J=7.2 Hz, 1H), 5.38-5.31 (m, 1H), 4.63 (s, 2H), 3.53-3.48 (m, 2H), 2.86 (t, J=6.0 Hz, 2H), 2.07-2.04 (m, 2H), 1.58 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 106 except that (S)-1-(4-cyanophenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, CDCl3) δ 7.98 (d, J=6.4 Hz, 1H), 7.68-7.58 (m, 3H), 7.49-7.42 (m, 6H), 7.36-7.33 (m, 2H), 7.16-7.09 (m, 2H), 7.05-7.02 (m, 1H), 6.49 (d, J=8.8 Hz, 1H), 6.19 (d, J=8.0 Hz, 1H), 5.35-5.30 (m, 1H), 4.64 (s, 2H), 3.51-3.48 (m, 2H), 2.87 (t, J=6.8 Hz, 2H), 2.07-2.00 (m, 2H), 1.57 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 106 except that (S)-1-(3-fluoro-4-methylphenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, CDCl3) δ 7.97 (d, J=8.0 Hz, 1H), 7.61-7.57 (m, 1H), 7.49-7.35 (m, 5H), 7.16-7.00 (m, 6H), 6.48 (d, J=8.8 Hz, 1H), 6.13 (d, J=7.2 Hz, 1H), 5.32-5.26 (m, 1H), 4.63 (s, 2H), 3.50 (t, J=6.4 Hz, 2H), 2.86 (t, J=5.6 Hz, 2H), 2.26 (s, 3H) 2.12-2.06 (m, 2H), 1.55 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 107 except that (S)-4′-((6-((1-(4-cyanophenyl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 110 was used instead of (S)-1-((2′-carbamoyl-3-fluoro-[1,1′-biphenyl]-4-yl)methyl)-N-(1-phenylethyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid.
1H NMR (400 MHz, CDCl3) δ 7.72 (d, J=8.0 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.54-7.43 (m, 6H), 7.36 (d, J=8.4 Hz, 1H), 7.23-7.15 (m, 3H), 6.48 (d, J=8.8 Hz, 1H), 6.17 (d, J=7.2 Hz, 1H), 5.48 (s, 1H), 5.41 (s, 1H), 5.36-5.29 (m, 1H), 4.64 (s, 2H), 3.51 (t, J=5.6 Hz, 2H), 2.88 (t, J=5.6 Hz, 2H), 2.09-2.05 (m, 2H), 1.58 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 107 except that (S)-3′-fluoro-4′-((6-((1-(4-nitrophenyl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 109 was used instead of (S)-1-((2′-carbamoyl-3-fluoro-[1,1′-biphenyl]-4-yl)methyl)-N-(1-phenylethyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid.
1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=8.8 Hz, 2H), 7.72 (d, J=6.8 Hz, 1H), 7.55-7.44 (m, 6H), 7.36 (d, J=5.6 Hz, 1H), 7.23-7.15 (m, 3H), 6.49 (d, J=8.8 Hz, 1H), 6.20 (d, J=7.2 Hz, 1H), 5.47 (s, 1H), 5.41 (s, 1H), 5.38-5.35 (m, 1H), 4.64 (s, 2H), 3.51 (t, J=5.6 Hz, 2H), 2.89 (t, J=6.0 Hz, 2H), 2.09-2.07 (m, 2H), 1.61 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 107 except that (S)-3′-fluoro-4′-((6-((1-(3-fluoro-4-methylphenyl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 111 was used instead of (S)-1-((2′-carbamoyl-3-fluoro-[1,1′-biphenyl]-4-yl)methyl)-N-(1-phenylethyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid.
1H NMR (400 MHz, CDCl3) δ 7.74-7.71 (m, 1H), 7.54-7.33 (m, 5H), 7.23-7.13 (m, 4H), 7.07-7.02 (m, 2H), 6.47 (d, J=8.4 Hz, 1H), 6.09 (d, J=7.6 Hz, 1H), 5.49 (s, 1H), 5.40 (s, 1H), 5.32-5.25 (m, 1H), 4.63 (s, 2H), 3.50 (t, J=5.2 Hz, 2H), 2.88 (t, J=6.0 Hz, 2H), 2.26 (s, 3H), 2.10-2.04 (m, 2H), 1.56 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 107 except that (S)-3′-fluoro-4′-((6-((1-(naphthalene-2-yl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 108 was used instead of (S)-1-((2′-carbamoyl-3-fluoro-[1,1′-biphenyl]-4-yl)methyl)-N-(1-phenylethyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid.
1H NMR (400 MHz, CDCl3) δ 7.85-7.83 (m, 4H), 7.73-7.71 (m, 1H), 7.53-7.43 (m, 7H), 7.37-7.35 (m, 1H), 7.22-7.14 (m 3H), 6.47 (d, J=8.8 Hz, 1H), 6.22 (d, J=7.6 Hz, 1H), 5.55-5.48 (m, 2H), 5.40 (s, 1H), 4.63 (s, 2H), 3.50 (t, J=5.6 Hz, 2H), 2.88 (t, J=6.0 Hz, 2H), 2.09-2.04 (m, 2H), 1.69 (d, J=6.8 Hz, 3H).
1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-3-yl)methyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (300 mg, 0.67 mmol) obtained in Preparative Example 4 was dissolved in CH2Cl2 (10 ml) in a 100 mL flask, to which HATU (386 mg, 1.01 mmol) and DIPEA (353 ul, 2.02 mmol) were added, followed by stirring at room temperature for 12 hours. Upon completion of the reaction, the organic layer was separated by using CH2Cl2 and H2O. The separated organic layer was dried over MgSO4 and filtered. The mixture was separated by column chromatography (EA/n-Hex=1:1) to give (S)-tert-butyl 3′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylate (169 mg, 0.29 mmol, 44%).
(S)-tert-butyl 3′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylate (168 mg, 0.3 mmol) obtained in step 1 was dissolved in CH2Cl2 (10 ml) in a 50 mL flask, to which 30% TFA (3 ml) was added, followed by stirring at room temperature for 5 hours. Upon completion of the reaction the reaction mixture was concentrated under reduced pressure. The mixture was separated by column chromatography (EA) to give (S)-3′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid (83 mg, 0.16 mmol, 54%).
1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=8.0 Hz, 1H), 7.56-7.52 (m, 1H), 7.43-7.32 (m, 10H), 7.27-7.21 (m, 2H), 7.14 (s, 1H), 6.46 (d, J=9.2 Hz, 1H), 6.17 (d, J=8.0 Hz, 1H), 5.35-5.28 (m, 1H), 4.56 (s, 2H), 3.44 (t, J=5.6 Hz, 2H), 2.81 (t, J=6.0 Hz, 2H), 2.02-1.96 (m, 2H), 1.56 (d, J=6.4 Hz, 3H).
(S)-3′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid (78 mg, 0.15 mmol) obtained in Example 116 was dissolved in CH2Cl2 (2 ml) in a 25 mL flask, to which EDCI (45 mg, 0.23 mmol) and HOBt (24 mg, 0.18 mmol) were added, followed by stirring at room temperature for 5 hours. Upon completion of the reaction, the organic layer was separated by using CH2Cl2 and H2O. The separated organic layer was dried over MgSO4 and filtered. The mixture was separated by column chromatography (MeOH/n-Hex/CH2Cl2=0.5:0.5:9) to give (S)-1-((2′-carbamoyl-[1,1′-biphenyl]-3-yl)methyl)-N-(1-phenylethyl)-1,2,3,4-tetrahydroquinoline-6-carboxamide (76 mg, 0.14 mmol, 97.6%).
1H NMR (400 MHz, CDCl3) δ 7.75-7.73 (m, 1H), 7.54-7.02 (m, 14H), 6.45 (d, J=8.8 Hz, 1H), 6.17 (d, J=8.0 Hz, 1H), 5.37-5.30 (m, 1H), 5.13 (s, 2H), 4.59 (s, 2H), 3.53-3.48 (m, 2H), 2.87 (t, J=6.4 Hz, 2H), 2.07-2.03 (m, 2H), 1.59 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 116 except that (S)-1-(4-cyanophenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=7.6 Hz, 1H), 7.60-7.53 (m, 3H), 7.45-7.33 (m, 8H), 7.26-7.23 (m, 1H), 7.14 (s, 1H), 6.44 (d, J=8.8 Hz, 1H), 6.28 (d, J=7.6 Hz, 1H), 5.31-5.24 (m, 1H), 4.58 (s, 2H), 3.47 (t, J=5.2 Hz, 2H), 2.82 (t, J=6.0 Hz, 2H), 2.07-1.99 (m, 2H), 1.51 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 116 except that (S)-1-(4-nitrophenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, CDCl3) δ 8.14 (d, J=8.8 Hz, 2H), 7.57-7.53 (m, 1H), 7.48-7.34 (m, 8H), 7.27-7.23 (m, 2H), 7.14 (s, 1H), 6.42 (d, J=8.8 Hz, 1H), 6.35 (d, J=7.2 Hz, 1H), 5.34-5.28 (m, 1H), 4.58 (s, 2H), 3.46 (t, J=6.0 Hz, 2H), 2.81 (t, J=6.0 Hz, 2H), 2.07-1.97 (m, 2H), 1.52 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 116 except that (S)-1-(naphthalene-2-yl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, CDCl3) δ 7.89-7.81 (m, 5H), 7.55-7.33 (m, 9H), 7.28-7.21 (m, 2H), 7.14 (s, 1H), 6.46 (d, J=9.2 Hz, 1H), 6.27 (d, J=8.0 Hz, 1H), 5.52-5.45 (m, 1H), 4.56 (s, 2H), 3.43 (t, J=5.6 Hz, 2H), 2.80 (t, J=6.0 Hz, 2H), 2.07-1.95 (m, 2H), 1.54 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 116 except that (S)-1-(3-fluoro-4-methylphenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, CDCl3) δ 7.88 (d, J=7.2 Hz, 1H), 7.56-7.52 (m, 1H), 7.42-7.34 (m, 5H), 7.25-7.21 (m, 2H), 7.14-7.11 (m, 2H), 7.04-6.99 (m, 2H), 6.46 (d, J=9.2 Hz, 1H), 6.15 (d, J=7.6 Hz, 1H), 5.29-5.21 (m, 1H), 4.57 (s, 2H), 3.44 (t, J=6.0 Hz, 2H), 2.81 (t, J=6.0 Hz, 2H), 2.25 (s, 3H), 2.01-1.98 (m. 2H), 1.52 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 117 except that (S)-3′-((6-((1-(4-cyanophenyl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 118 was used instead of (S)-3′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, CDCl3) δ 7.75-7.73 (m, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.54-7.31 (m, 11H), 6.46 (d, J=8.8 Hz, 2H), 6.29 (d, J=6.8 Hz, 2H), 5.34-5.27 (m, 1H), 5.14 (s, 2H), 4.60 (s, 2H), 3.53-3.47 (m, 2H), 2.87 (t, J=6.8 Hz, 2H), 2.09-2.03 (m, 2H), 1.57 (d, J=3.6 Hz, 3H).
The target compound was obtained by the same manner as described in Example 117 except that (S)-3′-((6-((1-(4-nitrophenyl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 119 was used instead of (S)-3′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, CDCl3) δ 8.20-8.18 (m, 2H), 7.75-7.73 (m, 1H), 7.55-7.49 (m, 3H), 7.46-7.41 (m, 4H), 7.38-7.36 (m, 2H), 7.31-7.28 (m, 2H), 6.46 (d, J=8.8 Hz, 1H), 6.34 (d, J=7.2 Hz, 1H), 5.36-5.32 (m, 1H), 5.14 (s, 2H), 4.60 (s, 2H), 3.54-3.48 (m, 2H), 2.87 (t, J=6.0 Hz, 2H), 2.09-2.03 (m, 2H), 1.59 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 117 except that (S)-3′-((6-((1-(naphthalene-2-yl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 120 was used instead of (S)-3′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, CDCl3) δ 7.98-7.81 (m, 4H), 7.74-7.73 (m, 1H), 7.54-7.28 (m, 12H), 6.46 (d, J=8.8 Hz, 1H), 6.27 (d, J=7.2 Hz, 1H), 5.52-5.49 (m, 1H), 5.13 (s, 2H), 4.59 (s, 2H), 3.51-3.48 (m, 2H), 2.87 (t, J=5.6 Hz, 2H), 2.09-2.05 (m, 2H), 1.67 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 117 except that (S)-3′-((6-((1-(3-fluoro-4-methylphenyl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 121 was used instead of (S)-3′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, CDCl3) δ 7.75-7.30 (m, 1H), 7.54-7.23 (m, 10H), 7.16-7.13 (m, 1H), 7.07-7.01 (m, 2H), 6.46 (d, J=8.8 Hz, 1H), 6.15 (d, J=8.0 Hz, 1H), 5.30-5.23 (m, 1H), 5.09 (s, 2H), 4.59 (s, 2H), 3.53-3.48 (m, 2H), 2.87 (t, J=6.0 Hz, 2H), 2.26 (s, 2H), 2.09-2.04 (m, 3H), 1.55 (d, J=6.8 Hz, 3H).
1-((2′-(tert-butoxycarbonyl)-2-fluoro-[1,1′-biphenyl]-3-yl)methyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (300 mg, 0.67 mmol) obtained in Preparative Example 5 was dissolved in CH2Cl2 (10 ml) in a 50 mL flask, to which HATU (386 mg, 1.01 mmol) and DIPEA (353 ul, 2.02 mmol) were added, followed by stirring. (S)-1-phenylethylamine (105 ul, 0.81 mmol) was added, followed by stirring at room temperature for 12 hours. Upon completion of the reaction, the organic layer was separated by using CH2Cl2 and H2O. The separated organic layer was dried over MgSO4 and filtered. The mixture was separated by column chromatography (EA/n-Hex=1:1) to give (S)-tert-butyl 2′-fluoro-3′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylate (169 mg, 0.29 mmol, 44%).
(S)-tert-butyl 2′-fluoro-3′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylate (168 mg, 0.3 mmol) obtained in step 1 was dissolved in CH2Cl2 (10 ml) in a 50 mL flask, to which 30% TFA (3 ml) was added, followed by stirring at room temperature for 5 hours. Upon completion of the reaction the reaction mixture was concentrated under reduced pressure. The mixture was separated by column chromatography (EA) to give (S)-2′-fluoro-3′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid (83 mg, 0.16 mmol, 54%).
1H NMR (400 MHz, CDCl3) δ 8.08 (d, J=7.2 Hz, 1H), 7.66-7.62 (m, 1H), 7.54-7.33 (m, 9H), 7.25-7.21 (m, 2H), 7.17-7.02 (m, 1H), 6.47 (d, J=8.4 Hz, 1H), 6.14 (d, J=7.6 Hz, 1H), 5.36-5.32 (m, 1H), 4.57 (s, 2H), 3.46 (d, J=5.6 Hz, 1H), 2.84 (t, J=6.0 Hz, 2H), 2.07-2.00 (m, 2H), 1.58 (d, J=6.8 Hz, 3H).
(S)-2′-fluoro-3′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid (78 mg, 0.15 mmol) obtained in Example 126 was dissolved in CH2Cl2 (2 ml) in a 25 mL flask, to which EDCI (45 mg, 0.23 mmol) and HOBt (24 mg, 0.18 mmol) were added, followed by stirring. Ammonium hydroxide solution (3 ml) was added thereto, followed by stirring at room temperature for 5 hours. Upon completion of the reaction, the organic layer was separated by using CH2Cl2 and H2O. The separated organic layer was dried over MgSO4 and filtered. The mixture was separated by column chromatography (MeOH/n-Hex/CH2Cl2=0.5:0.5:9) to give (S)-1-((2′-carbamoyl-2-fluoro-[1,1′-biphenyl]-3-yl)methyl)-N-(1-phenylethyl)-1,2,3,4-tetrahydroquinoline-6-carboxamide (76 mg, 0.14 mmol, 97.6%).
1H NMR (400 MHz, CDCl3) δ 7.83-7.81 (m, 1H), 7.59-7.54 (m, 1H), 7.52-7.48 (m, 2H), 7.45-7.26 (m, 8H), 7.21-7.13 (m, 2H), 7.31-7.28 (m, 2H), 6.46 (d, J=8.8 Hz, 1H), 6.15 (d, J=8.4 Hz, 1H), 5.45-5.32 (m, 3H), 4.62 (s, 2H), 3.49 (d, J=6.0 Hz, 1H), 2.87 (t, J=6.8 Hz, 2H), 2.09-2.03 (m, 2H), 1.59 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 126 except that (S)-1-(4-nitrophenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, CDCl3) δ 8.19-8.17 (m, 2H), 7.10-7.08 (m, 1H), 7.78-7.63 (m, 1H), 7.53-7.39 (m, 6H), 7.26-7.24 (m, 1H), 7.16-7.13 (m, 2H), 6.49 (d, J=8.4 Hz, 1H), 6.22 (d, J=6.8 Hz, 1H), 5.37-5.32 (m, 1H), 4.59 (s, 2H), 3.49 (t, J=6.0 Hz, 2H), 2.85 (t, J=6.4 Hz, 2H), 2.07-2.03 (m, 2H), 1.57 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 126 except that (S)-1-(naphthalene-2-yl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, CDCl3) δ 8.08-8.06 (m, 1H), 7.84-7.81 (m, 4H), 7.63-7.59 (m, 1H), 7.54-7.43 (m, 6H), 7.39-7.37 (m, 1H), 7.23-7.20 (m, 1H), 7.16-7.09 (m, 2H), 6.46 (d, J=8.4 Hz, 1H), 6.23 (d, J=8.4 Hz, 1H), 5.52-5.49 (m, 1H), 4.55 (s, 2H), 3.45 (t, J=6.0 Hz, 2H), 2.83 (t, J=6.0 Hz, 2H), 2.07-2.00 (m, 2H), 1.66 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 126 except that (S)-1-(3-fluoro-4-methylphenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, CDCl3) δ 8.10-8.08 (m, 1H), 7.66-7.62 (m, 1H), 7.54-7.39 (m, 4H), 7.25-7.21 (m, 1H), 7.16-7.10 (m, 3H), 7.06-7.00 (m, 2H), 6.48 (d, J=8.8 Hz, 1H), 6.10 (d, J=7.2 Hz, 1H), 5.29-5.26 (m, 1H), 4.58 (s, 2H), 3.47 (t, J=6.0 Hz, 2H), 2.85 (t, J=5.6 Hz, 2H), 2.25 (s, 3H), 2.07-2.01 (m, 2H), 1.54 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 127 except that (S)-2′-fluoro-3′-((6-((1-(4-nitrophenyl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 128 was used instead of (S)-2′-fluoro-3′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, CDCl3) δ 8.21-8.19 (m, 2H), 7.82-7.80 (m, 1H), 7.60-7.49 (m, 5H), 7.46-7.45 (m, 1H), 7.44-7.43 (m, 1H), 7.41-7.39 (m, 1H), 7.21-7.14 (m, 2H), 6.49 (d, J=8.8 Hz, 1H), 6.26 (d, J=6.8 Hz, 1H), 5.46-5.32 (m, 3H), 4.63 (s, 2H), 3.51 (t, J=5.6 Hz, 2H), 2.87 (t, J=6.0 Hz, 2H), 2.10-2.04 (m, 2H), 1.60 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 127 except that (S)-2′-fluoro-3′-((6-((1-(naphthalene-2-yl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 129 was used instead of (S)-2′-fluoro-3′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, CDCl3) δ 7.85-7.80 (m, 5H), 7.59-7.45 (m, 7H), 7.40-7.38 (m, 1H), 7.31-7.28 (m, 1H), 7.21-7.13 (m, 2H), 6.47 (d, J=8.8 Hz, 1H), 6.24 (d, J=8.0 Hz, 1H), 5.53-5.40 (m, 3H), 4.62 (s, 2H), 3.49 (t, J=5.6 Hz, 2H), 2.87 (t, J=6.0 Hz, 2H), 2.07-2.04 (m, 2H), 1.69 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 127 except that (S)-2′-fluoro-3′-((6-((1-(3-fluoro-4-methylphenyl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 130 was used instead of (S)-2′-fluoro-3′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, CDCl3) δ 7.83-7.81 (m, 1H), 7.59-7.54 (m, 1H), 7.52-7.48 (m, 2H), 7.44-7.39 (m, 2H), 7.32-7.28 (m, 2H), 7.21-7.13 (m, 3H), 7.07-7.02 (m, 2H), 6.47 (d, J=8.4 Hz, 1H), 6.11 (d, J=7.6 Hz, 1H), 5.45-5.40 (m, 2H), 5.32-5.25 (m, 1H), 4.63 (s, 2H), 3.49 (t, J=5.2 Hz, 2H), 2.87 (t, J=6.4 Hz, 2H), 2.26 (s, 3H), 2.09-2.03 (m, 2H), 1.56 (d, J=8.4 Hz, 3H).
1-((2′-(tert-butoxycarbonyl)-4-fluoro-[1,1′-biphenyl]-3-yl)methyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (300 mg, 0.67 mmol) obtained in Preparative Example 6 was dissolved in CH2Cl2 (10 ml) in a 100 mL flask, to which HATU (386 mg, 1.01 mmol) and DIPEA (353 ul, 2.02 mmol) were added, followed by stirring at room temperature for 12 hours. Upon completion of the reaction, the organic layer was separated by using CH2Cl2 and H2O. The separated organic layer was dried over MgSO4 and filtered. The mixture was separated by column chromatography (EA/n-Hex=1:1) to give (S)-tert-butyl 4′-fluoro-3′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylate (169 mg, 0.29 mmol, 44%).
(S)-tert-butyl 4′-fluoro-3′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylate (168 mg, 0.3 mmol) obtained in step 1 was dissolved in CH2Cl2 (10 ml) in a 50 mL flask, to which 30% TFA (3 ml) was added, followed by stirring at room temperature for 5 hours. Upon completion of the reaction the reaction mixture was concentrated under reduced pressure. The mixture was separated by column chromatography (EA) to give (S)-4′-fluoro-3′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid (83 mg, 0.16 mmol, 54%).
1H NMR (400 MHz, CDCl3) δ 7.85-7.83 (d, J=7.2 Hz, 1H), 7.54-7.44 (m, 2H), 7.39-7.34 (m, 7H), 7.25-7.23 (m, 2H), 7.15-7.10 (m, 1H), 6.44 (d, J=8.8 Hz, 1H), 6.21 (d, J=8.0 Hz, 1H), 5.32-5.28 (m, 1H), 4.61 (s, 2H), 3.45 (d, J=5.6 Hz, 1H), 2.79 (t, J=6.4 Hz, 2H), 2.01-1.95 (m, 2H), 1.53 (d, J=5.6 Hz, 3H).
(S)-4′-fluoro-3′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid (78 mg, 0.15 mmol) obtained in Example 134 was dissolved in CH2Cl2 (2 ml) in a 25 mL flask, to which EDCI (45 mg, 0.23 mmol) and HOBt (24 mg, 0.18 mmol) were added, followed by stirring at room temperature for 5 hours. Upon completion of the reaction, the organic layer was separated by using CH2Cl2 and H2O. The separated organic layer was dried over MgSO4 and filtered. The mixture was separated by column chromatography (MeOH/n-Hex/CH2Cl2=0.5:0.5:9) to give (S)-1-((2′-carbamoyl-4-fluoro-[1,1′-biphenyl]-3-yl)methyl)-N-(1-phenylethyl)-1,2,3,4-tetrahydroquinoline-6-carboxamide (76 mg, 0.14 mmol, 97.6%).
1H NMR (400 MHz, CDCl3) δ 7.64-7.62 (m, 1H), 7.49-7.33 (m, 11H), 7.25-7.23 (m, 1H), 7.19-7.15 (m, 1H), 6.43 (d, J=7.2 Hz, 1H), 6.20 (d, J=7.6 Hz, 1H), 5.34-5.30 (m, 1H), 5.10 (s, 1H), 5.01 (s, 1H), 4.62 (s, 2H), 3.52 (d, J=6.0 Hz, 1H), 2.87 (t, J=5.6 Hz, 2H), 2.07-2.04 (m, 2H), 1.59 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 134 except that (S)-1-(4-nitrophenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, CDCl3) δ 8.10-8.08 (m, 2H), 7.84-7.82 (m, 1H), 7.53-7.50 (m, 1H), 7.41-7.37 (m, 4H), 7.28-7.21 (m, 3H), 7.14-7.09 (m, 1H), 7.01-6.99 (m, 1H), 6.52 (d, J=7.6 Hz, 1H), 6.29 (d, J=8.4 Hz, 1H), 5.27-5.23 (m, 1H), 4.62 (s, 2H), 3.48 (t, J=5.2 Hz, 2H), 2.80 (t, J=6.4 Hz, 2H), 2.07-2.00 (m, 2H), 1.47 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 134 except that (S)-1-(naphthalene-2-yl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, CDCl3) δ 7.84-7.80 (m, 5H), 7.54-7.44 (m, 5H), 7.38-7.35 (m, 2H), 7.27-7.22 (m, 2H), 7.15-7.10 (m, 1H), 7.00-6.98 (m, 1H), 6.43 (d, J=8.8 Hz, 1H), 6.33 (d, J=8.0 Hz, 1H), 5.48-5.44 (m, 1H), 4.60 (s, 2H), 3.44 (t, J=6.0 Hz, 2H), 2.77 (t, J=6.0 Hz, 2H), 2.00-1.94 (m, 2H), 1.63 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 134 except that (S)-1-(3-fluoro-4-methylphenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, CDCl3) δ 7.84 (t, J=7.6 Hz, 2H), 7.54-7.49 (m, 1H), 7.44-7.34 (m, 4H), 7.26-7.23 (m, 2H), 7.15-7.11 (m, 2H), 7.04-6.99 (m, 3H), 6.43 (d, J=8.8 Hz, 1H), 6.20 (d, J=8.0 Hz, 1H), 5.25-5.22 (m, 1H), 4.62 (s, 2H), 3.46 (t, J=5.6 Hz, 2H), 2.80 (t, J=6.0 Hz, 2H), 2.25 (s, 3H), 2.07-1.98 (m, 2H), 1.51 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 135 except that (S)-4′-fluoro-3′-((6-((1-(4-nitrophenyl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 136 was used instead of (S)-4′-fluoro-3′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, CDCl3) δ 8.18-8.16 (m, 2H), 7.65-7.62 (m, 1H), 7.54-7.28 (m, 8H), 7.23-7.15 (m, 2H), 6.49 (d, J=7.2 Hz, 1H), 6.40 (d, J=8.4 Hz, 1H), 5.34-5.28 (m, 1H), 5.21 (s, 1H), 5.11 (s, 1H), 4.64 (s, 2H), 3.53 (t, J=5.6 Hz, 2H), 2.86 (t, J=6.0 Hz, 2H), 2.08-2.03 (m, 2H), 1.58 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 135 except that (S)-4′-fluoro-3′-((6-((1-(naphthalene-2-yl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 137 was used instead of (S)-4′-fluoro-3′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, CDCl3) δ 7.84-7.82 (m, 4H), 7.63-7.61 (m, 1H), 7.54-7.45 (m, 7H), 7.41-7.34 (m, 2H), 7.25-7.23 (m, 1H), 7.17-7.14 (m, 1H), 6.43 (d, J=9.2 Hz, 1H), 6.31 (d, J=7.6 Hz, 1H), 5.51-5.47 (m, 1H), 5.10 (s, 1H), 5.03 (s, 1H), 4.62 (s, 2H), 3.52 (t, J=6.0 Hz, 2H), 2.86 (t, J=6.4 Hz, 2H), 2.07-2.04 (m, 2H), 1.68 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 135 except that (S)-4′-fluoro-3′-((6-((1-(3-fluoro-4-methylphenyl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid obtained in Example 138 was used instead of (S)-4′-fluoro-3′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid.
1H NMR (400 MHz, CDCl3) δ 7.64-7.62 (m, 1H), 7.54-7.34 (m, 7H), 7.30-7.28 (m, 1H), 7.25-7.22 (m, 1H), 7.19-7.12 (m, 2H), 7.07-7.01 (m, 2H), 6.43 (d, J=9.2 Hz, 1H), 6.21 (d, J=7.2 Hz, 1H), 5.27-5.24 (m, 1H), 5.11 (s, 1H), 5.03 (s, 1H), 4.63 (s, 2H), 3.52 (t, J=6.0 Hz, 2H), 2.86 (t, J=6.4 Hz, 2H), 2.25 (s, 3H), 2.07-2.03 (m, 2H), 1.55 (d, J=6.8 Hz, 3H).
3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid (314 mg, 1.69 mmol) obtained in Preparative Example 7 was dissolved in CH2Cl2 (10 ml) in a 100 mL flask, to which HATU (969 mg, 1.54 mmol) and DIPEA (888 ul, 5.09 mmol) were added, followed by stirring. (S)-1-phenylethylamine (547 ul, 4.24 mmol) was added, followed by stirring at room temperature for 12 hours. Upon completion of the reaction, the organic layer was separated by using CH2Cl2 and H2O. The separated organic layer was dried over MgSO4 and filtered. The mixture was separated by column chromatography (EA/n-Hex=1:1) to give (S)—N-(1-phenylethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (210 mg, 1.34 mmol, 79%).
(S)—N-(1-phenylethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (210 mg, 0.83 mmol) was dissolved in DMF (3 ml) in a 25 mL flask, to which NaH (33 mg, 0.83 mmol) and methyl 2′-(bromomethyl)-[1,1′-biphenyl]-4-carboxylate (254 mg, 0.83 mmol) were added, followed by stirring at room temperature for 12 hours. The organic layer was separated by using ethyl acetate and brine. The separated organic layer was dried over MgSO4 and filtered. The solvent was eliminated from the mixture via vacuum distillation, followed by column chromatography to give (S)-methyl 2′-((7-((1-phenylethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-4-carboxylate (160 mg).
(S)-methyl 2′-((7-((1-phenylethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-4-carboxylate (160 mg, 0.31 mmol) was dissolved in MeOH (5 ml) and THF (10 ml) in a 25 mL flask, to which LiOH (2 g) dissolved in H2O (5 ml) was added, followed by stirring at room temperature for 12 hours. Upon completion of the reaction, the solvent was concentrated. PH of the reaction mixture was adjusted to 5 by using 2N-HCl. The mixture was extracted with EA. The organic layer was dried over MgSO4 and filtered. As a result, (S)-2′-((7-((1-phenylethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-4-carboxylic acid (180 mg) was obtained (3 g).
1H NMR (400 MHz, CDCl3) δ 8.18 (d, J=8.4 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 7.40-7.20 (m, 11H), 6.43 (d, J=8.8 Hz, 1H), 6.13 (d, J=7.6 Hz, 1H), 5.34-5.30 (m, 1H), 4.43 (s, 2H), 4.19 (t, J=4.0 Hz, 2H), 3.35 (t, J=4.4 Hz, 2H), 1.58 (d, J=6.8 Hz, 3H).
(S)-2′-((7-((1-phenylethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-4-carboxylic acid (70 mg, 0.14 mmol) obtained in Example 142 was dissolved in CH2Cl2 (2 ml) in a 25 mL flask, to which EDCI (41 mg, 0.21 mmol) and HOBt (23 mg, 0.17 mmol) were added, followed by stirring at room temperature for 5 hours. Upon completion of the reaction, the organic layer was separated by using CH2Cl2 and H2O. The separated organic layer was dried over MgSO4 and filtered. The mixture was separated by column chromatography (MeOH/n-Hex/CH2Cl2=0.5:0.5:9) to give (S)-4-((4′-carbamoyl-[1,1′-biphenyl]-2-yl)methyl)-N-(1-phenylethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (30 mg, 0.06 mmol, 42.9%).
1H NMR (400 MHz, CDCl3) δ 7.85 (d, J=8.4 Hz, 2H), 7.50-7.28 (m, 11H), 7.20-7.15 (m, 2H), 6.37 (d, J=8.4 Hz, 1H), 6.16-6.14 (m, 2H), 5.55 (s, 1H), 5.35-5.27 (m, 1H), 4.42 (s, 2H), 4.16 (t, J=4.0 Hz, 2H), 3.32 (t, J=4.4 Hz, 2H), 1.59 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 142 except that (S)-1-(4-cyanophenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, CDCl3) δ 8.17 (d, J=8.4 Hz, 2H), 7.62 (d, J=8.4 Hz, 2H), 7.48-7.45 (m, 4H), 7.42-7.24 (m, 4H), 7.22-7.02 (m, 2H), 6.42 (d, J=9.2 Hz, 1H), 6.16 (d, J=7.2 Hz, 1H), 5.34-5.27 (m, 1H), 4.44 (s, 2H), 4.19 (t, J=4.4 Hz, 2H), 3.35 (t, J=4.4 Hz, 2H), 1.57 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 142 except that (S)-1-(3-fluoro-4-methylphenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, CDCl3) δ 8.18 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 7.41-7.34 (m, 3H), 7.32-7.31 (m, 1H), 7.22-7.20 (m, 2H), 7.16-7.12 (m, 1H), 7.05-7.00 (m, 2H), 6.42 (d, J=9.2 Hz, 1H), 6.09 (d, J=7.6 Hz, 1H), 5.28-5.24 (m, 1H), 4.43 (s, 2H), 4.19 (t, J=4.0 Hz, 2H), 3.34 (t, J=4.0 Hz, 2H), 2.25 (s, 3H), 1.54 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 142 except that (S)-1-(4-nitrophenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, CDCl3) δ 8.21-8.15 (m, 4H), 7.54 (d, J=1.6 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 7.40-7.30 (m, 4H), 7.23-7.21 (m, 2H), 6.42 (d, J=9.2 Hz, 1H), 6.19 (d, J=6.8 Hz, 1H), 5.34-5.32 (m, 1H), 4.44 (s, 2H), 4.18 (t, J=4.0 Hz, 2H), 3.35 (t, J=4.0 Hz, 2H), 1.59 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 142 except that (S)-1-(naphthalene-2-yl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, CDCl3) δ 8.17 (d, J=8.4 Hz, 2H), 7.84-7.82 (m, 4H), 7.54-7.46 (m, 6H), 7.38-7.34 (m, 3H), 7.31-7.02 (m, 7H), 6.42 (d, J=8.0 Hz, 1H), 6.21 (d, J=7.2 Hz, 1H), 5.51-5.47 (m, 1H), 4.42 (s, 2H), 4.19 (t, J=4.0 Hz, 2H), 3.34 (t, J=4.8 Hz, 2H), 1.67 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 143 except that (S)-2′-((7-((1-(3-fluoro-4-methylphenyl)ethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-4-carboxylic acid obtained in Example 145 was used instead of (S)-2′-((7-((1-phenylethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-4-carboxylic acid.
1H NMR (400 MHz, CDCl3) δ 7.86 (d, J=7.6 Hz, 2H), 7.54-7.28 (m, 6H), 7.17-7.13 (m, 3H), 7.06-7.01 (m, 2H), 6.38 (d, J=8.4 Hz, 1H), 6.25-6.12 (m, 2H), 5.61 (s, 1H), 5.32-5.21 (m, 1H), 4.42 (s, 2H), 4.16 (t, J=4.0 Hz, 2H), 3.32 (t, J=4.0 Hz, 2H), 2.26 (s, 1H), 1.55 (d, J=6.4 Hz, 3H).
The target compound was obtained by the same manner as described in Example 143 except that (S)-2′-((7-((1-(4-cyanophenyl)ethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-4-carboxylic acid obtained in Example 144 was used instead of (S)-2′-((7-((1-phenylethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-4-carboxylic acid.
1H NMR (400 MHz, CDCl3) δ 7.86 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.0 Hz, 2H), 7.52-7.47 (m, 2H), 7.40-7.30 (m, 6H), 7.21-7.16 (m, 2H), 6.38 (d, J=8.4 Hz, 1H), 6.23 (d, J=6.8 Hz, 1H), 6.12 (s, 1H), 5.64 (s, 1H), 5.32-5.26 (m, 1H), 4.43 (s, 2H), 4.16 (t, J=4.0 Hz, 2H), 3.33 (t, J=4.4 Hz, 2H), 1.57 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 143 except that (S)-2′-((7-((1-(4-nitrophenyl)ethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-4-carboxylic acid obtained in Example 146 was used instead of (S)-2′-((7-((1-phenylethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-4-carboxylic acid.
1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=8.4 Hz, 2H), 7.85 (d, J=8.0 Hz, 2H), 7.54 (d, J=8.8 Hz, 2H), 7.42-7.30 (m, 6H), 7.21-7.16 (m, 2H), 6.38 (d, J=8.4 Hz, 1H), 6.27 (d, J=7.2 Hz, 1H), 6.11 (s, 1H), 5.60 (s, 1H), 5.37-5.28 (m, 1H), 4.43 (s, 2H), 4.17 (t, J=4.0 Hz, 2H), 3.33 (t, J=4.4 Hz, 2H), 1.62 (d, J=8.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 143 except that (S)-2′-((7-((1-(naphthalene-2-yl)ethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-4-carboxylic acid obtained in Example 147 was used instead of (S)-2′-((7-((1-phenylethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-4-carboxylic acid.
1H NMR (400 MHz, CDCl3) δ 7.86-7.82 (m, 6H), 7.53-7.45 (m, 3H), 7.41-7.27 (m, 6H), 7.22-7.17 (m, 2H), 7.21-7.16 (m, 2H), 6.39 (d, J=8.8 Hz, 1H), 6.25 (d, J=8.0 Hz, 1H), 6.17 (s, 1H), 5.62 (s, 1H), 5.54-5.45 (m, 1H), 4.41 (s, 2H), 4.16 (t, J=4.4 Hz, 2H), 3.31 (t, J=4.4 Hz, 2H), 1.68 (d, J=6.8 Hz, 3H).
1,2,3,4-tetrahydroquinoline-6-carboxylic acid (300 mg, 1.63 mmol) obtained in Preparative Example 8 was dissolved in CH2Cl2 (10 ml) in a 100 mL flask, to which HATU (934 mg, 2.45 mmol) and DIPEA (856 ul, 4.91 mmol) were added, followed by stirring at room temperature for 12 hours. Upon completion of the reaction, the organic layer was separated by using CH2Cl2 and H2O. The separated organic layer was dried over MgSO4 and filtered. The mixture was separated by column chromatography (EA/n-Hex=1:1) to give (S)—N-(1-phenylethyl)-1,2,3,4-tetrahydroquinoline-6-carboxamide (210 mg).
(S)—N-(1-phenylethyl)-1,2,3,4-tetrahydroquinoline-6-carboxamide (182 mg, 0.65 mmol) was dissolved in DMF (3 ml) in a 25 mL flask, to which NaH (26 mg, 0.65 mmol) and methyl 2′-(bromomethyl)-[1,1′-biphenyl]-4-carboxylate (200 mg, 0.65 mmol) were added, followed by stirring at room temperature for 12 hours. The organic layer was separated by using ethyl acetate and brine. The separated organic layer was dried over MgSO4 and filtered. The solvent was eliminated from the mixture via vacuum distillation, followed by column chromatography to give (S)-methyl 2′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-4-carboxylate (140 mg).
(S)-methyl 2′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-4-carboxylate (140 mg, 0.27 mmol) was dissolved in MeOH (5 ml) and THF (10 ml) in a 25 mL flask, to which LiOH (2 g) dissolved in H2O (5 ml) was added, followed by stirring at room temperature for 12 hours. Upon completion of the reaction, the solvent was concentrated. PH of the reaction mixture was adjusted to 5 by using 2N-HCl. The mixture was extracted with EA. The organic layer was dried over MgSO4 and filtered. As a result, (S)-2′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-4-carboxylic acid (99.4 mg) was obtained.
1H NMR (400 MHz, CDCl3) δ 8.19 (d, J=8.0 Hz, 2H), 7.48-7.44 (m, 4H), 7.41-7.25 (m, 9H), 7.58-7.27 (m, 8H), 6.28 (d, J=8.8 Hz, 1H), 6.12 (d, J=8.0 Hz, 1H), 5.36-5.32 (m, 1H), 4.42 (s, 2H), 3.34 (t, J=5.6 Hz, 2H), 2.80 (t, J=6.0 Hz, 2H), 2.01-1.95 (m, 2H), 1.59 (d, J=7.2 Hz, 3H).
(S)-2′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-4-carboxylic acid (66.4 mg, 0.14 mmol) obtained in Example 152 was dissolved in CH2Cl2 (2 ml) in a 25 mL flask, to which EDCI (41 mg, 0.21 mmol) and HOBt (23 mg, 0.17 mmol) were added, followed by stirring. Ammonium hydroxide solution (3 ml) was added thereto, followed by stirring at room temperature for 5 hours. Upon completion of the reaction, the organic layer was separated by using CH2Cl2 and H2O. The separated organic layer was dried over MgSO4 and filtered. The mixture was separated by column chromatography (MeOH/n-Hex/CH2Cl2=0.5:0.5:9) to give (S)-1-((4′-carbamoyl-[1,1′-biphenyl]-2-yl)methyl)-N-(1-phenylethyl)-1,2,3,4-tetrahydroquinoline-6-carboxamide (54.7 mg).
1H NMR (400 MHz, CDCl3) δ 7.86 (d, J=8.0 Hz, 2H), 7.43-7.26 (m, 12H), 6.26 (d, J=8.8 Hz, 2H), 6.20-6.11 (m, 2H), 6.64 (s, 1H), 5.37-5.30 (m, 1H), 4.41 (s, 2H), 3.31 (t, J=5.6 Hz, 2H), 2.78 (t, J=6.0 Hz, 2H), 1.99-1.93 (m, 2H), 1.57 (d, J=6.4 Hz, 3H).
The target compound was obtained by the same manner as described in Example 152 except that (S)-1-(3-fluoro-4-methylphenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, CDCl3) δ 8.18 (d, J=8.0 Hz, 2H), 7.47-7.42 (m, 3H), 7.38-7.28 (m, 5H), 7.16-7.12 (m, 1H), 7.06-7.00 (m, 2H), 6.27 (d, J=8.8 Hz, 1H), 6.08 (d, J=8.0 Hz, 1H), 5.32-5.26 (m, 1H), 4.42 (s, 2H), 3.33 (t, J=4.0 Hz, 2H), 2.78 (t, J=4.0 Hz, 2H), 2.25 (s, 3H), 1.99-1.97 (m, 2H), 1.54 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 152 except that (S)-1-(4-nitrophenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, CDCl3) δ 8.18 (d, J=8.4 Hz, 4H), 7.54-7.28 (m, 10H), 6.28 (d, J=8.4 Hz, 1H), 6.20 (d, J=6.8 Hz, 1H), 5.38-5.32 (m, 1H), 4.43 (s, 2H), 3.35 (t, J=4.4 Hz, 2H), 2.80 (t, J=5.6 Hz, 2H), 1.98 (t, J=4.8 Hz, 2H), 1.59 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 152 except that (S)-1-(naphthalene-2-yl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, CDCl3) δ 8.18 (d, J=7.6 Hz, 2H), 7.84-7.81 (m, 4H), 7.53-7.28 (m, 11H), 6.28 (d, J=8.8 Hz, 1H), 6.22 (d, J=7.6 Hz, 1H), 5.53-5.48 (m, 1H), 4.41 (s, 2H), 3.32 (t, J=4.4 Hz, 2H), 2.79 (t, J=5.6 Hz, 2H), 1.97 (t, J=4.8 Hz, 2H), 1.68 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 152 except that (S)-1-(4-cyanophenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, CDCl3) δ 8.18 (d, J=8.0 Hz, 2H), 7.62 (d, J=8.0 Hz, 2H), 7.48-7.28 (m, 10H), 6.27 (d, J=8.4 Hz, 1H), 6.16 (d, J=7.6 Hz, 1H), 5.34-5.30 (m, 1H), 4.43 (s, 2H), 3.34 (t, J=5.6 Hz, 2H), 2.80 (t, J=6.4 Hz, 2H), 2.00-1.97 (m, 2H), 1.57 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 153 except that (S)-2′-((6-((1-(3-fluoro-4-methylphenyl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-4-carboxylic acid obtained in Example 154 was used instead of (S)-2′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-4-carboxylic acid.
1H NMR (400 MHz, CDCl3) δ 7.87 (d, J=7.6 Hz, 2H), 7.44-7.32 (m, 8H), 7.17-7.13 (m, 1H), 7.07-7.02 (m, 2H), 6.26 (d, J=8.4 Hz, 1H), 6.10-6.08 (m, 2H), 5.57 (s, 1H), 5.33-5.25 (m, 1H), 4.42 (s, 2H), 3.32 (t, J=5.2 Hz, 2H), 2.79 (t, J=6.0 Hz, 2H), 2.26 (s, 3H), 1.98-1.95 (m, 2H), 1.55 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 153 except that (S)-2′-((6-((1-(4-nitrophenyl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-4-carboxylic acid obtained in Example 155 was used instead of (S)-2′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-4-carboxylic acid.
1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=8.8 Hz, 2H), 7.87 (d, J=8.0 Hz, 2H), 7.54 (d, J=8.8 Hz, 2H), 7.50-7.33 (m, 8H), 6.26 (d, J=8.4 Hz, 1H), 6.21 (d, J=7.2 Hz, 1H), 6.01 (s, 1H), 5.58 (s, 1H), 5.38-5.32 (m, 1H), 4.42 (s, 2H), 3.33 (t, J=5.6 Hz, 2H), 2.79 (t, J=5.6 Hz, 2H), 1.99-1.96 (m, 2H), 1.60 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 153 except that (S)-2′-((6-((1-(naphthalene-2-yl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-4-carboxylic acid obtained in Example 156 was used instead of (S)-2′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-4-carboxylic acid.
1H NMR (400 MHz, CDCl3) δ 7.87-7.83 (m, 6H), 7.54-7.26 (d, 11H), 6.27 (d, J=8.4 Hz, 1H), 6.21 (d, J=8.0 Hz, 1H), 6.13 (s, 1H), 5.55-5.48 (m, 2H), 4.41 (s, 2H), 3.31 (t, J=5.2 Hz, 2H), 2.78 (t, J=5.6 Hz, 2H), 2.01-1.96 (m, 2H), 1.68 (d, J=6.8 Hz, 3H).
The target compound was obtained by the same manner as described in Example 153 except that (S)-2′-((6-((1-(4-cyanophenyl)ethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-4-carboxylic acid obtained in Example 157 was used instead of (S)-2′-((6-((1-phenylethyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-yl)methyl)-[1,1′-biphenyl]-4-carboxylic acid.
1H NMR (400 MHz, CDCl3) δ 7.97 (d, J=8.8 Hz, 2H), 7.87 (d, J=8.0 Hz, 2H), 7.63 (d, J=8.0 Hz, 2H), 7.58-7.27 (m, 8H), 6.26 (d, J=8.8 Hz, 1H), 6.19-6.04 (m, 2H), 5.57 (s, 1H), 5.34-5.27 (m, 1H), 4.42 (s, 2H), 3.33 (t, J=5.6 Hz, 2H), 2.79 (t, J=6.0 Hz, 2H), 2.07-1.95 (m, 2H), 1.57 (d, J=6.4 Hz, 3H).
4-((2′-(tert-butoxycarbonyl)-2-fluoro-[1,1′-biphenyl]-4-yl)methyl)-3, 4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid (300 mg, 0.65 mmol) obtained in Preparative Example 9 was dissolved in CH2Cl2 (10 ml) in a 100 mL flask, to which HATU (386 mg, 1.01 mmol) and DIPEA (353 ul, 2.02 mmol) were added, followed by stirring. (S)-1-phenylethylamine (105 ul, 0.81 mmol) was added thereto, followed by stirring at room temperature for 12 hours. Upon completion of the reaction, the organic layer was separated by using CH2Cl2 and H2O. The separated organic layer was dried over MgSO4 and filtered. The mixture was separated by column chromatography (EA/n-Hex=1:1) to give (S)-tert-butyl 2′-fluoro-4′-((7-((1-phenylethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylate (180 mg, 0.31 mmol, 47%).
(S)-tert-butyl 2′-fluoro-4′-((7-((1-phenylethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylate (180 mg, 0.31 mmol) obtained in step 1 was dissolved in CH2Cl2 (10 ml) in a 50 mL flask, to which 30% TFA (3 ml) was added, followed by stirring at room temperature for 5 hours. Upon completion of the reaction the reaction mixture was concentrated under reduced pressure. The mixture was separated by column chromatography (EA) to give (S)-2′-fluoro-4′-((7-((1-phenylethyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid (100 mg, 0.19 mmol, 61%).
1H NMR (400 MHz, CDCl3) δ 8.07-8.05 (m, 1H), 7.65-7.61 (m, 1H), 7.51-7.47 (m, 1H), 7.40-7.33 (m, 6H), 7.30-7.11 (m, 3H), 7.11-7.09 (m, 1H), 7.05-6.96 (m, 3H), 6.62 (d, J=8.4 Hz, 1H), 6.19 (d, J=7.6 Hz, 1H), 5.29-5.22 (m, 1H), 4.55 (s, 2H), 4.29 (t, J=4.4 Hz, 2H), 3.50 (t, J=4.4 Hz, 2H), 2.25 (s, 3H), 1.53 (d, J=7.2 Hz, 3H).
The target compound was obtained by the same manner as described in Example 162 except that (S)-1-(naphthalene-2-yl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, DMSO-d6) δ 12.67 (br, OH, 1H), 8.56-8.53 (m, 1H), 7.87-7.81 (m, 5H), 7.63-7.48 (m, 5H), 7.38-7.35 (m, 4H), 7.17-7.08 (m, 2H), 6.75-7.71 (m, 1H), 5.30-5.28 (m, 1H), 4.65 (s, 2H), 4.27-4.21 (m, 2H), 3.54 (s, 2H), 1.56-1.47 (m, 3H).
The target compound was obtained by the same manner as described in Example 162 except that (S)-1-(3-fluoro-4-methylphenyl)ethaneamine was used instead of (S)-1-phenylethylamine.
1H NMR (400 MHz, CDCl3) δ 8.07-8.05 (m, 1H), 7.64-7.60 (m, 1H), 7.51-7.47 (m, 1H), 7.40-7.36 (m, 1H), 7.30-7.26 (m, 3H), 7.15-7.08 (m, 2H), 7.02-6.79 (m, 1H), 6.63 (d, J=8.4 Hz, 1H), 6.18 (d, J=7.6 Hz, 1H), 5.36-5.28 (m, 1H), 4.55 (s, 2H), 4.29 (t, J=4.4 Hz, 2H), 3.50 (t, J=4.4 Hz, 2H), 1.58 (d, J=7.8 Hz, 3H).
The chemical formulae of the compounds prepared in Examples 1-164 are shown in Table 1.
The following experiment was performed to investigate whether or not the compounds prepared in the examples of the invention could bind to PPARG but did not act as a CDK5 (cyclin-dependant kinase 5) promoter so that it did inhibit the phosphorylation of the 273rd amino acid serine of PPARG.
The compounds of examples 1-164 and SR1664 and SR1824 of the comparative examples were diluted in DMSO (dimethyl sulfoxide) to meet the final test concentration 2000×. The 2000× compounds were diluted in 50% DMSO (DMSO:DW=1:1) at the ratio of 1:100. Premix in total volume of 36 μL was prepared by mixing 0.43 μg of PPARG-LBD (ligand binding domain) (human recombinant) (Cayman, 10007941), Cdk5/p35, 100 ng of active (Millipore, 14-477), 10× kinase buffer (Cell Signaling, 9802S), and DW (Data warehousing) (the premix was prepared on the ice and stored in the ice).
2 μL of the compound of the invention was mixed in 36 μL of the premix, followed by reaction in the ice for 10 minutes. 2 μL of 10 mM ATP (negative control: DW 2 μL) was added thereto, followed by reaction in a 37° C. water bath for 15 minutes. Upon completion of the reaction, the mixture was transferred onto the ice swiftly so that the mixture was cooled down for 1-2 minutes. 10 μL of 5× sample buffer was mixed with the reaction mixture, followed by heating at 95° C. in heat block for 8-10 minutes. Upon completion of the treatment in heat block, the mixture was taken out and cooled down for a while, followed by SDS-PAGE (sodium dodecyl sulfate-polyacryl amide gel electrophoresis) on 10% SDS-gel.
Then, the protein on SDS-gel was transferred onto nitrocellulose membrane (IB3010-32, Invitrogen) by using iBlot (IB1001, Invitrogen).
Upon completion of the transfer, the membrane proceeded to blocking in 5% BSA-TBST (bovine serum albumin-tris buffered saline and tween 20) for 30 minutes-1 hour, followed by reaction with the primary antibody phospho-PPARG-Ser273 (Hyundai Pharm. Co., Ltd.) for at least 18 hours in a 4° C. refrigerator. The membrane was washed with TBST (Tris-Buffered Saline and Tween 20), followed by reaction with the secondary antibody Anti-rabbit IgG (HRP-linked antibody, 7074S, Cell Signaling) at room temperature for 1 hour. Upon completion of the reaction, the membrane was washed with TBST, followed by reaction in ECL (enhanced chemiluminescence) solution (NCI34095KR, Thermo Scientific). The band signal for phospho-PPARG-Ser273 was measured by Las4000mini (Fujifilm corp). After measuring the phospho-Ser273, the membrane was reacted in stripping buffer (NCI1059KR, Thermo Scientific) for 30 minutes, and then was washed, which was the ready for the total PPARG measurement.
The membrane was reacted with PPARG (E-8) antibody (sc-7273, Santa Cruz), the primary antibody, at room temperature for 1 hour, followed by another reaction with anti-mouse IgG (HRP-linked antibody, sc-2005, Santa Cruz), the secondary antibody, for 1 hour.
Upon completion of the reaction, the membrane was washed and reacted in ECL solution (RPN2232, GE Healthcare). The total PPARG band signal was measured by Las4000mini (Fujifilm corp).
The compounds prepared in the examples of the present invention were confirmed to bind to PPARG (peroxisome proliferator activated receptor-gamma) but not to act as a CDK5 (cyclin-dependant kinase 5) promoter, indicating that they are excellent in suppressing the phosphorylation of serine, the 273rd amino acid of PPARG.
Therefore, the compounds of examples of the invention bind to PPARG (peroxisome proliferator activated receptor-gamma) but do not activate CDK5 (cyclin-dependant kinase 5), the phosphorylation inducer, so that they can be effectively used as a therapeutic agent for PPARG-related disease by preventing side effects accompanied by the phosphorylation of serine, the 273rd amino acid of PPARG.
The following experiment was performed to evaluate the PPARG (peroxisome proliferator activated receptor-gamma) binding capacity and transcriptional activity of the compounds prepared in the examples of the invention.
For the experiment, LanthaScreen™ TR-FRET PPARG Competitive Binding Assay Kit (PV4894, Invitrogen) was used according to the manufacturer's instruction.
30 μL of the compound or the control substance (SR-1664, Rosiglitazone) diluted in assay buffer (50×) in a 96-well plate (SPL, 34096) was mixed with 15 μL of 5 nM Fluormone™ H Pan-PPAR Green, to which 15 μL of 5 nM GST-PPARG-LBD and 5 nM Tb-GST-antibody were added. The mixture was loaded in a 384-well plate (Greiner, 784075) by 20 μL per well, followed by reaction at room temperature for 1 hour.
Upon completion of the reaction, fluorescence value was measured by using Flexstation 3 (Molecular Devices) with time-resolved fluorescence (RFU) mode (excitation 1: 340 nm, emission 1: 518 nm, excitation 2: 340 nm, emission 2: 488 nm, integration delay 50 μs, integration 400 μs). The results were calculated by using 518 nm RFUs/488 nm RFUs ratio. The activity of the compounds of the invention was compared with that of the vehicle, which was calculated by ratio according to the formula [100%−compound of the example ratio/vehicle ratio]. At this time, the binding activity ratio to rosiglitazone was compared.
The following experiment was performed to evaluate PPARG (peroxisome proliferator activated receptor-gamma) transcriptional activity of the compounds of the invention.
HEK293 cells were plated in a 24-well plate (SPL, 30024) at the density of 2.5×104 cells/well. The cells were transfected with PPRE, PPARG or PPARα, RXR, and Renilla DNA by using FuGENE HD (Promega, E2312). Upon completion of the gene transfection, the cells were treated with rosiglitazone, SR1664, and the compounds of the invention respectively for 24 hours. 24 hours later, the cells were collected, followed by reporter gene assay with Dual Reporter gene assay kit (Promega, E1980). Luciferase assay activity was calculated by normalization of renilla activity.
In Table 2, NT (No Tested) means that the experiment was not performed; “+” indicates the degree of the binding activity, and as the number of “+” increases, the binding activity is stronger; “*” indicates the degree of the transcriptional activity, and as the number of “*” increases, the transcription activity is stronger; and “NA” indicates that no transcriptional activity is detected because the compound is not acting as an agonist.
As shown in Table 2, the compounds of the examples of present invention displayed excellent binding activity to PPARG (peroxisome proliferator activated receptor-gamma). At this time, the binding activity number indicates the binding or no binding and does not relate directly to the pharmacological activity.
The compounds of the examples of present invention were confirmed not to induce the transcription of PPARG (peroxisome proliferator activated receptor-gamma).
Therefore, the compounds of the examples of the present invention bind specifically to PPARG (peroxisome proliferator activated receptor-gamma) but do not induce the transcription of PPARG gene and thereby prevent the side effects due to PPARG phosphorylation, suggesting that the compounds can be effectively used as a therapeutic agent for PPARG-related diseases.
To evaluate the CYP (cytochrome P450)-suppressing activity of the compounds prepared in the examples of the invention, the following experiment was performed.
The analysis of CYP1A2, 2C19, and 3A4 suppressing activity was performed by using a BD GENTEST (459100, 459400, and 459500) kit, and the analysis of CYP 2C9- and 2D6-suppressing activity was performed by using an Invitrogen (P2861 and P2862) kit.
When the Invitrogen kit was used, the compounds of the present invention were diluted in Vivid CYP450 reaction buffer (1×) at the final concentration of 2.5×. The P450 BACULOSOMES sample and Regeneration system (100×) were diluted in Vivid CYP450 reaction buffer (1×) at different proper concentrations. 80 μL of the compound of the invention (2.5×) and 100 μL of the diluted P450 BACULOSOMES sample mixture were mixed in a U-bottom 96-well plate, followed by pre-incubation for 10 minutes. Vivid CYP450 Substrate and NADP+ (100×) were diluted in Vivid CYP450 reaction buffer (1×) at a desired concentration, respectively, according to their corresponding types of CYP450 and substrates. 20 μL of Substrate-NADP+ mix was loaded in the plate when the pre-incubation had been completed, followed by reaction for 1 hour. Upon completion of the reaction, the reaction mixture was transferred in a white plate and fluorescent wavelength was measured with a microplate reader (2C9 excitation 415 nm, emission 460 nm, 2D6 excitation 400 nm, emission 502 nm).
When the BD GENTEST kit was used, the compounds of the present invention were diluted in acetonitrile at the final concentration of 50×. The NADPH-Cofactor mix was prepared by diluting the Cofactor, G6PDH, and control protein provided by the kit in DW according to the instructed concentration. 4 μL of the compound of the example (50×) was mixed with 96 μL of NADPH-Cofactor mix in a 96-well plate, followed by pre-incubation in a 37° C. incubator for 10 minutes.
The enzyme/substrate mixture was diluted in the buffer (0.5 M potassium phosphate, pH 7.4) provided by the kit according to the instructed concentration. Each CYP450 enzyme substrate was diluted in DW at a desired concentration respectively according to the corresponding types of CYP450. 100 μL of the enzyme/substrate mixture was loaded in the plate when the pre-incubation had been completed, followed by reaction in a 37° C. incubator for 15 minutes (1A2) and 30 minutes (3A4 and 2C19). Upon completion of the reaction, the mixture was transferred to a white plate, and the fluorescent wavelength was measured with a microplate reader (1A2, 2C19 excitation 410 nm, emission 460 nm; 3A4, excitation 409 nm, emission 530 nm).
The test results were calculated by the following formula:
(1−(fluorescence value of the test material/fluorescence value of the vehicle))×100%.
As shown in Table 3, the compounds of the examples of 14, 36, 44, 56, 57, 58, 60, 74, 96, 110, 113, 115, 118, 123, 131, and 139 of the invention suppressed the CYP isozymes 1A2, 2C9, 2C19, and 2D6 less than the compounds of the comparative examples (SR1664 and SR1824).
Particularly, SR1664 suppressed the CYP isozyme 2C9 activity significantly, so that approximately 96% of the drug remained without being decomposed. Therefore, when SR1664 was used as a drug, the amount that reached a target was more than the proper dose as a drug, which could cause toxicity.
However, the compounds of the present invention suppressed the CYP activity moderately compared with SR1664, so the drug decomposition rate was at least 10 times higher than SR1664, suggesting that a proper amount of the drug would reach a target. Therefore, the compounds of the present invention were confirmed to be more effective as a drug than the conventional SR1664 and SR1824.
To evaluate the cardiotoxicity of the compounds prepared in the examples of the present invention, the following experiment was performed.
HEK293 cells expressing HERG (Human Ether-a-go-go-Related Gene) channel safely were cultured in MEM (Minimum Essential Medium) supplemented with 10% fetal bovine serum (FBS), 1 mM sodium pyruvate, 0.1 mM non-essential amino acid solution, 100 units/ml penicillin-streptomycin, 100 μg/ml streptomycin sulfate and 100 μg/ml zeocin under the condition of air:CO2=95:5. When the cells were grown to 60-80% confluency, the cells were loaded in the medium supplemented with 0.25% trypsin and 0.02% EDTA (ethylenediaminetertraacetic acid) for 3 minutes. The cells were then washed with a fresh medium and then dispensed on a new plastic culture dish. For the electrophysiological record, the cells were seeded on a glass cover slip of 5 mm in diameter, followed by incubation in a 24-well plate for 5-24 hours. Then, the cells were transferred into the recording chamber.
The current value of all the cells was measured by the conventional patch-clamp technique or Port-a-Patch (Nanion, Germany) semiautomatic technique. The pH of the external bath solution containing 136 mM NaCl, 5.4 mM KCl, 1.8 mM CaCl2, 1 mM MgCl2, 10 mM glucose, and 10 mM HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) was adjusted to 7.4 using NaOH. The pH of the intracellular pipette solution containing 130 mM KCl, 1 mM MgCl2, 10 mM EGTA (ethylene glycol tetraacetic acid), 5 mM Mg-ATP, and mM HEPES was adjusted to 7.2 using KOH.
In the conventional patch-clamp technique, the patch pipette was pulled by a PP-83 pipette puller (Narishige, Tokyo, Japan), so that it had 2-4 MΩ of resistance in the external bath solution. The ionic current was recorded by using EPC7 pulse amplifier (HEKA electronic, Germany). The voltage-clamp amplification was regulated using the pClamp computer program (Axon Instruments, USA), and the obtained data were analyzed. During the recording, the solution above was continually spread on HEK293 cells in the chamber. For the recording, the Port-a-Patch (Nanion, Germany) semiautomatic patch system was used, and the amplifier used herein was EPC10.
The membrane potential was maintained at −80 mV, which was changed to +20 mV for 4 seconds, then changed to −50 mV for 6 seconds and then maintained again at −80 mV. The changes were made every 25 seconds.
To obtain the concentration-reaction curve in the presence of the drug, dose-dependent inhibition was entered into the Hill formula represented by mathematical formula 1 below.
In mathematical formula 1, Idrug indicates the peak tail current in the presence of a drug, Icontrol indicates the maximum peak tail current in the absence of a drug, D indicates the concentration of a drug, h indicates Hill constant, and IC50 indicates the concentration when the half-maximum peak tail current was suppressed.
As shown in Table 4, SR-1664 displayed a significantly lower IC50 (2.7 uM) than an IC50 that can induce cardiotoxicity (10 uM), suggesting that, when it is used as a drug, there is a high chance of cardiotoxicity.
However, the compounds of the invention displayed a much higher IC50 than the IC50 that can induce cardiotoxicity (10 uM), suggesting that there is a low chance of cardiotoxicity when they are used as a drug.
Therefore, the compounds of the examples of the invention can be effectively used as a therapeutic agent for PPARG-related disease with significantly low chance of causing cardiotoxicity.
To evaluate the blood glucose-lowering effects and body weight-reducing effects of the compounds prepared in the examples of the invention, the following experiment was performed.
The male C57BL/6 mice at 4 seeks were given a high fat diet (Lab. Diet Co.) to construct a high fat diet-induced obesity (DIO) mouse model.
Among those mice that gained more weight by a high fat diet, those that weighed more than 40 g were selected. Groups were divided with the randomly selected mice (n=8). Each group was treated separately with a vehicle, the positive control drug, and the test compounds for 4 weeks at the different concentrations. Weight measurements were performed twice a week during the 4-week treatment period, and the weight changes were recorded.
Then, an oral glucose tolerance test (OGTT) was performed as follows.
30 minutes after the treatment of hte vehicle or the compounds of the example, the mice were orally administered 2 g/kg of glucose. Blood glucose was measured using an Accu-chek active strip (Roche Diagnostic Co.). The time point for the measurements were −30, 0, 20, 40, 60, and 120 minutes from the glucose administration via tail vein puncture. The obtained AUC results and the weight changes are shown in Table 5.
As shown in Table 5, the comparative example compound SR-1664 (20 mpk) reduced the weight of the mice by 1.6%, while the compounds of the examples of 56, 155, 156, and 157 (10 mpk each) reduced the mouse weight at least 5% even at a low dose.
Further, the comparative example compound SR-1664 (20 mpk) reduced blood glucose by 14%, while the compounds of the examples 56, 155, 156, and 157 (10 mpk each) reduced blood glucose at least 24% even at a low dose.
Therefore, the compounds of the examples of the present invention had a significant effect of lowering body weight and blood glucose even at a low dose, so that they can be effectively used as a therapeutic agent for PPARG-related disease.
Powders were prepared by mixing all the above components, which were filled in airtight packs according to the conventional method for preparing powders.
Tablets were prepared by mixing all the above components by the conventional method for preparing tablets.
Capsules were prepared by mixing all the above components, which were filled in gelatin capsules according to the conventional method for preparing capsules.
Injectable solutions were prepared by mixing all the above components, putting the mixture into 2 mL ampoules and sterilization thereof by the conventional method for preparing injectable solutions.
All the above components were dissolved in purified water. After adding lemon flavor, total volume was adjusted to be 100 mL by adding purified water. Liquid formulations were prepared by putting the mixture into brown bottles and sterilization thereof by the conventional method for preparing liquid formulations.
The compound represented by formula 1 or the optical isomer thereof of the present invention binds to PPARG at a high affinity but does not act as an agonist and thereby does not induce gene transcription. The compound also blocks CDK5, which is the cause of PPARG phosporylation, so that the compound can suppress the side effects of conventional anti-diabetic agents and at the same time can sufficiently improve pharmacophysical properties to produce a PPARG-related disease-treating effect. Therefore, the compound of the invention can be effectively used as a pharmaceutical composition for treating PPARG-related disease.
| Number | Date | Country | Kind |
|---|---|---|---|
| 10-2014-0033041 | Mar 2014 | KR | national |
This is a continuation of PCT Application No. PCT/KR2015/001941, filed on Feb. 27, 2015, which is incorporated by reference, and which claims priority to Korean Patent Application No. 10-2014-0033041, filed on Mar. 20, 2014.
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/KR2015/001941 | Feb 2015 | US |
| Child | 15244821 | US |
